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Carboplatin(AUC5)-Paclitaxel (21 day)

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC5)-PACLITAXEL (21 day) Regimen • Cervix-Carboplatin (AUC5)-Paclitaxel (21 day) In
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Cervical-cancer/CarboplatinAUC5-Paclitaxel-21day.pdf

Accelerated-Cyclophosphamide-Epirubicin-Paclitaxel(14) Ver1

Description
Chemotherapy Protocol BREAST CANCER CYCLOPHOSPHAMIDE-EPIRUBICIN-PACLITAXELACCELERATED Regimen • Breast Cancer – Cyclophosphamide-Epirubicin-Pacl
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Breastcancer/Accelerated-Cyclophosphamide-Epirubicin-Paclitaxel-14.pdf

Carboplatin(AUC5)-Paclitaxel (21 day)

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC5)-PACLITAXEL 21 day Regimen • Ovary-Carboplatin (AUC5)-Paclitaxel (21 day) Indic
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ovarian-cancer/CarboplatinAUC5-Paclitaxel21day.pdf

Carboplatin(AUC5)-Paclitaxel (21 day)

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC5)-PACLITAXEL (21 day) Regimen • Uterine-Carboplatin (AUC5)-Paclitaxel (21 day) I
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Uterine-cancer/CarboplatinAUC5-Paclitaxel21day.pdf

Enhertu (trastuzumab deruxtecan)

Description
Chemotherapy Protocol BREAST CANCER ENHERTU (trastuzumab deruxtecan) ENHERTU is NOT the same drug as Kadcyla (trastuzum
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Breastcancer/Enhertu-trastuzumab-deruxtecan.pdf

Cemiplimab

Description
Chemotherapy Protocol SKIN CANCER Cemiplimab (350mg) Regimen  Skin – Cemiplimab (350mg) Indication  Metastatic or l
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Skincancer/Cemiplimab.pdf

Tisacel-Cytarabine (500)-Etoposide (150)

Description
Chemotherapy Protocol CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T) THERAPY ALL – TISACEL – CYTARABINE (500) – ETOPOSIDE (150) Regimen This regimen will only be available to prescribe at the Wessex Blood and Marrow Transplant Unit • ALL - Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Indication • CAR-T therapy with Tisacel (Tisagenlecleucel) for the treatment paediatric and young adult patients up to and including 25 years of age with: -B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post- transplant or in second or later relapse. (See separate diffuse large B-cell lymphoma / follicular lymphoma protocol for use in DLBCL/ FL) • Lymphodepleting chemotherapy must be administered prior to Tisacel. This protocol includes both lymphodepletion and CAR-T administration. • For autologous use only. • This cytarabine and etoposide lymphodepleting regimen may be considered with Tisacel, in preference to the Tisacel – Fludarabine (30) – Cyclophosphamide (500), if the patient has experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy. Toxicity Drug Cytarabine Etoposide Adverse Effect Nausea, vomiting, diarrhoea, fever, rash, itching, anorexia, oral and anal inflammation or ulceration, hepatic dysfunction, ocular pain, foreign body sensation, photophobia and blurred vision, dizziness, headache, confusion, cerebellar toxicity, myalgia and bone pain Nausea, mucositis and alopecia, anaphylactic reactions Tisacel (tisagenlecleucel) Cytokine release syndrome (CRS), hepatic dysfunction, renal dysfunction, cardiac dysfunction, neurologic adverse reactions immune effector cell-associated neurotoxicity syndrome (ICANS), opportunistic infections, febrile neutropenia, HBV reactivation, prolonged cytopenias, hypogammaglobulinaemia, tumour lysis syndrome (TLS), hypersensitivity reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Symptoms of CRS or ICANS can occur weeks after infusion and therefore the patient must be issued with an alert card to carry with them at all times. Version 1 (August 2023) Page 1 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Any suspected adverse reaction to a CAR-T cell infusion should be reported. Reporting forms and information can be found at – www.mhra.gov.uk/yellowcard. Consideration should also be given to reporting adverse events to the relevant manufacturer via their usual channels. Monitoring Regimen • FBC, U&Es, renal, liver and bone, CRP, coagulation screen, ferritin and LDH prior to initiating treatment and daily thereafter. • Screening for HBV, HCV and HIV must be performed before collection of cells for Tisagenlecleucel manufacture. • Echocardiogram and baseline measure of lung function must be taken prior to initiating lymphodepletion Tisacel Nearly all patients treated with Tisacel experience some degree of CRS, including life-threatening and fatal reactions. -See WBMT Policy P-G-1 and SOP P-P-78 and P-P-79 for monitoring requirements. CRS: Symptoms: pyrexia, tiredness, cardiac failure, tachycardia, cardiac arrythmias, dyspnoea, hypoxia, capillary leak syndrome, chills, renal impairment, headache, malaise, transaminitis, nausea, diarrhoea, hypotension. • Temperature, blood pressure and oxygen saturation monitored 4-hourly after Tisacel administration on Day 0 and then twice daily as directed in accordance with local procedures. • This must be documented, and CRS graded on the WBMT CRS Assessment Form in the patient’s notes. ICANS: Symptoms: seizures, somnolence, headaches, confusion, agitation, speech disorders, tremor, encephalopathy, ataxia, memory impairment, mental status changes, hallucinations, depressed level of consciousness, delirium, dysmetria. • ICE score of the patient must be assessed twice daily and documented on the WBMT ICE Assessment Form in the patient’s notes. Version 1 (August 2023) Page 2 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Dose Modifications As a cell-based therapy and based on the mechanism of action, renal and hepatic impairment is not expected to impact tisagenlecleucel expansion and cellular kinetics; hence no formal renal and hepatic impairment studies have been performed. The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Confirm with consultant before proceeding if there are signs of possible disease relapse. Hepatic Impairment Drug Cytarabine Bilirubin (µmol/L) Greater than 34 AST/ALT units/L N/A Dose (% of original dose) 50% Etoposide 30-51* or 60-180 50% Greater than 51 or Greater than 180 Clinical decision *Limit reflects local practice and may vary from published sources Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Renal Impairment Drug Cytarabine Creatinine Clearance (ml/min) Less than 60 Less than 45 Less than 30 Dose (% of original dose) 60% 50% Clinical decision Etoposide 15-50 Less than 15 75% 50% Other Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of the cellular therapy and therefore, they should not be administered as part of the pre-medication. However, corticosteroids may be used in the treatment of CRS or ICANS under consultant advice. Cautions with Tisacel treatment: Version 1 (August 2023) Page 3 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) • Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies. • Active uncontrolled infection or inflammatory disease. • Active GVHD. Regimen Drug Cytarabine Dose 500 mg/m2 Days -5, -4 Etoposide 150 mg/m2 -5, -4, -3 Tisacel (tisagenlecleucel) 1.2 x 106 – 6 x108 cells Target dose: 0 Patients 50kg and below: 0.2 to 5 x 106 cells / kg body weight Patients above 50kg: 0.1 to 2.5 x 108 cells Route Intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Intravenous infusion of one or more infusion bags within 30 minutes -see below Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count ≤1,000 cells/µL within one week prior to infusion. Version 1 (August 2023) Page 4 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Dose Information • Lymphodepleting regimen must only be started after availability of Tisacel is confirmed. • Cytarabine will be dose banded according to the national dose bands (100mg/ml) • Etoposide will be dose banded according to the national dose bands • A minimum period of time must elapse between last dose of conditioning chemotherapy and CAR-T infusion, and a longer period is required for patients with renal insufficiency. This information can be found on the patient’s CAR-T cell schedule. • CAR-T administration should not occur out of core hours or over a weekend. • Tisacel for this indication has a different target doses depending on the patient’s weight and will vary between patients. : - For patients 50kg and below target dose is 0.2 to 5 x 106 cells / kg body weight - For patients above 50kg target dose is 0.1 to 2.5 x 108 cells (non-weight based) Version 1 (August 2023) Page 5 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Administration Information Tisacel • Tisacel contains genetically modified (GM) human blood cells. Exposure to Tisacel must be avoided. Procedures for handling, personal protective equipment, spills and waste disposal must be adhered to. • Tisacel cells are cryopreserved in a bag and require thawing prior to administration. -See WBMT SOP P-P-78. • One individual treatment dose comprises 1 or more infusion bags. Each infusion bag may contain either 10-30ml (50ml bag) or 30-50ml (250ml bag) cell dispersion. • The cells must be administered gravimetrically and must not be administered via a volumetric pump, as there is no data to assure cell integrity is maintained via a pump. • Administer via a latex-free giving set without a leukocyte depleting filter and primed with sodium chloride 0.9%. • The product should be administered immediately after thawing. • The infusion must be administered over a maximum of 30 minutes. The start and stop time of infusion must be documented, including any interruption. • Gently agitate the bag during infusion to prevent cell clumping. • If the volume of Tisacel to be administered is ≤20 mL, intravenous push may be used as an alternative method of administration. • All contents of the infusion bag(s) should be infused. If more than one infusion bag has been received for the treatment dose, the next bag should only be thawed after the contents of the preceding bag have been infused. • Once the full volume of Tisacel has been administered, rinse the tubing at the same rate with 10-30ml 0.9% sodium chloride solution to ensure all Tisacel is delivered. Once completed, the infusion bag(s) and giving set must be disposed of in clinical waste, in accordance with Trust policy. • If the bag is not fully administered, this must be documented, and the consultant & pharmacist notified. The manufacturer must be informed and the remaining Tisacel should be discarded in clinical waste, with their approval. • A GM spill-kit must be transported with Tisacel and available on the ward of administration. Local procedures must be followed in the event of a spill. Version 1 (August 2023) Page 6 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) • Local guidelines on handling of waste of human-derived-materials must be followed in case of accidental exposure. Work surfaces and materials which have potentially been in contact with Tisacel must be decontaminated with approved disinfectants. • See WBMT SOP P-P-78, P-P-79 and Policy P-G-1 for further administration direction. Extravasation • Etoposide - irritant • Cytarabine – neutral (irritant in large volumes) Additional Therapy • Antiemetics - metoclopramide 10mg three times a day oral or intravenous - ondansetron 8mg twice a day oral or intravenous • Anti-infective prophylaxis as follows: - Aciclovir 400mg oral twice a day - Fluconazole 100mg once a day - Pentamidine 300mg nebuliser during lymphodepletion. To be continued every 28 days until count recovery sufficient for co-trimoxazole use at consultant advice. - Posaconazole 300mg once daily if prolonged neutropenia or previous invasive fungal infection • Gastric protection with a proton pump inhibitor or a H2 antagonist to commence on first day on lymphodepletion until platelet count > 50 x109/L • Mouthwashes according to local or national policy on the treatment of mucositis. May include: - Nystatin 1ml four times a day - Sodium chloride 0.9% 10ml four times a day • Prednisolone eye drops 0.5% into each eye four times a day. Continue for 5 days after cytarabine administration Version 1 (August 2023) Page 7 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) • Prior to the administration of the Tisacel - Chlorphenamine 10mg intravenous - Paracetamol 1000mg oral Pethidine 25mg intravenous can be administered under the supervision of a doctor for the treatment of rigors. • Seizure prophylaxis may be considered due to the risk of neurotoxicity associated with Tisacel or if the patient has a history of seizures. - Levetiracetam 500mg twice daily orally commencing on day 0 until day +30. - For weaning, this may then be reduced to 250mg orally twice daily for two weeks, then 250mg once daily for one week and then stopped. • Tocilizumab must be prescribed as when required in advance of CAR-T infusion, in the event of CRS. - Tocilizumab 8mg/kg (maximum 800mg) intravenously 8-hourly if required. Maximum of four doses. - Four doses of tocilizumab must be available on the ward prior to infusion of Tisacel. Follow local procedures for administration. • Tumour lysis syndrome (TLS) prophylaxis should be prescribed according to the individual patient TLS risk and at consultant review. This must start on the day of lymphodepletion and be re-reviewed on the day of Tisacel infusion. TLS prophylaxis may include: - Allopurinol 300mg oral once a day - Rasburicase 7.5mg intravenous injection once a day References 1. Hann IM, Stevens RF, Goldstone AH et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 1997; 89(7): 2311-8. 2. P-P-78 Wessex Blood and Marrow Transplant – CAR-T and IEC infusion procedure Version 2 3. P-P-79 Wessex Blood and Marrow Transplant – Immune effector cells including CAR-T cells policy Version 2.1 4. P-G-1 Wessex Blood and Marrow Transplant -Patient monitoring after CAR-T cell infusion Version 2.0 5. Pan UK Pharmacy Working Group for ATMPs -Supportive medications recommended for adults receiving licensed chimeric antigen receptor -T (CAR-T) cell therapy Version 1 May 2022 6. Pan UK Pharmacy Working Group for ATMPs -Medication restrictions for patients having CAR-T cell therapy Version 4 July 2022 7. Summary of Product Characteristics for Kymriah cells dispersion for infusion (Novartis Pharmaceuticals UK Ltd) -Last updated 24 July 2023 8. Summary of Product Characteristics for Cytarabine injection solution (100mg/ml) (Hospira UK Ltd) ) -Last updated 26 April 2021 9. Summary of Product Characteristics for Etoposide 20mg/ml concentrate for solution for infusion (Medac) - Last updated 15 November 2022 10. Renal Drug Database monograph for Cytarabine-Last updated 06 November 2017 11. Renal Drug Database monograph for Etoposide -Last updated 20 February 2018 Version 1 (August 2023) Page 8 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) REGIMEN SUMMARY ALL – TISACEL – CYTARABINE (500) – ETOPOSIDE (150) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describe the agents that must be prescribed on the in-patient chart or general electronic prescribing system. Day – 5 1. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual CAR-T schedule for full details of the required supportive medicines. 1. Antibacterials in accordance with the individual CAR-T schedule 2. Antifungals in accordance with the individual CAR-T schedule 3. Antivirals in accordance with the individual CAR-T schedule 4. Tocilizumab 8mg/kg (maximum 800mg) intravenous 8-hourly when required in the event of CRS. Maximum four doses. 5. Metoclopramide 10mg three times a day oral or intravenous 6. Ondansetron 8mg twice a day oral or intravenous 7. Nystatin mouthwash 1ml four times a day 8. Sodium chloride 0.9% mouthwash 10ml four times a day 9. Chlorphenamine 10mg intravenous when required as a premedication 10. Paracetamol 1000mg when required as a premedication oral 11. Furosemide 20mg four times a day when required for the treatment of fluid overload oral or intravenous 12. Gastric protection 13. Heparin line lock in accordance with Trust central venous access device management procedure 14. Levetiracetam 500mg twice daily oral 15. Prednisolone 0.5% eye drops, 1 drop each eye four times a day. Continue for 5 days after cytarabine administration is complete 16. Reminders for chemotherapy administration and Tisacel. Ensure patient has been issued with Tisacel treatment alert card. 2. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes. 3. Cytarabine 500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes. Day -4 4. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes. 5. Cytarabine 500mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes. Day – 3 6. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes. Day 0 7. Chlorphenamine 10mg intravenous Administration Instructions Administer 30 minutes prior to Tisacel. Check on the in-patient system if the patient has already received a dose Version 1 (August 2023) Page 9 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) 8. Paracetamol 1000mg oral Administration Instructions Administer 30 minutes prior to Tisacel. Check to ensure the patient has not already been administered paracetamol. The maximum dose is 4000mg/24 hours. 9. Tisacel (Tisagenlecleucel) 1 dose intravenous infusion Administration Instructions Prescribed dose for this patient: ……………………… The cells must be administered gravimetrically and must not be administered via a volumetric pump. Administer via a non-leukodepleting filter latex-free giving set primed with sodium chloride 0.9%. Tisacel infusion should be infused within 30 minutes of thaw completion time. Version 1 (August 2023) Page 10 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150) Version 1 Date August 2023 DOCUMENT CONTROL Amendment None Written By Madeleine Norbury Pharmacist Approved By Hwai Jing Hiew Consultant This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; University Hospital Southampton NHS Foundation Trust 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 (August 2023) Page 11 of 11 ALL – Tisagenlecleucel – Cytarabine (500) – Etoposide (150)
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Brexucel - Cyclophosphamide (900) - Fludarabine (25)

Description
Chemotherapy Protocol CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T) THERAPY ALL – BREXUCEL – CYCLOPHOSPHAMIDE (900) – FLUDARABINE (25) This regimen will only be available to prescribe at the Wessex Blood and Marrow Transplant Unit Regimen • Acute Lymphoblastic Leukaemia- Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Indication • CAR-T therapy with Brexucel (brexucabtagene autoleucel) for the treatment of adult patients 26 years of age and above with: - Relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL). (See separate Mantle Cell Lymphoma a protocol for use in MCL) • Lymphodepleting chemotherapy must be administered prior to Brexucel. This protocol includes both lymphodepletion and CAR-T administration. • For autologous use only. Toxicity Drug Cyclophosphamide Fludarabine Brexucel (brexucabtagene autoleucel) Adverse Effect Chemical haemorrhagic cystitis, leucopenia, nausea and vomiting, hepatic toxicity, altered carbohydrate metabolism, pancreatitis, hyper and hypoglycaemia, inappropriate secretion of antidiuretic hormone, interstitial pulmonary fibrosis. Transfusion related GVHD, fever, malaise, neurotoxicity, opportunistic infections, GI disturbances -nausea, vomiting, diarrhoea. Cytokine release syndrome (CRS), hepatic dysfunction, renal dysfunction, cardiac dysfunction, neurologic adverse reactions -immune effector cell-associated neurotoxicity syndrome (ICANS), opportunistic infections, febrile neutropenia, HBV reactivation, prolonged cytopenias, hypogammaglobulinaemia, tumour lysis syndrome (TLS), hypersensitivity reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required, these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. Version 1(August 2023) Page 1 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Symptoms of CRS or ICANS can occur weeks after infusion and therefore the patient must be issued with an alert card to carry with them at all times. Any suspected adverse reaction to a CAR-T cell infusion should be reported. Reporting forms and information can be found at – www.mhra.gov.uk/yellowcard. Consideration should also be given to reporting adverse events to the relevant manufacturer via their usual channels. Monitoring Regimen • FBC, U&Es, renal, liver and bone, CRP, coagulation screen, ferritin and LDH prior to initiating treatment and daily thereafter. • Screening for HBV, HCV and HIV must be performed before collection of cells for Brexucel manufacture. • Echocardiogram and baseline measure of lung function must be taken prior to initiating lymphodepletion Brexucel Nearly all patients treated with Brexucel experience some degree of CRS, including life-threatening and fatal reactions. -See WBMT Policy P-G-1 and SOP P-P-78 and P-P-79 for monitoring requirements. CRS: • • • Symptoms: pyrexia, tiredness, cardiac failure, tachycardia, cardiac arrythmias, dyspnoea, hypoxia, capillary leak syndrome, chills, renal impairment, headache, malaise, transaminitis, nausea, diarrhoea, hypotension. Temperature, blood pressure and oxygen saturation monitored 4-hourly after Brexucel administration on Day 0 and then twice daily as directed in accordance with local procedures. This must be documented, and CRS graded on the WBMT CRS Assessment Form in the patient’s notes. ICANS: • Symptoms: seizures, somnolence, headaches, confusion, agitation, speech disorders, tremor, encephalopathy, ataxia, memory impairment, mental status changes, hallucinations, depressed level of consciousness, delirium, dysmetria. • ICE score of the patient must be assessed twice daily and documented on the WBMT ICE Assessment Form in the patient’s notes. Version 1(August 2023) Page 2 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Dose Modifications As a cell-based therapy and based on the mechanism of action, renal and hepatic impairment is not expected to impact brexucabtagene autoleucel expansion and cellular kinetics; hence no formal renal and hepatic impairment studies have been performed. The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Confirm with consultant before proceeding if there are signs of possible disease relapse. Hepatic Impairment No dose modification is recommended for hepatic dysfunction in those receiving fludarabine. Severe hepatic impairment may be associated with a decreased activation of cyclophosphamide. This may alter the effectiveness of the cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected. Renal Impairment Drug Cyclophosphamide Creatinine Clearance (ml/min) Greater than 50 30-50 Less than 30 Dose (% of original dose) 100% 75% High dose therapy not generally undertaken Fludarabine Greater than 70 50-69 30-49 Less than 30 100% Reduce dose by 20% Reduce dose by 40% Contraindicated -do not use fludarabine (consider alternative lymphodepletion regimen) Other Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of the cellular therapy and therefore, they should not be administered Version 1(August 2023) Page 3 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) as part of the pre-medication. However, corticosteroids may be used in the treatment of CRS or ICANS under consultant advice. Cautions with Brexucel treatment: • Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies. • Active uncontrolled infection or inflammatory disease. • Active GVHD. Regimen Drug Mesna Dose 200 mg/m2 Days -2 Cyclophosphamide 900 mg/m2 -2 Mesna 400 mg/m2 -2 Fludarabine 25mg/m2 -4, -3, -2 Brexucel Target dose: 0 (brexucabtagene 1 x106 cells/ kg autoleucel) Route Intravenous bolus in 100ml sodium chloride 0.9% over 15 minutes to start at the same time as the cyclophosphamide infusion Intravenous infusion in 1000ml sodium chloride over 60 minutes Oral for two doses taken at 2 and 6 hours after the start of the cyclophosphamide infusion Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion of approx. 68ml within 30 minutes -see below Version 1(August 2023) Page 4 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Dose Information • Lymphodepleting regimen must only be started after availability of Brexucel is confirmed. • Cyclophosphamide will be dose banded in accordance with national dose banding table (20mg/ml). • Mesna (intravenous) will be dose banded according to the national dose bands (national dose banding table-mesna). • Mesna (oral) will be rounded to the nearest 400mg (up if halfway) • Fludarabine will be dose banded according to the national dose band (25mg/ml). • A minimum period of time must elapse between last dose of conditioning chemotherapy and CAR-T infusion, and a longer period is required for patients with renal insufficiency. This information can be found on the patient’s CAR-T cell schedule. • CAR-T administration should not occur out of core hours or over the weekend. • Brexucel has a target dose of 1 x106 cells/ kg. However, the maximum dose is 1 x108 cells for 100kg and above. The dose will vary between patients. Version 1(August 2023) Page 5 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Administration Information Brexucel • Brexucel contains genetically modified human blood cells. Exposure to Brexucel must be avoided. Procedures for handling, personal protective equipment, spills and waste disposal must be adhered to. • Brexucel cells are cryopreserved in a bag and require thawing prior to administration. -See WBMT SOP P-P-78. • The cells must be administered gravimetrically and must not be administered via a volumetric pump, as there is no data to assure cell integrity is maintained via a pump. • Administer via a giving set with a non-leukodepleting filter • Cell infusion must begin within 30 minutes of thaw completion time. • The infusion must be administered over a maximum of 30 minutes. The start and stop time of infusion must be documented. • Gently agitate the bag during infusion to prevent cell clumping • Once the full volume of Brexucel has been administered, rinse the tubing at the same rate with 0.9% sodium chloride solution to ensure all Brexucel is delivered. Once completed, the infusion bag and giving set must be disposed of in clinical waste, in accordance with Trust policy. • If the bag is not fully administered, this must be documented and the consultant & pharmacist notified. The manufacturer must be informed and the remaining Brexucel should be discarded in clinical waste, with their approval. • A GM spill-kit must be transported with Brexucel and available on the ward of administration. Local procedures must be followed in the event of a spill. • Local guidelines on handling of waste of human-derived-materials must be followed in case of accidental exposure. Work surfaces and materials which have potentially been in contact with Brexucel must be decontaminated with approved disinfectants. • See WBMT SOP P-P-78, P-P-79 and Policy P-G-1 for further administration direction. Version 1(August 2023) Page 6 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Extravasation • Cyclophosphamide – non-vesicant • Mesna -neutral • Fludarabine – non-vesicant Additional Therapy • Antiemetics - metoclopramide 10mg three times a day oral or intravenous - ondansetron 8mg twice a day oral or intravenous • Anti-infective prophylaxis as follows: - Aciclovir 400mg oral twice a day - Fluconazole 100mg once a day - Pentamidine 300mg nebuliser during lymphodepletion. To be continued every 28 days until count recovery sufficient for co-trimoxazole use at consultant advice. - Posaconazole 300mg once daily if prolonged neutropenia or previous invasive fungal infection • Gastric protection with a proton pump inhibitor or a H2 antagonist to commence on first day on lymphodepletion until platelet count > 50 x109/L • Mesna intravenous at the start of cyclophosphamide infusion. - Oral mesna 400mg/m2 for two doses taken at 2 and 6 hours after the start of the cyclophosphamide infusion. • Mouthwashes according to local or national policy on the treatment of mucositis. May include: - Nystatin 1ml four times a day - Sodium chloride 0.9% 10ml four times a day • Prior to the administration of the Brexucel - Chlorphenamine 10mg intravenous - Paracetamol 1000mg oral Version 1(August 2023) Page 7 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) Pethidine 25mg intravenous can be administered under the supervision of a doctor for the treatment of rigors. • Seizure prophylaxis may be considered due to the risk of neurotoxicity associated with Brexucel or if the patient has a history of seizures. - Levetiracetam 500mg twice daily orally commencing on the first day of lymphodepletion until day +30. - For weaning, this may then be reduced to 250mg orally twice daily for two weeks, then 250mg once daily for one week and then stopped. • Tocilizumab must be prescribed as when required in advance of CAR-T infusion, in the event of CRS. - Tocilizumab 8mg/kg (maximum 800mg) intravenously 8-hourly if required. Maximum of four doses. - Four doses of tocilizumab must be available on the ward prior to infusion of Brexucel. Follow local procedures for administration. • Tumour lysis syndrome (TLS) prophylaxis should be prescribed according to the individual patient TLS risk and at consultant review. This must start on the day of lymphodepletion and be re-reviewed on the day of Brexucel infusion. TLS prophylaxis may include: - Allopurinol 300mg oral once a day - Rasburicase 7.5mg intravenous injection once a day References 1. Dosage Adjustments for Cytotoxics in Hepatic Impairment January 2009 University College London Hospitals 2. P-P-78 Wessex Blood and Marrow Transplant – CAR-T and IEC infusion procedure Version 1.3 3. P-P-79 Wessex Blood and Marrow Transplant – Immune effector cells including CAR-T cells policy Version 2.1 4. P-G-1 Wessex Blood and Marrow Transplant -Patient monitoring after CAR-T cell infusion Version 1.1 5. Pan UK Pharmacy Working Group for ATMPs -Supportive medications recommended for adults receiving licensed chimeric antigen receptor -T (CAR-T) cell therapy Version 1 May 2022 6. Pan UK Pharmacy Working Group for ATMPs -Medication restrictions for patients having CAR-T cell therapy Version 4 July 2022 7. Summary of Product Characteristics for Tecartus (Great Britain) (Gilead Sciences Ltd) -Last updated 1 February 2023 8. Summary of Product Characteristics for Fludarabine (Sanofi) -Last updated 18 March 2019 9. Summary of Product Characteristics for Cyclophosphamide (Sandoz Limited) -Last updated 6 April 2021 Version 1(August 2023) Page 8 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) REGIMEN SUMMARY ALL– BREXUCEL – CYCLOPHOSPHAMIDE (900) – FLUDARABINE (25) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describe the agents that must be prescribed on the in-patient chart or general electronic prescribing system. Day – 4 1. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual CAR-T schedule for full details of the required supportive medicines. 1. Antibacterials in accordance with the individual CAR-T schedule 2. Antifungals in accordance with the individual CAR-T schedule 3. Antivirals in accordance with the individual CAR-T schedule 4. Tocilizumab 8mg/kg (maximum 800mg) intravenous 8-hourly when required in the event of CRS. Maximum four doses. 5. Metoclopramide 10mg three times a day oral or intravenous 6. Ondansetron 8mg twice a day oral or intravenous 7. Nystatin mouthwash 1ml four times a day 8. Sodium chloride 0.9% mouthwash 10ml four times a day 9. Chlorphenamine 10mg intravenous when required as a premedication 10. Paracetamol 1000mg when required as a premedication oral 11. Furosemide 20mg four times a day when required for the treatment of fluid overload oral or intravenous 12. Gastric protection 13. Heparin line lock in accordance with Trust central venous access device management procedure 14. Consider levetiracetam 500mg twice daily oral 15. Mesna oral 400mg/m2 for two doses to be taken at 2 and 6 hours after the start of the cyclophosphamide infusion on Day -2. 16. Reminders for chemotherapy administration and Brexucel. Ensure patient has been issued with Brexucel treatment alert card. 2. Warning – Check blood transfusion status Administration instructions Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 3. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Day – 3 4. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Day – 2 5. Mesna 200mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 15 minutes Administration Instructions The mesna infusion should begin at the same time as the cyclophosphamide infusion. Oral mesna 400mg/m2 for two doses at 2 and 6 hours after the start of the cyclophosphamide infusion to be prescribed on in-patient chart. If the patient is vomiting please inform the medical staff and consider administering the mesna intravenously. Version 1(August 2023) Page 9 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) 6. Cyclophosphamide 900mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 7. Fludarabine 25mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Day 0 8. Chlorphenamine 10mg intravenous Administration Instructions Administer 30 minutes prior to Brexucel. Check on the in-patient system if the patient has already received a dose 9. Paracetamol 1000mg oral Administration Instructions Administer 30 minutes prior to Brexucel. Check to ensure the patient has not already been administered paracetamol. The maximum dose is 4000mg/24 hours. 10. Brexucel (brexucabtagene autoleucel) 1 dose intravenous infusion Administration Instructions Prescribed dose for this patient: ……………………… The cells must be administered gravimetrically and must not be administered via a volumetric pump. Administer via a giving set with a non-leukodepleting filter and primed with sodium chloride 0.9%. Brexucel infusion should commence within 30 minutes of thaw completion time. Infuse over a maximum of 30 minutes. Version 1(August 2023) Page 10 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25) DOCUMENT CONTROL Version 1 Date August 2023 Amendment None Written By Madeleine Norbury Pharmacist Approved By Hwai Jing Hiew Consultant This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; University Hospital Southampton NHS Foundation Trust 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(August 2023) Page 11 of 11 Acute Lymphoblastic Leukaemia – Brexucabtagene autoleucel – Cyclophosphamide (900) – Fludarabine (25)
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Endometrial Carboplatin-Cisplatin-PaclitaxelRT(21day)

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC5)-CISPLATIN-PACLITAXEL RT Regimen • Endometrial-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Indication • The treatment of endometrial carcinoma • WHO performance status 0, 1, 2 Toxicity Drug Carboplatin Cisplatin Paclitaxel Adverse Effect Thrombocytopenia, peripheral neuropathy, nephrotoxicity at high doses, electrolyte disturbances Neuropathy, nephrotoxicity, ototoxicity Hypersensitivity, hypotension, bradycardia, peripheral neuropathy, myalgia and back pain on 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 each cycle • EDTA or calculated creatinine clearance prior to each cycle Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. 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 1.1 (May 2023) Page 1 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Haematological Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Prior to each cycle the following criteria must be met; Criteria Neutrophil Platelets Eligible Level equal to or more than 1.5x109/L equal to or more than 100x109/L Cisplatin Toxicity Haematological Neutrophil less than 1.5x109/L Platelets less than 100x109/L Renal Toxicity GFR less than 50ml/min or 40mL/min measured creatinine or EDTA) Neurological Neuropathy 2 or greater Adjustment Remarks Delay for 7 days Delay for 7 days If recovery requires longer than 7 days stop the cisplatin If recovery requires longer than 7 days stop the cisplatin Delay for 7 days If recovery requires longer than 7 days stop the cisplatin. Do not use if the creatinine clearance as calculated by Cockroft is less than 40mL/min Stop the cisplatin Carboplatin and Paclitaxel Neutrophils (x109/L) 1.5 or greater less than 1.5 Platelets (x109/L) 100 or above 50-99 less than 50 Dose Modifications (carboplatin and paclitaxel) 100% Delay for 7 days. If the counts recover to at least 1.5x109/L within this time continue with the full dose. If the counts recover to 1x109/L resume treatment but add in growth factors. If the neutrophils do not recover to more than 1.5x109/L by the third week or if there is a second recurrence (with dose reduction) of neutrophils less than 1.5x109/L not resolving after 14 days then discontinue carboplatin and continue with single paclitaxel. Dose Modifications (carboplatin and paclitaxel) 100% Delay for 7 days. If the counts recover to at least 100x109/L within this time then continue with the full dose. If counts recover within 14 days the continue with the full dose of paclitaxel but reduce the dose of carboplatin to AUC 4. If counts do not recover within 7 days or repeated delays are required then delay until recovery then reduce dose by 20% Delay until recovery then reduce dose by 50% Version 1.1 (May 2023) Page 2 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Hepatic Impairment Drug Carboplatin Bilirubin (μmol/L) N/A AST/ALT units N/A Dose No dose adjustment needed Cisplatin N/A N/A No dose adjustment needed Paclitaxel less than 21 21-26 27-51 52-85 greater than 85 and less than 10xULN or greater than 10xULN 175mg/m2 135mg/m2 75mg/m2 50mg/m2 Contra indicated Renal Impairment Drug Carboplatin* Creatinine Clearance (ml/min) less than 20 Dose Omit Cisplatin Less than 40mL/min Do not use if the creatinine clearance as calculated by Cockroft is less than 40mL/min Paclitaxel N/A No dose adjustment needed * Significant changes in GFR of more than 10% may require dose adjustment. 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. For all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 1 or below. The dose of the causative agent should then be reduced to 75% of the original dose or discontinued as appropriate. Regimen Cisplatin The first concurrent cycle of cisplatin should be given within days 1-3 of radiotherapy and the second cycle 3 weeks after the first cycle (4th week of radiotherapy, within days 22-24, 16-18 Version 1.1 (May 2023) Page 3 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT of radiotherapy fractions). It will be set as a 21 day cycle for 2 cycles. The dates can be adjusted to fit with radiotherapy. On occasion the MDT may recommend giving the carboplatin-paclitaxel prior to the cisplatin-radiotherapy. For example if the risk of metastasis is significantly greater than that of local recurrence. 21 day cycle for 2 cycles Drug Cisplatin Dose 50mg/m2 Days 1 Administration Intravenous infusion in 1000ml sodium chloride 0.9% with 20mmol potassium chloride over a minimum of 120 minutes. The maximum rate is 1mg/mL. 21 day cycle for 4 cycles Adjuvant carboplatin and paclitaxel should be started within 3 weeks after termination of radiotherapy, and preferably 3-4 weeks after the last administration of cisplatin. There will be a 21 day gap set up in ARIA, the start date can be adjusted as necessary. Before starting adjuvant carboplatin and paclitaxel, the toxicity of the concomitant chemoradiotherapy should be resolved to less than grade 2. AUC for carboplatin should in principle be recalculated at each cycle but should at least be recalculated in case of increasing serum creatinine (increase of 10% and/or out of normal range) and/or weight changes. Drug Carboplatin Paclitaxel Dose AUC5 (maximum dose 790mg) 175mg/m2 Days 1 1 Administration Intravenous infusion in 500ml glucose 5% over 60 minutes Intravenous infusion in 500ml sodium chloride 0.9% over 180 minutes. Dose Information • The recommended maximum dose when using a calculated creatinine clearance at AUC5 is 750mg (creatinine clearance 125ml/min). This is not a dose included in the national dose banding table. The maximum dose has been set at 790mg in ARIA. Please check if this dose is appropriate. If you have an obese patient or an individual with a calculated creatinine clearance above 125ml/min please seek advice from the relevant consultant. • It should be noted that the dose of carboplatin may need to be altered if there is a change (improvement or reduction) in renal function of more than 10% from the previous cycle. Version 1.1 (May 2023) Page 4 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT • Carboplatin will be dose banded in accordance with the national dose bands (10mg/ml) • The maximum dose of carboplatin for AUC 5 is 750mg. This will be set as 790mg in ARIA to comply with national dose bands. • Cisplatin will be dose banded in accordance with the national dose bands (1mg/mL) • Paclitaxel will be dose banded in accordance with the national dose bands (6mg/mL) Administration Information Extravasation • Carboplatin – irritant • Cisplatin - exfolliant • Paclitaxel - vesicant Other • Hypersensitivity reactions tend to occur with the first or second infusion of paclitaxel. Paclitaxel infusion should be interrupted for minor symptoms such as flushing or localised rashes. If these resolve promptly (within 5 minutes) the infusion may be restarted at a lower rate with intensive monitoring. Immediately discontinue the infusion for server reactions which include profound hypotension, bronchospasm and generalised erythema. • Paclitaxel must be administered via a non-PVC administration set containing an in-line 0.22 micron filter. Additional Therapy • Cisplatin Antiemetics 15-30 minutes prior to chemotherapy - aprepitant 125mg oral - dexamethasone 4mg - ondansetron 8mg As take home medication - aprepitant 80mg once a day for 2 days starting on day two of the cycle oral - dexamethasone 4mg once a day for 3 days starting on day two of the cycle oral - ondansetron 8mg twice a day for 3 days starting on the evening of day 1 oral - metoclopramide 10mg three times a day when required oral Version 1.1 (May 2023) Page 5 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Cisplatin pre and post hydration as follows; Pre Furosemide 40mg oral or intravenous 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Post 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Patients should be advised to drink at least 3 litres of fluid in the 24 hours after administration of cisplatin. • Carboplatin and Paclitaxel Premedication to reduce of risk of hypersensitivity reaction 30 minutes before chemotherapy - chlorphenamine 10mg intravenous - dexamethasone 20mg oral or intravenous - H2 antagonist according to local formulary choice and availability Antiemetics 15-30 minutes prior to chemotherapy - ondansetron 8mg oral or intravenous As take home medication - dexamethasone 4mg oral twice a day for 3 days - metoclopramide 10mg oral three times a day as required 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. References 1. PORTEC Trial Protocol. Randomized phase III Trial Comparing Concurrent Chemoradiation and Adjuvant Chemotherapy with Pelvic Radiation Alone in High Risk and Advanced Stage Endometrial Carcinoma: PORTEC-3. Trial Protocol Version 12 April 2012. Version 1.1 (May 2023) Page 6 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT REGIMEN SUMMARY Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Cisplatin day 1 1. Aprepitant 125mg oral Administration instructions: administer 15-30 minutes before SACT 2. Dexamethasone 4mg oral or intravenous equivalent dose Administration instructions: administer 15-30 minutes before SACT 3. Ondansetron 8mg oral or intravenous Administration instructions: administer 15-30 minutes before SACT 4. Furosemide 40mg oral or intravenous Administration instructions: To be administered prior to pre-hydration. This may be given as furosemide 40mg IV stat if required. 5. 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Administration instructions: Monitor fluid balance, urine output and weight 6. Cisplatin 50mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% with 20mmol potassium chloride at a maximum rate of 1mg cisplatin/minute (minimum time 120 minutes) 7. 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Administration instructions: Monitor fluid balance, urine output and weight Take Home Medicines (day 1. Aprepitant 80mg once a day for two days starting on the day after cisplatin oral Administration Instructions Take 80mg once a day for two days starting on the day after cisplatin 2. Dexamethasone 4mg once a day for three days starting on the day after cisplatin oral Administration Instructions Take 4mg once a day for three days starting on day after cisplatin 3. Ondansetron 8mg twice a day for three days starting on the evening of the day of cisplatin administration Administration Instructions Take 8mg twice a day for three days starting on the evening of the day of cisplatin administration 4. Metoclopramide 10mg three times a day when required oral Administration Instructions Please supply 28 days or an original pack Version 1.1 (May 2023) Page 7 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT Carboplatin-Paclitaxel Day 1 1. Chlorphenamine 10mg intravenous Administration instructions: administer 30 minutes before SACT 2. Dexamethasone 20mg intravenous Administration instructions: administer 30 minutes before SACT 3. H2 antagonist according to local formulary choice and availability Administration Instructions: Administer according to local formulary choice and availability one of the following 30 minutes prior to chemotherapy; - famotidine 20mg oral once only - nizatidine 150mg oral once only - ranitidine 150mg oral once only - ranitidine 50mg intravenous once only There are stock shortages of H2 antagonists. The administration may proceed without these agents being given unless there is a specific instruction from the prescriber in the ARIA journal that a H2 antagonist must be administered. Many Trusts do not administer an H2 antagonist from cycle three onwards. They have been left in the ARIA protocols so that decisions can be made on an individual Trust and patient basis. 4. Ondansetron 8mg oral or intravenous Administration instructions: administer 15-30 minutes before SACT 5. Paclitaxel 175mg/m2 in 500ml sodium chloride 0.9% intravenous infusion over 180 minutes. Administration instructions: Administer via a non-PVC administration set containing an in-line 0.22 micron filter. 6. Warning - Carboplatin Maximum Dose Administration Instructions The dose of carboplatin is capped at a creatinine clearance of 125ml/min. The internationally recommended maximum dose of carboplatin for AUC 5 is 750mg. The national dose bands do not contain this dose so the cap has been set at 790mg in ARIA. Please check this dose is appropriate for your patient. 7. Carboplatin AUC 5 (maximum dose 790mg) intravenous infusion in 500ml glucose 5% over 60 minutes. Take Home Medicines 8. Dexamethasone 4mg oral twice a day for three days starting the day after chemotherapy 9. Metoclopramide 10mg oral three times a day for three days then 10mg three times a day when required for nausea Administration Instructions Please supply 28 tablets or an original pack as appropriate Version 1.1 (May 2023) Page 8 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT DOCUMENT CONTROL Version Date 1.1 May 2023 1 Feb 2021 Amendment Carboplatin amended with national dose bands and maximum dose amended. Administration instructions added to regimen summary Warning added None Written By Approved By Alexandra Pritchard Tom Hurst Pharmacist Pharmacy Technician Dr Deborah Wright Pharmacist Dr V McFarlane Consultant Clinical Oncologist Dr R Tarrant Consultant Clinical 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 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 2023) Page 9 of 9 Uterine-Carboplatin (AUC5)-Cisplatin-Paclitaxel RT
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Brexucel - Cyclophosphamide (500) - Fludarabine (30)

Description
Chemotherapy Protocol CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T) THERAPY MCL – BREXUCEL – CYCLOPHOSPHAMIDE (500) – FLUDARABINE (30) This regimen will only be available to prescribe at the Wessex Blood and Marrow Transplant Unit Regimen  Mantle Cell Lymphoma - Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Indication  CAR-T therapy with Brexucel (brexucabtagene autoleucel) for the treatment of adult patients with: - Relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton's tyrosine kinase (BTK) inhibitor. (See separate Acute Lymphoblastic Leukaemia protocol for use in ALL)  Lymphodepleting chemotherapy must be administered prior to Brexucel. This protocol includes both lymphodepletion and CAR-T administration.  For autologous use only. Toxicity Drug Cyclophosphamide Fludarabine Brexucel (brexucabtagene autoleucel) Adverse Effect Chemical haemorrhagic cystitis, leucopenia, nausea and vomiting, hepatic toxicity, altered carbohydrate metabolism, pancreatitis, hyper and hypoglycaemia, inappropriate secretion of antidiuretic hormone, interstitial pulmonary fibrosis. Transfusion related GVHD, fever, malaise, neurotoxicity, opportunistic infections, GI disturbances -nausea, vomiting, diarrhoea. Cytokine release syndrome (CRS), hepatic dysfunction, renal dysfunction, cardiac dysfunction, neurologic adverse reactions -immune effector cell-associated neurotoxicity syndrome (ICANS), opportunistic infections, febrile neutropenia, HBV reactivation, prolonged cytopenias, hypogammaglobulinaemia, tumour lysis syndrome (TLS), hypersensitivity reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required, these patients must receive only irradiated blood products for life. Local blood transfusion departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. Version 1.1 (May 2023) Page 1 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Symptoms of CRS or ICANS can occur weeks after infusion and therefore the patient must be issued with an alert card to carry with them at all times. Any suspected adverse reaction to a CAR-T cell infusion should be reported. Reporting forms and information can be found at – www.mhra.gov.uk/yellowcard. Consideration should also be given to reporting adverse events to the relevant manufacturer via their usual channels. Monitoring Regimen  FBC, U&Es, renal, liver and bone, CRP, coagulation screen, ferritin and LDH prior to initiating treatment and daily thereafter.  Screening for HBV, HCV and HIV must be performed before collection of cells for Brexucel manufacture.  Echocardiogram and baseline measure of lung function must be taken prior to initiating lymphodepletion Brexucel Nearly all patients treated with Brexucel experience some degree of CRS, including life-threatening and fatal reactions. -See WBMT Policy P-G-1 and SOP P-P-78 and P-P-79 for monitoring requirements. CRS:    Symptoms: pyrexia, tiredness, cardiac failure, tachycardia, cardiac arrythmias, dyspnoea, hypoxia, capillary leak syndrome, chills, renal impairment, headache, malaise, transaminitis, nausea, diarrhoea, hypotension. Temperature, blood pressure and oxygen saturation monitored 4-hourly after Brexucel administration on Day 0 and then twice daily as directed in accordance with local procedures. This must be documented, and CRS graded on the WBMT CRS Assessment Form in the patient’s notes. ICANS:  Symptoms: seizures, somnolence, headaches, confusion, agitation, speech disorders, tremor, encephalopathy, ataxia, memory impairment, mental status changes, hallucinations, depressed level of consciousness, delirium, dysmetria.  ICE score of the patient must be assessed twice daily and documented on the WBMT ICE Assessment Form in the patient’s notes. Version 1.1 (May 2023) Page 2 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Dose Modifications As a cell-based therapy and based on the mechanism of action, renal and hepatic impairment is not expected to impact brexucabtagene autoleucel expansion and cellular kinetics; hence no formal renal and hepatic impairment studies have been performed. The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Confirm with consultant before proceeding if there are signs of possible disease relapse. Hepatic Impairment No dose modification is recommended for hepatic dysfunction in those receiving fludarabine. Severe hepatic impairment may be associated with a decreased activation of cyclophosphamide. This may alter the effectiveness of the cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected. Renal Impairment Drug Cyclophosphamide Creatinine Clearance (ml/min) Greater than 50 30-50 Less than 30 Dose (% of original dose) 100% 75% High dose therapy not generally undertaken Fludarabine Greater than 70 50-69 30-49 Less than 30 100% Reduce dose by 20% Reduce dose by 40% Contraindicated -do not use fludarabine (consider alternative lymphodepletion regimen) Other Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of the cellular therapy and therefore, they should not be administered as part of the pre-medication. However, corticosteroids may be used in the treatment of CRS or ICANS under consultant advice. Version 1.1 (May 2023) Page 3 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Cautions with Brexucel treatment:  Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies.  Active uncontrolled infection or inflammatory disease.  Active GVHD. Regimen Drug Dose Cyclophosphamide 500 mg/m2 Fludarabine 30mg/m2 Days -5, -4, -3 -5, -4, -3 Brexucel Target dose: 0 (brexucabtagene 2 x106 cells/ kg autoleucel) Route Intravenous bolus over 10 minutes Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion of approx. 68ml within 30 minutes -see below Version 1.1 (May 2023) Page 4 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Dose Information  Lymphodepleting regimen must only be started after availability of Brexucel is confirmed.  Cyclophosphamide will be dose banded in accordance with national dose banding table (20mg/ml).  Fludarabine will be dose banded according to the national dose band (25mg/ml).  A minimum period of time must elapse between last dose of conditioning chemotherapy and CAR-T infusion, and a longer period is required for patients with renal insufficiency. This information can be found on the patient’s CAR-T cell schedule.  CAR-T administration should not occur out of core hours or over the weekend.  Brexucel has a target dose of 2 x106 cells/ kg. However, there is a dosing range of 1 x 106 – 2 x 106 cells/kg, with a maximum dose of 2 x108 cells. The dose will vary between patients. Version 1.1 (May 2023) Page 5 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Administration Information Brexucel  Brexucel contains genetically modified human blood cells. Exposure to Brexucel must be avoided. Procedures for handling, personal protective equipment, spills and waste disposal must be adhered to.  Brexucel cells are cryopreserved in a bag and require thawing prior to administration. -See WBMT SOP P-P-78.  The cells must be administered gravimetrically and must not be administered via a volumetric pump, as there is no data to assure cell integrity is maintained via a pump.  Administer via a Baxter non-filtered giving set primed with sodium chloride 0.9%.  Cell infusion must begin within 30 minutes of thaw completion time.  The infusion must be administered over a maximum of 30 minutes. The start and stop time of infusion must be documented.  Gently agitate the bag during infusion to prevent cell clumping  Once the full volume of Brexucel has been administered, rinse the tubing at the same rate with 0.9% sodium chloride solution to ensure all Brexucel is delivered. Once completed, the infusion bag and giving set must be disposed of in clinical waste, in accordance with Trust policy.  If the bag is not fully administered, this must be documented and the consultant & pharmacist notified. The manufacturer must be informed and the remaining Brexucel should be discarded in clinical waste, with their approval.  A Pharmacy Advanced Therapy Unit (PATU) spill-kit must be transported with Brexucel and available on the ward of administration. Local procedures must be followed in the event of a spill.  Local guidelines on handling of waste of human-derived-materials must be followed in case of accidental exposure. Work surfaces and materials which have potentially been in contact with Brexucel must be decontaminated with approved disinfectants.  See WBMT SOP P-P-78, P-P-79 and Policy P-G-1 for further administration direction. Version 1.1 (May 2023) Page 6 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Extravasation  Cyclophosphamide – non-vesicant  Fludarabine – non-vesicant Additional Therapy  Antiemetics - metoclopramide 10mg three times a day oral or intravenous - ondansetron 8mg twice a day oral or intravenous  Anti-infective prophylaxis as follows: - Aciclovir 400mg oral twice a day - Pentamidine 300mg nebuliser during lymphodepletion. To be continued every 28 days until count recovery sufficient for co-trimoxazole use at consultant advice. - Posaconazole 300mg once daily if prolonged neutropenia or previous invasive fungal infection  Gastric protection with a proton pump inhibitor or a H2 antagonist to commence on first day on lymphodepletion until platelet count > 50 x109/L  Mouthwashes according to local or national policy on the treatment of mucositis. May include: - Nystatin 1ml four times a day - Sodium chloride 0.9% 10ml four times a day  Prior to the administration of the Brexucel - Chlorphenamine 10mg intravenous - Paracetamol 1000mg oral Pethidine 25mg intravenous can be administered under the supervision of a doctor for the treatment of rigors.  Seizure prophylaxis may be considered due to the risk of neurotoxicity associated with Brexucel or if the patient has a history of seizures. - Levetiracetam 500mg twice daily orally commencing on the first day of lymphodepletion until day +30. Version 1.1 (May 2023) Page 7 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) - This may then be reduced to 250mg orally twice daily for one week and then stopped.  Tocilizumab must be prescribed as when required in advance of CAR-T infusion, in the event of CRS. - Tocilizumab 8mg/kg (maximum 800mg) intravenously 8-hourly if required. Maximum of four doses. - Four doses of tocilizumab must be available on the ward prior to infusion of Brexucel. Follow local procedures for administration.  Tumour lysis syndrome (TLS) prophylaxis should be prescribed according to the individual patient TLS risk and at consultant review. This must start on the day of lymphodepletion and be re-reviewed on the day of Brexucel infusion. TLS prophylaxis may include: - Allopurinol 300mg oral once a day - Rasburicase 7.5mg intravenous injection once a day References 1. Dosage Adjustments for Cytotoxics in Hepatic Impairment January 2009 University College London Hospitals 2. P-P-78 Wessex Blood and Marrow Transplant – CAR-T and IEC infusion procedure Version 1.3 3. P-P-79 Wessex Blood and Marrow Transplant – Immune effector cells including CAR-T cells policy Version 2.1 4. P-G-1 Wessex Blood and Marrow Transplant -Patient monitoring after CAR-T cell infusion Version 1.1 5. Pan UK Pharmacy Working Group for ATMPs -Supportive medications recommended for adults receiving licensed chimeric antigen receptor -T (CAR-T) cell therapy Version 1 May 2022 6. Pan UK Pharmacy Working Group for ATMPs -Medication restrictions for patients having CAR-T cell therapy Version 4 July 2022 7. Summary of Product Characteristics for Tecartus (Great Britain) (Gilead Sciences Ltd) -Last updated 6 December 2022 8. Summary of Product Characteristics for Fludarabine (Sanofi) -Last updated 18 March 2019 9. Summary of Product Characteristics for Cyclophosphamide (Sandoz Limited) -Last updated 6 April 2021 Version 1.1 (May 2023) Page 8 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) REGIMEN SUMMARY MCL– BREXUCEL – CYCLOPHOSPHAMIDE (500) – FLUDARABINE (30) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describe the agents that must be prescribed on the in-patient chart or general electronic prescribing system. Day – 5 1. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual CAR-T schedule for full details of the required supportive medicines. 1. Antibacterials in accordance with the individual CAR-T schedule 2. Antifungals in accordance with the individual CAR-T schedule 3. Antivirals in accordance with the individual CAR-T schedule 4. Tocilizumab 8mg/kg (maximum 800mg) intravenous 8-hourly when required in the event of CRS. Maximum four doses. 5. Metoclopramide 10mg three times a day oral or intravenous 6. Ondansetron 8mg twice a day oral or intravenous 7. Nystatin mouthwash 1ml four times a day 8. Sodium chloride 0.9% mouthwash 10ml four times a day 9. Chlorphenamine 10mg intravenous when required as a premedication 10. Paracetamol 1000mg when required as a premedication oral 11. Furosemide 20mg four times a day when required for the treatment of fluid overload oral or intravenous 12. Gastric protection 13. Heparin line lock in accordance with Trust central venous access device management procedure 14. Consider levetiracetam 500mg twice daily oral 14. Reminders for chemotherapy administration and Brexucel. Ensure patient has been issued with Brexucel treatment alert card. 2. Warning – Check blood transfusion status Administration instructions Patients treated with fludarabine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 3. Cyclophosphamide 500mg/m2 intravenous bolus over 10 minutes 4. Fludarabine 30mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Day – 4 5. Cyclophosphamide 500mg/m2 intravenous bolus over 10 minutes 6. Fludarabine 30mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Day – 3 7. Cyclophosphamide 500mg/m2 intravenous bolus over 10 minutes 8. Fludarabine 30mg/m2 intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Version 1.1 (May 2023) Page 9 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) Day 0 9. Chlorphenamine 10mg intravenous Administration Instructions Administer 30 minutes prior to Brexucel. Check on the in-patient system if the patient has already received a dose 10. Paracetamol 1000mg oral Administration Instructions Administer 30 minutes prior to Brexucel. Check to ensure the patient has not already been administered paracetamol. The maximum dose is 4000mg/24 hours. 11. Brexucel (brexucabtagene autoleucel) 1 dose intravenous infusion Administration Instructions Prescribed dose for this patient: ……………………… The cells must be administered gravimetrically and must not be administered via a volumetric pump. Administer via a Baxter non-filtered giving set primed with sodium chloride 0.9%. Brexucel infusion should commence within 30 minutes of thaw completion time. Infuse over a maximum of 30 minutes. Version 1.1 (May 2023) Page 10 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30) DOCUMENT CONTROL Version Date 1 December 2022 1.1 May 2023 Amendment None Spelling corrections Written By Madeleine Norbury Pharmacist Madeleine Norbury Pharmacist Approved By Dr Rob Lown Consultant Haematologist Dr Rob Lown Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; University Hospital Southampton 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 2023) Page 11 of 11 Mantle Cell Lymphoma – Brexucabtagene autoleucel – Cyclophosphamide (500) – Fludarabine (30)
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