A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Lymphomas

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and tolerability of the combination treatment of ibrutinib and MEDI4736 in subjects with relapsed or refractory lymphomas.

Official Title
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A Multi-Center Open-Label Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With MEDI4736, in Subjects With Relapsed or Refractory Lymphomas

Conditions
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Diffuse Large B-Cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: MEDI4736


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically documented relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) Measurable disease sites on CT scan (>1.5 cm in longest dimension) Adequate hematologic function: Absolute Neutrophil Count >1500 cells/mm3 Platelets >50000 cells/mm3 Hemoglobin >8.0 g/dL Adequate hepatic and renal function: AST or ALT ≤2.5 x ULN Bilirubin ≤1.5 x ULN Estimated creatinine clearance (Cockcroft-Gault) >40 mL/min ECOG 0 or 1 Exclusion Criteria: Received prior therapies: ibrutinib, or other BTK inhibitor and/or anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody Requires treatment or prophylaxis with a strong cytochrome P450 (CYP) 3A inhibitor Primary CNS lymphoma or evidence of CNS involvement by lymphoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b/ 2: Follicular lymphoma expansion cohort<br>In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. | Drug: Ibrutinib<br> <br> Drug: MEDI4736<br> <br> |
| Experimental: Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort<br>In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. | Drug: Ibrutinib<br> <br> Drug: MEDI4736<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b/2 : Overall Response Rate of Number of Participants | The response criteria is measured based on the revised criteria for malignant lymphoma described by the International Working Group for NHL (Cheson 2014). | From the date of first study treatment until progressive disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b/ 2: Duration of Response |  | Time from the date of initial response to the date of disease progression or the date of death due to any cause, whichever occurs first. | 
| Phase 1b/ 2: Progression-free Survival (PFS) |  | first dose date of study drug (ibrutinib or MEDI4736) to the first documentation of disease progression | 
| Phase 1b/2: Overall Survival |  | First dose date of study drug (ibrutinib or MEDI4736) to the date of death due to any cause | 
| Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib | Maximum observed plasma concentration of ibrutinib during the dosing interval on Lead-In Day 6/7 (ibrutinib only) or Cycle 3 Day 1 (ibrutinib + MEDI) | Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose) | 
| Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib | Time to corresponding maximum observed plasma concentration of ibrutinib during the dosing interval on Lead-In Day 6/7 (ibrutinib only) or Cycle 3 Day 1 (ibrutinib + MEDI) | Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose) | 
| Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib | Ibrutinib AUC0-24h calculated using linear trapezoidal summation after dosing from time 0 to 24 hours on Lead-In Day 6/7 (ibrutinib only) or Cycle 3 Day 1 (ibrutinib + MEDI) | Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose) | 
| Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib | Ibrutinib terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic plasma concentration-time curve, calculated as 0.693/λz on Lead-In Day 6/7 (ibrutinib only) or Cycle 3 Day 1 (ibrutinib + MEDI) | Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose) | 
| Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736 | Peak plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI) | Cycle 6 Day 1 (collected 10 minutes after end of infusion) | 
| Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736 | Trough plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI) | Cycle 6 Day 1 (predose) | 
| Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax | Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Cmax for MEDI4736 | Cycle 6 Day 1 (collected 10 minutes after end of infusion) | 
| Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough | Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Ctrough for MEDI4736 | Cycle 6 Day 1 (predose) | 
| Bruton Tyrosine Kinase (BTK) Occupancy | BTK occupancy | ibrutinib Lead-in Day 6 or 7 pre-dose | 
| Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas | BTK occupancy | Cycle 3 Day 1 Pre-dose | 
| Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas | Detectable Free Serum PD-L1 level | Cycle 3 Day1 Pre-dose |