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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 ..........
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AmB Carboplatin Etoposide Ifosfamide Rituximab (RICE)
Description
Chemotherapy Protocol LYMPHOMA CARBOPLATIN-ETOPOSIDE-IFOSFAMIDE-RITUXIMAB (RICE) Ambulatory Regimen Regimen • Lymphoma – AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab Indication • Non Hodgkin’s Lymphoma that is CD20 positive Toxicity Drug Carboplatin Etoposide Ifosfamide Rituximab Adverse Effect Neuropathy, nephrotoxicity, ototoxicity Hypotension on rapid infusion, hyperbilirubinaemia Haemorrragic cystitis, encephalopathy, nephrotoxicity Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each cycle • Urine diptest for protein every four hours the day of and the day after ifosfamide administration • Fluid balance monitoring every four hours the day of and the day after ifosfamide administration. Urine output should be maintained above 100ml/hour • Check hepatitis B status before starting treatment with rituximab 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. Version 1.1 (Feb 2023) Page 1 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab 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 There are no dose modifications for haematological toxicity. Treatment should be delayed until the minimum criteria, described in the table below, are reached. Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 50x109/L Consider blood transfusion if the patient is symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Carboplatin Bilirubin μmol/L N/A AST/ALT units/L N/A Dose (% of original dose) No dose adjustment needed Etoposide Ifosfamide *30-51 or more than 51 or 60-180 more than 180 more than 20 or more than 2.5xULN or ALP more than 2.5xULN 50% Clinical decision Not recommended Rituximab N/A N/A No dose adjustment needed *Limit reflects local practice and may vary from published sources Version 1.1 (Feb 2023) Page 2 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab Renal Impairment Drug Carboplatin Creatinine Clearance (ml/min) less than 20 Dose (% of original dose) omit Etoposide more than 50 15-50 less than15 100% 75% 50% Ifosfamide more than 60 40-59 Less than 40 100% 70% Clinical decision Rituximab N/A No dose adjustment needed Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Ifosfamide In the case of a NCI-CTC grade 1 neurological toxicity, the dose of ifosfamide may be reduced for the next cycle. If a NCI-CTC grade 2 neurological toxicity appears or neurological toxicity worsens despite dose reduction, the ifosfamide should be stopped. Risk factors for CNS toxicity include a low albumin, renal impairment, prior administration of cisplatin, poor performance status, CNS tumour, bulky pelvic disease, concomitant psychotropic drugs and younger age. Methylene blue 50mg four times a day intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes can be used to prevent or treat ifosfamide induced encephalopathy. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to Version 1.1 (Feb 2023) Page 3 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu like symptoms prior to treatment. Regimen 3 cycles (1 cycle will be set in ARA) New cycles may begin when haematological recovery has taken place. That is on the day that the neutrophil count recovers to more than 1x109/L and the unsupported platelet count is more than 50x109/L. Please note in the original CORAL study(1) an additional dose of rituximab 375mg/m2 was given on day -2, cycle 1 only. This does not appear in ARIA but can be added manually at the clinician’s discretion. There are no additional fluids incorporated into this regimen. The patient should be counselled to remain well hydrated and drink between 2-3 litres of fluid per day. Version 1.1 (Feb 2023) Page 4 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab Drug Carboplatin Etoposide Dose AUC 5 (max 790mg) 100mg/m2 Mesna 1000mg/m2 Day 2 1, 2, 3 2 Administration Intravenous infusion in 500ml glucose 5% over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Ifosfamide Mesna Mesna Rituximab 5000mg/m2 5000mg/m2 1800mg/m2 375mg/m2 2 Intravenous infusion in 1000ml sodium chloride 0.9% over 24 hours using a backpack and pump 2 Oral mesna tablets (rounded upwards 3 to the nearest 400mg) should be given at 0, 2 and 6 hours after the end of the last ifosfamide infusion. 1 Intravenous infusion in 500ml sodium chloride 0.9% New cycles begin on the day that the neutrophil count recovers to more than 1x109/L and the unsupported platelet count is more than 50x109/L. Version 1.1 (Feb 2023) Page 5 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab Dose Information • Carboplatin will be dose banded in accordance with the national dose bands (10mg/ml) • The maximum dose of carboplatin is 790mg • Etoposide will be dose banded in accordance with national dose bands (20mg/ml) • Ifosfamide will be dose banded in accordance with national dose bands (80mg/ml) • Mesna will be dose banded in accordance with national dose bands (100 NS) • Rituximab dose will be rounded to the nearest 100mg (up if halfway) Administration Information Extravasation • Carboplatin - irritant • Etoposide – irritant • Ifosfamide – neutral • Mesna – neutral • Rituximab – neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab prescribing and administration guidelines Additional Therapy This is an ambulatory regimen. Please ensure all supportive and take home medicines are collected / given to the patient. On days two and three ensure the patient has taken this medication before administering any chemotherapy. • Rituximab premedication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm Version 1.1 (Feb 2023) Page 6 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 5 days starting oral or intravenous - metoclopramide 10mg three times a day when required oral or intravenous - ondansetron 8mg twice a day for 5 days oral or intravenous • Growth factors continued until the neutrophil count is above 1x109/L. For example: - filgrastim or bioequivalent 30 million units once a day from day 6 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 6 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 4 subcutaneous Please check the intention is not to collect stems following the chemotherapy. In this instance the dose of biosimiliar filgrastim will be 10mcg/kg (rounded upwards to the nearest 300microgram or 480microgram). This normally occurs after cycle three. • Mouthwashes according to local or national policy on the treatment of mucositis • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Allopurinol 300mg once a day for the first cycle only • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only oral References 1.CORAL (Collaborative trial in relapsed aggressive lymphoma) protocol. June 18 2007 2.Kewalramani et al. Rituximab and ICE as second line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B cell lymphoma. Blood 2004; 103:3684-3688. Version 1.1 (Feb 2023) Page 7 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab REGIMEN SUMMARY AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab Day 1 1. Dexamethasone 8mg oral or intravenous Administration instructions: Administer 30 minutes prior to rituximab 2. Ondansetron 8mg oral or intravenous Administration instructions: Administer 30 minutes prior to treatment 3. Chlorphenamine 10mg intravenous Administration instructions: Administer 30 minutes prior to rituximab 4. Hydrocortisone 100mg intravenous injection Administration instructions: Administer 30 minutes prior to rituximab 5. Paracetamol 1000mg oral Administration instructions: Administer 30 minutes prior to rituximab 6. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 7. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 8. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 9. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines (day 1 only) 10. Dexamethasone 4mg twice a day for five days starting on day 2 of the cycle oral 11. Ondansetron 8mg twice a day for five days starting on the evening of day one of the cycle oral 12. Metoclopramide 10mg three times a day when required for the relief of nausea oral Administration Instructions Please supply 28 tablets or the nearest original pack size 13. Mesna 1800mg/m2 (rounded to the nearest 400mg) oral tablets should be given at 0, 2 and 6 hours after the end of the ifosfamide infusion 14. Aciclovir 400mg twice a day oral for 21 days 15. Co-trimoxazole 960mg once a day on Monday, Wednesday or Friday for 21 days oral Version 1.1 (Feb 2023) Page 8 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab 16. Growth factor continued until the neutrophil count is above 1x109/L, for example; - filgrastim or bioequivalent 30 million units once a day from day 6 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 6 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 4 subcutaneous Supply 7 days of biosimiliar filgrastim and lenograstim and one biosimiliar pegfilgrastim Please check the intention is not to collect stem cells following the chemotherapy. In this instance the dose of biosimiliar filgrastim will be 10mcg/kg (rounded upwards to the nearest 300microgram or 480microgram). This normally occurs after cycle three. 17. Allopurinol 300mg once a day for seven days oral (cycle one only) Administration Instructions Allopurinol is only required on cycle one. Day 2 1. Warning – Check supportive medication Administration instructions Check the patient has taken the prescribed dexamethasone and ondansetron. If they have forgotten administer; - dexamethasone 8mg oral or intravenous - ondansetron 8mg oral or intravenous 2. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 3. Carboplatin AUC 5 (max 790mg) intravenous infusion in 500ml glucose 5% over 60 minutes 4. Mesna 1000mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 5. Ifosfamide 5000mg/m2 with mesna 5000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 24 hours via a backpack Administration Instructions The ifosfamide should be mixed in the same bag as the mesna. Day 3 1. Warning – Check supportive medication Check the patient has taken the prescribed dexamethasone and ondansetron. If they have forgotten administer; - dexamethasone 8mg oral or intravenous - ondansetron 8mg oral or intravenous 2. Etoposide 100mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Version 1.1 (Feb 2023) Page 9 of 10 Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Approved By National dose bands added 1.1 February Maximum dose amended in line with 2023 national dose band 1 July 2017 None Alexandra Pritchard Pharmacist Dr Deborah Wright Pharmacist Tom Hurst Pharmacy Technician Dr Robert 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 Hospital 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 1.1 (Feb 2023) 10 Page 10 of Lymphoma-AmB-RICE-Carboplatin-Etoposide-Ifosfamide-Rituximab
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InP RIVAC (66) cytarabine etoposide ifosfamide rituximab
Description
Chemotherapy Protocol LYMPHOMA CYTARABINE-ETOPOSIDE-IFOSFAMIDE-RITUXIMAB (RIVAC) 66 years and above Inpatient Regimen There are multiple versions of this protocol in use. The choice of protocol depends on the age of the patient and whether there is CNS disease present at diagnosis. Please ensure you have the correct version and prescribe the correct number of cycles. Regimen Lymphoma – InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Indication • Non Hodgkin’s Lymphoma (Burkitts lymphoma or diffuse large B cell lymphoma) that is CD20 positive alternating with RCODOX-M in patient 66 years and above and / or with a poor performance status • Radical or curative intent Toxicity Drug Cytarabine Etoposide Ifosfamide Rituximab Adverse Effect CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Hypotension on rapid infusion, hyperbilirubinaemia Haemorrragic cystitis, encephalopathy, nephrotoxicity Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each cycle • Urine dip test for proteinuria and haematuria every four hours the day of and the day after ifosfamide administration. The patient should be instructed to report any signs Version 1 .1 (February 2018) Page 1 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab or symptoms of cystitis. • Fluid balance monitoring every four hours the day of and the day after ifosfamide administration. Urine output should be maintained above 100ml/hour • Hepatitis B screen prior to rituximab 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. 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 There are no dose modifications for haematological toxicity. Treatment should be delayed until the minimum criteria, described in the table below, are reached. Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 75x109/L Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Bilirubin µmol/L Cytarabine more than 34 AST/ALT units Dose (% of original dose) 50% Escalate doses on subsequent cycles in the absence of toxicity Etoposide 30-51 or 60-180 Consider dose reducing to 50% more than 51 or more than180 Clinical decision Ifosfamide more than 20 or more than 2.5xULN or ALP more than 2.5xULN Not recommended Rituximab N/A Version 1 .1 (February 2018) N/A No dose adjustments required Page 2 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Renal Impairment Drug Cytarabine Etoposide Ifosfamide Creatinine Clearance (ml/min) more than 60 46-60 31-45 less than 30 more than 50 15-50 less than15 more than 60 40-59 less than 40 Dose (% of original dose) 100% 60% 50% omit 100% 75% 50% 100% 70% Clinical decision Rituximab N/A N/A Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Cytarabine Cytarabine may cause conjunctivitis. The prophylactic use of corticosteroid eye drops may reduce the incidence of this ocular toxicity Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Ifosfamide In the case of a NCI-CTC grade 1 neurological toxicity, the dose of ifosfamide may be reduced for the next cycle. If a NCI-CTC grade 2 neurological toxicity appears or neurological toxicity worsens despite dose reduction, the ifosfamide should be stopped. Risk factors for CNS toxicity include a low albumin, renal impairment, prior administration of cisplatin, poor performance status, CNS tumour, bulky pelvic disease, concomitant psychotropic drugs and younger age. Methylene blue 50mg four times a day intravenous infusion in 100ml sodium chloride 0.9% can be used to prevent or treat ifosfamide induced encephalopathy. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Version 1 .1 (February 2018) Page 3 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu like symptoms prior to treatment. Regimen 2 cycles in high risk disease alternating with 2 cycles of R-CODOX-M. The order of administration is R-CODOX-M, R-IVAC, R-CODOX-M, R-IVAC. Two doses of rituximab should be given on days 21 and 42 after the end of the last R-IVAC to make 8 doses of rituximab in total. 1 cycle will be set in Aria The next cycle begins on the day that the unsupported neutrophil count is more than 1x109/L and the unsupported platelet count is more than 75x109/L. Version 1 .1 (February 2018) Page 4 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Drug Cytarabine Etoposide Dose 1000mg/m2 every 12 hours 60mg/m2 Mesna Ifosfamide Mesna Mesna 200mg/m2 1000mg/m2 1000mg/m2 600mg/m2 Rituximab 375mg/m2 Drug (intrathecal) Dose Methotrexate 12.5mg Days 1 and 2 (4 doses) 1,2,3,4,5 1,2,3,4,5 1,2,3,4,5 1,2,3,4,5 1 Days 5 Administration Intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes Intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes Intravenous infusion in sodium chloride 0.9% 100ml over 15 minutes Intravenous infusion in sodium chloride 0.9% 1000ml over 60 minutes (the ifosfamide and mesna are mixed in the same bag) Intravenous infusion in sodium chloride 0.9% 1000ml over 12 hours Intravenous infusion in 500ml sodium chloride 0.9% as per local guidelines Administration Intrathecal An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of R- CODOX-M and the first cycle of R-IVAC. For R-IVAC this is as follows: Drug Cytarabine Dose 70mg Days 7, 9 Administration Intrathecal Intrathecal doses that fall on a weekend should be deferred until the next working day Dose Information • Cytarabine will be dose banded according to the nationally agreed bands (100mg/ml) • Etoposide will be dose banded according to the nationally agreed bands (20mg/ml) • Ifosfamide will be dose banded according to the nationally agreed bands (80mg/ml) • Mesna will be dose banded according to the nationally agreed bands (100mg/ml) • Rituximab dose will be rounded to the nearest 100mg (up if halfway) Version 1 .1 (February 2018) Page 5 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Administration Information Extravasation • Cytarabine -neutral • Etoposide – irritant • Ifosfamide – neutral • Mesna - neutral • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines Additional Therapy This is an inpatient regimen please ensure all supportive and take home medication are prescribed on the inpatient chart or general electronic prescribing system. • Rituximab premedication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous bolus - hydrocortisone 100mg intravenous bolus (may be omitted if the patient is already taking corticosteroids) - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous bolus when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous bolus for rituximab related rigors that fail to respond to corticosteroids. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 7 days oral or intravenous bolus - metoclopramide 10mg three times a day for 7 days then when required oral or intravenous bolus - ondansetron 8mg twice a day for 7 days oral or intravenous bolus • Growth factors continued until the neutrophil count is above 1x109/L. For example: Version 1 .1 (February 2018) Page 6 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous • Folinic acid 15mg four times a day for one day starting 24 hours after the administration of the intrathecal methotrexate dose • Corticosteroid eye drops such as prednisolone 0.5% or dexamethasone 0.1% one drop into both eyes four times a day for 4 days • Mouthcare for the prophylaxis or treatment of mucositis in accordance with CSCCN guidelines • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - pentamidine 300mg nebule once a month - fluconazole 50mg once a day oral Additional Information • HSC 2008/001: Updated national guidance on the safe administration of intrathecal chemotherapy must be followed. Coding • Procurement – X71.5 • Delivery – Not Required References 1.NCRI Lymphoma Group. A Clinicopathological Study in Burkitt’s and Burkitt-Like Non-Hodgkin’s Lymphoma. LY10. Protocol Version 2.0. September 2002. 2.Mead GM, Sydes MY, Walewski J et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitts lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002; 13 (8): 1264-1274. Version 1 .1 (February 2018) Page 7 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab REGIMEN SUMMARY InP-RIVAC (65)-Cytarabine-Etoposide-Ifosfamide-Rituximab 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 1 1. Warning – Check supportive medication prescribed Administration instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10.Consider gastric protection 11.Consider mouthwashes 12.Consider norethisterone for menstruating women 13.Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 2. Chlorphenamine 10mg intravenous injection 3. Hydrocortisone 100mg intravenous injection Administration Instructions 1. Do not administer if corticosteroids have been given as part of the antiemetic or chemotherapy regimen 4. Paracetamol 1000mg oral 5. Rituximab 375mg/ m2 intravenous infusion in 500ml sodium chloride 0.9% (administer according to local guidelines) 6. Hydrocortisone 100mg intravenous bolus once only when required for the relief of rituximab infusion related reactions 7. Salbutamol 2.5mg nebule when required for rituximab related bronchospasm 8. Warning – Cytarabine is TWICE a day Administration Instructions The cytrarabine is to be given twice a day at twelve hourly intervals. 9. Cytarabine 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes twice a day Administration instructions Cytarabine doses are to be given at 12 hour intervals 10. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 11. Mesna 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Version 1 .1 (February 2018) Page 8 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab 12. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 13. Ifosfamide 1000mg/m2 and mesna 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9%. 14. Mesna 600mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions Starting immediately after the ifosfamide/mesna Day 2 15. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 16. Warning – Cytarabine is TWICE a day Administration Instructions The cytrarabine is to be given twice a day at twelve hourly intervals. 17. Cytarabine 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes twice a day Administration instructions Cytarabine doses are to be given at 12 hour intervals 18. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 19. Mesna 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 20. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 21. Ifosfamide 1000mg/m2 and mesna 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 22. Mesna 600mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions Starting immediately after the ifosfamide/mesna Version 1 .1 (February 2018) Page 9 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab Day 3, 4 23. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 24. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 25. Mesna 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 26. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 27. Ifosfamide 1000mg/m2 and mesna 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 28. Mesna 600mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions 1. Starting immediately after the ifosfamide/mesna Day 5 29. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 30. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 31. Mesna 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Version 1 .1 (February 2018) Page 10 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab 32. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 33. Ifosfamide 1000mg/m2 and mesna 1000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 34. Mesna 600mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instruction Starting immediately after the ifosfamide/mesna. This infusion may be replaced with oral mesna at a dose of 360mg/m2, rounded upwards to the nearest 400mg capsule, at 0, 2 and 6 hours post ifosfamide infusion. 35. Warning – Intrathecal Administration Instructions Methotrexate 12.5mg intrathecal is due on day 5 of the cycle. This must be prescribed on an intrathecal chart to comply with national guidance. Ensure Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate. This warning is a reminder, not a prescription. Day 7 and 9 36.Warning – CNS disease - Intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe cytarabine 70mg intrathecal at cycle 1 only . Intrathecal chemotherapy must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder, not a prescription. Version 1 .1 (February 2018) Page 11 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Warnings added to regimen summary in terms of cytarabine twice a day, cyclophosphamide and mesna combinations and intrathecal agents. Dose bands added Header changed Toxicities removed Hepatic impairment guidance updated Admin instructions for hydrocortisone pre med removed Metoclopramide dose and 1.1 February 2018 duration updated “Bolus” removed from “intravenous bolus” for Dr Deborah Wright Pharmacist supportive medication throughout text Growth factor units updated Mucositis recommendation changed “according to local practice” and “oral” added to folinic acid instructions following intrathecal methotrexate CSCCN agreed bands removed Cytarabine infusion changed to 1000ml Etoposide changed to 500ml Disclaimer added 1 August 2012 None Rebecca Wills Pharmacist Dr Deborah Wright Pharmacist Approved By Harriet Launders Pharmacist Dr Alison Milne Consultant Haematologist Dr Andrew Davies Consultant Medical Oncologist Version 1 .1 (February 2018) Page 12 of 12 Lymphoma-InP-RIVAC(66)-Cytarabine-Etoposide-Ifosfamide-Rituximab
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InP RIVAC (65) cytarabine etoposide ifosfamide rituximab
Description
Chemotherapy Protocol LYMPHOMA CYTARABINE-ETOPOSIDE-IFOSFAMIDE-RITUXIMAB (RIVAC) 65 years and below Inpatient Regimen There are multiple versions of this protocol in use. The choice of protocol depends on the age of the patient and whether there is CNS disease present at diagnosis. Please ensure you have the correct version and prescribe the correct number of cycles. Regimen Lymphoma – InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Indication • Non Hodgkin’s Lymphoma (Burkitts lymphoma or diffuse large B cell lymphoma) that is CD20 positive alternating with RCODOX-M • Radical or curative intent Toxicity Drug Cytarabine Etoposide Ifosfamide Rituximab Adverse Effect CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Hypotension on rapid infusion, hyperbilirubinaemia Haemorrragic cystitis, encephalopathy, nephrotoxicity Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each cycle • Urine dip test for proteinuria and haematuria every four hours the day of and the day after ifosfamide administration. The patient should be instructed to report any signs Version 1 .1 (February 2018) Page 1 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab or symptoms of cystitis. • Fluid balance monitoring every four hours the day of and the day after ifosfamide administration. Urine output should be maintained above 100ml/hour • Hepatitis B screen prior to rituximab 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. 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 There are no dose modifications for haematological toxicity. Treatment should be delayed until the minimum criteria, described in the table below, are reached. Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 75x109/L Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Cytarabine Bilirubin µmol/L more than 34 AST/ALT units Dose (% of original dose) 50% Escalate doses on subsequent cycles in the absence of toxicity Etoposide Ifosfamide 30-51 or more than 51 or 60-180 more than180 more than 20 or more than 2.5xULN or ALP more than 2.5xULN Consider dose reducing to 50% Clinical decision Not recommended Rituximab N/A Version 1 .1 (February 2018) N/A No dose adjustments required Page 2 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Renal Impairment Drug Cytarabine Etoposide Ifosfamide Creatinine Clearance (ml/min) more than 60 46-60 31-45 less than 30 more than 50 15-50 less than15 more than 60 40-59 less than 40 Dose (% of original dose) 100% 60% 50% omit 100% 75% 50% 100% 70% Clinical decision Rituximab N/A N/A Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Cytarabine Cytarabine may cause conjunctivitis. The prophylactic use of corticosteroid eye drops may reduce the incidence of this ocular toxicity Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Ifosfamide In the case of a NCI-CTC grade 1 neurological toxicity, the dose of ifosfamide may be reduced for the next cycle. If a NCI-CTC grade 2 neurological toxicity appears or neurological toxicity worsens despite dose reduction, the ifosfamide should be stopped. Risk factors for CNS toxicity include a low albumin, renal impairment, prior administration of cisplatin, poor performance status, CNS tumour, bulky pelvic disease, concomitant psychotropic drugs and younger age. Methylene blue 50mg four times a day intravenous infusion in 100ml sodium chloride 0.9% can be used to prevent or treat ifosfamide induced encephalopathy. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Version 1 .1 (February 2018) Page 3 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu like symptoms prior to treatment. Regimen 2 cycles in high risk disease alternating with 2 cycles of R-CODOX-M. The order of administration is R-CODOX-M, R-IVAC, R-CODOX-M, R-IVAC. Two doses of rituximab should be given on days 21 and 42 after the end of the last R-IVAC to make 8 doses of rituximab in total. 1 cycle will be set in Aria The next cycle begins on the day that the unsupported neutrophil count is more than 1x109/L and the unsupported platelet count is more than 75x109/L. Version 1 .1 (February 2018) Page 4 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Drug Cytarabine Etoposide Dose 2000mg/m2 every 12 hours 60mg/m2 Mesna Ifosfamide Mesna Mesna 300mg/m2 1500mg/m2 1500mg/m2 900mg/m2 Rituximab 375mg/m2 Drug (intrathecal) Dose Methotrexate 12.5mg Days 1 and 2 (4 doses) 1,2,3,4,5 1,2,3,4,5 1,2,3,4,5 1,2,3,4,5 1 Days 5 Administration Intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes Intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes Intravenous infusion in sodium chloride 0.9% 100ml over 15 minutes Intravenous infusion in sodium chloride 0.9% 1000ml over 60 minutes (the ifosfamide and mesna are mixed in the same bag) Intravenous infusion in sodium chloride 0.9% 1000ml over 12 hours Intravenous infusion in 500ml sodium chloride 0.9% as per local guidelines Administration Intrathecal An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of R- CODOX-M and the first cycle of R-IVAC. For R-IVAC this is as follows: Drug Cytarabine Dose 70mg Days 7, 9 Administration Intrathecal Intrathecal doses that fall on a weekend should be deferred until the next working day Dose Information • Cytarabine will be dose banded according to the nationally agreed bands (100mg/ml) • Etoposide will be dose banded according to the nationally agreed bands (20mg/ml) • Ifosfamide will be dose banded according to the nationally agreed bands (80mg/ml) • Mesna will be dose banded according to the nationally agreed bands (100mg/ml) • Rituximab dose will be rounded to the nearest 100mg (up if halfway) Version 1 .1 (February 2018) Page 5 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Administration Information Extravasation • Cytarabine -neutral • Etoposide – irritant • Ifosfamide – neutral • Mesna - neutral • Rituximab - neutral Other • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines Additional Therapy This is an inpatient regimen please ensure all supportive and take home medication are prescribed on the inpatient chart or general electronic prescribing system. • Rituximab premedication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous bolus - hydrocortisone 100mg intravenous bolus (may be omitted if the patient is already taking corticosteroids) - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous bolus when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous bolus for rituximab related rigors that fail to respond to corticosteroids. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 7 days oral or intravenous bolus - metoclopramide 10mg three times a day for 7 days then when required oral or intravenous bolus - ondansetron 8mg twice a day for 7 days oral or intravenous bolus • Growth factors continued until the neutrophil count is above 1x109/L. For example: Version 1 .1 (February 2018) Page 6 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab - filgrastim or bioequivalent 30 million unit once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million unit once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous • Folinic acid 15mg four times a day for one day starting 24 hours after the administration of the intrathecal methotrexate dose • Corticosteroid eye drops such as prednisolone 0.5% or dexamethasone 0.1% one drop into both eyes four times a day for 4 days • Mouthcare for the prophylaxis or treatment of mucositis in accordance with CSCCN guidelines • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - pentamidine 300mg nebule once a month - fluconazole 50mg once a day oral Additional Information • HSC 2008/001: Updated national guidance on the safe administration of intrathecal chemotherapy must be followed. Coding • Procurement – X71.5 • Delivery – Not Required References 1.NCRI Lymphoma Group. A Clinicopathological Study in Burkitt’s and Burkitt-Like Non-Hodgkin’s Lymphoma. LY10. Protocol Version 2.0. September 2002. 2.Mead GM, Sydes MY, Walewski J et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitts lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002; 13 (8): 1264-1274. Version 1 .1 (February 2018) Page 7 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab REGIMEN SUMMARY InP-RIVAC (65)-Cytarabine-Etoposide-Ifosfamide-Rituximab 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 1 1. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 2. Chlorphenamine 10mg intravenous injection 3. Hydrocortisone 100mg intravenous injection Administration Instructions 1. Do not administer if corticosteroids have been given as part of the antiemetic or chemotherapy regimen 4. Paracetamol 1000mg oral 5. Rituximab 375mg/ m2 intravenous infusion in 500ml sodium chloride 0.9% (administer according to local guidelines) 6. Hydrocortisone 100mg intravenous bolus once only when required for the relief of rituximab infusion related reactions 7. Salbutamol 2.5mg nebule when required for rituximab related bronchospasm 8. Warning – Cytarabine is TWICE a day Administration Instructions The cytrarabine is to be given twice a day at twelve hourly intervals. 9. Cytarabine 2000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes twice a day Administration instructions Cytarabine doses are to be given at 12 hour intervals 10. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 11. Mesna 300mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Version 1 .1 (February 2018) Page 8 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab 12. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 13. Ifosfamide 1500mg/m2 and mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9%. 14. Mesna 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions Starting immediately after the ifosfamide/mesna Day 2 15. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 16. Warning – Cytarabine is TWICE a day Administration Instructions The cytrarabine is to be given twice a day at twelve hourly intervals. 17. Cytarabine 2000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes twice a day Administration instructions Cytarabine doses are to be given at 12 hour intervals 18. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 19. Mesna 300mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 20. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 21. Ifosfamide 1500mg/m2 and mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 22. Mesna 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions Starting immediately after the ifosfamide/mesna Version 1 .1 (February 2018) Page 9 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab Day 3, 4 23. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 24. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 25. Mesna 300mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 26. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 27. Ifosfamide 1500mg/m2 and mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 28. Mesna 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions 1. Starting immediately after the ifosfamide/mesna Day 5 29. Warning – Check supportive medication prescribed Administration instructions 1.Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2.Metoclopramide 10mg three times a day, days 1 to 7 days then as required oral or intravenous 3.Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4.Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 1 to 4 5. Growth factor continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 7 subcutaneous 6. Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate (normally day 6) 7. Aciclovir 400mg oral twice a day 8. Pentamidine 300mg nebule once a month 9. Fluconazole 50mg once a day 10. Consider gastric protection 11. Consider mouthwashes 12. Consider norethisterone for menstruating women 13. Consider pethidine 25-50mg intravenous bolus for rituximab related rigors unresponsive to corticosteroids 30. Etoposide 60mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes 31. Mesna 300mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Version 1 .1 (February 2018) Page 10 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab 32. Warning – Ifosfamide and Mesna Combination Bag Administration Instructions The ifosfamide is mixed in the same infusion bag as the mesna. 33. Ifosfamide 1500mg/m2 and mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Administration Instructions The ifosfamide and mesna are mixed in the same infusion bag of 1000ml sodium chloride 0.9% 34. Mesna 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instruction Starting immediately after the ifosfamide/mesna. This infusion may be replaced with oral mesna at a dose of 360mg/m2, rounded upwards to the nearest 400mg capsule, at 0, 2 and 6 hours post ifosfamide infusion. 35. Warning – Intrathecal Administration Instructions Methotrexate 12.5mg intrathecal is due on day 5 of the cycle. This must be prescribed on an intrathecal chart to comply with national guidance. Ensure Folinic acid 15mg four times a day for one day starting 24 hours after the administration of intrathecal methotrexate. This warning is a reminder, not a prescription. Day 7 and 9 36.Warning – CNS disease - Intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe cytarabine 70mg intrathecal at cycle 1 only . Intrathecal chemotherapy must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder, not a prescription. Version 1 .1 (February 2018) Page 11 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab DOCUMENT CONTROL Version Date Amendment Written By Warnings added to regimen summary in terms of cytarabine twice a day, cyclophosphamide and mesna combinations and intrathecal agents. National dose bands added Growth factor units changed Header changed Toxicities removed Hepatic impairment guidance updated Admin instructions for hydrocortisone pre med removed 1.1 February 2018 Metoclopramide dose and duration updated “Bolus” removed from Dr Deborah Wright Pharmacist “intravenous bolus” for supportive medication throughout text Mucositis recommendation changed “according to local practice” and “oral” added to folinic acid instructions following intrathecal methotrexate CSCCN agreed bands removed Cytarabine infusion changed to 1000ml Etoposide changed to 500ml Disclaimer added 1 August 2012 None Rebecca Wills Pharmacist Dr Deborah Wright Pharmacist Approved By Harriet Launders Pharmacist Dr Alison Milne Consultant Haematologist Dr Andrew Davies Consultant Medical Oncologist Version 1 .1 (February 2018) Page 12 of 12 Lymphoma-InP-RIVAC(65)-Cytarabine-Etoposide-Ifosfamide-Rituximab
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InP RCODOX M(66) cyclophosphamide doxorubicin methotrexate rituximab vincristine
Description
Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE-DOXORUBICIN-METHOTREXATE-RITUXIMAB-VINCRISTINE (RCODOX-M) 66 years and above Inpatient Regimen There are multiple versions of this protocol in use. The choice of protocol depends on the age of the patient and whether there is CNS disease present at diagnosis. Please ensure you have the correct version and prescribe the correct number of cycles. Regimen • Lymphoma – InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-MethotrexateRituximab-Vincristine Indication • Non Hodgkin’s Lymphoma including Burkitt’s lymphoma either as a single regimen or alternating with R-IVAC Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrragic cystitis (rare), taste disturbances Doxorubicin Cardiomyopathy, alopecia, urinary discolouration (red) Methotrexate Rituximab Vincristine Stomatitis, conjunctivitis, renal toxicity Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Peripheral neuropathy, constipation, jaw pain The presence of a third fluid compartment e.g. ascites, pleural effusion or other oedema may delay the clearance of methotrexate and increase toxicity and should be resolved before methotrexate administration. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1.2 (Sept 2018) Page 1 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Monitoring Drugs R-CODOX-Cyclophosphamide-Doxorubicin-Rituximab-Vincristine • FBC, LFTs and U&Es (including uric acid and phosphate) prior to day one of treatment • Ensure adequate cardiac function before starting therapy. Baseline LVEF should be measured in patients with a history of cardiac problems, cardiac risk factors or in the elderly. Discontinue doxorubicin if cardiac failure develops • Intensive post chemotherapy biochemical monitoring is mandatory in patients with bulky disease and should be strongly considered in all patients during days 1 to 5 of treatment. This includes daily serum electrolytes, urea, creatinine, calcium and phosphorus • Check hepatitis B status before starting treatment with rituximab Methotrexate • FBC, LFTs and U&Es prior to day one of treatment • GFR measurement either by EDTA or 24 hour urine collection prior to methotrexate infusion. The creatinine clearance must be 50ml/min or more for the methotrexate in this regimen to be administered • Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L • Urinary pH every two hours as a minimum until the methotrexate level is below 0.1micromol/L • Strict fluid balance chart to be maintained throughout methotrexate administration with appropriate action taken if positive by more than 2kg/L. • Ensure the patient has no ascites, pleural effusion or oedema prior to administration of high dose methotrexate. 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. 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. Version 1.2 (Sept 2018) Page 2 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Haematological There are no dose modifications for haematological toxicity. New treatment cycles should be delayed until minimum criteria detailed below are reached (day 10 methotrexate will be given irrespective of the neutrophil or platelet count). Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 75x109/L Consider blood transfusion if the patient is symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Hepatic Impairment Please note that the approach may be different if the abnormal liver function tests are due to disease involvement. There is a higher risk of toxicity in patients with concomitantly impaired renal function, consider dose reduction. Drug Cyclophosphamide Bilirubin µmol/L N/A AST/ALT units/L N/A Dose (% of original dose) Evidence suggests no dose reduction is necessary Doxorubicin less than 30* *30-51 and/or 51-85 2-3xULN more than 3xULN N/A more than 85 N/A 75% 50% 25% omit Methotrexate less than 50 and 51-85 or more than 85 less than 180 more than 180 N/A 100% 75% omit Rituximab N/A N/A No dose adjustments required *30-51 or 60-180 50% Vincristine more than 51 and normal more than 51 and more than 180 * Limits reflect local practice and may vary from published sources 50% omit Version 1.2 (Sept 2018) Page 3 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Transient increases in bilirubin and transaminases, lasting up to two weeks, are likely following methotrexate infusion and should not be considered an indication to stop treatment. Persistent hyperbilirubinaemia and/or grade 3/4 hypertransaminasemia for longer than three weeks should result in discontinuation of the drug. Renal Impairment Drug Cyclophosphamide Creatinine Clearance (ml/min) more than 20 10-20 less than 10 Dose (% of original dose) 100% 75% 50% Doxorubicin N/A Consider dose reduction in severe renal failure Methotrexate *50 or greater 100% Rituximab N/A No dose adjustment needed Vincristine N/A No dose adjustment needed * Limits reflect local practice and may vary from published sources A creatinine clearance of 50ml/min or more is required to proceed with the methotrexate element of this regimen. Consider the appropriateness of regimen if dose reductions due to impaired renal function are required for other agents. Consider mesna in patients with pre-existing bladder disorders. Give an oral dose of 40% of the cyclophosphamide dose (rounded upwards to the nearest 400mg for oral mesna) at 0, 2 and 6 hours after the administration of cyclophosphamide. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Where appropriate, if dose reductions made at cycle one are well tolerated, dose increases can be considered on subsequent cycles according to tolerability. Cyclophosphamide Consider mesna in patients with pre-existing bladder disorders. Doxorubicin Discontinue doxorubicin if cardiac failure develops Version 1.2 (Sept 2018) Page 4 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Methotrexate Methotrexate can cause severe renal impairment that can then lead to raised levels and further toxicity. Renal function must be monitored daily until levels are below 0.1micromol/L. It is imperative that urinary pH is maintained above pH 7, through the administration of sodium bicarbonate, before starting and during the administration of methotrexate, and continued until methotrexate levels are less than 0.1micromol/L. Monitor fluid balance carefully and give intravenous furosemide if fluid overload occurs or urine output falls to less than 400ml/m2 in any 4-hour period. Folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards if the patient is able to tolerate oral therapy. If levels of methotrexate are above 2micromol/L at 72 hours additional folinic acid may be necessary. Always seek advice from a senior member of staff (consultant should always be informed of raised methotrexate levels or if a rapid deterioration in renal function occurs). Glucarpidase can be considered for methotrexate toxicity. The decision to prescribe glucarpidase must only be made by a consultant and in accordance with the NHSE commissioning policy on glucarpidase. The presence of a third fluid compartment e.g. ascites, pleural effusion or other oedema may delay the clearance of methotrexate and hence increase toxicity and should be resolved before methotrexate administration. In addition to the renal and hepatic dysfunction described above methotrexate can also cause significant mucositis. Ensure the patient has adequate mouthwashes and good oral hygiene practices. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or Version 1.2 (Sept 2018) Page 5 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu like symptoms prior to treatment. Vincristine Reduce the vincristine dose from 2mg to 1mg if a NCI-CTC grade 2 motor or grade 3 sensory neurological toxicity occurs. For higher toxicity grades or if toxicity increases despite dose reduction stop the vincristine. Regimen 3 cycles in low risk disease 2 cycles in high risk disease alternating with 2 cycles of R- IVAC 1 cycle will be set in Aria The next cycle begins on the day that the unsupported neutrophil count is more than 1x109/L and the unsupported platelet count is more than 75x109/L. Drug Dose Days Cyclophosphamide 800mg/m2 1 Administration Intravenous bolus over 10 minutes Cyclophosphamide 200mg/m2 2,3,4,5 Intravenous bolus over 10 minutes Doxorubicin 40mg/m2 1 Rituximab Vincristine Methotrexate 375mg/m2 1 1.5mg/m2 (max 2mg) 1, 8 100mg/m2 10 Methotrexate 900mg/m2 Drug (intrathecal) Dose Cytarabine 70mg 10 Days 1, 3 Intravenous bolus over 10 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per local guidelines Intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 23 hours Administration Intrathecal Methotrexate 12.5mg 15 Intrathecal An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of R- CODOX-M and the first cycle of R-IVAC. Version 1.2 (Sept 2018) Page 6 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine For R-CODOX-M this is as follows: Drug (intrathecal) Dose Cytarabine 70mg Days 5 Methotrexate 12.5mg 17 Administration Intrathecal Intrathecal Intrathecal doses that fall on a weekend should be deferred until the next working day Dose Information • Cyclophosphamide will be dose banded in accordance with the national bands (20PM) • Doxorubicin will be dose banded in accordance with the national bands (2PM) • The maximum lifetime cumulative dose of doxorubicin is 450mg/m². However prior radiotherapy to the mediastinal / pericardial area should receive a lifetime cumulative doxorubicin dose of no more than 400mg/m². • Methotrexate (intravenous) will be dose banded in accordance with the national bands (methotrexate HD) • Rituximab dose will be rounded to the nearest 100mg (up if halfway) • Vincristine will be dose banded in accordance with the national bands (1mg/ml) • The maximum dose of vincristine is 2mg Administration Information Extravasation • Cyclophosphamide – neutral • Doxorubicin – vesicant • Methotrexate – inflammitant • Rituximab - neutral • Vincristine - vesicant Other • The methotrexate infusion must not be started until the urinary pH is above 7. This urinary pH must be maintained throughout the methotrexate infusion and until the methotrexate level is 0.1micromol/L or below • The methotrexate infusion must be stopped 24 hours after the start of the first infusion regardless of the dose given Version 1.2 (Sept 2018) Page 7 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines Additional Therapy This is an inpatient regimen please ensure all supportive and take home medicines are prescribed on the inpatient chart or general electronic prescribing system. Day 1 - R-CODOX – Cyclophosphamide-Doxorubicin-Rituximab-Vincristine • Premedication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 7 days oral or intravenous - metoclopramide 10mg three times then when required oral or intravenous - ondansetron 8mg twice a day for 7 days oral or intravenous Day 10 - Methotrexate (Intravenous) • Hydration The following fluid regimen is recommended as hydration. Fluid hydration should start at least six hours prior to methotrexate. This schedule should be repeated every 12 hours until the methotrexate level is below 0.1 micromol/L - Furosemide 40mg once only dose oral or intravenous when required for the treatment of fluid overload or to maintain urine output - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 Version 1.2 (Sept 2018) Page 8 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - Glucose 5% (with or without potassium chloride 20 or 27mmol) 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 • Antiemetics Starting 15-30 minutes prior to intravenous methotrexate - dexamethasone 4mg twice a day for 3 days oral or intravenous - metoclopramide 10mg oral three times a day when required oral or intravenous - ondansetron 8mg twice a day for 3 days oral or intravenous • Post-treatment with intravenous methotrexate - folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards if the patient is able to tolerate oral therapy. If levels of methotrexate are above 2micromol/L at 72 hours additional folinic acid may be necessary. Seek advice from a senior member of staff. • Growth factor to be continued until the neutrophil count is above 1x109/L. For example: - filgrastim or bioequivalent 30 million units once a day from day 13 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 13 subcutaneous - pegfilgrastim or bioequivalent 6mg once only day 13 subcutaneous • Folinic acid 15mg four times a day oral for one day starting 24 hours after the administration of the intrathecal methotrexate dose, according to local practice • Mouthwashes according to local or national policy on the treatment of mucositis • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Tumour lysis prophylaxis with cycle one only including: - appropriate hydration - rasburicase for high risk patients - allopurinol 300mg once a day for the first cycle only Version 1.2 (Sept 2018) Page 9 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - pentamidine 300mg nebule once a month - fluconazole 50mg once a day oral Some centres avoid the use of azole antifungal agents due to the risk of peripheral neuropathy when combined with vinca alkaloids. Additional Information • A significant number of drugs interact with intravenous methotrexate. At the doses used in this protocol this can lead to significant toxicity or reduction in efficacy. Always check for drug interactions before prescribing any additional medication. • HSC 2008/001: Updated national guidance on the safe administration of intrathecal chemotherapy must be followed. • The National Patient Safety Agency report NPSA/2008/RRR04 must be followed in relation to intravenous administration of vinca alkaloids. Coding (OPCS) • Procurement – X71.5 • Delivery – not required References 1. NCRI Lymphoma Group. A Clinicopathological Study in Burkitt’s and Burkitt-Like Non-Hodgkin’s Lymphoma. LY10. Protocol Version 2.0. September 2002. 2.Mead GM, Sydes MY, Walewski J et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitts lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002; 13 (8): 1264-1274. - Version 1.2 (Sept 2018) Page 10 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine REGIMEN SUMMARY InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 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 1 1. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses 5. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% (administer according to local guidelines) 6. Doxorubicin 40mg/m2 intravenous bolus over 10 minutes 7. Vincristine 1.5mg/m2 (max dose 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 8. Cyclophosphamide 800mg/m2 intravenous bolus over 10 minutes 9. Warning – Prescribe intrathecal on intrathecal chart Administration Instructions Prescribe cytarabine 70mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times. 10. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 11. Salbutamol 2.5mg nebule when required for rituximab related bronchospasm Version 1.2 (Sept 2018) Page 11 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Day 2 12. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 13. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes Day 3 14. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 15. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes 16. Warning – Prescribe intrathecal on an intrathecal chart Administration Instructions Prescribe cytarabine 70mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times Day 4 17. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 18. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes Version 1.2 (Sept 2018) Page 12 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Day 5 19. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – may interact with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 20. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes 21. Warning – CNS disease extra intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe an additional cytarabine 70mg intrathecal on day 5 cycle one only Intrathecal chemotherapy must be prescribed on an intrathecal chart. This is a warning, not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times. Day 8 22. Warning – Check supportive medication prescribed Administration Instructions 1. Aciclovir 400mg twice a day oral 2. Pentamidine nebule 300mg once a month 3. Fluconazole 50mg once a day oral (consider – may interact with vincristine) 4. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 5. Consider gastric protection 6. Consider mouthwashes 7. Consider norethisterone 5mg three times a day in menstruating women 23. Vincristine 1.5mg/m2 (max dose 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes Day 10 24. Warning – Check supportive medication prescribed Administration Instructions 1. Furosemide 40mg when required oral or intravenous 2. Fluids repeated on a 12 hourly cycle to maintain fluid balance, urine output and pH above 7 until methotrexate level is below 0.1micromol/L - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - glucose 5% 1000ml (with or without potassium chloride 20 or 27mmol) intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary ph above 7 3. Dexamethasone 4mg twice a day for 3 days oral or intravenous 4. Metoclopramide 10mg three times a day when required oral or intravenous 5. Ondansetron 8mg twice a day for 3 days oral or intravenous 6. Folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. 7. Growth factors started and continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 13 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 13 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 13 subcutaneous 8. Aciclovir 400mg twice a day oral 9. Pentamidine 300mg nebule once a month 10.Fluconazole 50mg once a day oral 11.Tumour lysis prophylaxis including appropriate hydration (cycle one only) 12.Consider gastric protection 13.Consider mouthwashes 14.Consider norethisterone 5mg three times a day in menstruating women Version 1.2 (Sept 2018) Page 13 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 25. Methotrexate 100mg/m2 intravenous infusion in 250ml sodium chloride 0.9% over 1 hour Administration Instructions Monitor fluid balance, urine output, weight and urinary pH. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. 26. Methotrexate 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 23 hours Administration Instructions Monitor fluid balance, urine output, weight and urinary pH. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. Day 15 27. Warning – Prescribe intrathecal on intrathecal chart Administration Instructions Prescribe methotrexate 12.5mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times Day 17 28. Warning – CNS disease extra intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe an additional methotrexate 12.5mg intrathecal at cycle 1 only. Intrathecal chemotherapy must be prescribed on an intrathecal chart. This is a warning, not a prescription. National intrathecal guidance and local policies must be followed at all times. Folinic acid 15mg four times a day oral for one day starting 24 hours after the administration of intrathecal methotrexate, according to local practice Version 1.2 (Sept 2018) Page 14 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine DOCUMENT CONTROL Version Date Amendment Written By Approved By Check for additional fluid compartment added Renal toxicity added Dose bands changed to national bands 1.1 Aug 2018 Potassium changed to being optional in the glucose 5% methotrexate hydration Fluconazole interaction added Dr Deborah Wright Pharmacist Donna Kimber Pharmacy Technician Paracetamol administration instructions Methotrexate levels added to administration instructions Intrathecal changed to a warning Disclaimer updated Header changed Toxicities removed Hepatic and renal impairment guidance updated Antiemetics clarified Administration information for hydrocortisone pre med removed Metoclopramide dose and duration updated “Bolus” removed from “intravenous bolus” for supportive medication Donna Kimber throughout text 1.1 Sept 2016 Start of methotrexate levels changed from 24 hours after the end of the infusion 48 hours after the start of the Pharmacy Technician Rebecca Wills Dr Deborah Wright Pharmacist infusion Pharmacist Growth factor units updated Mucositis recommendation changed OPCS code updated 27mmol potassium chloride added to glucose hydration fluid “according to local practice” and “oral” added to folinic acid instructions following intrathecal methotrexate CSSCN agreed bands removed Regimen summary numbering updated. Disclaimer added Dr Andrew Davies Rebecca Wills Consultant Medical 1 August 2012 None Pharmacist Dr Deborah Wright Oncologist Dr Alison Milne Pharmacist Consultant Haematologist Version 1.2 (Sept 2018) Page 15 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 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 Hospital 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 1.2 (Sept 2018) Page 16 of 16 Lymphoma- InP-RCODOX-M(66)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine
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InP RCODOX M(65) cyclophosphamide doxorubicin methotrexate rituximab vincristine
Description
Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE-DOXORUBICIN-METHOTREXATE-RITUXIMAB-VINCRISTINE (RCODOX-M) 65 years and below Inpatient Regimen There are multiple versions of this protocol in use. The choice of protocol depends on the age of the patient and whether there is CNS disease present at diagnosis. Please ensure you have the correct version and prescribe the correct number of cycles. Regimen • Lymphoma – InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-MethotrexateRituximab-Vincristine Indication • Non Hodgkin’s Lymphoma including Burkitt’s lymphoma either as a single regimen or alternating with R-IVAC Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrragic cystitis (rare), taste disturbances Doxorubicin Cardiomyopathy, alopecia, urinary discolouration (red) Methotrexate Rituximab Vincristine Stomatitis, conjunctivitis, renal toxicity Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Peripheral neuropathy, constipation, jaw pain The presence of a third fluid compartment e.g. ascites, pleural effusion or other oedema may delay the clearance of methotrexate and increase toxicity and should be resolved before methotrexate administration. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Version 1.2 (Sept 2018) Page 1 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Monitoring Drugs R-CODOX-Cyclophosphamide-Doxorubicin-Rituximab-Vincristine • FBC, LFTs and U&Es (including uric acid and phosphate) prior to day one of treatment • Ensure adequate cardiac function before starting therapy. Baseline LVEF should be measured in patients with a history of cardiac problems, cardiac risk factors or in the elderly. Discontinue doxorubicin if cardiac failure develops • Intensive post chemotherapy biochemical monitoring is mandatory in patients with bulky disease and should be strongly considered in all patients during days 1 to 5 of treatment. This includes daily serum electrolytes, urea, creatinine, calcium and phosphorus • Check hepatitis B status before starting treatment with rituximab Methotrexate • FBC, LFTs and U&Es prior to day one of treatment • GFR measurement either by EDTA or 24 hour urine collection prior to methotrexate infusion. The creatinine clearance must be 50ml/min or more for the methotrexate in this regimen to be administered • Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L • Urinary pH every two hours as a minimum until the methotrexate level is below 0.1micromol/L • Strict fluid balance chart to be maintained throughout methotrexate administration with appropriate action taken if positive by more than 2kg/L. • Ensure the patient has no ascites, pleural effusion or oedema prior to administration of high dose methotrexate. 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. 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. Version 1.2 (Sept 2018) Page 2 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Haematological There are no dose modifications for haematological toxicity. New treatment cycles should be delayed until minimum criteria detailed below are reached (day 10 methotrexate will be given irrespective of the neutrophil or platelet count). Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 75x109/L Consider blood transfusion if the patient is symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Hepatic Impairment Please note that the approach may be different if the abnormal liver function tests are due to disease involvement. There is a higher risk of toxicity in patients with concomitantly impaired renal function, consider dose reduction. Drug Cyclophosphamide Bilirubin µmol/L N/A AST/ALT units/L N/A Dose (% of original dose) Evidence suggests no dose reduction is necessary Doxorubicin less than 30* *30-51 and/or 51-85 2-3xULN more than 3xULN N/A more than 85 N/A 75% 50% 25% omit Methotrexate less than 50 and 51-85 or more than 85 less than 180 more than 180 N/A 100% 75% omit Rituximab N/A N/A No dose adjustments required *30-51 or 60-180 50% Vincristine more than 51 and normal more than 51 and more than 180 * Limits reflect local practice and may vary from published sources 50% omit Version 1.2 (Sept 2018) Page 3 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Transient increases in bilirubin and transaminases, lasting up to two weeks, are likely following methotrexate infusion and should not be considered an indication to stop treatment. Persistent hyperbilirubinaemia and/or grade 3/4 hypertransaminasemia for longer than three weeks should result in discontinuation of the drug. Renal Impairment Drug Cyclophosphamide Creatinine Clearance (ml/min) more than 20 10-20 less than 10 Dose (% of original dose) 100% 75% 50% Doxorubicin N/A Consider dose reduction in severe renal failure Methotrexate *50 or greater 100% Rituximab N/A No dose adjustment needed Vincristine N/A No dose adjustment needed * Limits reflect local practice and may vary from published sources A creatinine clearance of 50ml/min or more is required to proceed with the methotrexate element of this regimen. Consider the appropriateness of regimen if dose reductions due to impaired renal function are required for other agents. Consider mesna in patients with pre-existing bladder disorders. Give an oral dose of 40% of the cyclophosphamide dose (rounded upwards to the nearest 400mg for oral mesna) at 0, 2 and 6 hours after the administration of cyclophosphamide. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Where appropriate, if dose reductions made at cycle one are well tolerated, dose increases can be considered on subsequent cycles according to tolerability. Cyclophosphamide Consider mesna in patients with pre-existing bladder disorders. Doxorubicin Discontinue doxorubicin if cardiac failure develops Version 1.2 (Sept 2018) Page 4 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Methotrexate Methotrexate can cause severe renal impairment that can then lead to raised levels and further toxicity. Renal function must be monitored daily until levels are below 0.1micromol/L. It is imperative that urinary pH is maintained above pH 7, through the administration of sodium bicarbonate, before starting and during the administration of methotrexate, and continued until methotrexate levels are less than 0.1micromol/L. Monitor fluid balance carefully and give intravenous furosemide if fluid overload occurs or urine output falls to less than 400ml/m2 in any 4-hour period. Folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards if the patient is able to tolerate oral therapy. If levels of methotrexate are above 2micromol/L at 72 hours additional folinic acid may be necessary. Always seek advice from a senior member of staff (consultant should always be informed of raised methotrexate levels or if a rapid deterioration in renal function occurs). Glucarpidase can be considered for methotrexate toxicity. The decision to prescribe glucarpidase must only be made by a consultant and in accordance with the NHSE commissioning policy on glucarpidase. The presence of a third fluid compartment e.g. ascites, pleural effusion or other oedema may delay the clearance of methotrexate and hence increase toxicity and should be resolved before methotrexate administration. In addition to the renal and hepatic dysfunction described above methotrexate can also cause significant mucositis. Ensure the patient has adequate mouthwashes and good oral hygiene practices. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or Version 1.2 (Sept 2018) Page 5 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection prior to treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu like symptoms prior to treatment. Vincristine Reduce the vincristine dose from 2mg to 1mg if a NCI-CTC grade 2 motor or grade 3 sensory neurological toxicity occurs. For higher toxicity grades or if toxicity increases despite dose reduction stop the vincristine. Regimen 3 cycles in low risk disease 2 cycles in high risk disease alternating with 2 cycles of R- IVAC 1 cycle will be set in Aria The next cycle begins on the day that the unsupported neutrophil count is more than 1x109/L and the unsupported platelet count is more than 75x109/L. Drug Dose Days Cyclophosphamide 800mg/m2 1 Administration Intravenous bolus over 10 minutes Cyclophosphamide 200mg/m2 2,3,4,5 Intravenous bolus over 10 minutes Doxorubicin 40mg/m2 1 Rituximab Vincristine Methotrexate 375mg/m2 1 1.5mg/m2 (max 2mg) 1, 8 300mg/m2 10 Methotrexate Drug (intrathecal) Cytarabine 2700mg/m2 Dose 70mg 10 Days 1, 3 Intravenous bolus over 10 minutes Intravenous infusion in 500ml sodium chloride 0.9% as per local guidelines Intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 23 hours Administration Intrathecal Methotrexate 12.5mg 15 Intrathecal An intensified intrathecal treatment is required for patients with CNS disease at diagnosis. This is given for the first cycle of R- CODOX-M and the first cycle of R-IVAC. Version 1.2 (Sept 2018) Page 6 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine For R-CODOX-M this is as follows: Drug (intrathecal) Dose Cytarabine 70mg Days 5 Methotrexate 12.5mg 17 Administration Intrathecal Intrathecal Intrathecal doses that fall on a weekend should be deferred until the next working day Dose Information • Cyclophosphamide will be dose banded in accordance with the national bands (20PM) • Doxorubicin will be dose banded in accordance with the national bands (2PM) • The maximum lifetime cumulative dose of doxorubicin is 450mg/m². However prior radiotherapy to the mediastinal / pericardial area should receive a lifetime cumulative doxorubicin dose of no more than 400mg/m². • Methotrexate (intravenous) will be dose banded in accordance with the national bands (methotrexate HD) • Rituximab dose will be rounded to the nearest 100mg (up if halfway) • Vincristine will be dose banded in accordance with the national bands (1mg/ml) • The maximum dose of vincristine is 2mg Administration Information Extravasation • Cyclophosphamide – neutral • Doxorubicin – vesicant • Methotrexate – inflammitant • Rituximab - neutral • Vincristine - vesicant Other • The methotrexate infusion must not be started until the urinary pH is above 7. This urinary pH must be maintained throughout the methotrexate infusion and until the methotrexate level is 0.1micromol/L or below • The methotrexate infusion must be stopped 24 hours after the start of the first infusion regardless of the dose given Version 1.2 (Sept 2018) Page 7 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine • The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines Additional Therapy This is an inpatient regimen please ensure all supportive and take home medicines are prescribed on the inpatient chart or general electronic prescribing system. Day 1 - R-CODOX – Cyclophosphamide-Doxorubicin-Rituximab-Vincristine • Premedication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 7 days oral or intravenous - metoclopramide 10mg three times then when required oral or intravenous - ondansetron 8mg twice a day for 7 days oral or intravenous Day 10 - Methotrexate (Intravenous) • Hydration The following fluid regimen is recommended as hydration. Fluid hydration should start at least six hours prior to methotrexate. This schedule should be repeated every 12 hours until the methotrexate level is below 0.1 micromol/L - Furosemide 40mg once only dose oral or intravenous when required for the treatment of fluid overload or to maintain urine output - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 Version 1.2 (Sept 2018) Page 8 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - Glucose 5% (with or without potassium chloride 20 or 27mmol) 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 • Antiemetics Starting 15-30 minutes prior to intravenous methotrexate - dexamethasone 4mg twice a day for 3 days oral or intravenous - metoclopramide 10mg oral three times a day when required oral or intravenous - ondansetron 8mg twice a day for 3 days oral or intravenous • Post-treatment with intravenous methotrexate - folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards if the patient is able to tolerate oral therapy. If levels of methotrexate are above 2micromol/L at 72 hours additional folinic acid may be necessary. Seek advice from a senior member of staff. • Growth factor to be continued until the neutrophil count is above 1x109/L. For example: - filgrastim or bioequivalent 30 million units once a day from day 13 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 13 subcutaneous - pegfilgrastim or bioequivalent 6mg once only day 13 subcutaneous • Folinic acid 15mg four times a day oral for one day starting 24 hours after the administration of the intrathecal methotrexate dose, according to local practice • Mouthwashes according to local or national policy on the treatment of mucositis • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Tumour lysis prophylaxis with cycle one only including: - appropriate hydration - rasburicase for high risk patients - allopurinol 300mg once a day for the first cycle only Version 1.2 (Sept 2018) Page 9 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - pentamidine 300mg nebule once a month - fluconazole 50mg once a day oral Some centres avoid the use of azole antifungal agents due to the risk of peripheral neuropathy when combined with vinca alkaloids. Additional Information • A significant number of drugs interact with intravenous methotrexate. At the doses used in this protocol this can lead to significant toxicity or reduction in efficacy. Always check for drug interactions before prescribing any additional medication. • HSC 2008/001: Updated national guidance on the safe administration of intrathecal chemotherapy must be followed. • The National Patient Safety Agency report NPSA/2008/RRR04 must be followed in relation to intravenous administration of vinca alkaloids. Coding (OPCS) • Procurement – X71.5 • Delivery – not required References 1. NCRI Lymphoma Group. A Clinicopathological Study in Burkitt’s and Burkitt-Like Non-Hodgkin’s Lymphoma. LY10. Protocol Version 2.0. September 2002. 2.Mead GM, Sydes MY, Walewski J et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitts lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002; 13 (8): 1264-1274. - Version 1.2 (Sept 2018) Page 10 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine REGIMEN SUMMARY InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 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 1 1. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 2. Chlorphenamine 10mg intravenous 3. Hydrocortisone 100mg intravenous 4. Paracetamol 1000mg oral Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses 5. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% (administer according to local guidelines) 6. Doxorubicin 40mg/m2 intravenous bolus over 10 minutes 7. Vincristine 1.5mg/m2 (max dose 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 8. Cyclophosphamide 800mg/m2 intravenous bolus over 10 minutes 9. Warning – Prescribe intrathecal on intrathecal chart Administration Instructions Prescribe cytarabine 70mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times. 10. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 11. Salbutamol 2.5mg nebule when required for rituximab related bronchospasm Version 1.2 (Sept 2018) Page 11 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Day 2 12. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 13. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes Day 3 14. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 15. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes 16. Warning – Prescribe intrathecal on an intrathecal chart Administration Instructions Prescribe cytarabine 70mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times Day 4 17. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – interacts with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 18. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes Version 1.2 (Sept 2018) Page 12 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine Day 5 19. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 7 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 7 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Pentamidine nebule 300mg once a month 6. Fluconazole 50mg once a day oral (consider – may interact with vincristine) 7. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone 5mg three times a day in menstruating women 11.Consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to corticosteroids 20. Cyclophosphamide 200mg/m2 intravenous bolus over 10 minutes 21. Warning – CNS disease extra intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe an additional cytarabine 70mg intrathecal on day 5 cycle one only Intrathecal chemotherapy must be prescribed on an intrathecal chart. This is a warning, not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times. Day 8 22. Warning – Check supportive medication prescribed Administration Instructions 1. Aciclovir 400mg twice a day oral 2. Pentamidine nebule 300mg once a month 3. Fluconazole 50mg once a day oral (consider – may interact with vincristine) 4. Tumour lysis prophylaxis including appropriate hydration (cycle one only) 5. Consider gastric protection 6. Consider mouthwashes 7. Consider norethisterone 5mg three times a day in menstruating women 23. Vincristine 1.5mg/m2 (max dose 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes Day 10 24. Warning – Check supportive medication prescribed Administration Instructions 1. Furosemide 40mg when required oral or intravenous 2. Fluids repeated on a 12 hourly cycle to maintain fluid balance, urine output and pH above 7 until methotrexate level is below 0.1micromol/L - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - glucose 5% 1000ml (with or without potassium chloride 20 or 27mmol) intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary ph above 7 3. Dexamethasone 4mg twice a day for 3 days oral or intravenous 4. Metoclopramide 10mg three times a day when required oral or intravenous 5. Ondansetron 8mg twice a day for 3 days oral or intravenous 6. Folinic acid 30mg every 3 hours intravenous beginning 36 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. 7. Growth factors started and continued until the neutrophil count is above 1x109/L - filgrastim or bioequivalent 30 million units once a day from day 13 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 13 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 13 subcutaneous 8. Aciclovir 400mg twice a day oral 9. Pentamidine 300mg nebule once a month 10.Fluconazole 50mg once a day oral 11.Tumour lysis prophylaxis including appropriate hydration (cycle one only) 12.Consider gastric protection 13.Consider mouthwashes 14.Consider norethisterone 5mg three times a day in menstruating women Version 1.2 (Sept 2018) Page 13 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 25. Methotrexate 300mg/m2 intravenous infusion in 250ml sodium chloride 0.9% over 1 hour Administration Instructions Monitor fluid balance, urine output, weight and urinary pH. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. 26. Methotrexate 2700mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 23 hours Administration Instructions Monitor fluid balance, urine output, weight and urinary pH. Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L. Day 15 27. Warning – Prescribe intrathecal on intrathecal chart Administration Instructions Prescribe methotrexate 12.5mg intrathecal. This must be prescribed on an intrathecal chart to comply with national guidance. This warning is a reminder not a prescription. National intrathecal guidance and local intrathecal policies must be followed at all times Day 17 28. Warning – CNS disease extra intrathecal cycle 1 only Administration Instructions For patients presenting with CNS disease please prescribe an additional methotrexate 12.5mg intrathecal at cycle 1 only. Intrathecal chemotherapy must be prescribed on an intrathecal chart. This is a warning, not a prescription. National intrathecal guidance and local policies must be followed at all times. Folinic acid 15mg four times a day oral for one day starting 24 hours after the administration of intrathecal methotrexate, according to local practice Version 1.2 (Sept 2018) Page 14 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine DOCUMENT CONTROL Version Date Amendment Written By Approved By Check for additional fluid compartment added Renal toxicity added Dose bands changed to national bands 1.1 Aug 2018 Potassium changed to being optional in the glucose 5% methotrexate hydration Fluconazole interaction added Dr Deborah Wright Pharmacist Donna Kimber Pharmacy Technician Paracetamol administration instructions Methotrexate levels added to administration instructions Intrathecal changed to a warning Disclaimer updated Header changed Toxicities removed Hepatic and renal impairment guidance updated Antiemetics clarified Administration information for hydrocortisone pre med removed Metoclopramide dose and duration updated “Bolus” removed from “intravenous bolus” for supportive medication Donna Kimber throughout text 1.1 Sept 2016 Start of methotrexate levels changed from 24 hours after the end of the infusion 48 hours after the start of the Pharmacy Technician Rebecca Wills Dr Deborah Wright Pharmacist infusion Pharmacist Growth factor units updated Mucositis recommendation changed OPCS code updated 27mmol potassium chloride added to glucose hydration fluid “according to local practice” and “oral” added to folinic acid instructions following intrathecal methotrexate CSSCN agreed bands removed Regimen summary numbering updated. Disclaimer added Dr Andrew Davies Rebecca Wills Consultant Medical 1 August 2012 None Pharmacist Dr Deborah Wright Oncologist Dr Alison Milne Pharmacist Consultant Haematologist Version 1.2 (Sept 2018) Page 15 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine 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 Hospital 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 1.2 (Sept 2018) Page 16 of 16 Lymphoma- InP-RCODOX-M(65)-Cyclophosphamide-Doxorubicin-Methotrexate-Rituximab-Vincristine
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/InP-RCODOX-M65-cyclophosphamide-doxorubicin-methotrexate-rituximab-vincristine.pdf
Unwise decisions
Description
Patients do not often disagree with the clinician who is treating them. When disagreement occurs, under some circumstances, this may lead to the patient's capacity to make decisions being questioned.
Url
/HealthProfessionals/Clinical-law-updates/Unwise-decisions.aspx
Vestibular disorders in children - patient information
Description
This factsheet contains information about vestibular disorders in children.
Url
/Media/UHS-website-2019/Patientinformation/Audiology/Vestibular-disorders-in-children-2874-PIL.pdf
InP IVE-Epirubicin-Etoposide-Ifosfamide Ver1.1
Description
Chemotherapy Protocol LYMPHOMA EPIRUBICIN-ETOPOSIDE-IFOSFAMIDE (IVE) Inpatient Regimen Regimen • Lymphoma – InP-IVE-Epirubicin-Etoposide-Ifosfamide Indication • Non Hodgkin’s Lymphoma • Hodgkin’s Lymphoma Toxicity Drug Epirubicin Etoposide Ifosfamide Adverse Effect Cardiotoxicity, urinary discolouration (red) Hypotension on rapid infusion, hyperbilirubinaemia Haemorrragic cystitis, encephalopathy, nephrotoxicity Patients with Hodgkin’s Lymphoma carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required these patients must receive irradiated blood products for life. 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 (May 2015) Page 1 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide Monitoring Drugs • FBC, LFTs (including albumin) and U&Es prior to day one of treatment • EDTA or calculated creatinine clearance prior to each cycle • Ensure adequate cardiac function before starting therapy. Baseline LVEF should be measured in patients with a history of cardiac problems, cardiac risk factors or in the elderly. Discontinue epirubicin if cardiac failure develops. • Urine dip test for protein every four hours the day of and the day after ifosfamide administration • Fluid balance monitoring every four hours the day of and the day after ifosfamide administration. Urine output should be maintained above 100ml/hour 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. 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 There are no dose modifications for haematological toxicity. Treatment should be delayed until the minimum criteria, described in the table below, are reached. Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 100x109/L Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Version 1.1 (May 2015) Page 2 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. Drug Epirubicin Bilirubin μmol/L 30-50 or 51-85 or more than 85 AST/ALT units 2-4xULN more than 4xULN Dose (% of original dose) 50% 25% omit Etoposide 30-51 or more than 51 or 60-180 more than180 Consider dose reducing to 50% Clinical decision Ifosfamide more than 20 or more than 2.5xULN or ALP more than 2.5xULN Not recommended Renal Impairment Drug Epirubicin Creatinine Clearance (ml/min) less than10 Dose (% of original dose) Consider dose reduction in severe renal failure Etoposide more than 50 15-50 less than15 100% 75% 50% Ifosfamide more than 60 40-59 less than 40 100% 70% Clinical decision Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Where appropriate, if dose reductions made at cycle one are well tolerated, dose increases can be considered on subsequent cycles according to tolerability. Epirubicin Discontinue epirubicin if cardiac failure develops Version 1.1 (May 2015) Page 3 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Ifosfamide In the case of a NCI-CTC grade 1 neurological toxicity, the dose of ifosfamide may be reduced for the next cycle. If a NCI-CTC grade 2 neurological toxicity appears or neurological toxicity worsens despite dose reduction, the ifosfamide should be stopped. Risk factors for CNS toxicity include a low albumin, renal impairment, prior administration of cisplatin, poor performance status, CNS tumour, bulky pelvic disease, concomitant psychotropic drugs and younger age. Methylene blue 50mg four times a day intravenous infusion in 100ml sodium chloride 0.9% can be used to prevent or treat ifosfamide induced encephalopathy. Regimen 3 cycles (1 cycle will be set in Aria) Drug Epirubicin Etoposide Mesna Ifosfamide Mesna Mesna Dose 50mg/m2 200mg/m2 Days 1 1,2,3 600mg/m2 1500mg/m2 twice a day (total daily dose 3000mg/m2) 1500mg/m2 twice a day (total daily dose 3000mg/m2) 1800mg/m2 1 1,2,3 4 Administration Intravenous injection over 10 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Intravenous infusion in sodium chloride 0.9% 100ml over 15 minutes Intravenous infusion in sodium chloride 0.9% 1000ml over 12 hours (the ifosfamide and mesna are mixed in the same bag) Intravenous infusion in sodium chloride 0.9% 1000ml over 12 hours New cycles begin on the day that the neutrophil count recovers to more than 1x109/L and the unsupported platelet count is more than 100x109/L. Dose Information • Epirubicin will be dose banded according to the CSCCN agreed bands • The maximum lifetime cumulative dose of epirubicin is 900mg/m² • Etoposide will be dose banded according to the CSCCN agreed bands • Ifosfamide will be dose banded according to the CSCCN agreed bands • Mesna will be dose banded according to the CSCCN agreed bands Version 1.1 (May 2015) Page 4 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide Administration Information Extravasation • Epirubicin - vesicant • Etoposide – irritant • Ifosfamide – neutral • Mesna - neutral Additional Therapy This is an inpatient regimen please ensure all supportive and take home medication are prescribed on the inpatient chart or general electronic prescribing system. • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 5 days oral or intravenous - metoclopramide 10mg three times a day for 5 days then when required oral or intravenous - ondansetron 8mg twice a day for 5 days oral or intravenous • Growth factor to be continued until the neutrophil count is above 1x109/L. For example: - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 5 subcutaneous • Mouthwashes according to local or national policy on the treatment of mucositis • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Allopurinol 300mg once a day for the first cycle only • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only oral Version 1.1 (May 2015) Page 5 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide Coding (OPCS 4.6) • Procurement – X71.1 • Delivery – Not required References 1.Proctor SJ, Taylor PR, Angus B et al. High dose ifosfamide in combination with etoposide and epirubicin (IVE) in the treatment of relapsed / refractory Hodgkins disease and non-Hodgkins lymphoma: a report on toxicity and efficacy. Eur J Haematol 2001; 64: 28 - 32. 2.McQuaker IG, Haynes AP, Stainer C et al. Stem cell mobilization in resistant or relapsed lymphoma: a superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide. Br J Haematol; 1997; 98:228-233. 3. Bishton MJ, Lush RJ, Byrne JL et al. Ifosfamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilistaion regimen for transplant eligible patients with non-Hodgkins lymphoma and Hodgkin disease. Br J Haematol; 2007: 136: 752-761. Version 1.1 (May 2015) Page 6 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide REGIMEN SUMMARY InP-IVE-Epirubicin-Etoposide-Ifosfamide 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 1 1. Warning – Check supportive medication prescribed Administration instructions 1. Dexamethasone 4mg twice a day, days 1 to 5 oral or intravenous 2. Metoclopramide 10mg three times a day, days 1 to 5 then as required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 5 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday oral 6. Growth factors continued until the neutrophil count is above 1x109/L, for example: - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 5 subcutaneous 7. Allopurinol 300mg once a day oral (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone for menstruating women 2. Epirubicin 50mg/m2 intravenous injection over 10 minutes 3. Etoposide 200mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 4. Mesna 600mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes 5. Ifosfamide 1500mg/m2 plus mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours 6. Ifosfamide 1500mg/m2 plus mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Days 2, 3 1. Warning – Check supportive medication prescribed Administration instructions 1. Dexamethasone 4mg twice a day, days 1 to 5 oral or intravenous 2. Metoclopramide 10mg three times a day, days 1 to 5 then as required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 5 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday oral 6. Growth factors continued until the neutrophil count is above 1x109/L, for example: - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 5 subcutaneous 7. Allopurinol 300mg once a day oral (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone for menstruating women 2. Etoposide 200mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Version 1.1 (May 2015) Page 7 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide 3. Ifosfamide 1500mg/m2 plus mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours 4. Ifosfamide 1500mg/m2 plus mesna 1500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Day 4 1. Warning – Check supportive medication prescribed Administration instructions 1. Dexamethasone 4mg twice a day, days 1 to 5 oral or intravenous 2. Metoclopramide 10mg three times a day, days 1 to 5 then as required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 5 oral or intravenous 4. Aciclovir 400mg twice a day oral 5. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday oral 6. Growth factors continued until the neutrophil count is above 1x109/L, for example: - filgrastim or bioequivalent 30 million units once a day from day 7 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 7 subcutaneous - pegfilgrastim or bioequivalent 6mg once only on day 5 subcutaneous 7. Allopurinol 300mg once a day oral (cycle one only) 8. Consider gastric protection 9. Consider mouthwashes 10.Consider norethisterone for menstruating women 2. Mesna 1800mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 12 hours Administration instructions 1. To start immediately after the final ifosfamide/mesna infusion bag Version 1.1 (May 2015) Page 8 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide DOCUMENT CONTROL Version Date Amendment Written By Approved By Header changed Toxicities removed Hepatic table updated Metoclopramide dose changed to 10mg Donna Kimber 1.1 Mar 2015 Growth factor units updated Pharmacy Bolus removed from intravenous Technician Rebecca Wills Pharmacist bolus throughout text Mucositis recommendation changed Disclaimer added Dr Alison Milne Rebecca Wills Consultant Pharmacist Haematologist 1 Feb 2013 None Dr Deborah Wright Dr Andrew Davies Pharmacist Consultant Medical Oncologist 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 which occur as a result of following these guidelines. Version 1.1 (May 2015) Page 9 of 9 Lymphoma-InP-IVE-Epirubicin-Etoposide-Ifosfamide
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/InP-IVE-Epirubicin-Etoposide-Ifosfamide.pdf
InP cytarabine methotrexate
Description
Chemotherapy Protocol LYMPHOMA CYTARABINE-METHOTREXATE Inpatient Regimen Regimen • Lymphoma – InP-Cytarabine-Methotrexate Indication • Non-Hodgkin’s Lymphoma (CNS disease) Toxicity Drug Cytarabine Methotrexate Adverse Effect CNS toxicity, conjunctivitis, flu-like syndrome, pulmonary toxicity, gastro-intestinal toxicity Stomatitis, mucositis, conjunctivitis, renal toxicity The presence of a third fluid compartment e.g. ascites, pleural effusion or other oedema may delay the clearance of methotrexate and hence increase toxicity and should be resolved before methotrexate administration. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment • GFR measurement either by EDTA or a 24 hour urine collection prior to methotrexate infusion. The creatinine clearance must be 50ml/min or more for the methotrexate in this regimen to be administered • Methotrexate levels taken every 24 hours starting 48 hours after the start of the infusion until the level is below 0.1micromol/L • Urinary pH every two hours as a minimum until the methotrexate level is below 0.1micromol/L • Strict fluid balance chart to be maintained throughout methotrexate administration with appropriate action taken if positive by more than 2 kg/L. Version 1.2 (February 2017) Page 1 of 8 Lymphoma-InP-Cytarabine-Methotrexate 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. 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 There are no dose modifications for haematological toxicity. Treatment should be delayed until the minimum criteria, described in the table below, are reached. Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 100x109/L Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Hepatic Impairment Please note that the approach may be different if abnormal liver function tests are due to disease involvement. There is a higher risk of methotrexate toxicity in patients with concomitantly impaired renal function, consider dose reduction. Drug Cytarabine Bilirubin (µmol/L) more than 34 AST/ALT units/L Dose (% of original dose) 50% Escalate doses on subsequent cycles in the absence of toxicity Methotrexate less than 50 and less than180 51-85 or more than 180 more than 85 N/A 100% 75% omit Transient increases in bilirubin and transaminases lasting up to 2 weeks are likely following methotrexate infusion and should not be considered and indication to stop treatment. Persistent hyperbilirubinaemia and/or NCI-CTC grade 3-4 hypertransaminasemia for longer than 3 weeks should result in discontinuation of the drug. Version 1.2 (February 2017) Page 2 of 8 Lymphoma-InP-Cytarabine-Methotrexate Renal Impairment Drug Cytarabine Creatinine Clearance (ml/min) *50 or greater Dose (% of original dose) 100% Methotrexate *50 or greater * Limits reflect local practice and may vary from published sources 100% Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Where appropriate, if dose reductions made at cycle one are well tolerated, dose increases can be considered on subsequent cycles according to tolerability. Cytarabine Cytarabine may cause conjunctivitis. The prophylactic use of corticosteroid eye drops may reduce the incidence of this ocular toxicity Regimen 21 day cycle for up to 4 cycles Drug Methotrexate Methotrexate Cytarabine Dose 500mg/m2 3000mg/m2 2000mg/m2 every 12 hours Days 1 1 2 and 3 (4 doses) Administration Intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes Intravenous infusion in 100ml sodium chloride 0.9% over 60 minutes New cycles begin on the day that the neutrophil count recovers to 1x109/L or more and the unsupported platelet count is 100x109/L or greater Dose Information • Cytarabine will be dose banded according to the agreed bands • Methotrexate will be dose banded according to the agreed bands Version 1.2 (February 2017) Page 3 of 8 Lymphoma-InP-Cytarabine-Methotrexate Administration Information Extravasation • Cytarabine - neutral • Methotrexate - inflammitant Other • The methotrexate infusion must not be started until the urinary pH is above 7. This urinary pH must be maintained throughout the methotrexate infusion and until the methotrexate level is 0.1micromol/L or below Additional Therapy This is an inpatient regimen please ensure all supportive and take home medicines are prescribed on the inpatient chart or general electronic prescribing system. • Methotrexate hydration The following fluid regimen is recommended as hydration. Fluid hydration should start at least six hours prior to methotrexate. This schedule should be repeated every 12 hours until the methotrexate level is below 0.1 micromol/L - Furosemide 40mg once only dose when required for the treatment of fluid overload or to maintain urine output oral or intravenous - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - Sodium chloride 0.9% with 20mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - Glucose 5% with 27mmol potassium chloride 1000ml intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 • Antiemetics Starting 15-30 minutes prior to chemotherapy - dexamethasone 4mg twice a day for 5 days oral or intravenous - metoclopramide 10mg three times a day when required oral or intravenous - ondansetron 8mg twice a day for 5 days oral or intravenous Version 1.2 (February 2017) Page 4 of 8 Lymphoma-InP-Cytarabine-Methotrexate • Post-treatment with intravenous methotrexate - Folinic acid 30mg every 3 hours intravenous beginning 24 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards if the patient is able to tolerate oral therapy. If levels of methotrexate are above 2micromol/L additional folinic acid may be necessary. Seek advice from a senior member of staff. • Corticosteroid eye drops such as prednisolone 0.5% or dexamethasone 0.1% one drop into both eyes four times a day for 4 days starting on day 2. • Growth factor to be continued until the neutrophil count is above 1x109/L. For example: - filgrastim or bioequivalent 30 million units once a day from day 6 subcutaneous - lenograstim or bioequivalent 33.6 million units once a day from day 6 subcutaneous - pegfilgrastim or bioequivalent 6mg once only day 4 subcutaneous • Mouthwashes according to local or national policy on the treatment of mucositis • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. • In female patients consider norethisterone 5mg three times a day oral to delay menstruation • Anti-infective prophylaxis as follows: - aciclovir 400mg twice a day oral - pentamidine 300mg nebule once a month - fluconazole 50mg once a day Additional Information • A significant number of drugs interact with intravenous methotrexate. At the doses used in this protocol this can lead to significant toxicity or reduction in efficacy. Always check for drug interactions. Coding • Procurement – X71.2 • Delivery – Not Required References 1.Ferreri AJ, Reni M, Foppoli M et al. International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374 (9700):1512-20. Version 1.2 (February 2017) Page 5 of 8 Lymphoma-InP-Cytarabine-Methotrexate REGIMEN SUMMARY InP-Cytarabine-Methotrexate 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 1 1. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 5 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 5 oral or intravenous 4. Furosemide 40mg when required oral or intravenous 5. Fluids repeated on a 12 hourly cycle to maintain fluid balance, urine output and pH above 7 until methotrexate level is below 0.1micromol/L - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - glucose 5% 1000ml with potassium chloride 27mmol intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary ph above 7 6. Folinic acid 30mg every 3 hours intravenous beginning 24 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards 7. Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 2 to 5 8. Aciclovir 400mg twice a day oral 9. Fluconazole 50mg once a day oral 10.Pentamidine nebule 300mg once a month 11.Growth factors continued until the neutrophil count is above 1x109/L - Filgrastim or bioequivalent 30 million units once a day from day 6 subcutaneous - Lenograstim or bioequivalent 33.6 million units once a day from day 6 subcutaneous - Pegfilgrastim or bioequivalent 6mg once only on day 4 subcutaneous 12.Consider gastric protection 13.Consider mouthwashes 14.Consider norethisterone 5mg three times a day in menstruating women 2. Methotrexate 500mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Administration Instructions Monitor fluid balance, urine output, weight and urinary pH 3. Methotrexate 3000mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 180 minutes Administration Instructions Monitor fluid balance, urine output, weight and urinary pH Days 2 and 3 4. Warning – Check supportive medication prescribed Administration Instructions 1. Dexamethasone 4mg twice a day, days 1 to 5 oral or intravenous 2. Metoclopramide 10mg three times a day when required oral or intravenous 3. Ondansetron 8mg twice a day, days 1 to 5 oral or intravenous 4. Furosemide 40mg when required oral or intravenous 5. Fluids repeated on a 12 hourly cycle to maintain fluid balance, urine output and pH above 7 until methotrexate level is below 0.1micromol/L - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - sodium chloride 0.9% with potassium chloride 20mmol 1000ml intravenous infusion over 240 minutes with 50- 100mmol sodium bicarbonate adjusted to maintain urinary pH above 7 - glucose 5% 1000ml with potassium chloride 27mmol intravenous infusion over 240 minutes with 50-100mmol sodium bicarbonate adjusted to maintain urinary ph above 7 6. Folinic acid 30mg every 3 hours intravenous bolus beginning 24 hours after the start of the methotrexate infusion and continued until the methotrexate levels are below 0.1micromol/L. This may be given orally from dose 5 onwards Version 1.2 (February 2017) Page 6 of 8 Lymphoma-InP-Cytarabine-Methotrexate 7. Prednisolone 0.5% or dexamethasone 0.1% eye drops one drop into both eyes four times a day, days 2 to 5 8. Aciclovir 400mg twice a day oral 9. Fluconazole 50mg once a day oral 10.Pentamidine nebule 300mg once a month 11.Growth factors continued until the neutrophil count is above 1x109/L - Filgrastim or bioequivalent 30 million units once a day from day 6 subcutaneous - Lenograstim or bioequivalent 33.6 million units once a day from day 6 subcutaneous - Pegfilgrastim or bioequivalent 6mg once only on day 4 subcutaneous 12.Consider gastric protection 13.Consider mouthwashes 14.Consider norethisterone 5mg three times a day in menstruating women 4. Cytarabine 2000mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 60 minutes twice a day Administration Instructions Cytarabine doses are to be given at 12 hour intervals Version 1.2 (February 2017) Page 7 of 8 Lymphoma-InP-Cytarabine-Methotrexate DOCUMENT CONTROL Version Date Amendment Written By Approved By Donna Kimber 1.2 Feb 2018 Cytarabine infusion volume changed to 100ml Dr Deborah Wright Pharmacist Pharmacy Technician Header changed Toxicities removed Start time for methotrexate levels changed from 24 hours to 48 hours after the start of the infusion Renal impairment guidance updated 1.1 Aug 2016 Metoclopramide dose and duration updated “Bolus” removed from “intravenous bolus” for supportive medication throughout text Growth factor units updated Mucositis recommendation changed Donna Kimber Pharmacy Technician Rebecca Wills Pharmacist Dr Deborah Wright Pharmacist OPCS code updated 27mmol potassium chloride added to glucose hydration fluid CSCCN bands removed Platelets levels changed to 100x109/L from 90x109/L Disclaimer added Dr Alison Milne Rebecca Wills Consultant 1 August 2012 None Pharmacist Dr Deborah Wright Haematologist Dr Andrew Davies Pharmacist Consultant Medical Oncologist 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 Hospital 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 1.2 (February 2017) Page 8 of 8 Lymphoma-InP-Cytarabine-Methotrexate
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