Diffuse Large B-Cell Lymphoma, Follicular Lymphoma
Conditions
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.
Interventions
DRUGIbrutinib
DRUGMEDI4736
Sponsors
AstraZeneca
Janssen Research & Development, LLC
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 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: 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) |
| 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: 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 |
| 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 |
| Bruton Tyrosine Kinase (BTK) Occupancy | ibrutinib Lead-in Day 6 or 7 pre-dose | BTK occupancy |
| Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas | Cycle 3 Day 1 Pre-dose | BTK occupancy |
| Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas | Cycle 3 Day1 Pre-dose | Detectable Free Serum PD-L1 level |
| 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) |
Countries
United States
Participant flow
Pre-assignment details
While the study include Phase 1b and 2, the dosing was not changed between phases (following the study design because there were no DLTs and thus no dose adjustments in from Phase 1b to Phase 2). Thus the study data were reported with Phases 1b and 2 combined.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b/2: Follicular Lymphoma Expansion Cohort: All participants who received at least one dose of study treatment. | 27 |
| Phase 1b/2: Diffuse Large B-cell Lymphoma Expansion Cohort: All participants who received at least one dose of study treatment. | 34 |
| Total | 61 |
Baseline characteristics
| Characteristic | Phase 1b/2: Diffuse Large B-cell Lymphoma Expansion Cohort: | Total | Phase 1b/2: Follicular Lymphoma Expansion Cohort: |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 27 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 34 Participants | 19 Participants |
| Age, Continuous | 61.2 years STANDARD_DEVIATION 15.15 | 59.3 years STANDARD_DEVIATION 13.85 | 57 years STANDARD_DEVIATION 11.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 32 Participants | 55 Participants | 23 Participants |
| Region of Enrollment United States | 34 participants | 61 participants | 27 participants |
| Sex: Female, Male Female | 13 Participants | 23 Participants | 10 Participants |
| Sex: Female, Male Male | 21 Participants | 38 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 27 | 24 / 34 |
| other Total, other adverse events | 27 / 27 | 33 / 34 |
| serious Total, serious adverse events | 10 / 27 | 23 / 34 |
Outcome results
Primary
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).
Time frame: From the date of first study treatment until progressive disease
Population: While the study include Phase 1b and 2, the dosing was not changed between phases (following the study design because there were no DLTs and thus no dose adjustments in from Phase 1b to Phase 2). Thus the study data were reported with Phases 1b and 2 combined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phase 1b/2 : Overall Response Rate of Number of Participants | 7 Participants |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phase 1b/2 : Overall Response Rate of Number of Participants | 8 Participants |
Secondary
Bruton Tyrosine Kinase (BTK) Occupancy
BTK occupancy
Time frame: ibrutinib Lead-in Day 6 or 7 pre-dose
Population: All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Bruton Tyrosine Kinase (BTK) Occupancy | 77.6 BTK % occupancy | Standard Error 8.4 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Bruton Tyrosine Kinase (BTK) Occupancy | 91.2 BTK % occupancy | Standard Error 3.4 |
Secondary
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)
Time frame: Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib | Lead-In Day 6/7 | 196 ng/mL | Standard Deviation 245 |
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib | Cycle 3 Day 1 | 155 ng/mL | Standard Deviation 102 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib | Lead-In Day 6/7 | 140 ng/mL | Standard Deviation 117 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib | Cycle 3 Day 1 | 183 ng/mL | Standard Deviation 101 |
Secondary
Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas
BTK occupancy
Time frame: Cycle 3 Day 1 Pre-dose
Population: All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas | 83.1 BTK % occupancy | Standard Error 9.4 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas | 94.4 BTK % occupancy | Standard Error 3.1 |
Secondary
Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas
Detectable Free Serum PD-L1 level
Time frame: Cycle 3 Day1 Pre-dose
Population: In Follicular lymphoma expansion cohort, 7 subjects are below limit of quantitation. In Diffuse large B-cell lymphoma expansion cohort, all subjects below limit of quantitation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas | 18.4 pg/mL |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas | NA pg/mL |
Secondary
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)
Time frame: Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib | Lead-In Day 6/7 | 1078 ng*h/mL | Standard Deviation 1013 |
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib | Cycle 3 Day 1 | 1096 ng*h/mL | Standard Deviation 748 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib | Lead-In Day 6/7 | 936 ng*h/mL | Standard Deviation 691 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib | Cycle 3 Day 1 | 1606 ng*h/mL | Standard Deviation 901 |
Secondary
Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736
Peak plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)
Time frame: Cycle 6 Day 1 (collected 10 minutes after end of infusion)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data. Result data for both cohorts was pre-specified to be combined, and was not reported separately.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736 | 388 ug/mL | Geometric Coefficient of Variation 14.1 |
Secondary
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)
Time frame: Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib | Lead-In Day 6/7 | 5.35 hour | Standard Deviation 2.16 |
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib | Cycle 3 Day 1 | 6.14 hour | Standard Deviation 1.96 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib | Lead-In Day 6/7 | 6.43 hour | Standard Deviation 1.92 |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib | Cycle 3 Day 1 | 5.27 hour | Standard Deviation 1.21 |
Secondary
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)
Time frame: Lead-In Day 6/7 or Cycle 3 Day 1 (collected at predose, 1, 2, 4, and 6 hours post-dose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib | Lead-In Day 6/7 | 1.95 hour |
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib | Cycle 3 Day 1 | 2.00 hour |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib | Lead-In Day 6/7 | 2.01 hour |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib | Cycle 3 Day 1 | 2.07 hour |
Secondary
Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736
Trough plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)
Time frame: Cycle 6 Day 1 (predose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data. Result data for both cohorts was pre-specified to be combined, and was not reported separately.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736 | 207 ug/mL | Geometric Coefficient of Variation 12.8 |
Secondary
Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax
Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Cmax for MEDI4736
Time frame: Cycle 6 Day 1 (collected 10 minutes after end of infusion)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data. Result data for both cohorts was pre-specified to be combined, and was not reported separately.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax | 1.90 ratio | Standard Deviation 0.51 |
Secondary
Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough
Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Ctrough for MEDI4736
Time frame: Cycle 6 Day 1 (predose)
Population: All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data. Result data for both cohorts was pre-specified to be combined, and was not reported separately.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough | 3.31 ratio | Standard Deviation 0.8 |
Secondary
Phase 1b/ 2: Duration of Response
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phase 1b/ 2: Duration of Response | 11.3 Months |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phase 1b/ 2: Duration of Response | NA Months |
Secondary
Phase 1b/2: Overall Survival
Time frame: First dose date of study drug (ibrutinib or MEDI4736) to the date of death due to any cause
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phase 1b/2: Overall Survival | NA Months |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phase 1b/2: Overall Survival | 5.1 Months |
Secondary
Phase 1b/ 2: Progression-free Survival (PFS)
Time frame: first dose date of study drug (ibrutinib or MEDI4736) to the first documentation of disease progression
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b/ 2: Follicular Lymphoma Expansion Cohort | Phase 1b/ 2: Progression-free Survival (PFS) | 10.2 Months |
| Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort | Phase 1b/ 2: Progression-free Survival (PFS) | 2.6 Months |