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DH IVIg approved indications full guidance July 2011

Description: DH INFORMATION READER BOX Policy HR / Workforce Management Planning / Clinical Performance Document Purpose Gateway Reference Title Author Publication Date Target Audience Estates Commissioning IM & T Finance Social Care / Partnership Best Practice Guidance 16290 ROCR Ref: ROCR approval applied for Clinical guidelines for immunoglobulin use: update to second edition Department of Health 01 Aug 2011 PCT CEs, NHS Trust CEs, SHA CEs, Foundation Trust CEs , Medical Directors, Directors of Finance, GPs, Communications Leads, Emergency Care Leads, Chief Pharmacists Circulation List #VALUE! Description The Clinical Guidelines for Immunoglobulin Use were implemented in 2008. The Guidelines were developed utilising an evidence review and extensive consultations. This Update fulfills the commitment to undertake a biennial review from 2009. The Second Edition Guidelines remain in place and this Update should be used in conjunction with them. Cross Ref Superseded Docs Action Required Timing Contact Details Clinical Guidelines for Immunoglobulin Use (Second Edition) N/A N/A N/A Tina Lee Blood Safety & Supply Team Room 30 Wellington House 133-155 Waterloo Road London SE1 8UG 020 7972 4750 0 For Recipient's Use Clinical guidelines for IMMUNOGLOBULIN Use seCOND eDITION UPDATe second edition Update Working Group Dr Jennie Wimperis Consultant Haematologist, Norfolk and Norwich NHS Trust Dr Michael Lunn Consultant Neurologist, National Hospital for Neurology and Neurosurgery Dr Alison Jones Consultant Immunologist, Great Ormond Street Hospital Dr Richard Herriot Consultant Immunologist, NHS Grampian Dr Philip Wood Consultant Immunologist, Leeds Teaching Hospitals NHS Trust Dr Denise O'shaughnessy Blood Policy, Department of Health Mr Malcolm Qualie Pharmaceutical Advisor Department of Health CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Contents ...................................................................................... 2 eXeCUTIVe sUMMARY ....................................................................... 6 Selection criteria for appropriate use of immunoglobulin .................................. 6 Efficacy outcomes to assess treatment success ........................................... 6 Modification of existing indications and inclusion of new indications .................... 7 Commissioning of immunoglobulin ........................................................... 7 INTRODUCTION ................................................................................ 8 Insights from the National Immunoglobulin Database ..................................... 8 CONTeNTs Changes to the colour-coded prioritisation employed in the Demand Management Programme ...................................................................... 8 Automatic assignment of Red and Blue prioritisation ................................. 9 Grey indications ............................................................................. 9 Reclassification of diseases .............................................................. 10 11 12 12 13 14 14 14 15 16 18 26 27 27 Introduction of specific selection and outcome criteria in the Demand .................................................................... Definitions of duration of immunoglobulin treatment ..................................... Recommended dosing of immunoglobulin ................................................ Ideal body weight-adjusted dosing of immunoglobulin .................................. Western Australia pilot study ............................................................. Hospital Corporation of America ........................................................ The Ohio State University Medical Centre, Columbus, Ohio ........................ Infusion rates for intravenous immunoglobulin ............................................ Subcutaneous administration ............................................................... sUMMARY TABLes .......................................................................... sUMMARY Of GReY INDICATIONs ...................................................... Removed from Grey ........................................................................... INDICATIONs fOR WHICH IVIG Is NOT ReCOMMeNDeD .......................... Management Programme CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Replacement pages IMMUNOLOGY HAeMATOLOGY ............................................................................... .............................................................................. 29 35 Primary immunodeficiencies (replacing relevant content on pages 28-29) Coagulation factor inhibitors (replacing relevant content on pages 32-33) Haemolytic disease of the foetus and newborn (replacing relevant content on pages 32-33) Immune thrombocytopenic purpura (replacing relevant content on pages 34-35) NeUROLOGY ................................................................................. 40 Introduction (replacing relevant content on page 41) Chronic inflammatory demyelinating polyradiculoneuropathy (replacing relevant content on page 41) Inflammatory myopathies (replacing relevant content on page 42) TRANsPLANTATION ........................................................................ 43 Antibody Incompatible Transplant (AIT) (replacing relevant content on page 65) Antibody-Mediated Rejection (AMR) (replacing relevant content on page 65) Viral pneumonitis (replacing relevant content on page 65) CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Summary table of conditions for which intravenous immunoglobulin use is appropriate Condition Primary and secondary antibody deficiency states Primary immunodeficiencies Thymoma with immunodeficiency HSCT in primary immunodeficiencies Specific antibody deficiency Secondary antibody deficiency (any cause) Haematology Acquired red cell aplasia Alloimmune thrombocytopenia (foeto-maternal/neonatal) Autoimmune haemolytic anaemia Coagulation factor inhibitors (alloantibodies and autoantibodies) Haemolytic disease of the newborn Haemophagocytic syndrome Immune thrombocytopenic purpura (acute and persistent, excluding chronic*) Post-transfusion purpura Neurology Chronic inflammatory demyelinating polyradiculoneuropathy** Guillain-Barr? syndrome Inflammatory myopathies Myasthenia gravis (including Lambert-Eaton myasthenic syndrome) Multifocal motor neuropathy Paraprotein-associated demyelinating neuropathy (IgM, IgG or IgA) Rasmussen syndrome Stiff person syndrome short duration Long duration continued * Chronic immune thrombocytopenic purpura is a grey indication ** The disease should be life-threatening to allow database entry as red CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Summary table of conditions for which intravenous immunoglobulin use is appropriate continued Condition Others Autoimmune congenital heart block Autoimmune uveitis Immunobullous diseases Kawasaki disease Necrotising (PVL-associated) staphylococcal sepsis Severe or recurrent Clostridium difficile colitis Staphylococcal or streptococcal toxic shock syndrome Toxic epidermal necrolysis, Stevens Johnson syndrome Transplantation (solid organ) short duration Long duration CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use eXeCUTIVe sUMMARY The Clinical Guidelines for Immunoglobulin Use were implemented in 2008. The Guidelines were developed utilising an evidence review and extensive consultations with clinicians and other stakeholders. This update fulfils the commitment made in the Second Edition to undertake a biennial review from 2009. The Second Edition Guidelines remain in place and this update should be used in conjunction with the Second Edition. This update did not review all of the Second Edition Guidelines content, but limited its focus to three key areas: defining selection criteria for appropriate use; efficacy outcomes to assess treatment success; and reassignment of existing indications /inclusion of new indications. should be fulfilled if immunoglobulin is to be used, including particular disease characteristics, disease severity and any requirement for other treatments to have been demonstrably unsuccessful before immunoglobulin is considered. This reflects the approach taken by the National Blood Authority in Australia in defining appropriate prescribing of immunoglobulin. efficacy outcomes to assess treatment success The Guidelines did not include efficacy tracking of immunoglobulin treatment, although Immunoglobulin Assessment Panels (IAP) were encouraged to request parameters by which efficacy could be assessed. This update provides efficacy outcomes to be measured in all indications (except primary immunodeficiencies), and it is expected that all Grey indications will have efficacy parameters defined and monitored on a case by case basis. Efficacy outcomes are expected to play an important role in the IAP decision-making process for patients in whom continuation of immunoglobulin treatment is requested beyond the short- and long-term durations defined in this update. This change reflects the wider change of focus in the NHS to patient outcomes, as presented in The NHS Outcomes Framework. selection criteria for appropriate use of immunoglobulin The Guidelines did not provide explicit selection criteria for the appropriate use of immunoglobulin. Review of data in the National Immunoglobulin Database showed a considerable volume of immunoglobulin was used in patients for whom no specific diagnosis was provided. Clearly, this was less than optimal and caused concern among commissioners. This update provides criteria that CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Modification of existing indications and inclusion of new indications Changes to existing indications required proponents to submit new evidence to the Update Working Group for review. However, allocation of diseases to Red, Blue or Grey did not solely depend on the level of evidence presented, but included expert clinical advice and the availability of effective alternative therapies or treatment approaches. The British Transplantation Society made a strong case to change certain defined transplant cases to Blue, despite limited high-quality evidence for some of the clinical scenarios and the Update Working Group accepted the Society's view. For complex regional pain syndrome, although randomised evidence from a small study showed benefit, this was regarded by the Update Working Group as an emerging indication for refractory cases; a number of important questions concerning optimal treatment doses and duration of treatment remain unanswered. Therefore, this disease has been added to the Grey list. It remains the responsibility of the local IAP to decide with the PCT (or specialised commissioning group) if treatment with immunoglobulin is appropriate on a case by case basis. Other Grey indications have been updated and others, for which there was little or no prescribing recorded in the database, deleted. Grey indications are now listed as immune-mediated disorders with limited evidence of immunoglobulin efficacy, or presumed immune-mediated disorders with little or no evidence of efficacy. Review of Red and Blue indications identified a number of disease entities with the same underlying pathophysiology that were listed separately; these are now grouped together under single disease headings. Commissioning of immunoglobulin Ensuring immunoglobulin prescribing is consistent with the evidence-base and restricted to those patients for whom there are no alternative treatments and for those most likely to benefit is the central aim of these guidelines. But from a commissioner's viewpoint, cost-effectiveness and affordability play an important role in their discussions with IAPs regarding prescribing. The commissioning aspects of this guideline update are included in a separate document and this should be reviewed to understand the requirements of commissioners around immunoglobulin prescribing, in particular regarding National Immunoglobulin Database entry and treatment duration. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use INTRODUCTION This update of the Department of Health's (DH) immunoglobulin guidelines fulfils the commitment made in the Second Edition to undertake a biennial review from 2009. This review was informed by changes in the clinical evidence base for immunoglobulin, the findings of the National Immunoglobulin Database (Reference number ROCR/ OR/0221), and a change of focus in the NHS to patient outcomes, as presented in The NHS Outcomes Framework. The DH has consulted widely in this review and the changes have been discussed at length with clinicians and commissioners involved in the demand management of immunoglobulin. National Immunoglobulin Database was launched on 2nd June 2008. These documents and the National Immunoglobulin Database are accessible through the immunoglobulin website www.ivig.org.uk. The first data review from the National Immunoglobulin Database, published in January 2010, contained data on immunoglobulin prescribing in 5119 patients, and offered a unique, detailed view of prescribing practice of immunoglobulin in England as well as providing, for the first time, a baseline of immunoglobulin use. This was a major step forward in establishing the Demand Management Programme and, in particular, gave insights into the appropriate use of this treatment across all indications. Generally, the data demonstrated appropriate and controlled prescribing of immunoglobulin for a wide range of conditions, most of which was evidence based. The review also identified a number of issues regarding the Demand Management Programme, which are addressed in this guideline update. Insights from the National Immunoglobulin Database The DH's Demand Management Programme for Immunoglobulin was a key output from the 2006 review that assessed the opportunities available to secure the supply of immunoglobulin. The review recommended two complementary work streams, one based on securing supply and the other giving structure to the process of fulfilling demand (the Demand Management Programme). The Demand Management Programme was fully launched in late May 2008, when DH published the Second Edition of `Clinical Guidelines for Immunoglobulin Use' and the `Demand Management Plan for Immunoglobulin Use' (Gateway reference 10012 and 10013). The Changes to the colour-coded prioritisation employed in the Demand Management Programme Automatic assignment of Red and Blue prioritisation The Demand Management Programme introduced colour coding to reflect the prioritisation of immunoglobulin treatment CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use in times of shortage, based on the availability of alternative treatments and strength of clinical evidence. The database review showed many cases for which diseases were mis-assigned to an incorrect prioritisation. In particular, there were many cases of misassignment of diseases to Red and Blue. `Red' indicates conditions for which treatment is considered the highest priority because of a risk to life without treatment. The intention remains that Trusts will protect supply for these high-priority diseases in times of immunoglobulin shortage, particularly for patients with primary immunodeficiencies. To ensure accurate prioritisation assignment, the database will now automatically assign the colour coding upon patient entry on the basis of patient characteristics. The Immunoglobulin Assessment Panels (IAP) at Trusts should continue to manage local demand for immunoglobulin; in times of shortage, local panels should continue to identify Red indications as those of most clinical need. The database will automatically assign diseases to `Blue', but prescribing of immunoglobulin in Blue indications will continue to require prior approval of the IAP . because the disease is rare. Approval from both the local IAP and the Primary Care Trust (PCT) (or specialised commissioning group) is required for immunoglobulin treatment. As previously specified in the Demand Management Plan for Immunoglobulin Use, treatment should be considered on a caseby-case basis, and prioritised against other competing demands for immunoglobulin, especially in times of shortage. It is not possible or desirable to list every disease that could potentially be prescribed immunoglobulin. In cases of `unlisted' diseases, it is important to restate that those not listed in the guidelines are to be considered as Grey. The database review showed a considerable volume of immunoglobulin prescribed without a specific diagnosis being provided. Even if the disease is unlisted, the diagnosis and agreed efficacy criteria are to be recorded in the database. Grey indications are now listed as immune-mediated disorders with limited evidence of immunoglobulin efficacy, or presumed immune-mediated disorders with little or no evidence of efficacy. It is accepted that the lack of an evidence base may reflect the rarity of these diseases; it remains the responsibility of the local IAP to decide with the PCT (or specialised commissioning group) if treatment with immunoglobulin is appropriate on a caseby case basis. Grey indications `Grey' indications are those diseases for which the evidence is weak, in many cases 10 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Reclassification of diseases 1. Grey to Blue The database review identified two of the top 10 immunoglobulin-using indications as Grey (secondary antibody deficiencies and antibody-mediated rejection following solid organ transplantation). In many Trusts, commissioners have permitted pre-approval of immunoglobulin use for these indications despite the limited evidence base. Therefore, these indications were reviewed in detail and the evidence base was reassessed. Secondary antibody deficiencies were identi- Acquired von Willebrand disease has now been included with acquired haemophilia, in the general disease grouping of `Coagulation factor inhibitors', which is listed under appropriate use of immunoglobulin. Immunoglobulin use carries selection criteria, including that these rare and severe bleeding disorders are managed in a comprehensive care centre for haemophilia. Polymyositis and Inclusion body myositis have now been grouped with dermatomyositis under the general disease grouping of inflammatory myopathies, with strict selection criteria. Post-transfusion hyperhaemolysis has now been fied by a number of stakeholders as a key area for revision. In the previous edition, they were listed under immunosuppressive pharmacotherapy, and separately under some of the haematological malignancies such as CLL, without listing other mature B-cell malignancies such as non-Hodgkin's lymphoma. These have been revised into a single indication. The outcome of this review is that use of immunoglobulin for these indications is appropriate and is now listed as Blue (see replacement page 30). Antibody-mediated rejection following solid grouped under the more general heading of haemolytic anaemia. SLE with secondary immunocytopenias should be considered under the relevant immune cytopenia. 2. Blue to Red Specific antibody deficiency, as a recognised primary antibody deficiency disorder, has been reclassified as a Red indication (for those cases where immunoglobulin replacement therapy is required). Haemolytic disease of the newborn has been organ transplantation and antibody-incompatible transplantation were reviewed, and a single grouping of `Transplantation (solid organ)' has been introduced and listed as Blue. updated to reflect recommendations in NICE clinical guideline 98 on neonatal jaundice [1]. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 11 Introduction of specific selection and outcome criteria in the Demand Management Programme Selection criteria The database review also raised an important issue over patient diagnosis ? a considerable volume of immunoglobulin was used in patients in which there was no specific diagnosis listed (13% of total recorded immunoglobulin use). Clearly, this was less than optimal and caused concern among commissioners. In addition, this showed that improvements were required before the database was sufficiently robust to be able to link to payments by use. Further feedback from commissioners indicated widespread approval of the system used in Australia, with each indication for immunoglobulin carrying specific selection criteria for use, in particular, the need to use immunoglobulin as second- or third-line treatment in diseases for which there are a number of alternative treatment options. This approach, with selection criteria for each approved indication for immunoglobulin, has now been adopted in this guideline update. The need to employ selection criteria before prescribing will largely remove the need for panel decisions on prescribing, reducing the burden on IAPs and increasing focus on assessing patient outcome. Efficacy outcomes The database was not successful in the capture of data regarding the efficacy of immunoglobulin. Panels were encouraged to request up to three parameters by which efficacy could be determined in each patient [e.g., platelet count in patients with immune thrombocytopenic purpura (ITP)]. The purpose of this exercise was both to obtain preliminary data about efficacy in various conditions (fully accepting that lack of diagnostic criteria and other issues would make this a very crude analysis) and to provide feedback to individual Panels about the quality of their decision making. For example, if Panels repeatedly approved indications prioritised as Grey by the Demand Management Programme and the treatment was largely ineffective, review of these findings would improve IAP decision making. The decision has been taken to introduce efficacy outcomes for most indications. Monitoring of efficacy outcomes by commissioners may result in withholding payments to Trusts if efficacy outcomes have not been recorded in the database. Efficacy outcomes are expected to play an important role in the decision-making process of IAPs in cases in which continuation of immunoglobulin treatment is requested beyond the short- and long-term durations defined in the next section. 1 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Definitions of duration of immunoglobulin treatment The definitions of short-term and longterm treatment durations are refined in this update, with each approved indication for immunoglobulin now approved on the basis of short-term (3 months) and long-term (3 months) treatment needs. The definitions of duration of treatment are included in the table below. IAPs and commissioners together will make decisions on treatment extensions. short-term treatment Three prescribed doses of up to 2 g/kg, given at appropriate clinical intervals 3 months The treatment episode ends at 3 months. The National Immunoglobulin Database will record treatment re-initiation as a new treatment episode based on a new panel decision. It is expected that the IAP decision will be influenced by the outcome measures recorded on the database. 3 months Treatment reviews should be conducted annually. The National Immunoglobulin Database will record treatment re-initiation as a new treatment episode based on a new panel decision. It is expected that the IAP decision will be influenced by the outcome measures recorded on the database.* Long-term treatment *The primary immunodeficiencies are exempt from funding termination at 1 year. Recommended dosing of immunoglobulin The Second Edition of the Clinical Guidelines did not provide specific dosing recommendations; it is widely accepted that the standard immunomodulatory dose of 2 g/kg is usually divided into five daily infusions of 0.4 g/kg, although some physicians prefer to use two daily doses of 1 g/kg each. The database infusion records were incomplete and, therefore, it was not possible to fully interpret the data and decipher the dosing that had been used. This update to the guidelines now provides specific dosing recommendations for each of the conditions for which prescribing is regarded as appropriate. Immunoglobulin users are expected to record the dosing employed in the national database. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 An ongoing issue for diseases that require long-term immunoglobulin treatment is that once responsiveness to intravenous immunoglobulin (IVIg) is proven for a patient using standard immunomodulatory dosing, the `maintenance' dosing required to maintain the therapeutic response is not well characterised. In this update, the dosing recommendations for some neurological indications include `time to relapse' as the interval between doses. This approach is supported by recent evidence from The Oxford Programme for Immunomodulatory Immunoglobulin Therapy, which was set up to review multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) treatment with immunoglobulin. In view of the uncertainty of both remission and disease progression in CIDP and MMN, The Oxford Programme reviewed the dose and infusion frequency of patients on a regular basis and showed that increasing the infusion interval proved successful in some patients and resulted in treatment discontinuation [2]. The study also indicated that the precise dose and infusion interval to keep each patient asymptomatic was not predictable, but the authors suggested a rough guide: patients in whom responses last 20% more than IBW, prescribers should consider using adjusted-bodyweight dosing of immunoglobulin. Infusion rates for intravenous immunoglobulin Initial intravenous infusion rates are low, and if well tolerated, the rate of administration may be increased, as specified in the products' Summary of Product Characteristics (SPC). For certain products, the SPC indicates that if the higher rate is tolerated, the rate may be further increased in primary immunodeficiency (PID) patients to the maximum infusion rate. Higher infusion rates may lead to improved convenience for patients and may reduce nursing time and the need for hospital resources. Infusion rates for each of the licensed immunoglobulins are provided in the table below. Immunoglobulin should be administered according to the manufacturers' recommendations. The table below gives the infusion rates, and the infusion time at maximum infusion rate of 1 g/kg dose in a 70 kg person. Infusion rates Infusion time of 0 g in minutes at max. rate 100 250 500 640 125 200 125 241 83 Product Baxter Kiovig BPL Gammaplex BPL Vigam Biotest Intratect CsL Privigen Grifols flebogamma Grifols flebogamma 10 Octapharma Octagam Octapharma Octagam 10 Initial 0.5 mL/kg/h for 30 mins 0.01?0.02 mL/kg/min for 15 mins 0.01?0.02 mL/kg/min for 30 mins 1.4 mL/kg/h for 30 mins 0.3 mL/kg/h 0.01?0.02 mL/kg/min for 30 mins 0.01 mL/kg/min for 30 mins 1 mL/kg/h for 30 mins 0.01?0.02 ml/kg/min for 30 mins Maximum 6 mL/kg/h (8 ml/kg/h in PID) 0.04?0.08 mL/kg/min 0.04 mL/kg/min (max. 3mL/min) 1.9 mL/kg/h 4.8 mL/kg/h (7.2 mL/kg/h in PID) 0.1 mL/kg/min 0.08 mL/kg/min 5 mL/kg/h 0.12 ml/kg/min 1 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use subcutaneous administration Subcutaneous immunoglobulin (SCIg) as replacement therapy for primary immune deficiency disease and as immunomodulatory therapy for some autoimmune diseases, including peripheral neuropathies, can be a safe, effective, and convenient alternative to intravenous therapy. Subcutaneous administration can offer advantages that may be important for many patients [3]. Although SCIg is typically administered weekly by infusion pump, administration by a rapid push technique may provide a greater degree of convenience, and recent evidence suggests it is a safe and effective method. Seventy-four patients with primary immune deficiency disease received an average SCIg dose of 32 g/month split into an average of three times per week. Volume per site ranged from 3 to 20 mL, typically administered over 5?20 min. Mean serum IgG levels did not differ significantly compared with those receiving infusion and only two patients discontinued therapy because of an adverse event [4]. Recent evidence suggests that individualising the dosage based on measured serum IgG levels and the clinical response is preferable to using mean pharmacokinetic parameters [5]. Findings from the Oxford Self Infusion at Home Programme for CIDP and MMN also suggest that the dose of immunoglobulin and the serum IgG trough level are individual to each patient [2]. Recommendation Prescribers should consider the comparative advantages of intravenous and subcutaneous administration for individual patients requiring immunoglobulin treatment where this is clinically appropriate. Table. Subcutaneous immunoglobulin products licensed in the UK CSL Vivaglobin Baxter Subcuvia Octapharma Gammanorm BPL Subgam CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 RefeReNCes 1. NICE clinical guideline 98. Neonatal Jaundice. Nice, 2010. 2. Lucas M, Hugh-Jones K, Welby A, et al. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol 2010;30 Suppl 1:S84?9. 3. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112:1?7. 4. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis. J Clin Immunol 2010;30:301?7. 5. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin Immunol 2011;139:133?41. 1 sUMMARY TABLes PRIMARY AND seCONDARY ANTIBODY DefICIeNCY sTATes selection criteria A specific PID diagnosis must be established by a clinical immunologist Outcome measures are not required Condition s L Outcomes for review Dosing Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Initiate at 0.4?0.6 g/kg/month; dose requirements may increase and should be based on clinical outcome Primary immunodeficiencies (associated with significant antibody defects) Profound B cell depletion and/or significant antibody deficiency Outcome measures are not required Thymoma with immunodeficiency HSCT in primary immunodeficiencies PID patients undergoing HSCT Outcome measures are not required CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Specific antibody deficiency Approval by a clinical immunologist, AND Severe, persistent, opportunistic or recurrent bacterial infections despite continuous oral antibiotic therapy for 3 months, AND Documented failure of serum antibody response to unconjugated pneumococcal or other polysaccharide vaccine challenge Underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated; OR Hypogammaglobulinaemia associated with NHL, CLL, MM or other relevant B-cell malignancy confirmed by haematologist; AND ? Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 3 months ? IgG 1 dose required if thrombocytopenia persists Clinical suspicion in antenatal or neonatal setting based on clinical and laboratory features: Thrombocytopenia or spontaneous haemorrhage in the foetus; OR Thrombocytopenia with or without haemorrhage in the neonate; OR Unexplained foetal death in a previous pregnancy and the presence of maternal platelet-specific allo-antibodies that are known or suspected to cause this condition (most commonly HPA-1a or HPA-5b) Symptomatic or severe anaemia (Hb 15, acute rising Any significant clearance of C. diff. creatinine and/or signs/symptoms Duration of hospital in-patient stay of colitis) not responding to oral vancomycin 125 mg qds, highdosage oral vancomycin +/- iv metronidazole 500 mg tds is recommended; the addition of oral rifampicin (300 mg bd) or IVIg may be considered. If multiple recurrences, especially if evidence of malnutrition, wasting etc., consider IVIg Severe or recurrent Clostridium difficile colitis 0.4 g/kg, one dose, and consider repeating continued Other selection criteria Diagnosis of streptococcal or staphylococcal TSS, preferably with isolation of organism; AND Failure to achieve rapid improvement with antibiotic therapy and other supportive measures; AND Life-threatening Diagnosis by a dermatologist; AND Involved body surface area > 10%; AND When other treatments are contraindicated; OR The condition is life-threatening Resolution of the disease 2 g/kg, preferably as a single dose, or divided over 3 consecutive days Improvement of FBC, ALK, CPK Reduction in hospital inpatient stay Survival (yes/no) 2 g/kg as a single dose continued Outcomes for review Dosing Condition s L Staphylococcal or streptococcal toxic shock syndrome Toxic epidermal necrolysis, Stevens Johnson syndrome Transplantation (solid organ) AIT Up to 2 g/kg to be repeated as per DSA, in renal desensitisation at 0.1 g/kg for 8?12 doses AMR Up to 2 g/kg to be repeated for 2?3 doses Viral pneumonitis 0.5 g/kg for 5 days CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Antibody Incompatible Transplant AIT and AMR* (AIT) Renal Patients in whom renal, heart or Type of renal transplant lung transplant is prevented HLA class DSA because of antibodies Rejection episodes Patient survival Antibody Mediated Rejection Graft survival (AMR) Renal function = eGFR (MDRD) Patients experiencing steroid Cardiothoracic resistant rejection or where other DSA therapies are contraindicated after Patient survival renal, heart and/or lung transplant Length of ITU and hospital stay Graft function (heart = ejection Viral pneumonitis fraction; lung = spirometry) Patients experiencing viral pneumonitis following heart and/or Viral pneumonitis* lung transplant (viruses to include Cardiothoracic HSV, VZV, CMV, RSV, but excluding Virus type influenza virus) Reversal of radiological infiltrates Length of hospital stay Survival *These parameters will be reviewed after one year, at which time specific outcome criteria will be formulated. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use sUMMARY Of GReY INDICATIONs Grey indications are those diseases for which the evidence is weak, in many cases because the disease is rare. Approval from both the local IAP and the PCT is required for immunoglobulin treatment. In cases of `unlisted' diseases, those not listed in the guidelines are to be considered as Grey. Even if the disease is unlisted, the diagnosis and locally agreed efficacy criteria are to be recorded in the database. Immune-mediated disorders with limited evidence of immunoglobulin efficacy Acute disseminated encephalomyelitis (if high-dose steroids have failed) Autoimmune encephalitis (including NMDA and VGKC antibodies, among others) Catastrophic antiphospholipid syndrome Cerebral infarction with antiphospholipid antibodies Chronic ITP Complex regional pain syndrome CNS vasculitis Intractable childhood epilepsy Neuromyotonia Opsoclonus Myoclonus Post-exposure prophylaxis for viral or pathogenic infection if intramuscular injection is contraindicated, or treatment when hyperimmune immunoglobulins are unavailable Pyoderma gangrenosum Systemic juvenile idiopathic arthritis Systemic vasculitides and ANCA disorders Urticaria (severe, intractable) Presumed immune-mediated disorders with little or no evidence of efficacy Acquired red cell aplasia NOT due to parvovirus B19 Acute idiopathic dysautonomia Aplastic anaemia/pancytopenia Atopic dermatitis/eczema Autoimmune neutropenia Chronic facial pain Diabetic proximal neuropathy Haemolytic uraemic syndrome PANDAS Paraneoplastic disorders that are known not to be B- or T-cell mediated POEMS SLE without secondary immunocytopenias (including juvenile) CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Removed from Grey: ? Secondary antibody deficiencies INDICATIONs fOR WHICH IVIG Is NOT ReCOMMeNDeD (now Blue) ? Acquired vWd (now Blue) ? Post-transfusion hyperhaemolysis (now with haemolytic anaemia) ? Graft versus host disease (delete) ? SLE with secondary immunocytopenias (included in the relevant cytopenias) ? Infection following BMT or HSCT (included in Blue) ? Polymyositis (now Blue) ? Transplantation indications (now Blue) ? Immunodeficiency secondary to paediatric HIV infection ? Autologous BMT ? Adrenoleukodystrophy ? Alzheimer's disease ? Amyotrophic lateral sclerosis ? Chronic fatigue syndrome ? Critical illness neuropathy ? Multiple sclerosis ? Rheumatoid arthritis ? Neonatal sepsis (prevention or treatment) ? Sepsis in the intensive care unit not related to specific toxins or C. difficile ? Asthma ? Graves' ophthalmopathy ? IVF failure ? Recurrent spontaneous pregnancy loss CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Next section contains the replacement pages of second edition CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use Update for pages 28?30 IMMUNOLOGY Primary immunodeficiency disorders (associated with significant antibody defects) Antibody deficiencies may arise as primary disorders with a known or suspected genetic basis or secondary to a variety of other diseases, drugs and environmental or iatrogenic factors. They may occur in isolation or in association with defects in other effector components of the immune system (combined defects). Significant primary antibody deficiencies collectively account for the majority of primary immunodeficiency syndromes encountered in clinical practice [1,2]. The hallmark clinical presentation is recurrent or persistent bacterial infection, but these disorders are also associated with a heterogeneous variety of other infectious and non-infectious complications and with a high incidence of chronic, structural tissue damage, particularly in the respiratory tract. Clinical recognition of primary antibody deficiency is frequently delayed with consequent acute and chronic ill health, diminished Common Common variable immunodeficiency group (CVID) X-linked agammaglobulinaemia quality of life, and decreased life expectancy. Primary antibody deficiency can present at any age. Taken together, the primary antibody deficiency disorders account for at least half of all primary immunodeficiency syndromes. For some conditions, internationally-agreed diagnostic criteria have been established [3], but in other disorders formal case-definition criteria are lacking. The evidence base for current practice in the recognition, diagnosis and management of antibody deficiency has recently been reviewed [4]. Disorders which generally require immunoglobulin replacement as a central component of their management are presented below. Diagnosis, particularly of primary deficiencies, is frequently delayed or overlooked [1,5]. Many patients present with established structural tissue damage, especially in the lungs, which is essentially irreversible even with optimal treatment. Diagnostic aims are to a) identify, or exclude, significant antibody deficiency, b) differentiate primary from secondary disease and c) delineate, where possible, a precise diagnosis. Less common Germinal centre class switch recombination defects (`Hyper-IgM syndromes') Other primary antibody deficiency (XLA) (including unclassifiable disorders) Combined immunodeficiencies (including severe combined immunodeficiency (SCID) and unclassifiable disorders) 0 CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use The goals of management are to prevent complications or retard their progression, optimise quality of life, working capacity and life expectancy and, in children, ensure optimal growth and development [6]. Replacement therapy with polyclonal human normal immunoglobulin is the cornerstone of management for significant primary antibody deficiency disorders. No viable alternatives exist to this essential, basic component of treatment, particularly in the context of severe, persistent or recurrent bacterial infections. For most patients, replacement therapy is a lifelong requirement. Existing formulations replace deficient IgG only and are given by either intravenous or subcutaneous infusion in a hospital setting or, increasingly, within domestically-based programmes. Subcutaneous and intravenous preparations are therapeutically equivalent [7]. All preparations carry risks of adverse, infusion-related reactions and both real (hepatitis C) and theoretical (vCJD) risks of transmissible disease. Replacement therapy increases life expectancy and reduces the frequency and severity of infections, antibiotic usage and hospital admissions [4]; however, patients remain susceptible to sporadic breakthrough infections [8]. Optimal dosing and target levels for IgG are not known but higher doses are more effective than low-dose regimens in reducing infection rates and risk of chronic tissue damage. However, even apparently adequate treatment may fail to completely retard progression of established disease complications such as bronchiectasis [9]. Replacement therapy is frequently targeted at achieving a sustained or pre-infusion trough serum IgG level within the normal range (6?16 g/L). There is evidence that improved outcomes, particularly in respect of respiratory infection, are associated with higher serum IgG levels up to at least 10 g/L [10]. Dosage should generally be initiated at 0.4?0.6 g/kg/month, but individual patients may require higher doses in the long term. The goal of therapy in individual cases should be to improve clinical outcome rather than achieve a minimum target level of serum IgG [11]. Dose requirements are commonly increased in the context of secondary structural tissue damage (especially in the respiratory tract) or co-existent chronic inflammatory conditions. Risk assessments for ongoing therapy with immunoglobulin should be carried out regularly (including the need to continue with active treatment). Recommendation Replacement immunoglobulin therapy in patients with significant, symptomatic primary defects of antibody production or function should be tailored to individual patient outcomes with the minimum aim of maintaining serum IgG levels within the age-related normal range (grade B recommendation, level IIb evidence). CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 1 Other specific Disorders Thymoma with immunodeficiency (Good's Syndrome) Good's syndrome is a complex CVID-like condition where thymoma is found in association with profound B cell lymphopenia and quantitative or functional antibody deficiency. Infection frequencies correlate better with numerical B-cell depletion than with hypogammaglobulinemia. Thymectomy rarely results in normalisation of immunoglobulin levels and the syndrome may therefore constitute, and be classified as, a primary rather than secondary defect and, in respect of any antibody deficiency, be treated as for other primary antibody defects [2,12]. diagnosis is established. Pre-existing infection in the high-risk situation of a combined primary immunodeficiency reduces the chances of a successful outcome from a haemopoietic stem cell transplant. Treatment with immunoglobulin should be continued following transplantation until reconstitution of B cells and antibody production has been achieved. In some cases, prolonged immunoglobulin replacement therapy is required. Recommendation Immunoglobulin replacement therapy should be considered an important adjunct to haemopoietic stem cell transplantation in the management of some primary immunodeficiency disorders. Duration of treatment should be based on individual reconstitution of B-cell function post-transplantation (grade C recommendation, level III evidence). Recommendation Immunoglobulin replacement is recommended for patients with thymoma associated with profound B-cell depletion and/or significant antibody deficiency (grade C recommendation, level III evidence). specific antibody deficiency Specific antibody deficiency is characterised by an inability to mount adequate humoral responses to polysaccharide antigens, with otherwise normal immunoglobulins [13]. Robust case definition is currently hampered by a lack of consensus on in-vitro diagnostic criteria. Consequently, uniform recommendations for treatment are yet to be developed. Most cases appear to have a relatively mild clinical phenotype (encompassing mainly respiratory infections) which Combined immunodeficiencies requiring haemopoietic stem cell transplantation In this group of disorders, including Severe Combined Immunodeficiency and occurring predominantly in children, immunoglobulin therapy is required as a central measure to protect against infection and should be implemented as soon as possible after the CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use can be managed with prophylactic antibiotics and acute treatment of breakthrough infections. Immunoglobulin replacement is reserved for those cases where prophylactic antibiotics fail to control either the frequency or severity of breakthrough infections. Recommendation Immunoglobulin replacement therapy may be required in a proportion of infants with prolonged physiological delay of native immunoglobulin production. Where required, the planned duration of therapy should be defined prior to initiation of active treatment (grade C recommendation, level III evidence). Recommendation Immunoglobulin replacement therapy is recommended in specific antibody deficiency in cases of failure of prophylactic antibiotic treatment where severe, persistent, opportunistic or recurrent breakthrough infections are encountered (grade C recommendation, level III evidence). secondary antibody deficiency Secondary antibody defects are found in a wide range of circumstances (in association with drugs, malignant disease, chronic infections, protein-losing states, systemic inflammatory diseases, trauma and iatrogenic factors such as splenectomy). Infections associated with low measured antibody levels appear to be relatively uncommon in secondary deficiencies, with the exceptions of hypogammaglobulinaemia linked with haematological malignant disease, occasional cases of drug-associated deficiency and rare cases of nephrotic syndrome [15]. Dosage and treatment duration are important factors in drug-associated deficiencies. The deficit may, or may not, be reversible on cessation of therapy. The selection criteria for IVIg to treat hypogammaglobulinaemia linked with haematological malignancy includes the requirement to document failure of serum antibody response to Transient hypogammaglobulinaemia of infancy Hypogammaglobulinaemia in young children is often transient, reflecting delayed maturation of the immune system. In the majority of such children, immunoglobulin levels normalise by the age of around 4 years, but in a minority this can be delayed until 11 or 12 years of age. Most of these children are affected by frequent, minor infections, which can be managed with early, acute antibiotic usage or antibiotic prophylaxis [14]. However, in a small minority, infections are more severe and cannot be controlled or prevented with antibiotics alone. In such circumstances, immunoglobulin replacement is required until normalisation of endogenous antibody production. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use unconjugated pneumococcal or other polysaccharide vaccine challenge. Although this may sound onerous from a practical point of view, the intention is simply to ensure that a patient's response to polysaccharide vaccination is included as a component of the evaluation for IVIg therapy. For example, if a patient received pneumococcal polysaccharide vaccine 3 months previously and their specific antibody levels are low, it would seem reasonable to prescribe immunoglobulin. However, if the patient was vaccinated many years previously, it would be reasonable to vaccinate again and assess the functional antibody response before immunoglobulin was prescribed. Recommendation Immunoglobulin replacement therapy is recommended in secondary antibody deficiency if the underlying cause of hypogammaglobulinaemia cannot be reversed or reversal is contraindicated, or is associated with B-cell malignancy where severe infections with encapsulated bacteria are persistent despite prophylactic antibiotic therapy (grade C recommendation, level III evidence). RefeReNCes 1. Eadles-Perner A-M, Gathmann B, Knerr V, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06. Clin Exp Immunol 2007;177:306?12. 2. Geha RS, Notarangelo LD, Casanova JL, et al. for the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776?94. 3. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Clin Immunol 1999;93:190?7. 4. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol 2007;149:410?23. 5. Seymour B, Miles J, Haeney MR. Primary antibody deficiency and diagnostic delay. J Clin Pathol 2005;58:546?7. 6. Folds JD, Schmitz JL. Clinical and laboratory assessment of immunity. J Allergy Clin Immunol 2003;111(Suppl. 2):S702?11. 7. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin therapy. J Clin Immunol 2000;20:94?100. 8. Pettit SJ, Bourne H, Spickett GP. Survey of infection in patients receiving antibody replacement treatment for immune deficiency. J Clin Pathol 2002;55:577?80. CLINICAL GUIDeLINes fOR IMMUNOGLOBULIN Use 9. Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allerg
Url: /Media/SUHTExtranet/TrustMedicinesFormulary/Forms/DH-IVIg-approved-indications-Full-Guidance-July-2011.pdf

ACCORD-2 master protocol

Description: CONFIDENTIAL ACCORD-2-001 – Master Protocol TITLE PAGE Protocol Title: ACCORD-2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients Master Protocol Number: ACCORD-2-001 Product: Multiple candidate agents Study Phase: 2 Sponsor Name: University Hospital Southampton NHS Foundation Trust Legal Registered Address: Southampton General Hospital Level E, Laboratory & Pathology Block, SCBR - MP138 Tremona Road Southampton SO16 6YD, UK Regulatory Agency Identifying Number(s): IRAS Number: RHM Number: EudraCT 2020-001736-95 282769 Date of Protocol: 22 April 2020 Version: Final Final, 22 April 2020 1 CONFIDENTIAL Chief Investigator Signatory: ACCORD-2-001 – Master Protocol I have read this protocol in its entirety and agree to conduct the study accordingly: Professor Tom Wilkinson MA Cantab MBBS PhD FRCP Professor of Respiratory Medicine and Honorary NHS Consultant Physician 22/04/2020 Date Final, 22 April 2020 2 CONFIDENTIAL ACCORD-2-001 – Master Protocol TABLE OF CONTENTS TABLE OF TABLES...............................................................................................................6 TABLE OF FIGURES.............................................................................................................7 1.0 PROTOCOL SUMMARY ..........................................................................................8 1.1 Synopsis.............................................................................................................8 1.2 Schema ............................................................................................................13 1.3 Example Schedule of Activities.....................................................................14 2.0 INTRODUCTION......................................................................................................18 2.1 Study Rationale ..............................................................................................18 2.2 Background ....................................................................................................18 2.3 Benefit/Risk Assessment ................................................................................19 3.0 OBJECTIVES AND ENDPOINTS ..........................................................................20 4.0 STUDY DESIGN........................................................................................................22 4.1 Overall Design ................................................................................................22 4.2 Scientific Rationale for Study Design...........................................................24 4.3 Justification for Dose .....................................................................................24 4.4 End of Study Definition .................................................................................24 5.0 STUDY POPULATION ............................................................................................25 5.1 Inclusion Criteria ...........................................................................................25 5.2 Exclusion Criteria ..........................................................................................25 5.3 Lifestyle Considerations ................................................................................26 5.4 Screen Failures ...............................................................................................26 6.0 STUDY TREATMENT .............................................................................................27 6.1 Study Treatment(s) Administered................................................................27 6.2 Preparation/Handling/Storage/Accountability ...........................................27 6.3 Measures to Minimise Bias: Randomisation and Blinding ........................28 6.4 Study Treatment Compliance.......................................................................28 6.5 Concomitant Therapy....................................................................................28 6.5.1 Rescue Medicine ...............................................................................29 6.6 Dose Modification ..........................................................................................29 6.7 Treatment after the End of the Study ..........................................................29 7.0 DISCONTINUATION OF STUDY TREATMENT AND PATIENT DISCONTINUATION/WITHDRAWAL ................................................................30 7.1 Discontinuation of Study Treatment ............................................................30 Final, 22 April 2020 3 CONFIDENTIAL ACCORD-2-001 – Master Protocol 7.2 Patient Discontinuation/Withdrawal from the Study.................................30 7.3 Lost to Follow-up ...........................................................................................30 8.0 STUDY ASSESSMENTS AND PROCEDURES ....................................................32 8.1 Efficacy Assessments .....................................................................................33 8.1.1 Improvement on the 9-Point Scale ....................................................33 8.1.2 Other Efficacy Assessments ..............................................................34 8.2 Safety Assessments.........................................................................................34 8.2.1 Physical Examinations.......................................................................34 8.2.2 Vital Signs and Blood Gases .............................................................34 8.2.3 Clinical Safety Laboratory Assessments ...........................................35 8.3 Virologic Load ................................................................................................35 8.4 Adverse Events ...............................................................................................35 8.4.1 Time Period and Frequency for Collecting AE and SAE Information ........................................................................................35 8.4.2 Method of Detecting AEs and SAEs .................................................36 8.4.3 Follow-up of AEs and SAEs .............................................................36 8.4.4 Regulatory Reporting Requirements for SAEs .................................36 8.4.5 Pregnancy ..........................................................................................37 8.4.6 Adverse Events of Special Interest ....................................................37 8.4.7 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as Adverse Events or Serious Adverse Events.........37 8.5 Treatment of Overdose..................................................................................37 8.6 Pharmacokinetics ...........................................................................................37 8.7 Pharmacodynamics........................................................................................38 8.8 Immunology....................................................................................................38 8.9 Genomics.........................................................................................................38 8.10 Serology Research (Host Response) .............................................................39 9.0 STATISTICAL CONSIDERATIONS .....................................................................39 9.1 Design Overview.............................................................................................39 9.2 Statistical Hypotheses ....................................................................................39 9.3 Sample Size Determination ...........................................................................40 9.4 Populations for Analyses ...............................................................................42 9.5 Statistical Analyses.........................................................................................42 9.5.1 Efficacy Analyses ..............................................................................43 9.5.2 Safety Analyses .................................................................................43 9.5.3 Other Analyses ..................................................................................44 9.5.4 Missing Data......................................................................................44 9.6 Interim Analyses ............................................................................................45 9.7 Review Committees........................................................................................45 9.7.1 Steering Committee (Scientific Review Committee) ........................45 9.7.2 Independent Data and Safety Monitoring Committee.......................45 Final, 22 April 2020 4 CONFIDENTIAL ACCORD-2-001 – Master Protocol 10.0 REFERENCES...........................................................................................................47 11.0 APPENDICES ............................................................................................................48 Appendix 1 Abbreviations ...................................................................................49 Appendix 2 Regulatory, Ethical, and Study Oversight Considerations..........51 Protocol Compliance........................................................................................51 Regulatory and Ethical Considerations............................................................51 Financial Disclosure.........................................................................................52 Indemnity .........................................................................................................52 Informed Consent Process ...............................................................................52 Data Protection.................................................................................................53 Administrative Structure ..................................................................................54 Dissemination of Clinical Study Data..............................................................54 Data Quality Assurance ...................................................................................54 Source Documents ...........................................................................................55 Study and Study Centre Closure ......................................................................55 Publication Policy ............................................................................................56 Appendix 3 Clinical Laboratory Tests ...............................................................57 Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting .....................................59 Appendix 5 Collection of Pregnancy Information ............................................63 Appendix 6 Genetics ............................................................................................65 Appendix 7 Signature of Investigator ................................................................66 Final, 22 April 2020 5 CONFIDENTIAL ACCORD-2-001 – Master Protocol Table 1 Table 2 Table 3 Table 4 Table 5 TABLE OF TABLES Study Objectives and Endpoints ......................................................................20 Sample Size for 80% and 90% Power for Time to Improvement, Discharge from Hospital, or Fit for Discharge Using Log-rank Test for a Hazard Ratio of 1.6 in Treatment Arm to Standard of Care ...................41 Analysis Sets ....................................................................................................42 Efficacy Analyses ............................................................................................43 Protocol-required Safety Laboratory Assessments..........................................58 Final, 22 April 2020 6 CONFIDENTIAL ACCORD-2-001 – Master Protocol Figure 1 TABLE OF FIGURES Study Schema...................................................................................................13 Final, 22 April 2020 7 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.0 PROTOCOL SUMMARY 1.1 Synopsis Protocol Title: ACCORD-2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients Rationale: There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death Final, 22 April 2020 8 CONFIDENTIAL ACCORD-2-001 – Master Protocol Secondary • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29. • To evaluate the number of oxygen-free days. • Duration (days) of oxygen use and oxygen-free days. • To evaluate ventilator-free days and incidence and • Duration (days) of ventilation and ventilation-free duration of any form of new ventilation use. days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, 22, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Final, 22 April 2020 9 CONFIDENTIAL ACCORD-2-001 – Master Protocol Exploratory • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative PCR determination of SARS-CoV-2 in blood and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 (may be become a secondary endpoint once the assays are available). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Overall Design: ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised – mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub-protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require equivalent blood samples from controls). The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the Final, 22 April 2020 10 CONFIDENTIAL ACCORD-2-001 – Master Protocol study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe adverse events (AEs), overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. Number of Investigators and Study Centres: Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Number of Patients: The expected number of patients for each treatment arm is presented as part of the sample size determination below. It is estimated that up to 1800 patients will participate in the overall study. Treatment Groups and Duration: In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Statistical methods: Sample size determination: Stage 1: Based on the chosen endpoint, a preliminary analysis will be carried out when an estimated 81 events have been observed across each agent treatment and SoC or 28 days after the last patient has been randomised, whichever occurs sooner, as determined by the Independent Data and Safety Monitoring Committee (IDMC). In order to achieve this number of events, it is expected that 54 patients are needed per arm, which will provide 80% power to detect a hazard ratio of 1.6 for the occurrence of the event, when comparing each candidate agent with SoC. To allow for uncertainty in the recruitment rates, it is expected that up to 60 patients will be randomised to each arm in order to achieve the required number of events for the preliminary analysis. Stage 2: The number of patients will be determined more precisely at the end of Stage 1, but approximately 126 patients will be randomised to each arm. Analysis sets: • Intention to Treat (ITT): All patients who are randomised and match the inclusion/exclusion criteria of the Master Protocol and relevant sub-protocol will be included in the ITT. • Safety Set: All patients who are randomised and take at least 1 dose of study medication will be included in the safety set. Final, 22 April 2020 11 CONFIDENTIAL ACCORD-2-001 – Master Protocol • Pharmacokinetic Analysis Set (PKS): All patients who are randomised and take at least 1 dose of the candidate agent and have quantifiable candidate agent concentrations postdose without protocol deviations or events affecting the pharmacokinetic results will be included in the PKS. • Pharmacodynamic Analysis Set (PDS): All patients who are randomised and take at least 1 dose of study medication (candidate agent or SoC) and have evaluable results for at least 1 pharmacodynamic endpoint postdose. All analyses of the PDS will be based on each patient’s randomised assigned treatment (not actual treatment received). Efficacy, safety, pharmacokinetic, and pharmacodynamic results will be listed and summarised by stage, dose, and scheduled time for the respective analysis sets, where appropriate. Candidate agent concentration versus response variables may be graphically displayed for selected endpoints. Exposure-response data obtained from this study may be combined with data from other studies and used for modelling and simulations. Data Monitoring Committee: A Steering Committee will evaluate interim analysis data to make decisions on further progression of the candidate agents within the study, and will provide guidance, advice, and recommendations to the ACCORD program on relevant clinical issues related to the strategy, implementation, and conduct of the study. An IDMC will objectively monitor safety data throughout the study to make recommendations to the Steering Committee regarding study conduct. Final, 22 April 2020 12 CONFIDENTIAL 1.2 Schema Figure 1 Study Schema ACCORD-2-001 – Master Protocol IA=interim analysis; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SoC=standard of care. Note: This figure shows a hypothetical situation, where in Stage 1 of the study there are 4 candidate agents being compared with the SoC, of which 2 candidate agents progress to Stage 2. Final, 22 April 2020 13 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.3 Example Schedule of Activities Screening Baseline Day (± Window) ELIGIBILITY Informed consent Demographics Relevant medical historyb Review of SARS-CoV-2 diagnostic tests Inclusion and exclusion criteria 12-lead Electrocardiogram STUDY INTERVENTION Randomisation Administration of candidate agent Treatment with SoC STUDY PROCEDURES Clinical frailty score Diagnostic imaging (X-ray and/or computed tomography) Physical examination (including presenting symptoms, height, weight) Targeted physical examination (focused on lung auscultation) Vital signs, including oral temperature, pulse rate, blood pressure, respiratory rate, SpO2 Day -1 or Day 1 X X X X X X X X X Day 1 X X Xc Daily Until Hospital Discharge Day 15a (±2 days) Defined in subprotocol X X X X Day 29a (±3 days) X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Final, 22 April 2020 14 CONFIDENTIAL ACCORD-2-001 – Master Protocol Screening Baseline Day (± Window) Clinical assessmentsd Targeted medication review (including use of vasopressors) Adverse event evaluation Disease-related co-infection evaluation (including microbiologic/infectious agent assessment/results; bacteria, viral, fungi) Survival status Blood gases and FiO2 at worst PO2e SAFETY LABORATORY Haematology, chemistry, liver function tests, coagulationf Day -1 or Day 1 X Xg Day 1 Xc Xc X X X X Xc,h Pregnancy test for females of childbearing potential Xg RESEARCH LABORATORY Blood (SST) for exploratory inflammatory cytokine analysis X (others to be defined in sub-protocols) Blood (sodium heparin tube) for PBMC phenotypingi X Blood (EDTA) for SARS-CoV-2 PCR (qualitative and quantitative) X Daily Until Hospital Discharge X X X X X X Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 8 Day 8 Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 15a (±2 days) X X X X X X X X Day 29a (±3 days) X X X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) X X X X X X X X Final, 22 April 2020 15 CONFIDENTIAL ACCORD-2-001 – Master Protocol Screening Baseline Day (± Window) Day -1 or Day 1 Day 1 Daily Until Hospital Discharge Day 15a (±2 days) Day 29a (±3 days) Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Oropharyngeal/nasal swab for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Saliva for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Blood (SST) for SARS-CoV-2 serology research (host response) X Day 8 X X X Blood (PAXGENE) for transcriptome analysis (host genome)j X Day 8 X Blood (EDTA) host genome (host DNA)j X Mid-turbinate nasal swab viral genomej X EDTA=ethylenediaminetetraacetic acid; FiO2=fraction of inspired oxygen; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PO2=partial pressure of oxygen; RT PCR=reverse transcription polymerase chain reaction; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2; SoC=standard of care; SpO2=oxygen saturation; SST=serum separator tube. Note: Additional assessments, if required, will be defined in the sub-protocol. a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, in-person visits are preferred, but recognising that quarantine and other factors may limit the patient’s ability to return to the clinic, these visits may be conducted by telephone or with a home visit by study staff. For visits conducted by telephone, it will not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will also be performed, where possible, for patients who discontinue the study prematurely. b Medical history includes estimated date and time of first symptoms and number of co-morbidities (eg, respiratory, cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). c Baseline assessments should be performed prior to study drug administration. d Includes ordinal score, National Early Warning Score 2 (NEWS2), oxygen requirement, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen supply or of any form of ventilation etc. e If done as part of SoC, blood gases results to be fully recorded with date and time. f For parameters, see Table 5. Final, 22 April 2020 16 CONFIDENTIAL ACCORD-2-001 – Master Protocol g Laboratory tests performed in the 48 hours prior to enrolment will be accepted for determination of eligibility. h Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. i Samples collected for immediate laboratory processing and frozen storage. j Samples collected dependent on capacity of study centre, need for reduced study burden on staff, and potentially limited access to patients. Final, 22 April 2020 17 CONFIDENTIAL ACCORD-2-001 – Master Protocol 2.0 INTRODUCTION 2.1 Study Rationale There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. 2.2 Background Coronaviruses are single-stranded RNA viruses, capable of causing life-threatening disease in humans and animals. The novel coronavirus SARS-CoV-2 was initially identified during an outbreak of viral pneumonia cases of unknown cause in China. Most of the initial infections outside of China were travel associated (ie, from people who had travelled from the infected regions of China to other countries), although person-to-person transmission in other countries was quickly established. The disease caused by the SARS-CoV-2 virus has been designated COVID-19. SARS-CoV-2 binds via the angiotensin-converting enzyme (ACE) receptor located on alveolar cells and intestinal epithelia.1 The virus is mutating, indicating that virulence and transmission will shift over time, and showing diversity in critical surface protein. New evidence suggests there are 2 groups of SARS-CoV-2; L-type and S-type.2 S-type is the less aggressive (30%); the L-type is now the most prevalent version (70%) and is more aggressive. Additionally, individuals appear to be affected to different degree with varying symptoms and outcomes. These findings strongly support an urgent need for immediate comprehensive studies and robust validation of testing methods that combine genomic data, chart records and clinical symptoms, to help better understand the disease, enable risk assessment, triage and support public health resource planning. Due to the rapid global widespread of SARS-CoV-2, there is an urgent need to develop efficacious treatments for the disease. Current clinical studies involve the use of already approved medications for other indications (repurposing) where it is thought that they might also be effective in the treatment of COVID-19 disease, as well as development of antibody-based therapies against the virus. Final, 22 April 2020 18 CONFIDENTIAL ACCORD-2-001 – Master Protocol This platform study will test multiple candidate agents, with the aim of identifying potentially efficacious treatments in the shortest timeframe possible. In addition, it will support secondary research objectives that are critical for understanding the disease, spread of infection and robust tests to track it. 2.3 Benefit/Risk Assessment There are currently no approved therapeutic agents available to treat coronaviruses such as SARS-CoV-2, and so while there may not be benefits for an individual patient participating in this study, there may be benefits to society if a safe and efficacious therapeutic agent can be identified during the global COVID-19 outbreak. Detailed information about the known and expected risks and reasonably expected adverse events (AEs) of each candidate agent may be found in the corresponding sub-protocol for that agent. Final, 22 April 2020 19 CONFIDENTIAL ACCORD-2-001 – Master Protocol 3.0 OBJECTIVES AND ENDPOINTS Table 1 Study Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Secondary • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • To evaluate the number of oxygen-free days. • To evaluate ventilator-free days and incidence and duration of any form of new ventilation use. • To evaluate SARS-CoV-2 viral load. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29. • Duration (days) of oxygen use and oxygen-free days. • Duration (days) of ventilation and ventilation-free days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 Final, 22 April 2020 20 CONFIDENTIAL ACCORD-2-001 – Master Protocol • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Exploratory • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative PCR determination of SARS-CoV-2 in blood and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 (may be become a secondary endpoint once the assays are available). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Final, 22 April 2020 21 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.0 STUDY DESIGN 4.1 Overall Design ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or validated point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised - mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale, which was detailed in the World Health Organization R&D Blueprint “Novel Coronavirus - COVID-19 Therapeutic Trial Synopsis” (February 2020). Medical history will record the estimated date and time of first symptoms. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. A Steering Committee will evaluate candidate agents for progression in the study (see Section 9.7.1). This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require Final, 22 April 2020 22 CONFIDENTIAL ACCORD-2-001 – Master Protocol equivalent blood samples from controls). Additional patients will be recruited into the study each time a new sub-protocol (candidate agent) is added. The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe AEs, overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. It is estimated that up to 1800 patients will participate in the overall study. Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Final, 22 April 2020 23 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.2 Scientific Rationale for Study Design There are currently no approved therapeutic agents available to treat coronaviruses such SARS-CoV-2, the causative agent of as COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. This study utilises an adaptive design that maximises efficiency in identifying a safe and efficacious therapeutic agent for COVID-19. Some candidate agents may be in limited supply and this study design enables continuation of the study even if an agent becomes unavailable. In addition, the adaptive design allows for the evaluation of new candidate agents as they are identified. 4.3 Justification for Dose Justification for the dose of each candidate agent will be included in the corresponding sub-protocol. 4.4 End of Study Definition For each sub-protocol, the end of the study for that candidate agent will be defined as the date on which the last patient completes the last visit for that sub-protocol. For the overall study, the end of the study will be defined as the date on which the last patient completes the last visit for the final sub-protocol to be concluded. Once a patient has completed this study, there are no restrictions on them entering another study, subject to the eligibility criteria of that subsequent study. Final, 22 April 2020 24 CONFIDENTIAL ACCORD-2-001 – Master Protocol 5.0 STUDY POPULATION Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol waivers or exemptions, is not permitted. The inclusion and exclusion criteria listed below may be supplemented by additional criteria stipulated in the sub-protocols that are specific to the target candidate being tested (eg, criteria related to prohibited medications). In order to enrol, a patient or legally authorised representative must sign an informed consent form (ICF) and meet all entry criteria for both the Master Protocol and at least 1 respective sub-protocol. 5.1 Inclusion Criteria Patients are eligible to be included in the study only if all of the following criteria apply (as well as all criteria from the appropriate sub-protocol): 1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or point of care tests. 2. A score of Grade 3 to 5 on the 9-point ordinal scale. 3. Is a woman who is not of childbearing potential (as defined in Appendix 5) or The patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study and for at least 6 weeks after termination of study therapy. 4. Ability to provide informed consent signed by the study patient or legally authorised representative. 5.2 Exclusion Criteria Patients are excluded from the study if any of the following criteria apply (or any of the criteria from the appropriate sub-protocol): 1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale. 2. Any patient whose interests are not best served by study participation, as determined by a senior attending clinician. 3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 5 × the upper limit of normal (ULN). 4. Known active infection with HIV or hepatitis B or C. 5. Stage 4 severe chronic kidney disease or requiring dialysis (ie, estimated glomerular filtration rate 500 ms. 8. Anticipated transfer to another hospital that is not a study centre within 72 hours. 9. Allergy to any study medication. 10. Experimental off-label usage of medicinal products as treatments for COVID-19. 11. Patients participating in another clinical study of an investigational medicinal product. 5.3 Lifestyle Considerations Any lifestyle considerations that are specific to the candidate agent will be defined in the corresponding sub-protocol. Female patients are advised to avoid becoming pregnant during the study. 5.4 Screen Failures Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently randomly assigned to study treatment. A minimal set of screen failure information is required to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). Individuals who do not meet the criteria for participation in this study (screen failure) due to hypokalaemia, hypomagnese
Url: /Media/Southampton-Clinical-Research/COVID-19/ACCORD/ACCORD-2-master-protocol.pdf

BEACON protocol v8.0 07Mar2023 signed

Description: A randomised phase IIb trial of BE AC v izumab added to Temozolomide O ± Irin tecan for children with N refractory/relapsed euroblastoma Version 8.0 dated 07-Mar-2023 Dinutuximab beta amendment Coordinating Sponsor: Sponsor Protocol Number: CAS Code: EudraCT Number: ISRCTN Reference Number: ITCC Number: Roche Study Reference Number: Email: University of Birmingham RG_ 11-087 BN2008 2012-000072-42 40708286 032 MO28245 beacon@trials.bham.ac.uk This application is supported by the facilities funded through Birmingham Science City: Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project which forms part of the Science City University of Warwick and University of Birmingham Research Alliance. BEACON-Neuroblastoma Protocol_vn 8.0_vd 07Mar2023 Page1 of 157 BEACON-Neuroblastoma Trial Protocol AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version Amendment Date of number amendment Protocol version number Type of amendment SA 1 29-Jan-2013 2.0 Substantial Amendment N/A 23-Apr-2013 2.0a Non-Substantial Amendment N/A 01-Jul-2013 2.0b Non-Substantial Amendment Summary of amendment Introduction of the recommendation of weekly monitoring of blood counts for all patients receiving irinotecan. Addition of planned vaccination with live vaccination to exclusion criteria and prohibited medications section. ITCC Number has been corrected. Roche Study Reference Number and ISRCTN Reference Number have been added. Contact details for Plasma & Tumour Angiogenesis-Related Biomarkers have been amended. Table numbers have been corrected. Addition of guidance for research bone marrow sampling in Schedule of Activities table and sections 7.4.2.2 and 7.5.2. Addition of paragraph to sections 7.2, 7.6.1 – 7.6.4 detailing arrangements for handling dose modifications for Irinotecan + Temozolomide for patients receiving Bevacizumab. Discontinuation rules for osteonecrosis of the jaw and eye disorders added to table 13 in section 7.6.4. Correction to table number references in section 7.6.3. Clarification made in section 13.4.1 concerning Planned Interim Analysis. SA 3 06-Oct-2014 4.0 Substantial Amendment Changes to the Trial Personnel section of the protocol to include the addition of contact details for Denmark and Ireland Lead Investigators. Amendments to reflect the changes in study sampling requirements to Trial Synopsis, Schedule of Activities table and sections 1.2.6, 2.1, 2.2, 5.1, 5.2, 7.3, 7.4.2 and 7.5. Amendment to exclusion criteria in Trial Synopsis and section 4.2. Changes to the Schedule of Activities table to include the addition of an echocardiogram to be performed at screening and Tanner staging at screening and yearly in follow up. Changes to the time line for measuring renal function prior to commencing treatment in the Trial Synopsis, Schedule of Activities and section 4.1. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 3 of 157 BEACON-Neuroblastoma Trial SA 4 06-Oct-2014 4.0 SA 5 30-Jul-2015 5.0 Substantial Amendment Substantial Amendment Protocol Option to fax emergency randomisation removed. Telephone only in section 6.2 Changes to guidelines in section 7.2 for dose calculation in patients whose weight exceeds the 98th centile for age. Removal of enhanced data collection for Adverse Events of Special Interest (AESI) in section 7.6 and 9.1.2. Addition of option to extend treatment delay with agreement from Sponsor in Section 7.6.1 Addition of necrotising fasciitis as an adverse event requiring bevacizumab discontinuation in section 7.6.4. Changes to section 7.10 concerning the documenting of concomitant medications in patient medical notes and administration of bisphosphonates. Changes to section 9.1 regarding reporting of laboratory adverse events. Clarification on the arrangements for Follow Up Form completion for patients who do not require further follow up visits in section 11. Changes to bevacizumab and irinotecan preparation and dispensing guidelines in sections 8.2.4 and 8.3.3. Clarification on fasting arrangements prior to temozolomide administration added to section 8.4.3. Changes to events that should be reported on an Expected SAR Form in section 9.1.3.1. Clarification on SAEs that should be reported to F.Hoffman-La Roche Ltd in section 9.2.6 Addition of Trial Management Group meeting frequency in section 14.4. Changes to the wording of irinotecan randomisation in section 13.4.2. Addition of guidelines for dose reduction and discontinuation of temozolomide for liver toxicity in tables 8, 9, 10 & 11. Reference to the National Coordinating Centres has been changed to National CoSponsor throughout. Reference to Sponsor has been changed to Coordinating Sponsor. Change of Chief Investigator to Professor Pamela Kearns. Change of Principal Investigator at Royal Marsden Hospital to Dr Sucheta Vaidya. No changes made to the Protocol version. Chief Investigator and UK Lead Investigator changed to Dr Lucas Moreno Switzerland details added Schedule of events table amended for End Of Treatment clarity BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 4 of 157 BEACON-Neuroblastoma Trial N/A 23-Sep-2015 5.0a SA 6 16-Jan-2019 6.0a Protocol Topotecan added to the study as a new trial question and 2 new randomisation arms. The following sections are amended accordingly: Synopsis (Primary Objectives, sample size, Trial Duration, Trial therapy) Section 1 Background and rationale (Trial rationale) Section 3 Trial design (Randomisation) Section7.1 and 7.2 Treatment details Section7.6.1 Dose modifications Table 6 amended, Tables 11 and 12 added Section 8.4 Pharmaceutical Information Section 13 Statistical considerations The following changes were made to the Eligibility: Inclusion criteria – further details regarding birth control Exclusion criteria – Defined wash out period following prior IMP according to IMP half-life or 14 days. Lifestyle guidelines - further details regarding birth control Section 7.6 Dose modifications Figure 1 – reference to “chemo” changed to Temozolomide/Irinotecan/Topotecan” for clarity Section 8.2.4 Reference to “chemo” removed for clarity Section 7.6.4 AEs requiring Bevacizumab discontinuation – additional AEs added following Bevacizumab IB v22 Addendum Additional mRNA and exploratory sampling. Non-Substantial Amendment Substantial amendment The requirement for confirmatory scans was removed from the Schedule of Activities and Response assessment section 7.4.3. Lead Investigator for France amended to Dr Marion Gambart Minor wording corrections and clarifications Schedule of events table corrected Introduction of two new treatment arms (dinutuximab beta) for additional 64 patients Addition of eligibility criteria, schedule of events, treatment details, duration, cross over and dose modification details for new dinutuximab beta arms Adaptation of objectives, trial design, supporting treatment, pharmaceutical information and statistical consideration sections with new, relevant information. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 5 of 157 BEACON-Neuroblastoma Trial N/A 11-Apr-2019 6.0b SA 7 07-Feb-2020 7.0 SA 22 07-Mar-2023 8.0 Protocol Non-Substantial Amendment Substantial Amendment Substantial Amendment Minor wording corrections and clarifications Version amended from 6.0 to 6.0a to add. Additional rationale to update typographical errors.) Trial Synopsis: Clarification of recruitment targets Clarification of Section 10 title: “Dinutuximab beta and topotecan randomisations” Clarification that not all biological studies will be open at any one time (Section 10.2 and 15.5) Minor wording corrections and clarifications Urgent Safety Measure – implemented on 28th January 2020 Closure of Temozolomide (T) and Dinutuximab beta and Temozolomide (dBT) arms with immediate effect. Section 1.1 Background Section 1.2.3 Benefit Risk assessment Section 3.1 Randomisation Section 10 Headings changed Section 10.3 Trial therapy Update of contact details Change of definition of End of Trial (Section 21). Protocol previously defined two stages of end of trial (6 months after last patient completes treatment and 12 months after last data capture after 5 years follow up). This has been combined into one End of Trial definition: 6 months after last patient last visit (i.e. after 5 years follow up) Also addition of option to email SAE form (Section 18.2.1.2) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 6 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL PERSONNEL Chief Investigator: Co-Investigators: Exploratory Biomarkers Dr Lucas Moreno Dr. Lucas Moreno, MD, PhD Director Paediatric Oncology & Haematology Division Vall d’Hebron Barcelona Hospital Campus Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain  +34 93 489 3000  +34 93 489 4060  lucas.moreno@vhebron.net Professor Keith Wheatley Professor of Clinical Trials Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 415 9119  k.wheatley@bham.ac.uk Dr Juliet Gray Associate Professor and Consultant in Paediatric Oncology Southampton Children’s Hospital Tremona Road Southampton SO16 6YD  +44 (0) 790 1507929  juliet.gray@uhs.nhs.uk Dr Gudrun Schleiermacher Senior Scientist Institute Curie 26 rue d'Ulm 75248 Paris cedex 05 France  +33 (0)1 56 24 45 50  +33 (0)1 56 24 66 30  gudrun.schleiermacher@curie.net Professor Louis Chesler Paediatric Tumour Biology Team Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0) 208 722 4035 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 7 of 157 BEACON-Neuroblastoma Trial Protocol  louis.chesler@icr.ac.uk Functional Imaging Study: Professor Andrew Peet Institute of Child Health University of Birmingham Whittall Street Birmingham, UK B4 6NH  +44 (0) 121 333 8234  +44 (0) 121 333 8241  a.peet@bham.ac.uk Dr Dow-Mu Koh Consultant Radiologist in Functional Imaging Royal Marsden Hospital Downs Road, Sutton, Surrey, UK SM2 5PT  +44 (0) 208 6613857  dow-mu.koh@icr.ac.uk Professor Martin Leach Co-Director, Cancer Research UK and EPSRC Centre for Cancer Imaging, Director, NIHR Clinical Research Facility Deputy Head, Division of Radiotherapy and Imaging Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0 208 661 3338  Martin.Leach@icr.ac.uk Molecular Monitoring mRNA Study: Professor Sue Burchill Leeds Institute of Cancer & Pathology St. James University Hospital Beckett Street Leeds, UK LS9 7TF  +44 (0) 113 206 5873  +44 (0) 113 242 9886  S.A.Burchill@leeds.ac.uk Professor Walter Gregory Clinical Trials Research Unit (CTRU) University of Leeds Clinical Trials Research House 71-75 Clarendon Road Leeds LS2 9PH  +44 (0) 113 343 1489  +44 (0) 113 343 1471 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 8 of 157 BEACON-Neuroblastoma Trial Protocol Trial Statistician: Trial Coordinator & Trial Office: Randomisation Service: SAE Reporting:  W.M.Gregory@leeds.ac.uk Miss Grace Holt Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 8328  +44 (0)121 414 3700  G.C.Holt@bham.ac.uk Miss Punam Mistry Children’s Cancer Trials Team Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  beacon@trials.bham.ac.uk Provided by the CRCTU at the University of Birmingham Randomisation should be performed by sites online at: https://www.cancertrials.bham.ac.uk/BEACONLive In case of any problems with online randomisation, randomisation can be performed over the phone by the CRCTU on: 0800 371 969 or +44 (0)121 414 3366 SAEs should be faxed to the BEACON-Neuroblastoma Trial Office, CRCTU, University of Birmingham, UK  + 44 (0)121 414 9520 or +44 (0)121 414 3700 National Coordinating Investigators: Austria – Lead Investigator: Prof Dr Ruth Ladenstein St. Anna Children’s Hospital and CCRI /Studies and Statistics Department for Integrated Research and Projects (S²IRP) Kinderspitalgasse 6, Zimmermannplatz 10 A-1090 Vienna Austria +43-1-40470-4750  +43-1- 40470- 7430  ruth.ladenstein@ccri.at BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 9 of 157 BEACON-Neuroblastoma Trial Belgium Lead Investigator: Prof Genevieve Laureys Ghent University Hospital 9000 Ghent De Pinterlaan 185 Belgium  +32 93 32 34 48  genevieve.laureys@uzgent.be Denmark – Lead Investigator: Dr Karsten Nysom Dept. of Paediatrics & Adolescent Medicine Rigshospitalet Blegdamsvej 9 DK2100 Copenhagen Denmark  +45 35 45 08 09  +45 35 45 50 55  Karsten.nysom@regionh.dk France – Lead Investigator: Dr Marion Gambart Unité d'Hémato-Oncologie Hôpital des Enfants 330, avenue de Grande Bretagne TSA 70034 31059 Toulouse Cedex France  +33 (0)5 34 55 86 11  +33 (0)5 34 55 86 12  gambart.m@chu-toulouse.fr Germany - Lead Investigator: Dr. Simone Hettmer Zentrum für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM FREIBURG Mathildenstr. 1, 79106 Freiburg Germany  +49 761 270-43000  +49 761 270-45180  simone.hettmer@uniklinik-freiburg.de Ireland – Lead Investigator: Dr Cormac Owens Our Lady’s Children’s Hospital Crumlin Road, Crumlin Dublin 12 Ireland  +35314096659  +35313453041  Cormac.owens@olchc.ie Protocol BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 10 of 157 BEACON-Neuroblastoma Trial Protocol Italy – Lead Investigator: Dr. Aurora Castellano U.O.Oncoematologia Ospedale Pediatrico Bambino Gesù Pzza S. Onofrio 4 00165 Roma Italy +39 06 68592957-2678  +39 06 68592826  aurora.castellano@opbg.net Netherlands – Lead Investigator: Dr. C Michel Zwaan Erasmus Medical Center Sophia’s Children's Hospital Dr. Molewaterplein 60 3015 GJ Rotterdam +31 (0) 10 703 6691  +31(0) 10 703 6681  c.m.zwaan@erasmusmc.nl Spain – Lead Investigator: Dr. Victoria Castel Instituto de Investigación Sanitaria Unidad de Oncología Pediátrica Hospital Universitario La Fe Bulevar Sur, S/N 46026 Valencia Spain +34 963862758 Ext 50040  +34 963494416  castel_vic@gva.es Switzerland – Lead Investigator: Dr. Nicolas Gerber University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland +41 44 266 31 17  +41 44 266 34 61  Nicolas.gerber@kispi.uzh.ch UK – Lead Investigator: Dr Lucas Moreno Honorary Research Fellow University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  lucas.moreno@vhebron.net, lmorenom@ext.cnio.es BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 11 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL SYNOPSIS Title A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma – BEACON-Neuroblastoma Trial Trial Design A phase II, randomised, open label, international multicentre 3x2 factorial trial. The dinutuximab beta amendment did utilise a 2x2 factorial design it will now be a simple two-way randomisation. Objectives Primary: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan + temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma - To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma (“topotecan randomisation”) - To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma (“dinutuximab beta randomisation”) Secondary: - To evaluate the safety of the regimens Tertiary: - To undertake preliminary evaluation of the changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis - To undertake preliminary evaluation of the role of circulating mRNA levels for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and doublecortin (DCX) as prognostic/predictive biomarkers in this refractory/relapsed setting - To undertake a preliminary evaluation of the role of tumour molecular profiles in blood and archival tumour tissue profiles as prognostic and predictive biomarkers - To undertake a preliminary evaluation of biomarkers of response to anti-GD2 therapy (Fc/KIR polymorphisms, Antibody Dependant Cell-Mediated Cytotoxicity (ADCC) and Anti-Drug Antibodies (ADAs) and of dinutuximab beta pharmacokinetics (PK) Outcome Measures Primary Endpoint: - Best response (Complete Response [CR] or Partial Response [PR]) [1] at any time during the first 6 cycles of trial treatment - For the bevacizumab part 2 only: Progression-free survival (PFS) Secondary Endpoints: - Safety of the regimens: Incidence and severity of Adverse Events (AE)s - PFS - Overall survival (OS) - Event-free survival (EFS) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 12 of 157 BEACON-Neuroblastoma Trial Protocol Exploratory/Tertiary Endpoints: - Changes in (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2* - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples - Pilot descriptive study of angiogenesis and neuroblastoma markers that may include O6methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling - A preliminary correlation of the different biomarkers [Fc/KIR polymorphisms, Antibody – Dependent Cellular Toxicity (ADCC), and Anti-Drug Antibodies (ADAs)] will be made with parameters of anti-tumour activity (response rate, PFS and OS). PK parameters (dinutuximab beta trough levels) for this chemo-immunotherapy regimen will be described. Patient Population Children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma. Sample Size Approximately 224 patients, including 160 for the bevacizumab randomisation and 64 for the dinutuximab beta amendment. Trial Duration 8 years of patient recruitment, 5 years of patient follow up BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 13 of 157 BEACON-Neuroblastoma Trial Protocol Abbreviations ADA ANTI-DRUG ANTIBODIES ADCC ANTIBODY – DEPENDENT CELL-MEDIATED CYTOTOXICITY AE ADVERSE EVENT AESI ADVERSE EVENT OF SPECIAL INTEREST AFSAPPS COMPETENT AUTHORITY FOR FRANCE ALT ALANINE AMINOTRANSFERASE ANC ABSOLUTE NEUTROPHIL COUNT APPT ACTIVATED PARTIAL THROMBOPLASTIN TIME ASCT AUTOLOGOUS STEM CELL TRANSPLANTATION AST ASPARTATE AMINOTRANSFERASE AUC AREA UNDER THE CURVE AR ADVERSE REACTION BIT BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM BM BONE MARROW BP BLOOD PRESSURE BSA BODY SURFACE AREA BT BEVACIZUMAB + TEMOZOLOMIDE ARM BTTo BEVACIZUMAB + TEMOZOLOMIDE + TOPOTECAN ARM CI CHIEF INVESTIGATOR CIs CONFIDENCE INTERVALS COG CHILDREN’S ONCOLOGY GROUP CNS CENTRAL NERVOUS SYSTEM CR COMPLETE RESPONSE CRF CASE REPORT FORM CR UK CANCER RESEARCH UK CRCTU CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) CRN CLINICAL RESEARCH NETWORK CSR CLINICAL STUDY REPORT CT COMPUTERISED TOMOGRAPHY CTC COMMON TERMINOLOGY CRITERIA CTCAE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS CXR CHEST X-RAY dBT DINUTUXIMAB BETA + TEMOZOLOMIDE ARM dBTTo DINUTUXIMAB BETA + TEMOZOLOMIDE + TOPOTECAN ARM DCX DOUBLECORTIN DLT DOSE LIMITING TOXICITY DMC DATA MONITORING COMMITTEE DNA DEOXYRIBONUCLEIC ACID ECHO ECHOCARDIOGRAM ECOG EASTERN COOPERATIVE ONCOLOGY GROUP EFS EVENT FREE SURVIVAL EMA EUROPEAN MEDICINES AGENCY ERDC ELECTRONIC REMOTE DATA CAPTURE EOT END OF TREATMENT FFPE FORMALIN-FIXED PARAFFIN EMBEDDED GCP GOOD CLINICAL PRACTICE G-CSF GRANULOCYTE COLONY STIMULATING FACTOR BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 14 of 157 BEACON-Neuroblastoma Trial Protocol GFR GM-CSF GGT GP GPOH HR IB ICF ICH IMP INR INRC INRG INSS IRF ISF IT ITCC IV MGMT MIBG MHRA MRD MRI MSKCC MTD MYCN NANT NCI NCS NR OS OTC PCP PD PFS PHOX2B PI PIS PK PMA PRES PO PPTP PR REC RECIST RNA GLOMERULAR FILTRATION RATE GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR GAMMA-GLUTAMYL TRANSPEPTIDASE GENERAL PRACTITIONER GERMAN SOCIETY FOR PAEDIATRIC ONCOLOGY & HAEMATOLOGY HEART RATE INVESTIGATOR BROCHURE INFORMED CONSENT FORM INTERNATIONAL CONFERENCE ON HARMONISATION INVESTIGATIONAL MEDICINAL PRODUCT INTERNATIONAL NORMALISED RATIO INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA INTERNATIONAL NEUROBLASTOMA RISK GROUP INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM INSTITUTIONAL REVIEW BOARD INVESTIGATOR SITE FILE IRINOTECAN + TEMOZOLOMIDE ARM INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER INTRAVENOUS O6-METHYGUANINE METHYLTRANSFERASE META-IODO-BENZYL-GUANIDINE MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY MINIMAL RESIDUAL DISEASE MAGNETIC RESONANCE IMAGING MEMORIAL SLOAN KETTERING CANCER CENTRE MAXIMUM TOLERATED DOSE MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE NEW AGENTS FOR NEUROBLASTOMA THERAPY NATIONAL COORDINATING INVESTIGATOR NATIONAL CO-SPONSOR NO RESPONSE OVERALL SURVIVAL OVER THE COUNTER PNEUMOCYSTIS CARNI PNEUMONITIS PROGRESSSIVE DISEASE PROGRESSION FREE SURVIVAL PAIRED-LIKE HOMEOBOX2B PRINCIPAL INVESTIGATOR PATIENT INFORMATION SHEET PHARMACOKINETICS POPULATION-MODELLING ANALYSIS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME ORALLY PAEDIATRIC PRECLINICAL TESTING PROGRAM PARTIAL RESPONSE RESEARCH ETHICS COMMITTEE RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS RIBONUCLEIC ACID BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 15 of 157 BEACON-Neuroblastoma Trial Protocol RTKI RT-qPCR SAE SAR SCT SD SFOP SIOPEN SNP SPC SUSAR SWFI T TH TMA TMG TSC TTo TVD UAR UKCCSG ULN VTE VEGF VGPR WMA RECEPTOR TYROSINE KINASE INHIBITORS REVERSE TRANSCRIPTASE QUANTITATIVE POLYMERASE CHAIN REACTION SERIOUS ADVERSE EVENT SERIOUS ADVERSE REACTION STEM CELL TRANSPLANT STABLE DISEASE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN NEUROBLASTOMA GROUP SINGLE NUCLEOTIDE POLYMORPHISM SUMMARY OF PRODUCT CHARACTERISTICS SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION STERILE WATER FOR INJECTION TEMOZOLOMIDE ARM TYROSINE HYDROXYLASE TISSUE MICROARRAY TRIAL MANAGEMENT GROUP TRIAL STEERING COMMITTEE TEMOZOLOMIDE + TOPOTECAN ARM TOPOTECAN, VINCRISTINE & DOXORUBICIN UNEXPECTED ADVERSE REACTION UNITED KINGDOM CHILDREN’S CANCER STUDY GROUP UPPER LIMIT OF NORMAL VENOUS THROMBO-EMBOLISM VASCULAR ENDOTHELIAL GROWTH FACTOR VERY GOOD PARTIAL RESPONSE WORLD MEDICAL ASSOCIATION FORMULAE Mosteller formula: BSA (m²) = BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 16 of 157 BEACON-Neuroblastoma Trial Protocol Table of Contents Trial Synopsis ...................................................................................................................................... 12 Title .................................................................................................................................................... 12 Trial Design ........................................................................................................................................ 12 Objectives .......................................................................................................................................... 12 Outcome Measures............................................................................................................................ 12 Patient Population .............................................................................................................................. 13 Sample Size ....................................................................................................................................... 13 Trial Duration...................................................................................................................................... 13 Abbreviations ..................................................................................................................................... 14 1. Background and Rationale ............................................................................................................. 22 1.1 Background............................................................................................................................ 22 1.1.1 Background for the dinutuximab beta amendment............................................................ 28 1.2 Trial Rational.......................................................................................................................... 29 1.2.1 Justification for design ....................................................................................................... 29 1.2.2 Rationale for patient population ......................................................................................... 30 1.2.3 Benefit-risk assessment .................................................................................................... 31 1.2.4 Rationale for the selected backbone schedules: Temozolomide, irinotecan + temozolomide and temozolomide + topotecan .............................................................................. 31 1.2.5 Rationale for dosing schedule of bevacizumab................................................................. 32 1.2.6 Rationale for evaluating chemo-immunotherapy in the BEACON-Neuroblastoma Trial... 32 1.2.7 Rationale for dosing schedule of dinutuximab beta........................................................... 33 1.2.8 Rationale for the use of biomarker studies ........................................................................ 34 1.3 Relevance and future importance ......................................................................................... 35 2. Objectives and Outcome Measures ............................................................................................. 36 2.1 Objectives .............................................................................................................................. 36 2.2 Outcome Measures ............................................................................................................... 37 3. Trial Design ..................................................................................................................................... 37 3.1 Randomisation....................................................................................................................... 37 3.2 Duration of treatment............................................................................................................. 38 3.3 Frequency and duration of follow-up ..................................................................................... 38 4. Eligibility.......................................................................................................................................... 39 4.1 Lifestyle guidelines ................................................................................................................ 39 5. Schedule of activities..................................................................................................................... 39 6. Screening and Consent ................................................................................................................. 40 6.1 Informed Consent .................................................................................................................. 40 6.2 Screening............................................................................................................................... 41 7. Trial Entry........................................................................................................................................ 42 7.1 Procedure for online patient randomisation........................................................................... 42 7.2 Emergency Randomisation ................................................................................................... 42 8. Treatment Details ........................................................................................................................... 43 8.1 Definition of Investigational Medicinal Products (IMPs) ........................................................ 43 9. Bevacizumab randomisation......................................................................................................... 43 9.1 Eligibility criteria for the bevacizumab randomisation............................................................ 43 9.1.1 Inclusion criteria for the bevacizumab randomisation ....................................................... 43 9.1.2 Exclusion criteria for the bevacizumab randomisation ...................................................... 44 9.2 Schedule of activities for the bevacizumab randomisation ................................................... 45 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 17 of 157 BEACON-Neuroblastoma Trial Protocol 9.3 Trial Therapy (bevacizumab randomisation) ......................................................................... 49 9.3.1 Bevacizumab randomisation trial treatment ...................................................................... 49 9.4 Treatment Schedule..................................................................................................................... 51 9.4.1 Day 1 of Cycle 1 ................................................................................................................ 51 9.4.2 Day 1 of subsequent cycles............................................................................................... 51 9.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12) ........................................................ 52 9.4.4 End of Treatment ............................................................................................................... 52 9.4.5 Treatment Duration............................................................................................................ 52 9.5 Dose Modifications for the bevacizumab randomisation ....................................................... 53 9.5.1 Dose Modifications for AEs due to chemotherapy - for the bevacizumab randomisation. 56 9.5.2 Bevacizumab – Infusion-related Reaction/Infusional Site Extravasation Management Guidelines ...................................................................................................................................... 62 9.5.3 Bevacizumab - Treatment Delays ..................................................................................... 63 9.5.4 Bevacizumab - Discontinuation ........................................................................................ 64 9.5.5 Bevacizumab - Toxicity Management guidelines .............................................................. 65 9.6 Central Venous Access Device (CVAD)................................................................................ 67 10 Dinutuximab beta and topotecan randomisations...................................................................... 68 10.1 Eligibility for the dinutuximab beta randomisation ................................................................. 68 10.1.1 Inclusion criteria for the dinutuximab beta randomisation ............................................. 68 10.1.2 Exclusion criteria for the dinutuximab beta randomisation ............................................ 69 10.2 Schedule of events for the dinutuximab beta and topotecan randomisations....................... 70 10.3 Trial therapy (dinutuximab beta and topotecan randomisations) .......................................... 74 10.3.1 Dinutuximab beta and topotecan trial treatment................................................................ 75 10.4 Treatment Schedule .............................................................................................................. 76 10.4.1 Day 1 of Cycle 1 ............................................................................................................ 76 10.4.2 Day 1 of subsequent cycles........................................................................................... 76 10.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12 on chemotherapy only) ............... 77 10.4.4 End of Treatment ........................................................................................................... 77 10.4.5 Treatment Duration............................................................................................................ 78 10.4.6 Cross-over ......................................................................................................................... 78 10.5 Dose Modifications – dinutuximab beta and topotecan randomisations ............................... 79 10.5.1 Dose modifications for dinutuximab beta specific toxicities .......................................... 79 10.5.2 Dose modifications for haematological toxicity.............................................................. 81 10.5.3 Dose modifications for hepatic toxicity .......................................................................... 82 11 Treatment Compliance................................................................................................................... 84 12 Supportive Treatment .................................................................................................................... 84 12.1 Nausea and Vomiting ............................................................................................................ 84 12.2 Growth Factors ...................................................................................................................... 84 12.3 Fever and neutropenia .......................................................................................................... 84 12.4 Blood products....................................................................................................................... 84 12.5 Pneumocystis jirovecii pneumonia (PJP) prophylaxis ........................................................... 84 12.6 Management of side effects caused by non-selective NSAIDs as cyclooxygenase (COX) type I and II inhibitors ......................................................................................................................... 84 12.7 Supportive care during Dinutuximab beta infusion................................................................ 85 12.7.1 Pain Management.......................................................................................................... 85 12.7.2 Prevention of dinutuximab beta related infusion reactions............................................ 86 13 Concomitant Medication................................................................................................................ 87 14 Assessments .................................................................................................................................. 87 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 18 of 157 BEACON-Neuroblastoma Trial Protocol 14.1 Response assessment .......................................................................................................... 88 15 Biomarkers...................................................................................................................................... 88 15.1 Blood sampling safety ........................................................................................................... 88 15.2 MRI-derived functional imaging biomarkers of angiogenesis................................................ 90 15.3 Molecular monitoring mRNA.................................................................................................. 90 15.4 Neuroblastoma exploratory biomarker analyses ................................................................... 90 15.5 Sample Collection.................................................................................................................. 92 15.5.1 Peripheral blood samples .............................................................................................. 92 15.5.2 Bone Marrow Samples .................................................................................................. 92 15.5.3 Archival tumour samples ............................................................................................... 92 16 Patient Follow Up ........................................................................................................................... 93 16.1 Patient Withdrawal................................................................................................................. 93 17 Pharmaceutical Information .......................................................................................................... 94 17.1 Definition of Investigational Medicinal Product ...................................................................... 94 17.2 Bevacizumab ......................................................................................................................... 94 17.2.1 Bevacizumab - Drug Supply .......................................................................................... 94 17.2.2 Bevacizumab - Ordering ............................................................................................... 94 17.2.3 Bevacizumab - Formulation, Packaging and Labelling ................................................. 94 17.2.4 Bevacizumab - Preparation and Dispensing ................................................................. 95 17.2.5 Compatibility information ............................................................................................... 95 17.2.6 Bevacizumab - Administration ....................................................................................... 95 17.2.7 Bevacizumab – Accountability....................................................................................... 96 17.2.8 Bevacizumab - Destruction............................................................................................ 96 17.3 Cyclophosphamide ................................................................................................................ 96 17.4 Dinutuximab beta................................................................................................................... 96 17.5 Irinotecan ............................................................................................................................... 96 17.5.1 Irinotecan - Drug Supply ............................................................................................... 96 17.5.2 Irinotecan - Formulation, Packaging and Labelling ....................................................... 96 17.5.3 Irinotecan - Preparation and Dispensing ....................................................................... 97 17.5.4 Compatibility information ............................................................................................... 97 17.5.5 Irinotecan - Administration ............................................................................................. 97 17.6 Temozolomide ....................................................................................................................... 97 17.6.1 Temozolomide – Drug Supply ....................................................................................... 97 17.6.2 Temozolomide - Formulation, Packaging and Labelling ............................................... 97 17.6.3 Temozolomide - Administration ..................................................................................... 97 17.7 Topotecan.............................................................................................................................. 98 17.7.1 Topotecan - Drug Supply.............................................................................................. 98 17.7.2 Topotecan - Formulation, Packaging and Labelling ..................................................... 98 17.7.3 Topotecan - Preparation and Dispensing ..................................................................... 98 17.7.4 Topotecan - Compatibility information ........................................................................... 98 17.7.5 Topotecan - Administration........................................................................................... 99 18 Adverse Event Reporting .............................................................................................................. 99 18.1 Reporting Requirements........................................................................................................ 99 18.1.1 Adverse Events (AE) ..................................................................................................... 99 18.1.2 AESIs of Bevacizumab .................................................................................................. 99 18.1.3 Serious Adverse Advents (SAE).................................................................................... 99 18.1.4 Reporting period .......................................................................................................... 100 18.2 Reporting Procedure ........................................................................................................... 100 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 19 of 157 BEACON-Neuroblastoma Trial Protocol 18.2.1 Site............................................................................................................................... 100 18.2.2 Trial Office ................................................................................................................... 102 18.2.3 Reporting to the Competent Authority and main Research Ethics Committee ........... 102 18.2.4 Investigators ................................................................................................................ 102 18.2.5 Data Monitoring Committee ......................................................................................... 102 18.2.6 Manufacturer of Investigational Medicinal Product...................................................... 102 19 Data Handling and Record Keeping ........................................................................................... 103 19.1 Data Collection .................................................................................................................... 103 19.2 Archiving .............................................................................................................................. 103 20 Quality Management .................................................................................................................... 103 20.1 Site Set-up and Initiation ..................................................................................................... 103 20.2 On-site Monitoring ............................................................................................................... 104 20.3 Central Monitoring ............................................................................................................... 104 20.4 Audit and Inspection ............................................................................................................ 104 20.5 Notification of Serious Breaches ......................................................................................... 104 21 End of Trial Definition .................................................................................................................. 105 22 Statistical Considerations ........................................................................................................... 105 22.1 Trial Design.......................................................................................................................... 105 22.2 Definition of Outcome Measures ......................................................................................... 106 22.2.1 Primary ........................................................................................................................ 106 22.2.2 Secondary.................................................................................................................... 106 22.2.3 Exploratory/Tertiary ..................................................................................................... 106 22.3 Sample Size......................................................................................................................... 106 22.4 Interim and Main Analyses of Outcome Measures.............................................................. 108 22.4.1 Planned Interim Analyses ............................................................................................ 108 22.4.2 Main Analysis............................................................................................................... 108 22.5 Stopping Guidelines ............................................................................................................ 110 23 Trial Organisational Structure..................................................................................................... 110 23.1 Coordinating Sponsor .......................................................................................................... 110 23.2 Co-Sponsor Centres ........................................................................................................... 110 23.3 Relationship of trial committees........................................................................................... 112 23.4 Trial Management Group..................................................................................................... 112 23.5 Trial Steering Committee ..................................................................................................... 112 23.6 Data Monitoring Committee................................................................................................. 112 23.7 Finance ................................................................................................................................ 113 23.8 NIHR CRN Portfolio ............................................................................................................. 113 24 Ethical Considerations ................................................................................................................ 113 25 Confidentiality and Data Protection ........................................................................................... 114 26 Insurance and Indemnity ............................................................................................................. 115 27 Publication Policy ........................................................................................................................ 116 28 Reference List............................................................................................................................... 117 Appendix 1 – WMA Declaration of Helsinki .................................................................................... 124 Appendix 2 - Definition of Adverse Events ..................................................................................... 127 Appendix 3 - Common Toxicity Criteria Grading ........................................................................... 129 Appendix 4 – RECIST Criteria 1.1 .................................................................................................... 130 Appendix 5 – Tumor Response at Metastatic Soft Tissue and Bone Sites (Park et al. 2017) ... 133 Appendix 6 - CURIE & SIOPEN scoring methods for neuroblastoma ......................................... 134 Appendix 7 – Temozolomide Dosing............................................................................................... 136 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 20 of 157 BEACON-Neuroblastoma Trial Protocol Appendix 8 – Blood Pressure Levels by Age and Height Percentile for Children and Adolescents ....................................................................................................................................... 139 Appendix 9 – Height for Age Chart - Girls ...................................................................................... 144 Appendix 10 – Height for Age Chart - Boys.................................................................................... 149 Appendix 11 – Lansky and Karnofsky/ECOG Scales .................................................................... 154 Appendix 12 – Tanner Staging ......................................................................................................... 156 Appendix 13 – Clinical studies of anti-GD2 therapies in combination with chemotherapy ...... 157 LIST OF TABLES Table 1 - Second line chemotherapy regimens tested in phase II in relapsed or refractory neuroblastoma since 2000 ..........
Url: /Media/UHS-website-2019/Docs/PaediatricOncology/beacon-protocol-v8.0-07mar2023-signed.pdf

AmB LEAM (split)-Lomustine-Cytarabine-Etoposide-Melphalan

Description: Chemotherapy Protocol LYMPHOMA LOMUSTINE-CYTARABINE-ETOPOSIDE (split)-MELPHALAN (LEAM) Ambulatory Regimen This regimen is for AMBULATORY CARE pathway use only and will only be available to prescribe at units which carry out autograft transplantation. Regimen Lymphoma – AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide-Melphalan Indication • Conditioning for autologous peripheral blood stem cell transplant (PBSCT) / bone marrow transplant in individuals with either Non Hodgkin Lymphoma (NHL) or Hodgkin Lymphoma Toxicity Drug Lomustine Cytarabine Etoposide Adverse Effect Pulmonary toxicity CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Hypotension on rapid infusion, hyperbilirubinaemia Melphalan Gastro-intestinal disturbances, stomatitis Patients treated with LEAM are at risk of transfusion-associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive irradiated blood products for the 1 week prior to harvest and for at least 12 weeks after the transplant has taken place. Patients with Hodgkin lymphoma carry a lifelong risk of graft versus host disease and must always receive irradiated blood products. Local blood transfusion departments must be notified as soon as a diagnosis is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1 (August 2023) Page 1 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each melphalan infusion • Monitor the fluid balance during the administration of melphalan, including throughout the administration of the pre and post hydration. Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Dose Modifications The dose modifications listed are for haematological, liver and renal function and some limited drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Treatment will be given regardless of blood results. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Irradiated blood products must be used. Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Lomustine Bilirubin μmol/L N/A AST/ALT units/L N/A Dose (% of original dose) No dose adjustment necessary Cytarabine more than 34 50% The dose may be escalated dependent on toxicity Etoposide Melphalan 30-51 or 60-180 more than 51 or more than 180 N/A N/A Consider dose reducing to 50% Clinical decision No dose adjustment necessary Version 1 (August 2023) Page 2 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Renal Impairment Drug Lomustine Creatinine Clearance (ml/min) more 60 45-60 30-<45 less than 30 Dose (% of original dose) 100% 75% 50% Clinical decision Cytarabine N/A No dose adjustment necessary Etoposide more than 50 15-50 less than 15 100% 75% 50% Melphalan more than 50 30-50 less than 30 100% 75% Clinical decision Other Lomustine It may be necessary to reduce the dose of lomustine in patients with reduced pulmonary function. Lomustine dose reductions in this situation are to be made at the discretion of the consultant oncologist/haematologist only. Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Regimen 1 cycle will be set in Aria Drug Lomustine Cytarabine Etoposide Dose 200mg/m2 1600 mg/m2 (8 doses of 200mg/m2 every 12 hours) 200mg/m2 Days -6 200mg/m2 BD Every 12 hours at 9am and 9pm. -5,-4,-3,-2 (8 doses total) -5,-4,-3,-2 Administration Oral Administer via CADD Solis VIP pump. Each CADD cassette contains 8 doses (240ml total volume). Connect cassette on day -5 and disconnect on day -1 (AM) Each dose: IV infusion of 200mg/m2 in 30ml of sodium chloride 0.9% over 15 minutes at 120ml/hr. Intravenous infusion in 2000ml sodium chloride 0.9% over 120 minutes (this will be administered as two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes administered Version 1 (August 2023) Page 3 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Melphalan 140mg/m2 sequentially) -1 Intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Dose Information • Lomustine will be dose rounded to the nearest 40mg (down if halfway) • Cytarabine will be dose banded in accordance with the national dose bands (100mg/ml) • Etoposide will be dose banded in accordance with the national dose bands (20mg/ml) • The melphalan dose will be dose rounded to the nearest 10mg (down if halfway). The National Dose Banding Team have advised not to use dose banding tables for this product in view of the 90 minute expiry (must be made locally for individual patient), the 50mg vial size and frequent stock shortages. Administration Information CADD pump • Total 8 doses provided as one infusion bag in cassette of CADD pump, to be administered as intermittent infusion on day -5 to -2. • Sodium chloride 0.9% 100ml to be run as continuous infusion to keep CADD infusion line patent. • Administer concurrently with cytarabine via Y-site with at 0.5 mL/hour on days -5 to 1. Extravasation • Cytarabine – non-vesicant • Etoposide – irritant • Melphalan – irritant Other • Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. • Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Version 1 (August 2023) Page 4 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Additional Therapy This regimen is to be administered in the ambulatory setting. Please ensure all supportive and take home medicines are prescribed on the in-patient chart or general electronic prescribing system on admission. Please refer to the transplant schedule for each individual patient. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 2mg twice a day for 10 days oral or intravenous starting on day -6 of the cycle - metoclopramide 10mg three times a day for 10 days oral or intravenous starting on day -6 of the cycle - ondansetron 8mg twice a day for 10 days oral or intravenous - aprepitant 125mg once only orally on the day of the melphalan infusion then 80mg once a day for the subsequent two days • Anti-infectives - aciclovir 400mg oral twice a day until day +180 - ciprofloxacin 250mg oral twice a day from day+1 (stop when neutrophils are greater than 1) - pentamidine 300mg by nebuliser prior to discharge - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday (start from 28 days post discharge, if neutrophils are greater than 1 and platelets are greater than 50, and continue until day +180) - fluconazole 100mg once a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids) - nystatin suspension 1ml four times a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids) • Thromboprophylaxis, continued until platelets are less than 50x109/L, or as directed by the consultant, according to local formulary choices; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection • Growth factors such as filgrastim biosimilar 30million units (300mcg) once a day subcutaneous from day +5 (stop when neutrophils are greater than 1x109/L for at least 24 hours, or greater than 3 on any occasion) • Hormone replacement In menstruating women consider norethisterone 5mg three times a day oral to prevent menstruation. This may be stopped when the platelets are more than 50x109/L. • Mouthcare Commence oral cryotherapy approximately 15mins prior to melphalan infusion, replenishing to cover melphalan infusion and 75 mins afterwards. Version 1 (August 2023) Page 5 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Mouthcare for the prophylaxis or treatment of mucositis in accordance with local or national guidelines. • Gastric protection with a proton pump inhibitor or a H2 antagonist according to local formulary choice; - esomeprazole 20mg once a day oral - omeprazole 20mg once a day oral - lansoprazole 15mg once a day oral - pantoprazole 20mg once a day oral - rabeprazole 20mg once a day oral - cimetidine 400mg twice a day oral - famotidine 20mg once a day oral - nizatidine 150mg twice a day oral - ranitidine 150mg twice a day oral • Hydration - Encourage 3L oral fluids daily. If ambulatory patients are unable to maintain this (e.g. due to nausea), they should be admitted for intravenous hydration. - Intravenous hydration before and after melphalan infusion should be prescribed on inpatient prescribing system or using paper proforma (Appendix 1) Before and after melphalan infusion - Encourage oral hydration at least 1 litre between 8pm and 8am the night before melphalan infusion. 0830hrs Contact pharmacy on ext 5037 to inform them that the patient is present. Confirm that they have melphalan prescription (on ARIA). Request melphalan infusion to be on the ward by 11:30hrs. Start fluid chart and daily weights. Start fluid 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 0915hrs Administer anti-emetics and supportive medication as per ARIA prescription 0930hrs 20mg furosemide intravenous bolus Warning – Check hydration and fluid balance 1000hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 1030hrs 20mg furosemide intravenous bolus Measure urine output since 0900hrs - If more than 500ml continue with melphalan infusion - If less than 500ml give second furosemide 20mg dose Version 1 (August 2023) Page 6 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan 1130hrs 1200hrs Thereafter intravenous bolus check urine output since 0900hrs again at 1100hrs: o if more than 500ml go ahead with melphalan o if less than 500ml contact the prescriber. Give melphalan intravenous infusion over thirty minutes (This product has a short expiry so adhering to set timing is essential) 1000ml sodium chloride 0.9% intravenous infusion over 120 minutes Encourage 2L oral fluid intake over subsequent 12 hours Instruct patient to take all supportive medications with particular reference to antiemetics Advise patient to drink 1000 ml of oral fluids over the evening Emergency contact details for AOS given to patient Patient and carer to return to C7 at 08:30 on day 0 • The day after melphalan infusion (Day 0): 0830hrs - 1000ml sodium chloride 0.9% intravenous infusion over 480 minutes then restart routine intravenous fluids Additional Information • Irradiated blood products must be used • Autologous stem cells/ bone marrow will be infused on day 0, at least 24 hours after the melphalan infusion References 1.Mills W, Chopra R, McMillan A et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol (1995);13(3): 588-95 2.Kelsey P, Pearce R, Perry J et al. Substituting carmustine for lomustine is safe and effective in the treatment of relapsed or refractory Lymphoma – a retrospective study from the BSBMT (BEAM versus LEAM) 3. Stabilis (manufacturers data) Stability of Alexan "Ebewe" infusion solutions. Ebewe Pharma 2007 from http://www.stabilis.org/ (Date accessed: 03/07/23). Version 1 (August 2023) Page 7 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan REGIMEN SUMMARY AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describes the agents which must be prescribed on the in-patient chart or general electronic prescribing system. Supportive care should be prescribed on ARIA and given to the patient on day -6. Supportive care should be transcribed to the electronic inpatient prescribing system on admission to hospital. Day -6 1. Warning – Check blood transfusion status Administration Instructions Patients treated with LEAM carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Dexamethasone 2mg oral or intravenous 3. Ondansetron 8mg oral or intravenous 4. Metoclopramide 10mg oral or intravenous 5. Lomustine 200mg/m2 once a day for one day oral Administration Instructions This should be given before midday. Swallow whole with a full glass of water. Do not open or chew 6. Warning -Ensure take home medicines are supplied Take home medicines 7. Aprepitant 80mg once a day oral for 2 days starting the day after melphalan (i.e. start day 0). 8. Dexamethasone 2mg once a day in the afternoon for 6 days starting on day -6 the day of lomustine. Then take 2mg twice a day for 4 days. 9. Ondansetron 8mg once a day in the evening for 6 days starting on day -6 the day of lomustine. Then take 8mg twice a day for 4 days. 10. Metoclopramide 10mg twice a day in the afternoon and evening for 6 days starting on day -6 the day of lomustine. Then take 10mg three times a day for 4 days. Administration instructions –Please supply 28 tablets or an original pack as appropriate 11. Aciclovir 400mg three times a day for 28 days Administration Instructions Please supply 28 days or an original pack if appropriate. 12. Ciprofloxacin 250mg twice a day starting on day +1 (2 days after melphalan administration) for 14 days Administration Instructions Please supply 14 days with no stop date 13. Fluconazole 100mg oral once a day for 14 days Administration instructions – please supply 14 days with no stop date Version 1 (August 2023) Page 8 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan 14. Nystatin 1ml four times a day Administration instructions – please supply 1 x OP 15. Gastric Protection Administration Instructions The choice of gastric protection is dependent on local formulary choice and may include; - esomeprazole 20mg once a day oral - omeprazole 20mg once a day oral - lansoprazole 15mg once a day oral - pantoprazole 20mg once a day oral - rabeprazole 20mg once a day oral - cimetidine 400mg twice a day oral - famotidine 20mg once a day oral - nizatidine 150mg twice a day oral - ranitidine 150mg twice a day oral Please supply 28 days or the nearest original pack size. 16. Sodium Chloride 0.9% oral rinse 10mL four times a day Administration instructions – pharmacy please supply 50 x 10mL pods 17. Thromboprophylaxis according to local formulary choice Continued until platelets are less than 50x109/L, or as directed by the consultant, according to local formulary choices: - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Day -5 18. Dexamethasone 2mg oral or intravenous 19. Ondansetron 8mg oral or intravenous 20. Metoclopramide 10mg oral or intravenous 21. Warning – Cytarabine delivered via one CADD. Administration Instructions Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) via CADD pump. Sodium chloride infusion must be administered concurrently. 22. Cytarabine 1600mg/m2 intravenous infusion in 240ml sodium chloride 0.9% as intermittent infusions via CADD pump. Administration Instructions One dose: Cytarabine 200mg/m2 in 30ml sodium chloride 0.9% over 15 minutes at 120ml/hour. Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) on days -5 to -2 (8 doses in total). Connect cassette on day -5 and disconnect on day -1 (AM). 23. Sodium Chloride 0.9% 100ml continuous infusion at 0.5ml/hr. Administration Instructions Sodium chloride 0.9% to be administered via folfusor pump at 0.5ml/hr on Days -5 to -1. To be connected via Y-site with CADD pump to maintain line patency. Disconnect folfusor at the same time as disconnecting CADD cassette 24. Warning – Etoposide is TWO infusions Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. Version 1 (August 2023) Page 9 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan 25. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 26. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes Day -4, Day -3, Day -2 27. Dexamethasone 2mg oral or intravenous 28. Ondansetron 8mg oral or intravenous 29. Metoclopramide 10mg oral or intravenous 30. Warning – Etoposide is TWO infusions Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 31. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 32. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes Day -1 33. Warning – Check CADD pump and sodium chloride pump removal 34. Aprepitant 125mg oral 35. Dexamethasone 2mg oral or intravenous 36. Ondansetron 8mg oral or intravenous 37. Metoclopramide 10mg oral or intravenous 38. Furosemide 20mg injection bolus Administration instructions – to be given if required for fluid overload. Version 1 (August 2023) Page 10 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan 39. Warning – Check hydration and fluid balance Administration Instructions See separate fluid prescription for the pre hydration: The evening before melphalan infusion (to be completed by 0930 on the morning of the infusion) Sodium chloride 0.9% with potassium chloride 27mmol 1000ml The day of melphalan infusion: 0830hrs Contact Pharmacy on ext 5037 to inform them that the patient is present. Confirm that they have melphalan prescription (on ARIA) □ Request melphalan to be on the ward by 11:30 □ Start fluid balance sheet and start daily weight measurement 0915hrs Administer anti-emetics and supportive medication as per ARIA prescription 0930hrs 20mg furosemide intravenous bolus 1000hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 1030hrs 20mg furosemide intravenous bolus Measure urine output since 0900hrs If more than 500ml continue with melphalan infusion If less than 500ml give second furosemide 20mg intravenous bolus dose and check urine output since 0900hrs again at 1100hrs: if more than 500ml go ahead with melphalan if less than 500ml contact the prescriber. 1130hrs – give melphalan intravenous infusion over thirty minutes (this product has a short expiry so adhering to set timing is essential) 1200hrs - 1000ml sodium chloride 0.9% intravenous infusion over 120 minutes 40. Time– Administer melphalan at 1130hrs 41. Melphalan 140mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions - see separate fluid prescription for the post hydration requirements Day 0 42. Chlorphenamine 10mg Intravenous bolus Administration instructions – to be given pre stem cell infusion 43. Paracetamol 1000mg Tablet Oral Administration instructions – to be given pre stem cell infusion 44. Stem Cell Return – see separate chart Version 1 (August 2023) Page 11 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 August 2023 New document Madeleine Norbury Pharmacist Hwai Jing Hiew Consultant This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; University Hospital Southampton NHS Foundation Trust -Wessex Blood and Marrow Transplant All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. These protocols should be used in conjunction with other references such as the Summary of Product Characteristics and relevant published papers. Version 1 (August 2023) Page 12 of 12 Lymphoma- AmB-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan
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Inotuzumab Ozogamicin

Description: Relapsed or refractory CD22-positive B-Cell acute lymphoblastic leukaemia.
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/ALL/Inotuzumab-Ozogamicin.pdf

Home video telemetry (HVT) – patient information

Description: This factsheet explains what home video telemetry (HVT) is, what the test involves and how to perform it safely at home.
Url: /Media/UHS-website-2019/Patientinformation/Brain-and-spine/Home-video-telemetry-HVT-2969-PIL.pdf

Azacitidine Oral

Description: Chemotherapy Protocol ACUTE MYELOID LEUKAEMIA -AZACITADINE (ORAL) Regimen • AML – AZACITADINE (ORAL) Indication Oral azacitidine as maintenance therapy in newly diagnosed AML patients in remission following at least induction chemotherapy and who are not candidates for, or who choose not to proceed to, haemopoietic stem cell transplantation where the following criteria is met: • The patient has newly diagnosed acute myeloid leukaemia (AML) • The patient has been treated with standard intensive cytarabine-based induction chemotherapy. • The patient is currently in complete remission (CR) or is in complete remission with incomplete blood count recovery (CRi) • The patient is not a candidate for, or has chosen not to proceed to, haemopoietic stem cell transplantation (HSCT). • Maintenance therapy with oral azacitadine will be as monotherapy • Oral azacitadine maintenance therapy will be continued until disease progression up to a maximum of 15% blasts is observed in peripheral blood/bone marrow or until unacceptable toxicity occurs or there is a withdrawal of patient consent, whichever is sooner. • The prescribing clinician understands that the usual 300mg once daily 14 day treatment scheduled every 28 days for oral azacitadine can be extended to a 21 day treatment schedule every 28 days if disease relapse with a blast count of 5-15% is observed in the peripheral blood or bone marrow. • The patient is fit for treatment with oral azacitadine maintenance therapy and has an ECOG performance status of 0-3. • Oral azacitadine can only be prescribed in this maintenance indication in this group of AML patients and cant be used interchangeably with injectable azacitadine. Toxicity Drug Azacitadine Adverse Effect nausea, vomiting, diarrhoea, neutropenia, fatigue/asthenia, constipation, thrombocytopenia, abdominal pain, respiratory tract infection, arthralgia, decreased appetite, febrile neutropenia, back pain, leucopenia, pain in extremity, pneumonia The adverse effects listed are not exhaustive. Please refer to the relevant summary of product characteristics for further details. Version 1 (June 2022) Page 1 of 7 AML- oral Azacitidine Monitoring • Full blood counts should be performed prior to initiation of therapy. Full blood count monitoring is also recommended every other week for the first 2 cycles (56 days), every other week for the next 2 cycles after dose adjustment, and monthly thereafter, prior to the start of subsequent cycles of treatment. • U&Es and LFTs prior to each cycle. Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Consider blood transfusion or the use of erythropoietin according to NICE TA323 if patient symptomatic of anaemia or has haemoglobin of less than 8g/dL (80g/L). Criteria Recommended action Grade 4 neutropenia or grade 3 neutropenia with fever First occurrence • Interrupt azacitadine • Resume the treatment cycle at the same dose once neutrophils return to Grade 2 or lower. • Use supportive care such as granulocyte colony stimulating factor (GCSF), as clinically indicated Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding Occurrence in 2 consecutive cycles • Interrupt Azacitadine • Resume the treatment cycle at a reduced dose of 200 mg after neutrophils return to Grade 2 or lower. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or re-occurs after dose and schedule reduction, discontinue azacitadine. • Use supportive care such as GCSF, as clinically indicated First occurrence • Interrupt azacitadine. • Resume the treatment cycle at the same dose once platelets return to Grade 2 or lower. Occurrence in 2 consecutive cycles • Interrupt azacitadine. • Resume the treatment cycle at a reduced dose of 200 mg Version 1 (June 2022) Page 2 of 7 AML- oral Azacitidine after platelets return to Grade 2 or lower. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • • If the toxicity continues or re-occurs after dose and schedule reduction, discontinue azacitadine. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (BIL) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or BIL 1 to 1.5 × ULN and any AST). Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN) should be monitored more frequently for adverse reactions and appropriate dose adjustment should be made. Renal Impairment Azacitadine can be administered to patients with mild, moderate or severe renal impairment without initial dose adjustment. Other Criteria Recommended action Grade 3 or higher nausea, vomiting or diarrhoea Other Grade 3 or higher non haematological events • Interrupt Azacitadine • Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower. • Use supportive care such as antiemetic therapy and treat diarrhoea at the onset of symptoms • If event re-occurs, interrupt dose until resolved to Grade 1 or lower and reduce the dose to 200 mg. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or re-occurs after dose and schedule reduction, discontinue azacitadine. • Interrupt azacitadine and provide medical support according to local recommendations. • Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower. • If the toxicity re-occurs, interrupt Azacitadine until resolved to Grade 1 or lower and reduce dose to 200 mg. • If a patient continues to experience Version 1 (June 2022) Page 3 of 7 AML- oral Azacitidine the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Azacitadine. Regimen 28 day cycle until disease progression or intolerance (12 cycles will be set in ARIA) Drug Dose Days Administration Azacitadine 300mg once a day 1-14* oral *In the case of disease relapse, with 5% to 15% blasts in peripheral blood or bone marrow, in conjunction with a clinical assessment, an extension of the dosing schedule from 14 to 21 days of repeated 28-day cycles should be considered. Dosing should not exceed 21 days during any 28-day period. Azacitadine should be discontinued if more than 15% blasts are observed in either the peripheral blood or bone marrow or at the physician’s discretion. Dose Information • Azacitadine is available as 200mg and 300mg film-coated tablets Administration Information • If a dose of azacitadine is missed, or not taken at the usual time, the dose should be taken as soon as possible on the same day. Then, the next scheduled dose should be taken at the normal time the following day. Two doses should not be taken on the same day • If a dose is vomited, another dose must not be taken on the same day. Instead return to the normal time of dose administration the following day. • Azacitadine can be taken with or without food. The tablets should be swallowed whole with a glass of water at about the same time each day. They should not be split, crushed, dissolved or chewed. Additional Therapy • Anti-emetics As take home medication - metoclopramide 10mg three times when required oral – - ondansetron 8mg twice a day on days 1-14 oral • Anti-infective prophylaxis with - aciclovir 400mg twice a day • Senna 15mg at night when required for the relief of constipation Version 1 (June 2022) Page 4 of 7 AML- oral Azacitidine Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to azacitadine. • It must be made clear to all staff, including those in the community, that azacitadine is should only be prescribed under the supervision of a consultant haematologist or oncologist. • There are many drug interactions associated with azacitadine. Please check for interactions when initiating treatment. • Azacitadine has minor influence on the ability to drive and use machines. Fatigue has been reported with the use of Azacitadine. Therefore, caution is recommended when driving or operating machines. References 1. Bristol-Myers Squibb Pharma. Onureg 200 mg film-coated tablets summary of product characteristics. Available from: https://mhraproducts4853.blob.core.windows.net/docs//858bc5ecf70c5ee203df4b39987e83f32e7e8a9c. Last updated 01/07/2021. 2. Wei AH et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med 2020; 383:2526-2537. Version 1 (June 2022) Page 5 of 7 AML- oral Azacitidine REGIMEN SUMMARY Azacitadine (oral) Take Home Medicines 1. Azacitadine 300mg once a day oral for 14 days Administration instructions: Oral SACT Swallow whole To be taken at the same time each day starting on day 1 of the cycle. 2. Ondansetron 8mg twice a day oral for 14 days Administration instructions: To be taken 15-30 minutes prior to azacitadine. A further dose can be taken 12 hours later. 3. Aciclovir 400mg twice a day oral for 28 days 4. Senna 15mg at night when required for the relief of constipation oral Version 1 (June 2022) Page 6 of 7 AML- oral Azacitidine DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 November 2022 None Alexandra Pritchard Dr Deborah Richardson Pharmacist Consultant Haematologis This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (June 2022) Page 7 of 7 AML- oral Azacitidine
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CH003 regimen validation checklist ver2.0x

Description: Central South Coast Cancer Network Strength through Partnership Checklist for Verification of Treatment Regimens in ARIA Version 10 Regimen’s Name and Disease Site Internal Name/ Version Date Regimen Last Updated The regimen above has been checked against (Tick as appropriate): □ CSCCN Protocol, version number: □ Other, please specify and cross reference: Entered By: Signature: Date Checked By: Signature: Date: To access the regimen for testing log into “CSCCN” in Medonc Planner. In the “Open Plan” window select: Plan Type - “Regimen” or “Symptom Mgmt.” and Plan Status - “In Testing” and “Active”. Highlight the plan for testing and double-click or click the “open” button. PLAN AGENDA WINDOW – DEFINITION (from the toolbar click the “Definition” button) DEFINITION TAB: Correct (√ ) Incorrect ( X ) • Plan name (20 character limit - NOTE unable to have 2 plans with the same name therefore may have extra spaces in title) • Display name • Version number (check version is the same as stated above) • Plan type (should be “regimen” or “symptom management”) • Sponsor (should always be “internal”) • Owner (should always be “CSCCN”) • Brief description (correctly describes agents, doses, administration route, frequency and duration) • Clinical Trial (should NOT be selected) • Amendments Mandatory (should NOT be selected) NB only applicable to regimen CLASSIFICATION TAB: • Sex (Should always be N/A) • Age range (should always be blank) • Classification type – check the following classifications have been selected correctly Disease site Cancer categories (includes OPCS codes, disease sub categories and trial status where applicable) Problems ( NB only applicable to symptom management) AUTHORS TAB: • There should be no entries in this field AUTHORIZED USERS TAB: • This list should consist of the following names only; Kimber Donna, P Basker Nanda, P Burgin Ali, P Harrison Liz, P Robertson Debra, P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |1 Central South Coast P Wills Rebecca , Wright (IP) Debbie, Vms Ks MEDICAL MANAGEMENT TAB: Cancer Network Strength through Partnership • Classification – Toxicity Grading - NCI CTCAE v4.0 (SI units) should be selected • Estimated GFR – only selected if a formula other than Cockcroft & Gault is required SPONSOR TAB: • There should be no entries in this field PLAN AGENDA WINDOW – MODIFY PHASE (click on the “Modify” button in the “Plan Agenda” window) Correct (√ ) Incorrect ( X ) • Phase (should always be phase 1) • Phase name (Should be Phase 1 for a regimen or a description for a symptom management plan) • Purpose (should always be blank or N/A) • Service type ( should always be blank) • Modality (should always be blank) • Toxicity cause required (should NOT be selected) • Closed to accrual (should NOT be selected) • Schedule type (ensure correct schedule type has been selected) Dependent on the schedule type please complete the following: CYCLICAL (√ ) or ( X ) LINEAR (√ ) or ( X ) LINEAR-NEG DAYS (√ ) or ( X ) AD HOC (√ ) or ( X ) Cycle length (days): Length (days): Length (days): Length (days): Number of cycles: Max. Drift (days): (Should always be “0”) Max. Drift (days): (Should always be “0”) Starting day: Max. Drift (days): (Should always be “0”) Max. Drift (days): (Should always be “0”) • Description (correctly describes agents, doses, administration route, frequency and duration) • Toxicity Risk (NO scores should be selected) • Chemo order instructions (should always be blank) PLAN AGENDA WINDOW – AGENTS (from the toolbar click the “Agents” button to view all the agents attached to this regimen) Correct (√ ) Incorrect ( X ) • Check that all of the regimen’s drugs specified as per the CSCCN protocol are listed in the “Agents” window • Check that all of supportive care drugs and pre and post hydration are included as per the CSCCN protocol summary page • Ensure that all drugs are listed in the correct administration order and amend the sequence number if needed (using plan utilities) • IMPORTANT – all drugs must be in UPPER CASE (as taken from First Data Bank). For investigational or unlicensed drugs please check spelling and entry of drug. Specify total number of agents on this list: ………… • Double click on each individual agent to open and then list each individual agent in table 1 on Page 5 and table 2 on Page 6 and repeat for each agent. PLAN AGENDA WINDOW – TESTS/TOXICITIES (from the toolbar click the “Tests” and “Toxicities” buttons) Correct (√ ) Incorrect ( X ) P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |2 Central South Coast Cancer Network Strength through Partnership • Tests (there should be NO “Selected Tests” • Toxicities (there should be NO “Selected Toxicities”) PLAN AGENDA WINDOW – SCHEDULE (from the tool bar click the “Schedule” button.) Correct (√ ) Incorrect ( X ) • Starting on (this field should be blank except where the regimen includes an agent scheduled for specific days e.g. M/W/F) • View (‘cycle day’ should always be selected) • Maintain (‘schedule’ should always be selected) Click on the “List” button to view how drugs are scheduled for this regimen. • Select ‘Cyclical’ to bring up a list of ALL agents that have been scheduled cyclically. Complete table 1 on Page 5 to indicate whether each agent is scheduled correctly. Print the cyclical list and attach it to this document. • Select ‘Non-cyclical’ to bring up a list of ALL agents that have been scheduled non-cyclically. Complete table 1 on Page 5 to indicate whether each agent is scheduled correctly. Print the non-cyclical list and attach it to this document. PLAN DETAILS MENU – Summary (from the “Plan Details” menu select Summary to open the “Plan Summary” window) Correct (√ ) Incorrect ( X ) • The “Plan Summary” window shows free-typed information about the regimen. This should contain the link to the correct protocol on the CSCCN website or reference the trial protocol. PLAN DETAILS MENU – Access (from the “Plan Details” menu select Access to open the “Plan Access for Institution/User” window) Correct (√ ) Incorrect ( X ) • Institutions tab (check that the relevant institutions have been selected) o For adult regimens this includes all institutions except “PIAM Brown” o For paediatric regimens select “PIAM Brown” and “RSH Outpt Clinic” only • User tab (check that all users have access to the regimen – i.e. none are ticked) TESTING THE REGIMEN IN ARIA Correct (√ ) Incorrect ( X ) Follow the Validation of CSCCN Chemotherapy Protocols in Aria (SOP:CH003)and review this regimen using the appropriate number of test patients. (For most regimens this will involve 3 test patients but for simple regimens where the doses for all agents are flat only one patient need be completed) Once the test patients have been completed successfully and all necessary amendments made return to the regimen in planner. In the “Plan Agenda” window click the “Approve” button, then click “Analyse”, then “Approve for Use”. APPROVED FOR USE IN ARIA Print Signature Date Occupation P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |3 DOCUMENTATION Central South Coast Cancer Network Strength through Partnership The completed form must be returned to the CSCCN system manager along with the check list for testing chemotherapy regimens and validation prescriptions within two weeks of regimen approval. A message must be broadcast to all users of the system as soon as the regimen has been approved for use stating either that the regimen has been added to Aria or an update implemented (with a brief description of the update). Date Sent / Sign Date Received / Sign Message Broadcast on Aria Date Sign Checklist for Verification Date Sign Date Sign Checklist for Prescription Verification (S / M / L) Date Sign Date Sign Test Prescriptions (S / M / L) Only the L prescription need be printed Date Sign Date Sign P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |4 Central South Coast Cancer Network Strength through Partnership Checklist for verification of Treatment Regimens in ARIA Version 10 – Table 1 Agents and their Schedule DRUG (AGENT) NAME, DOSE & FORM AGENT SEQ# Check the sequence number corresponds with the order of administration DETAILS TAB Check all fields for accuracy (as per table on page 6) ADMIN TAB Check free text is appropriat e for the agent COURSE TAB Check there are NO entries here Tick to indicate how each agent has been scheduled SCHEDULE Check the following for each agent and indicate if correct (√ )or incorrect ( X ) SEQ# (√ )or( X ) (√ )or ( X ) (√ )or ( X ) (√ )or ( X ) Cyclical Noncyclical Indicate if agent has been entered correctly (√ )or incorrectly ( X ) Treatment Day Treatment Cycle Frequency Duration P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |5 Central South Coast Cancer Network Strength through Partnership Checklist for verification of Treatment Regimens in ARIA Version 10 – Table 2 Agents Details Insert a (√), (X) or (N/A) in each box DRUG (AGENT) NAME, DOSE & FORM Agent Placeholder (not selected) Fixed dose (always selected) Form, Dose/Range and Units correct Route Strength (if Dose banded) Rounding Method (if applicable) Max Single dose (if applicable) Prescription type (internal or pick-up internal only) Record Dose (for pickup only – “no dose recordings” selected) Refill (for pick-up only – not selected) Agent Category correct (treatment/hydration etc ) Infusion Mode Duration Diluent Volume Diluent ID Line No – should be blan k Substitution allowed – always YES P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |6 Central South Coast Cancer Network Strength through Partnership DOCUMENT CONTROL Checklist for Verification of Treatment Regimens in ARIA Version 10 Version Number Description of Change Amended By 2.0 Plan details menu – Access – Institutions tab: “For adult regimens this includes all Rebecca Wills institutions except “PIAM Brown”, For paediatric regimens select “PIAM Brown” and “RSH CSCCN Electronic Prescribing Outpt Clinic” only” added Pharmacist Testing the regimen in Aria – Option for one patient testing for regimens with flat doses added 1.9 Title changed to ARIA Version 10 Rebecca Wills Instructions on how to access regimen added CSCCN Electronic Prescribing “Modify Plan Window” title changed to “ “Plan Agenda Window – Definition” with associated Pharmacist information Definition Tab: “Billable plan” removed, “Amendments mandatory” added, “symptom management” included as an option for the plan type. Classification Tab: Diseasse stage, cell categories, Tx line, Tx intent removed. Coding included in under cancer categories with disease sub categories and trial status added. “Problems” added Authorised User Tab: P Burgin Ali added, list arranged alphabetically. Medical Management Tab: NCI CTCAE v3.0 changed to v4.0, Estimated GFR changed to “only selected if a formula other than Cockcroft and Gault is required” Modify Phase – sub-window: Title merged into section above. Phase name – “for a regimen or a description of symptom management plan” added, “Closed to accrual” added, “Toxicity risk” added, “Chemo order instructions” added Agents: Title amended. Table page numbers changed from 4 and 5 to 5 and 6. Tests/Toxicities: title amended, wording changed to reflect new format in V10. Schedule: Title amended. Starting on field – supplementary information added. Cyclical/Non cyclical lists -wording updated. Plan summary: changed to include reference to CSCCN website or trial protocol. P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 Date 22nd January 2013 20th January 2013 P a ge |7 Central South Coast Cancer Network Strength through Partnership Access: user tab – wording amended – all users to have access. Testing the regimen in ARIA: The last three statements removed and incorporated into the pharmacist checklist. Instructions on how to approve for use added Tables 1 and 2 – “Central South Coast Cancer Network” title removed (already in header) Table 2: Extra line added, Maximum Variation column removed, Agent placeholder, Fixed dose, Form, dose/range and units, Record dose and Refill columns added “(√) (X)” from columns moved to title with “(N/A)” option added 1.8 Documentation changed so that only the large prescription need be printed. Dr Deborah Wright Testing the regimen changed to state that each cycle must be checked if doses change CSCCN Lead Pharmacist between cycles 1.7 Nanda Basker added to approved list of users and Sara Brown removed Dr Deborah Wright CSCCN Lead Pharmacist 1.6 Summary section changed to reflect the removal of the protocol and it’s replacement with Dr Deborah Wright the link to the website CSCCN Lead Pharmacist 1.5 Section on not including antiemetics removed Dr Deborah Wright Document control added CSCCN Lead Pharmacist 1.4 Coding added as a check under classification Dr Deborah Wright CSCCN Lead Pharmacist 1.3 Section added describing documentation Dr Deborah Wright CSCCN Lead Pharmacist 1.2 Approval table re-formatted Dr Deborah Wright CSCCN Lead Pharmacist 1.1 Authorised users amended Dr Deborah Wright CSCCN Lead Pharmacist 13th June 2012 31st May 2012 18/11/10 09/09/10 05/08/10 29/07/10 May 10 Feb 10 P:CH003 Version: 2.0 Written: D Kimber CSCCN E-Prescribing System Manager Issue Date: Jan 2010 Rev Date: Jan 2015 Approved: Date of Amendments: Dr D Wright February 2010, May 2010, July 2010, August 2010, Sept 2010, CSCCN Lead Pharmacist November 2010, May 2012, June 2012, Jan 2013, Jan 2013 P a ge |8
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InP-LEAM

Description: Chemotherapy Protocol LYMPHOMA LOMUSTINE-CYTARABINE-ETOPOSIDE (split)-MELPHALAN (LEAM) Inpatient Regimen Regimen Lymphoma – InP-LEAM (split)-Lomustine-Cytarabine-Etoposide-Melphalan Indication  Conditioning for autologous peripheral blood stem cell transplant (PBSCT) / bone marrow transplant in individuals with either Non Hodgkin Lymphoma (NHL) or Hodgkin Lymphoma Toxicity Drug Lomustine Cytarabine Etoposide Adverse Effect Pulmonary toxicity CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Hypotension on rapid infusion, hyperbilirubinaemia Melphalan Gastro-intestinal disturbances, stomatitis Patients treated with LEAM are at risk of transfusion-associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive irradiated blood products for the 1 week prior to harvest and for at least 12 weeks after the transplant has taken place. Patients with Hodgkin lymphoma carry a lifelong risk of graft versus host disease and must always receive irradiated blood products. Local blood transfusion departments must be notified as soon as a diagnosis is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1 (September 2022) Page 1 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Monitoring Drugs  FBC, LFTs (including albumin) and U&Es prior to day one of treatment  EDTA or calculated creatinine clearance prior to each melphalan infusion  Monitor the fluid balance during the administration of melphalan, including throughout the administration of the pre and post hydration. Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Dose Modifications The dose modifications listed are for haematological, liver and renal function and some limited drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Treatment will be given regardless of blood results. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Irradiated blood products must be used. Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Lomustine Bilirubin μmol/L N/A AST/ALT units/L N/A Dose (% of original dose) No dose adjustment necessary Cytarabine more than 34 50% The dose may be escalated dependent on toxicity Etoposide Melphalan 30-51 or more than 51 or N/A 60-180 more than 180 N/A Consider dose reducing to 50% Clinical decision No dose adjustment necessary Version 1 (September 2022) Page 2 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Renal Impairment Drug Lomustine Creatinine Clearance (ml/min) more 60 45-60 30-<45 less than 30 Dose (% of original dose) 100% 75% 50% Clinical decision Cytarabine N/A No dose adjustment necessary Etoposide more than 50 15-50 less than 15 100% 75% 50% Melphalan more than 50 30-50 less than 30 100% 75% Clinical decision Other Lomustine It may be necessary to reduce the dose of lomustine in patients with reduced pulmonary function. Lomustine dose reductions in this situation are to be made at the discretion of the consultant oncologist/haematologist only. Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Regimen 1 cycle will be set in Aria Drug Lomustine Cytarabine Etoposide Melphalan Dose 200mg/m2 200mg/m2 every 12 hours 200mg/m2 140mg/m2 Days -6 -5,-4,-3,-2 -5,-4,-3,-2 -1 Administration Oral Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion in 2000ml sodium chloride 0.9% over 120 minutes (this will be administered as two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes administered sequentially) Intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Dose Information Version 1 (September 2022) Page 3 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan  Lomustine will be dose rounded to the nearest 40mg (down if halfway)  Cytarabine will be dose banded in accordance with the national dose bands (20mg/ml)  Etoposide will be dose banded in accordance with the national dose bands (20mg/ml)  The melphalan dose will be dose rounded to the nearest 10mg (down if halfway). The National Dose Banding Team have advised not to use dose banding tables for this product in view of the 90 minute expiry (must be made locally for individual patient), the 50mg vial size and frequent stock shortages. Administration Information Extravasation  Cytarabine – non-vesicant  Etoposide – irritant  Melphalan – irritant Other  Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes.  Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Additional Therapy This is an in-patient regimen. Please ensure all supportive and take home medicines are prescribed on the in-patient chart or general electronic prescribing system. Please refer to the transplant schedule for the individual patient.  Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 2mg twice a day for 10 days oral or intravenous starting on day -6 of the cycle - metoclopramide 10mg three times a day for 10 days oral or intravenous starting on day -6 of the cycle - ondansetron 8mg twice a day for 10 days oral or intravenous - aprepitant 125mg once only orally on the day of the melphalan infusion then 80mg once a day for the subsequent two days Version 1 (September 2022) Page 4 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan  Anti-infectives - aciclovir 400mg oral twice a day until day +90 - ciprofloxacin 250mg oral twice a day from day+1 (stop when neutrophils are greater than 1) - pentamidine 300mg by nebuliser prior to discharge - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday (start from 28 days post discharge, if neutrophils are greater than 1 and platelets are greater than 50, and continue until day +120) - fluconazole 100mg once a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids) - nystatin suspension 1ml four times a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids)  Thromboprophylaxis, continued until platelets are less than 50x109/L, or as directed by the consultant, according to local formulary choices; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection  Growth factors such as filgrastim biosimilar 30million units (300mcg) once a day subcutaneous from day +5 (stop when neutrophils are greater than 1x109/L for at least 24 hours, or greater than 3 on any occasion)  Intravenous hydration before and after melphalan infusion The evening before melphalan infusion (to be completed by 0930 on the morning of the infusion) sodium chloride 0.9% with potassium chloride 27mmol 1000ml The day of melphalan infusion 0900hrs Start fluid chart and daily weights. Contact pharmacy to make melphalan infusion for delivery to ward at 1045hrs 0930hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 1010hrs 20mg furosemide intravenous bolus 1045hrs Measure urine output since 0900hrs  If more than 500ml continue with melphalan infusion  If less than 500ml give second furosemide 20mg dose intravenous bolus check urine output since 0900hrs again at 1100hrs:  if more than 500ml go ahead with melphalan  if less than 500ml contact the prescriber. 1100hrs – give melphalan intravenous infusion over thirty minutes (This product has a short expiry so adhering to set timing is essential) Version 1 (September 2022) Page 5 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan 1130hrs - 1000ml sodium chloride 0.9% intravenous infusion over 120 minutes 1330hrs - 1000ml sodium chloride 0.9% with potassium chloride 27mmol intravenous infusion over 240 minutes 1730hrs - 1000ml sodium chloride 0.9% intravenous infusion over 360 minutes 2330hrs - 1000ml sodium chloride 0.9% with potassium chloride 27mmol intravenous infusion over 480 minutes  The day after melphalan infusion; 0730hrs - 1000ml sodium chloride 0.9% intravenous infusion over 480 minutes then restart routine intravenous fluids  Furosemide 20mg oral or intravenous bolus to maintain fluid balance and a urine output of more than 250ml/hour immediately prior to melphalan administration  In menstruating women consider norethisterone 5mg three times a day oral to prevent menstruation. This may be stopped when the platelets are more than 50x109/L.  Mouthcare for the prophylaxis or treatment of mucositis in accordance with local or national guidelines  Gastric protection with a proton pump inhibitor or a H2 antagonist according to local formulary choice; - esomeprazole 20mg once a day oral - omeprazole 20mg once a day oral - lansoprazole 15mg once a day oral - pantoprazole 20mg once a day oral - rabeprazole 20mg once a day oral - cimetidine 400mg twice a day oral - famotidine 20mg once a day oral - nizatidine 150mg twice a day oral - ranitidine 150mg twice a day oral Additional Information  Irradiated blood products must be used  Autologous stem cells/ bone marrow will be infused on day 0, at least 24 hours after the melphalan infusion Coding Version 1 (September 2022) Page 6 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan  Procurement – X70.5  Delivery – Not Required References 1.Mills W, Chopra R, McMillan A et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol (1995);13(3): 588-95 2.Kelsey P, Pearce R, Perry J et al. Substituting carmustine for lomustine is safe and effective in the treatment of relapsed or refractory Lymphoma – a retrospective study from the BSBMT (BEAM versus LEAM) Version 1 (September 2022) Page 7 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan REGIMEN SUMMARY InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describes the agents which must be prescribed on the in-patient chart or general electronic prescribing system Day -6 1. Warning – Check blood transfusion status Administration Instructions Patients treated with LEAM carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual transplant schedule. In general the following is required; 1. Aprepitant 125mg once a day oral on the day of melphalan administration followed by 80mg once a day for two days after melphalan administration 2. Dexamethasone 2mg twice a day, days -6 to +3 oral or intravenous 3. Metoclopramide 10mg three times a day, days -6 to +3 then as required oral or intravenous 4. Ondansetron 8mg twice a day, days -6 to +3 oral or intravenous 5. Growth factors such as biosimiliar filgrastim 30million units once a day from day +5 (stop when neutrophils are greater than 1x109/L for at least 24 hours or are greater than 3x109/L on any occasion 6. Aciclovir 400mg oral twice a day until day +90 7. Ciprofloxacin 250mg twice a day from day +1 and continued until neutrophils are greater than 1x109/L. 8. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday (start from 28 days post discharge if the neutrophils are greater than 1x109/L and platelets are greater than 50x109/L and continue until day +120) 9. Fluconazole 100mg once a day (stop when neutrophils are greater than 1x109/L) 10.Pentamidine 300mg nebuliser prior to discharge 11.Thromboprophylaxis with a low molecular weight heparin until platelets are less than 50x109/L 12.Furosemide 20mg when required oral or intravenous bolus 13.Melphalan pre and post hydration 14.Gastric protection 15.Consider mouthwashes 16.Consider norethisterone for menstruating women 3. Lomustine 200mg/m2 once a day for one day oral Administration Instructions This should be given before midday. Swallow whole with a full glass of water. Do not open or chew Day -5, -4, -3, -2 4. Warning – Cytarabine is TWICE a day (12hrs apart) Administration Instructions Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) 5. Cytarabine 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes every 12 hours (9am and 9pm) Administration Instructions Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) 6. Warning – Etoposide is TWO infusions () Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 7. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Version 1 (September 2022) Page 8 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 8. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes Day -1 9. Warning – Check hydration and fluid balance Administration Instructions See separate fluid prescription for the pre hydration: 1. Overnight to be completed at 0930hrs on day of melphalan infusion, 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion The day of melphalan infusion: 2. 0900hrs on the day of melphalan start fluid chart and daily weights. Contact pharmacy to make melphalan infusion for delivery to ward at 1045hrs 3. 0930hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 4. 1010hrs 20mg furosemide intravenous bolus 5. 1045hrs Measure urine output since 0900hrs If more than 500ml continue with melphalan infusion If less than 500ml give second furosemide 20mg dose intravenous bolus and recheck urine output since 0900hrs again at 1100hrs: • if more than 500ml go ahead with melphalan • if less than 500ml contact prescriber. 10. Time– Administer melphalan at 1100 11. Melphalan 140mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions - see separate fluid prescription for the post hydration requirements 1. 1100hrs – give melphalan intravenous infusion over thirty minutes 2. 1130hrs - 1000ml sodium chloride 0.9% intravenous infusion over two hours 3. 1330hrs - 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion over four hours 4. 1730hrs - 1000ml sodium chloride 0.9% intravenous infusion over six hours 5. 2330hrs - 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion over eight hours 6. The day after melphalan infusion: 0730hrs - 1000ml sodium chloride 0.9% intravenous infusion over eight hours and then restart routine intravenous fluids Version 1 (September 2022) Page 9 of 10 Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan Version Date DOCUMENT CONTROL Amendment Written By Approved By 1 September 2022 None Nanda Basker Pharmacist Dr Rob Lown Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. These protocols should be used in conjunction with other references such as the Summary of Product Characteristics and relevant published papers. Version 1 (September 2022) 10 Page 10 of Lymphoma- InP-LEAM (split)-Lomustine-Cytarabine-Etoposide (split)-Melphalan
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/InP-LEAM.pdf

InP-BEAM

Description: Chemotherapy Protocol LYMPHOMA CARMUSTINE-CYTARABINE-ETOPOSIDE (split)-MELPHALAN (BEAM) Inpatient Regimen Regimen Lymphoma – InP-BEAM (split)-Carmustine-Cytarabine-Etoposide-Melphalan Indication • Conditioning for autologous peripheral blood stem cell transplant (PBSCT) / bone marrow transplant in individuals with either Non Hodgkin Lymphoma (NHL) or Hodgkin Lymphoma Toxicity Drug Carmustine Cytarabine Etoposide Adverse Effect Pulmonary toxicity CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Hypotension on rapid infusion, hyperbilirubinaemia Melphalan Gastro-intestinal disturbances, stomatitis Patients treated with BEAM are at risk of transfusion-associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive irradiated blood products for the 1 week prior to harvest and for at least 12 weeks after the transplant has taken place. Patients with Hodgkin lymphoma carry a lifelong risk of graft versus host disease and must always receive irradiated blood products. Local blood transfusion departments must be notified as soon as a diagnosis is made and the patient must be issued with an alert card to carry with them at all times. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1.1 (August 2018) Page 1 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each melphalan infusion • Monitor the fluid balance during the administration of melphalan, including throughout the administration of the pre and post hydration. Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Dose Modifications The dose modifications listed are for haematological, liver and renal function and some limited drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Treatment will be given regardless of blood results. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Irradiated blood products must be used. Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Carmustine Bilirubin µmol/L N/A AST/ALT units/L N/A Dose (% of original dose) No dose adjustment necessary Cytarabine more than 34 50% The dose may be escalated dependent on toxicity Etoposide Melphalan 30-51 or 60-180 Consider dose reducing to 50% more than 51 or more than 180 Clinical decision N/A N/A No dose adjustment necessary Version 1.1 (August 2018) Page 2 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan Renal Impairment Drug Carmustine Creatinine Clearance (ml/min) more 60 46-60 30-45 less than 30 Dose (% of original dose) 100% 80% 75% Clinical decision Cytarabine N/A No dose adjustment necessary Etoposide more than 50 15-50 less than 15 100% 75% 50% Melphalan more than 50 30-50 less than 30 100% 75% Clinical decision Other Carmustine It may be necessary to reduce the dose of carmustine in patients with reduced pulmonary function. Carmustine dose reductions in this situation are to be made at the discretion of the consultant oncologist/haematologist only. Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Regimen 1 cycle will be set in Aria Drug Carmustine Cytarabine Etoposide Melphalan Dose 300mg/m2 200mg/m2 every 12 hours 200mg/m2 140mg/m2 Days -6 -5,-4,-3,-2 -5,-4,-3,-2 -1 Administration Intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion in 2000ml sodium chloride 0.9% over 120 minutes (this will be administered as two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes administered sequentially) Intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Version 1.1 (August 2018) Page 3 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan Dose Information • Carmustine will be dose rounded to the nearest 10mg (down if halfway) • Cytarabine will be dose banded in accordance with the national dose bands (20mg/ml) • Etoposide will be dose banded in accordance with the national dose bands (20mg/ml) • The melphalan dose will be dose rounded to the nearest 10mg (down if halfway). The National Dose Banding Team have advised not to use dose banding tables for this product in view of the 90 minute expiry (must be made locally for individual patient), the 50mg vial size and frequent stock shortages. Administration Information Extravasation • Carmustine – irritant • Cytarabine – non-vesicant • Etoposide – irritant • Melphalan – irritant Other • Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. • Ensure the urine output is more than 250ml/hour immediately prior to the administration of melphalan Additional Therapy This is an in-patient regimen. Please ensure all supportive and take home medicines are prescribed on the in-patient chart or general electronic prescribing system. Please refer to the transplant schedule for the individual patient. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 2mg twice a day for 10 days oral or intravenous starting on day -6 of the cycle - metoclopramide 10mg three times a day for 10 days oral or intravenous starting on day -6 of the cycle - ondansetron 8mg twice a day for 10 days oral or intravenous Version 1.1 (August 2018) Page 4 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan - aprepitant 125mg once only orally on the day of the melphalan infusion then 80mg once a day for the subsequent two days • Anti-infectives - aciclovir 400mg oral twice a day until day +90 - ciprofloxacin 250mg oral twice a day from day+1 (stop when neutrophils are greater than 1) - pentamidine 300mg by nebuliser prior to discharge - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday (start from 28 days post discharge, if neutrophils are greater than 1 and platelets are greater than 50, and continue until day +120) - fluconazole 100mg once a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids) - nystatin suspension 1ml four times a day oral (stop when neutrophils are greater than 1 unless the patient remains on corticosteroids) • Thromboprophylaxis, continued until platelets are less than 50x109/L, or as directed by the consultant, according to local formulary choices; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection • Growth factors such as filgrastim biosimilar 30million units (300mcg) once a day subcutaneous from day +5 (stop when neutrophils are greater than 1x109/L for at least 24 hours, or greater than 3 on any occasion) • Intravenous hydration before and after melphalan infusion The evening before melphalan infusion (to be completed by 0930 on the morning of the infusion) sodium chloride 0.9% with potassium chloride 27mmol 1000ml The day of melphalan infusion 0900hrs Start fluid chart and daily weights. Contact pharmacy to make melphalan infusion for delivery to ward at 1045hrs 0930hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 1010hrs 20mg furosemide intravenous bolus 1045hrs Measure urine output since 0900hrs If more than 500ml continue with melphalan infusion If less than 500ml give second furosemide 20mg dose intravenous bolus check urine output since 0900hrs again at 1100hrs: • if more than 500ml go ahead with melphalan • if less than 500ml contact the prescriber. Version 1.1 (August 2018) Page 5 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan 1100hrs – give melphalan intravenous infusion over thirty minutes (This product has a short expiry so adhering to set timing is essential) 1130hrs - 1000ml sodium chloride 0.9% intravenous infusion over 120 minutes 1330hrs - 1000ml sodium chloride 0.9% with potassium chloride 27mmol intravenous infusion over 240 minutes 1730hrs - 1000ml sodium chloride 0.9% intravenous infusion over 360 minutes 2330hrs - 1000ml sodium chloride 0.9% with potassium chloride 27mmol intravenous infusion over 480 minutes • The day after melphalan infusion; 0730hrs - 1000ml sodium chloride 0.9% intravenous infusion over 480 minutes then restart routine intravenous fluids • Furosemide 20mg oral or intravenous bolus to maintain fluid balance and a urine output of more than 250ml/hour immediately prior to melphalan administration • In menstruating women consider norethisterone 5mg three times a day oral to prevent menstruation. This may be stopped when the platelets are more than 50x109/L. • Mouthcare for the prophylaxis or treatment of mucositis in accordance with local or national guidelines • Gastric protection with a proton pump inhibitor or a H2 antagonist according to local formulary choice; - esomeprazole 20mg once a day oral - omeprazole 20mg once a day oral - lansoprazole 15mg once a day oral - pantoprazole 20mg once a day oral - rabeprazole 20mg once a day oral - cimetidine 400mg twice a day oral - famotidine 20mg once a day oral - nizatidine 150mg twice a day oral - ranitidine 150mg twice a day oral Additional Information • Irradiated blood products must be used • Autologous stem cells/ bone marrow will be infused on day 0, at least 24 hours after the melphalan infusion Version 1.1 (August 2018) Page 6 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan Coding • Procurement – X70.5 • Delivery – Not Required References 1.Mills W, Chopra R, McMillan A et al. BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol (1995);13(3): 588-95 Version 1.1 (August 2018) Page 7 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan REGIMEN SUMMARY InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describes the agents which must be prescribed on the in-patient chart or general electronic prescribing system Day -6 1. Warning – Check blood transfusion status Administration Instructions Patients treated with BEAM carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 2. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual transplant schedule. In general the following is required; 1. Aprepitant 125mg once a day oral on the day of melphalan administration followed by 80mg once a day for two days after melphalan administration 2. Dexamethasone 2mg twice a day, days -6 to +3 oral or intravenous 3. Metoclopramide 10mg three times a day, days -6 to +3 then as required oral or intravenous 4. Ondansetron 8mg twice a day, days -6 to +3 oral or intravenous 5. Growth factors such as biosimiliar filgrastim 30million units once a day from day +5 (stop when neutrophils are greater than 1x109/L for at least 24 hours or are greater than 3x109/L on any occasion 6. Aciclovir 400mg oral twice a day until day +90 7. Ciprofloxacin 250mg twice a day from day +1 and continued until neutrophils are greater than 1x109/L. 8. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday (start from 28 days post discharge if the neutrophils are greater than 1x109/L and platelets are greater than 50x109/L and continue until day +120) 9. Fluconazole 100mg once a day (stop when neutrophils are greater than 1x109/L) 10.Pentamidine 300mg nebuliser prior to discharge 11.Thromboprophylaxis with a low molecular weight heparin until platelets are less than 50x109/L 12.Furosemide 20mg when required oral or intravenous bolus 13.Melphalan pre and post hydration 14.Gastric protection 15.Consider mouthwashes 16.Consider norethisterone for menstruating women 3. Carmustine 300mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes Day -5, -4, -3, -2 4. Warning – Cytarabine is TWICE a day (12hrs apart) Administration Instructions Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) 5. Cytarabine 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes every 12 hours (9am and 9pm) Administration Instructions Cytarabine is administered TWICE a day at 12 hour intervals (0900 and 2100) 6. Warning – Etoposide is TWO infusions () Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes. 7. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion Version 1.1 (August 2018) Page 8 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan is complete. The total duration of etoposide administration is 120minutes. 8. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions Due to the stability of etoposide the total dose of 200mg/m2 will be split into two infusions of 100mg/m2 in 1000ml sodium chloride 0.9% over 60 minutes. The two infusions are given sequentially, the second is started as soon as the first infusion is complete. The total duration of etoposide administration is 120minutes Day -1 9. Warning – Check hydration and fluid balance Administration Instructions See separate fluid prescription for the pre hydration: 1. Overnight to be completed at 0930hrs on day of melphalan infusion, 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion The day of melphalan infusion: 2. 0900hrs on the day of melphalan start fluid chart and daily weights. Contact pharmacy to make melphalan infusion for delivery to ward at 1045hrs 3. 0930hrs 1000ml sodium chloride 0.9% intravenous infusion over 90 minutes 4. 1010hrs 20mg furosemide intravenous bolus 5. 1045hrs Measure urine output since 0900hrs If more than 500ml continue with melphalan infusion If less than 500ml give second furosemide 20mg dose intravenous bolus and recheck urine output since 0900hrs again at 1100hrs: • if more than 500ml go ahead with melphalan • if less than 500ml contact prescriber. 10. Time– Administer melphalan at 1100 11. Melphalan 140mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions - see separate fluid prescription for the post hydration requirements 1. 1100hrs – give melphalan intravenous infusion over thirty minutes 2. 1130hrs - 1000ml sodium chloride 0.9% intravenous infusion over two hours 3. 1330hrs - 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion over four hours 4. 1730hrs - 1000ml sodium chloride 0.9% intravenous infusion over six hours 5. 2330hrs - 1000ml sodium chloride 0.9% with potassium chloride 0.2% (27mmol) intravenous infusion over eight hours 6. The day after melphalan infusion: 0730hrs - 1000ml sodium chloride 0.9% intravenous infusion over eight hours and then restart routine intravenous fluids Version 1.1 (August 2018) Page 9 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan DOCUMENT CONTROL Version Date Amendment Written By Approved By Split added to regimen name. Etoposide changed to two infusions of 100mg/m2 Furosemide dose changed to 20mg Administration instructions updated to describe the two 1.1 August etoposide infusions. 2018 Warning added regarding the Dr Deborah Wright Pharmacist Harriet Launders Pharmacist two infusions Corticosteroid statement removed from fluconazole. Gastricprotection added Thromboprophylaxis change to include formulary choices Disclaimer added Rebecca Wills Dr Rob Lown 1 August 2017 None Pharmacist Dr Deborah Wright Consultant Haematologist Pharmacist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. These protocols should be used in conjunction with other references such as the Summary of Product Characteristics and relevant published papers. Version 1.1 (August 2018) Page 10 of 10 Lymphoma- InP-BEAM (split)-Carmustine-Cytarabine-Etoposide (split)-Melphalan
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/InP-BEAM.pdf

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