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

Phase 1

Completed

• Conditions: Diffuse Large B-Cell Lymphoma; Follicular Lymphoma
• Interventions: Drug: Ibrutinib; Drug: MEDI4736

• Registration Number: NCT02401048
• Lead Sponsor: Pharmacyclics LLC.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-03-04
• Study First Submitted QC: 2015-03-23
• Study First Posted: 2015-03-27
• Study Start: 2015-05
• Primary Completion: 2017-11
• Study Completion: 2017-11
• Results First Submitted: 2018-11-16
• Status Verified: 2019-06
• Results First Submitted QC: 2019-06-03
• Last Update Submitted: 2019-06-03
• Results First Posted: 2019-06-27
• Last Update Posted: 2019-06-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

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:

  1. Absolute Neutrophil Count >1500 cells/mm3
  2. Platelets >50000 cells/mm3
  3. Hemoglobin >8.0 g/dL

• Adequate hepatic and renal function:

  1. AST or ALT ≤2.5 x ULN
  2. Bilirubin ≤1.5 x ULN
  3. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Phase 1b/ 2: Follicular lymphoma expansion cohort	MEDI4736	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.
Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort	MEDI4736	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.
Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort	Ibrutinib	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.
Phase 1b/ 2: Follicular lymphoma expansion cohort	Ibrutinib	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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: 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.
Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736	Cycle 6 Day 1 (predose)	Trough plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)
Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib	Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)	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)
Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib	Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)	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)
Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax	Cycle 6 Day 1 (collected 10 minutes after end of infusion)	Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Cmax for MEDI4736
Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas	Cycle 3 Day 1 Pre-dose	BTK occupancy
Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib	Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)	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)
Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736	Cycle 6 Day 1 (collected 10 minutes after end of infusion)	Peak plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)
Phase 1b/2: Overall Survival	First dose date of study drug (ibrutinib or MEDI4736) to the date of death due to any cause
Bruton Tyrosine Kinase (BTK) Occupancy	ibrutinib Lead-in Day 6 or 7 pre-dose	BTK occupancy
Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib	Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)	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)
Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough	Cycle 6 Day 1 (predose)	Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Ctrough for MEDI4736
Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas	Cycle 3 Day1 Pre-dose	Detectable Free Serum PD-L1 level

Trial Locations

Locations (11)

Site-0343; 🇺🇸 Hackensack, New Jersey, United States

Site-0397; 🇺🇸 Birmingham, Alabama, United States

Site-0047; 🇺🇸 Duarte, California, United States

Site-0038; 🇺🇸 Stanford, California, United States

Site-0126; 🇺🇸 Chicago, Illinois, United States

Site-0020/0173; 🇺🇸 Boston, Massachusetts, United States

Site-0388; 🇺🇸 Miami, Florida, United States

Site-0729; 🇺🇸 Ann Arbor, Michigan, United States

Site-0130; 🇺🇸 Detroit, Michigan, United States

Site-0402; 🇺🇸 Philadelphia, Pennsylvania, United States

Site-0114; 🇺🇸 Seattle, Washington, United States