IBRUTINIB + Rituximab, Treatment Period - ENRICH Study

Transcription

1 IBRUTINIB + Rituximab, Treatment Period - Study Randomised, open label study of Rituximab/Ibrutinib vs Rituximab/Chemotherapy in older patients with untreated mantle cell lymphoma ***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 Untreated Mantle Cell Lymphoma Treatment Intent Palliative Anti-Emetics Pre-chemotherapy nil Post-chemotherapy A Single Dose Rituximab Day 1 Ibrutinib (Trial Stock) 560mg (4x140mg capsules) Oral once daily continuously Prednisolone 100mg Oral 30 minutes prior to Chlorphenamine 10mg Intravenous bolus 30 minutes prior to Hydrocortisone 100mg Intravenous bolus 30 minutes prior to Paracetamol 1g Oral 30 minutes prior to Rituximab* 375mg/m 2 Intravenous infusion in 500ml sodium chloride 0.9% using first infusion rate Pethidine 25mg Intravenous bolus STAT if required for febrile infusion reaction Allopurinol 300mg Oral once daily for at least 1 st cycle (See notes below) Co-trimoxazole 480 mg Oral once daily for the duration of treatment with Ibrutinib Aciclovir 400 mg Oral twice daily for the duration of treatment with Ibrutinib AUTHORISED BY: Dr J Addada PAGE 1 of 7

2 * Rituximab may be given as a split dose, see below. Confirmed with Trial Sponsor, dated & Split Dose Rituximab Day 1 Ibrutinib (Trial Stock) Prednisolone Chorphenamine Hydrocortisone Paracetamol 560mg (4x140mg capsules) 100mg 10mg 100mg 1g Oral once daily continuously Oral 30 minutes prior to Intravenous bolus 30 minutes prior to Intravenous bolus 30 minutes prior to Oral 30 minutes prior to Rituximab 100mg Intravenous infusion in 100ml sodium chloride 0.9% over 4 hours Pethidine 25mg Intravenous bolus STAT if required for febrile infusion reaction Allopurinol 300mg Oral once daily for at least 1 st cycle (See notes below) Cotrimoxazole 480 mg Oral once daily for the duration of treatment with Ibrutinib. Aciclovir 400 mg Oral twice daily for the duration of treatment with Ibrutinib. Day 2 Prednisolone 100mg Oral 30 minutes prior to Chorphenamine 10mg Intravenous bolus 30 minutes prior to Hydrocortisone 100mg Intravenous bolus 30 minutes prior to Paracetamol 1g Oral 30 minutes prior to Rituximab 375mg/m 2 minus 100mg (i.e. remainder of dose) Intravenous infusion in 500ml sodium chloride 0.9% using first infusion rate Pethidine 25mg Intravenous bolus STAT if required for febrile infusion reaction AUTHORISED BY: Dr J Addada PAGE 2 of 7

3 Frequency & Duration Rituximab is given every 21 or 28 days for 6 or 8 cycles (depending on randomisation), see Protocol for more details. Ibrutinib is given daily from Day 1, Cycle 1 until disease progression, withdrawal from treatment or the end of study. Notes: 1. Baseline Investigations Inclusion criteria: Absolute neutrophil count >1.0 x 10 9 /l or Platelets >100 x 10 9 /l independent of growth factor support or unless related to lymphoma Calculated creatinine clearance >30ml/min Hepatic function o Alanine aminotransferase (ALT) <3 x upper limit of normal (ULN) o Aspartate aminotransferase (AST) <3 x ULN o Total bilirubin 1.5 x ULN, unless bilirubin rise is due to Gilbert s syndrome or of non-hepatic origin 2. Randomisation should take place in enough time before cycle 1, day 1 to allow preparation time at the site pharmacy. 3. BSA will be capped at 2.2m 2. National dose banding tables can be used 4. Rituximab This section should be read in conjunction with the Guidelines for the Administration of Rituximab Premedication consisting of analgesia and an antihistamine and an intravenous corticosteroid should always be administered 30 minutes before each infusion of. (e.g. paracetamol 1g oral STAT and chlorphenamine 4mg oral or 10mg IV bolus STAT and hydrocortisone 100mg IV STAT). In addition pethidine 25mg IV should be available in case of a severe infusion reaction. Premedication consisting of 100mg prednisolone orally given 30 minutes before should be given in cycle 1 in addition to the normal premedication listed above. If the patient develops a severe febrile reaction to, consider giving 100mg prednisolone prior to in subsequent cycles. Rituximab doses should be rounded to the nearest 100mg. Pre-made infusions bags can be used. Use rate calculator to assist with rate escalation of infusion. Only when the patient has successfully received a full dose of at the licensed rate should infusion by the rapid rate be considered. AUTHORISED BY: Dr J Addada PAGE 3 of 7

4 Occurrence of an infusion-related event or hypersensitivity Stop the infusion and contact a doctor. When symptoms improve, continue the infusion at half the rate prior to the reaction. Accelerate the infusion rate more slowly as tolerated by the patient. 5. Ibrutinib a) 560 mg (4 x 140mg capsules) of ibrutinib should be taken orally once daily with approximately 240mls of water. The capsules should be swallowed intact with or without food at approximately the same time each day. The first dose will be given in clinic on day 1, cycle 1 after is administered. For all subsequent cycles, the participant will take ibrutinib at home prior to attending clinic. b) If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the normal schedule the following day. If the dose is more than 6 hours late, the dose should not be taken and the participant should take the next dose at the scheduled time the following day. c) Strongly or moderately inhibitors of CYP3A Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A can increase ibrutinib exposure and should be avoided. Strong inhibitors of CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone and cobicistat) and moderate inhibitors (e.g., voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) should be avoided. If the benefit outweighs the risk and a strong CYP3A inhibitor must be used, reduce the ibrutinib dose to 140 mg or withhold treatment temporarily (for 7 days or less). If a moderate CYP3A inhibitor must be used, reduce ibrutinib treatment to 140 mg for the duration of the inhibitor use. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during ibrutinib treatment as these contain moderate inhibitors of CYP3A. d) Strong inducers of CYP3A Administration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma concentrations by up to 90%. Avoid concomitant use of strong CYP3A AUTHORISED BY: Dr J Addada PAGE 4 of 7

5 inducers (eg, carbamazepine, rifampin, phenytoin and St. John s Wort). Consider alternative agents with less CYP3A induction. e) Anticoagulants and Antiplatelets Warfarin or equivalent vitamin K inhibitors should not be given concomitantly whilst the participant is receiving ibrutinib. For participants requiring anticoagulant therapy, LMW heparin or an alternative new oral anticoagulant drug should be considered instead. Anti-platelet drugs may be used with ibrutinib but can be associated with increased bruising and bleeding. Therefore participants on these agents should be monitored for any significant change in bruising or bleeding. f) QT Prolonging Agents Any medications known to cause QT prolongation (see Protocol, Appendix 4) should be used with caution; periodic monitoring with electrocardiograms (ECGs) and serum electrolytes should be considered. Use of these medications should first be discussed with the Chief Investigator or delegated deputy. g) Surgery Ibrutinib should be held at least 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding, see Protocol section for further details. h) Live Vaccines Use of live vaccinations is prohibited during the study and for three months after last dose of the ibrutinib. 6. Toxicities - Dose Delay, Reduction and Discontinuation Ibrutinib Possible drug toxicities: Grade 3 or greater neutropenia with infection or fever Grade 4 neutropenia (absolute neutrophil count <0.5 x 10 9 /L) Grade 3 thrombocytopenia (platelets <50 x 10 9 /L) in the presence of significant bleeding Grade 4 thrombocytopenia (platelets <25 x 10 9 /L) Grade 3 or greater non-haematological toxicity Ibrutinib Dose Modifications AUTHORISED BY: Dr J Addada PAGE 5 of 7

6 Occurrence First Second Third Fourth Action Hold ibrutinib until recovery to Grade 1; may restart at original dose level Hold ibrutinib until recovery to Grade 1; restart at one dose level lower (420 mg daily) Hold ibrutinib until recovery to Grade 1; restart a further dose level lower (280 mg daily) Discontinue ibrutinib A maximum of two dose level reductions are permitted during the study. Once the ibrutinib dose is reduced, it cannot be re-escalated. Study drug may be omitted for a maximum of 28 consecutive days for toxicity. It should be permanently discontinued in the event of a toxicity lasting more than 28 days, unless agreement is sought from the Chief Investigator. Renal Impairment No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 ml/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically. Hepatic Impairment Ibrutinib is metabolized in the liver and preliminary data shows an increase in ibrutinib exposure in patients with hepatic impairment. For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily (two capsules). For patients with moderate liver impairment (Child-Pugh class B), the recommended dose is 140 mg daily (one capsule). It is not recommended for patients with severe hepatic impairment. Rituximab No dose reductions of are recommended. Rituximab can be withheld for a maximum of 28 consecutive days. A hold greater than 28 days must be reviewed and approved by the Chief Investigator. Rituximab should be permanently discontinued if it cannot be restarted within a further 28 days due to toxicity or in the opinion of the Chief Investigator. If is discontinued for toxicity, treatment with ibrutinib may continue. 7. Supportive care Allopurinol 300mg/day is recommended for at least the first 28 days of therapy for patients in both arms of the trial. This can be given after day 28 at the discretion of the Investigator. AUTHORISED BY: Dr J Addada PAGE 6 of 7

7 GCSF may be given as per routine practice. References 1. Janssen-Cilag Ltd Summary of Product Characteristics Ibrutinib (Imbruvica), last updated 29th March 2016 (accessed online 18 th April 2016). 2. Protocol V4, 19 th October 2016 AUTHORISED BY: Dr J Addada PAGE 7 of 7