Durvalumab (previously known as MEDI 4736) Maintenance (Arm A3) PLATFORM study PLAnning Treatment For Oesophago-gastric cancer: a Randomised Maintenance therapy trial. ***See Protocol for further details*** Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Oesophageal and Gastric cancer Treatment Intent Palliative Anti-Emetics Pre-chemotherapy Post-chemotherapy Standard supportive treatments such as anti-emetics (e.g. metoclopramide), antipyrexials (e.g. paracetamol) or antihistamines (e.g. chlorphenamine) may be used alongside Durvalumab at the local investigator s discretion**. Day 1 Durvalumab 10mg/kg Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes (+/- 10 minutes) through 0.2µ in-line filter* Flush line with sodium chloride 0.9% to ensure full dose is given Day 15 Durvalumab 10mg/kg Intravenous infusion in 250ml sodium chloride 0.9% over 60 minutes (+/- 10 minutes) through 0.2µ in-line filter* Flush line with sodium chloride 0.9% to ensure full dose is given Frequency & duration: Day 1 & 15 of every 28 day cycle, for a total of 12 cycles in the absence of disease progression, unacceptable toxicity or patient withdrawal, also see note 2 below. * If Durvalumab administration has to be delayed, temporally interrupted or the infusion rate decreased for any reason, the total time between reconstitution and completion of the infusion should not exceed 6 hours. Time between reconstitution of Durvalumab AUTHORISED BY: Dr P Das PAGE 1 of 5
to start of administration should not exceed 4 hour at room temperature or 24 hours at 2-8 C. **For example: Paracetamol 1000mg Oral/IV 1 hour prior to Durvalumab, Chlorphenamine 10 mg Intravenous bolus 1 hour prior to Durvalumab Metoclopramide 20mg Oral before Durvalumab, followed by, Metoclopramide 10mg Oral four times a day. Notes: 1. Inclusion criteria: Completion of 6 cycles of standard first-line chemotherapy (platinumfluoropyrimidine based doublet or triplet regimen in HER-2 negative patients; CX/CF + trastuzumab in HER-2 positive patients). Please note: if your patient has been receiving a regime delivered every three weeks they should have completed 6 cycles. If your patient has been receiving a regime delivered every 2 weeks they should have received 8 cycles of treatment. Maintenance treatment must start within 28 days of last day of last cycle of chemotherapy Adequate bone marrow function o Absolute neutrophil count 1.5 x 10 9 /l o White blood cell count 3 x 10 9 /l o Platelets 100 x 10 9 /l o Haemoglobin 9g/dl (can be post-transfusion) Calculated creatinine clearance 50ml/min Hepatic function o Alanine aminotransferase (ALT), aspartate aminotransferase (AST) & alkaline phosphatase 2.5 x upper limit of normal (ULN) (5 ULN is acceptable if liver metastases are present) o Serum bilirubin 1.5 x ULN 2. Doses will be based on body weight. Patient s weight must be checked up to 3 days before day 1 of each cycle, as per Study Procedures section in the Protocol. Doses only need to be recalculated if weight changes by >10% from baseline. 3. Patients who complete 12 cycles of Durvalumab therapy without progressive disease should discontinue treatment and continue regular follow-up. Upon evidence of subsequent disease progression, subjects will re-commence Durvalumab treatment for up to another 12 cycles. Only one round of retreatment with Durvalumab will be allowed. AUTHORISED BY: Dr P Das PAGE 2 of 5
4. Durvalumab Dosage Adjustments Durvalumab leads to T-cell activation and proliferation, giving rise to the possibility of observing immune-related AEs (iraes). The identified risks with durvalumab monotherapy include the following: pneumonitis, ALT/AST increased, hepatitis, diarrhoea, colitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypopituitarism, type 1 diabetes mellitus, blood creatinine increased, nephritis, rash, pruritus, dermatitis, neuropathy/ neuromuscular toxicity, hypersensitivity and infusion related reaction. Patients should therefore be monitored for signs and symptoms of iraes and an immune-mediated cause of symptoms should be considered in the absence of an alternate aetiology (e.g. infection or PD). Guidelines for the management of Immune-mediated reactions Infusion-related reactions Non-immune-mediated reactions for durvalumab monotherapy are provided in the Dosing Modification and Toxicity Management Guidelines see Protocol, Appendix C. (Management of infusion-related reactions is also shown in the table below). Criteria for Discontinuation of Durvalumab A patient should not receive any further investigational product if any of the following occur: Grade 3 infusion reaction. Adverse event related to durvalumab which meets the criteria for discontinuation as defined in Protocol, Appendix C. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further dosing. Confirmation of disease progression by RECIST 1.1 criteria. If RECIST-defined disease progression occurs solely due to the appearance of new lesions, then patients may be permitted to continue therapy if they are felt to be deriving benefit. Durvalumab-Related Infusion Reactions - Grading Infusion reactions will be graded according to the CTCAE (Version 4.0) definition of an allergic reaction/infusion reaction and anaphylaxis, as below: Grade 1: Transient flushing or rash, drug fever <38º C (<100.4º F); intervention not indicated. Grade 2: Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated for <24 hours. Grade 3: Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related edema/angioedema; hypotension. Grade 4: Life-threatening consequences; urgent intervention indicated. AUTHORISED BY: Dr P Das PAGE 3 of 5
For dose modification and management of durvalumab relation infusion reactions please follow the guidance in table below: Severity Grade Any grade Grade 1 Grade 2 Dose Modifications The infusion rate of study drug/study regimen may be decreased by 50% or temporarily interrupted until resolution of the event The infusion rate of study drug/study regimen may be decreased 50% or temporarily interrupted until resolution of the event Subsequent infusions may be given at 50% of the initial infusion rate Grade 3/4 Permanently discontinue study drug/study regimen Toxicity Management - Management per institutional standard at the discretion of investigator - Monitor subjects for signs and symptoms of infusion-related reactions (e.g., fever and/or shaking chills, flushing and/or itching, alterations in heart rate and blood pressure, dyspnea or chest discomfort, skin rashes etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, For Grade 1 or Grade 2: - Paracetamol and/or antihistamines may be administered per institutional standard at the discretion of the investigator - Consider premedication per institutional standard prior to subsequent doses For Grade 3 or 4: Manage severe infusion-related reactions per institutional standards (e.g., IM adrenaline, followed by IV chlorpeniramine and ranitidine, and IV glucocorticoid) 5. Non-permitted medication Any cytotoxic chemotherapy. Any other novel targeted drugs, biological response modifiers or investigational agents. Live attenuated vaccines within 30 days of last dose of durvalumab. Immunosuppressive medications, including but not limited to methotrexate, azathioprine, TNFa-blockers, or systemic corticosteroids at doses beyond 10 mg/day of prednisone or equivalent. Use of immunosuppressive medications for the management of investigational product-related AEs and in subjects with contrast allergies is permitted. In addition, the use of inhaled and intranasal corticosteroids is permitted. AUTHORISED BY: Dr P Das PAGE 4 of 5
References: 1. PLATFORM Protocol version 7.0, 2 nd May 2017 2. PLATFORM Pharmacy Pack v3 4 th August 2017 AUTHORISED BY: Dr P Das PAGE 5 of 5