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

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02401048
• Collaborator: AstraZeneca (Industry), Janssen Research & Development, LLC (Industry)
• Enrollment: 61
• Locations: 11
• Arms: 2
• Duration (Months): 30.1
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma; Follicular Lymphoma	Drug: Ibrutinib; Drug: MEDI4736	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b/ 2: Follicular lymphoma expansion cohort 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; Drug: MEDI4736
Experimental: Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort 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; Drug: MEDI4736

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.]

2. Phase 1b/ 2: Progression-free Survival (PFS) [first dose date of study drug (ibrutinib or MEDI4736) to the first documentation of disease progression]

3. Phase 1b/2: Overall Survival [First dose date of study drug (ibrutinib or MEDI4736) to the date of death due to any cause]

4. 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)

5. 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)

6. 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)

7. 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)

8. 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)

9. 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)

10. 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

11. 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

12. Bruton Tyrosine Kinase (BTK) Occupancy [ibrutinib Lead-in Day 6 or 7 pre-dose]

    BTK occupancy

13. Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas [Cycle 3 Day 1 Pre-dose]

    BTK occupancy

14. Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas [Cycle 3 Day1 Pre-dose]

    Detectable Free Serum PD-L1 level

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site-0397	Birmingham	Alabama	United States	35294
2	Site-0047	Duarte	California	United States	91010
3	Site-0038	Stanford	California	United States	94305
4	Site-0388	Miami	Florida	United States	33136
5	Site-0126	Chicago	Illinois	United States	60637
6	Site-0020/0173	Boston	Massachusetts	United States	02114
7	Site-0729	Ann Arbor	Michigan	United States	48109
8	Site-0130	Detroit	Michigan	United States	48201
9	Site-0343	Hackensack	New Jersey	United States	07601
10	Site-0402	Philadelphia	Pennsylvania	United States	19104
11	Site-0114	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Pharmacyclics LLC.
• AstraZeneca
• Janssen Research & Development, LLC

Investigators

• Study Director: Emily Liu, Pharmacyclics LLC.

Study Documents (Full-Text)

• Study Protocol - Feb 20, 2015
• Statistical Analysis Plan - Jan 10, 2018

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02401048
• Other Study ID Numbers: PCYC-1136-CA
• First Posted: Mar 27, 2015
• Last Update Posted: Jun 27, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse; Durvalumab

Study Results

Participant Flow

Pre-assignment Detail	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/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	27	34
COMPLETED	5	4
NOT COMPLETED	22	30

Baseline Characteristics

Arm/Group Title	Phase 1b/2: Follicular Lymphoma Expansion Cohort:	Phase 1b/2: Diffuse Large B-cell Lymphoma Expansion Cohort:	Total
Arm/Group Description	All participants who received at least one dose of study treatment.	All participants who received at least one dose of study treatment.	Total of all reporting groups
Overall Participants	27	34	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	19 70.4%	15 44.1%	34 55.7%
>=65 years	8 29.6%	19 55.9%	27 44.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (11.88)	61.2 (15.15)	59.3 (13.85)
Sex: Female, Male (Count of Participants)
Female	10 37%	13 38.2%	23 37.7%
Male	17 63%	21 61.8%	38 62.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3.7%	1 2.9%	2 3.3%
White	23 85.2%	32 94.1%	55 90.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 11.1%	1 2.9%	4 6.6%
Region of Enrollment (participants) [Number]
United States	27 100%	34 100%	61 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1b/2 : Overall Response Rate of Number of Participants
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment.	All participants who received at least one dose of study treatment.
Measure Participants	27	34
Count of Participants [Participants]	7 25.9%	8 23.5%

2. Secondary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment.	All participants who received at least one dose of study treatment.
Measure Participants	7	8
Median (95% Confidence Interval) [Months]	11.3	NA

3. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment.	All participants who received at least one dose of study treatment.
Measure Participants	27	34
Median (95% Confidence Interval) [Months]	10.2	2.6

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment.	All participants who received at least one dose of study treatment.
Measure Participants	27	34
Median (95% Confidence Interval) [Months]	NA	5.1

5. Secondary Outcome

Title	Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib
Description	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)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	27	28
Lead-In Day 6/7	196 (245)	140 (117)
Cycle 3 Day 1	155 (102)	183 (101)

6. Secondary Outcome

Title	Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib
Description	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)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	27	28
Lead-In Day 6/7	1.95	2.01
Cycle 3 Day 1	2.00	2.07

7. Secondary Outcome

Title	Pharmacokinetics: Mean Area Under the Plasma Concentration-Time Curve From Time 0-24 Hours (AUC0-24h) for Ibrutinib
Description	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)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	27	28
Lead-In Day 6/7	1078 (1013)	936 (691)
Cycle 3 Day 1	1096 (748)	1606 (901)

8. Secondary Outcome

Title	Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib
Description	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)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	27	28
Lead-In Day 6/7	5.35 (2.16)	6.43 (1.92)
Cycle 3 Day 1	6.14 (1.96)	5.27 (1.21)

9. Secondary Outcome

Title	Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma & DLBCL Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [ug/mL]	388 (14.1)

10. Secondary Outcome

Title	Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736
Description	Trough plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)
Time Frame	Cycle 6 Day 1 (predose)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma & DLBCL Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	20
Geometric Mean (Geometric Coefficient of Variation) [ug/mL]	207 (12.8)

11. Secondary Outcome

Title	Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma & DLBCL Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	17
Mean (Standard Deviation) [ratio]	1.90 (0.51)

12. Secondary Outcome

Title	Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough
Description	Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Ctrough for MEDI4736
Time Frame	Cycle 6 Day 1 (predose)

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma & DLBCL Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacokinetic data.
Measure Participants	19
Mean (Standard Deviation) [ratio]	3.31 (0.8)

13. Secondary Outcome

Title	Bruton Tyrosine Kinase (BTK) Occupancy
Description	BTK occupancy
Time Frame	ibrutinib Lead-in Day 6 or 7 pre-dose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.
Measure Participants	18	22
Mean (Standard Error) [BTK % occupancy]	77.6 (8.4)	91.2 (3.4)

14. Secondary Outcome

Title	Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas
Description	BTK occupancy
Time Frame	Cycle 3 Day 1 Pre-dose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.

Arm/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.
Measure Participants	14	6
Mean (Standard Error) [BTK % occupancy]	83.1 (9.4)	94.4 (3.1)

15. Secondary Outcome

Title	Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas
Description	Detectable Free Serum PD-L1 level
Time Frame	Cycle 3 Day1 Pre-dose

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort
Arm/Group Description	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.	All participants who received at least one dose of study treatment and had evaluable pharmacodynamics data.
Measure Participants	8	6
Number [pg/mL]	18.4	NA

Adverse Events

Time Frame	All AEs, whether serious or non-serious, are documented in the source documents from the time the signed and dated ICF is obtained until 30 days following the last dose of ibrutinib and 90 days following the last dose of MEDI4736.
Arm/Group Title	Phase 1b/2: Follicular Lymphoma Expansion Cohort:		Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort:
Arm/Group Description	All subjects who received at least one dose of study treatment.		All subjects who received at least one dose of study treatment.
All Cause Mortality
	Phase 1b/2: Follicular Lymphoma Expansion Cohort:		Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/27 (22.2%)		24/34 (70.6%)
Serious Adverse Events
	Phase 1b/2: Follicular Lymphoma Expansion Cohort:		Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/27 (37%)		23/34 (67.6%)
Blood and lymphatic system disorders
Neutropenia	1/27 (3.7%)	2	1/34 (2.9%)	1
Febrile Neutropenia	1/27 (3.7%)	2	0/34 (0%)	0
Cardiac disorders
Atrial Fibrillation	1/27 (3.7%)	3	3/34 (8.8%)	4
Left Ventricular Failure	0/27 (0%)	0	1/34 (2.9%)	1
Endocrine disorders
Hypercalcaemia of malignancy	0/27 (0%)	0	1/34 (2.9%)	1
Gastrointestinal disorders
Oesophagitis	0/27 (0%)	0	1/34 (2.9%)	1
General disorders
Oedema peripheral	1/27 (3.7%)	1	1/34 (2.9%)	1
Pyrexia	0/27 (0%)	0	2/34 (5.9%)	2
Fatigue	0/27 (0%)	0	1/34 (2.9%)	1
Hepatobiliary disorders
Autoimmune hepatitis	0/27 (0%)	0	1/34 (2.9%)	2
Infections and infestations
Cellulitis	1/27 (3.7%)	1	1/34 (2.9%)	1
Pneumonia	0/27 (0%)	0	2/34 (5.9%)	2
Urinary tract infection	0/27 (0%)	0	2/34 (5.9%)	2
Bronchopulmonary aspergillosis	1/27 (3.7%)	1	0/34 (0%)	0
Investigations
Alanine aminotransferase increased	1/27 (3.7%)	1	0/34 (0%)	0
Blood creatinine increased	0/27 (0%)	0	1/34 (2.9%)	1
Electrocardiogram QT prolonged	1/27 (3.7%)	1	0/34 (0%)	0
Metabolism and nutrition disorders
Hypercalcaemia	0/27 (0%)	0	2/34 (5.9%)	2
Dehydration	0/27 (0%)	0	1/34 (2.9%)	2
Electrolyte imbalance	1/27 (3.7%)	1	0/34 (0%)	0
Failure to thrive	1/27 (3.7%)	2	0/34 (0%)	0
Musculoskeletal and connective tissue disorders
Muscular weakness	2/27 (7.4%)	2	0/34 (0%)	0
Back pain	1/27 (3.7%)	1	0/34 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse large B-cell lymphoma	0/27 (0%)	0	6/34 (17.6%)	7
Lymphoma	0/27 (0%)	0	3/34 (8.8%)	3
B-cell lymphoma	1/27 (3.7%)	1	0/34 (0%)	0
Tumour rupture	0/27 (0%)	0	1/34 (2.9%)	1
Nervous system disorders
Syncope	1/27 (3.7%)	1	1/34 (2.9%)	1
Dizziness	1/27 (3.7%)	1	0/34 (0%)	0
Tremor	1/27 (3.7%)	1	0/34 (0%)	0
Psychiatric disorders
Mental status changes	1/27 (3.7%)	2	0/34 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/27 (0%)	0	1/34 (2.9%)	1
Ureteric obstruction	0/27 (0%)	0	1/34 (2.9%)	1
Urinary retention	0/27 (0%)	0	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/27 (3.7%)	1	1/34 (2.9%)	1
Dyspnoea exertional	1/27 (3.7%)	1	0/34 (0%)	0
Pneumonitis	1/27 (3.7%)	1	0/34 (0%)	0
Respiratory failure	0/27 (0%)	0	1/34 (2.9%)	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform	1/27 (3.7%)	1	0/34 (0%)	0
Rash generalised	0/27 (0%)	0	1/34 (2.9%)	1
Vascular disorders
Deep vein thrombosis	0/27 (0%)	0	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Phase 1b/2: Follicular Lymphoma Expansion Cohort:		Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort:
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		33/34 (97.1%)
Blood and lymphatic system disorders
Neutropenia	6/27 (22.2%)	13	11/34 (32.4%)	21
Thrombocytopenia	4/27 (14.8%)	4	6/34 (17.6%)	11
Increased tendancy to bruise	5/27 (18.5%)	7	4/34 (11.8%)	5
Anaemia	0/27 (0%)	0	6/34 (17.6%)	8
Leukopenia	0/27 (0%)	0	4/34 (11.8%)	7
Lymphadenopathy	4/27 (14.8%)	5	0/34 (0%)	0
Eye disorders
Cataract	1/27 (3.7%)	1	3/34 (8.8%)	3
Dry eye	3/27 (11.1%)	3	1/34 (2.9%)	1
Gastrointestinal disorders
Diarrhoea	16/27 (59.3%)	23	16/34 (47.1%)	27
Nausea	9/27 (33.3%)	9	12/34 (35.3%)	15
Constipation	3/27 (11.1%)	3	7/34 (20.6%)	7
Dry mouth	4/27 (14.8%)	5	6/34 (17.6%)	6
Abdominal distension	2/27 (7.4%)	2	6/34 (17.6%)	8
Gastrooesophageal reflux disease	3/27 (11.1%)	3	3/34 (8.8%)	3
Stomatitis	4/27 (14.8%)	5	2/34 (5.9%)	2
Abdominal pain	1/27 (3.7%)	1	4/34 (11.8%)	4
Dyspepsia	5/27 (18.5%)	6	0/34 (0%)	0
Dysphagia	1/27 (3.7%)	1	4/34 (11.8%)	5
General disorders
Fatigue	12/27 (44.4%)	13	16/34 (47.1%)	19
Oedema peripheral	7/27 (25.9%)	10	13/34 (38.2%)	22
Pyrexia	3/27 (11.1%)	3	6/34 (17.6%)	7
Peripheral swelling	2/27 (7.4%)	2	2/34 (5.9%)	4
Infections and infestations
Upper respiratory tract infection	12/27 (44.4%)	19	3/34 (8.8%)	4
Urinary tract infection	3/27 (11.1%)	5	3/34 (8.8%)	4
Injury, poisoning and procedural complications
Contusion	3/27 (11.1%)	4	3/34 (8.8%)	6
Fall	2/27 (7.4%)	3	4/34 (11.8%)	6
Investigations
Blood creatinine increased	1/27 (3.7%)	2	3/34 (8.8%)	9
Weight decreased	2/27 (7.4%)	2	2/34 (5.9%)	3
Weight increased	0/27 (0%)	0	4/34 (11.8%)	7
Metabolism and nutrition disorders
Decreased appetite	8/27 (29.6%)	8	11/34 (32.4%)	11
Hyperuricaemia	5/27 (18.5%)	6	5/34 (14.7%)	8
Hyponatraemia	2/27 (7.4%)	4	5/34 (14.7%)	8
Hypercalcaemia	2/27 (7.4%)	6	4/34 (11.8%)	6
Hypokalaemia	3/27 (11.1%)	4	3/34 (8.8%)	3
Dehydration	2/27 (7.4%)	2	3/34 (8.8%)	3
Hypomagnesaemia	3/27 (11.1%)	3	2/34 (5.9%)	2
Hypophosphataemia	1/27 (3.7%)	1	4/34 (11.8%)	4
Musculoskeletal and connective tissue disorders
Back pain	5/27 (18.5%)	9	5/34 (14.7%)	7
Muscle spasms	6/27 (22.2%)	8	3/34 (8.8%)	3
Arthralgia	4/27 (14.8%)	9	2/34 (5.9%)	3
Musculoskeletal pain	3/27 (11.1%)	4	3/34 (8.8%)	4
Myalgia	4/27 (14.8%)	4	1/34 (2.9%)	1
Neck pain	4/27 (14.8%)	5	1/34 (2.9%)	1
Pain in extremity	3/27 (11.1%)	4	2/34 (5.9%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/27 (0%)	0	5/34 (14.7%)	8
Nervous system disorders
Dizziness	3/27 (11.1%)	4	6/34 (17.6%)	7
Headache	6/27 (22.2%)	10	1/34 (2.9%)	1
Peripheral sensory neuropathy	4/27 (14.8%)	4	3/34 (8.8%)	3
Hypoaesthesia	4/27 (14.8%)	7	2/34 (5.9%)	2
Dysguesia	2/27 (7.4%)	2	3/34 (8.8%)	3
Memory impairment	3/27 (11.1%)	3	2/34 (5.9%)	2
Paraesthesia	2/27 (7.4%)	4	3/34 (8.8%)	3
Somnolence	3/27 (11.1%)	4	1/34 (2.9%)	2
Psychiatric disorders
Insomnia	4/27 (14.8%)	4	6/34 (17.6%)	7
Anxiety	5/27 (18.5%)	5	2/34 (5.9%)	2
Renal and urinary disorders
Urinary incontinence	0/27 (0%)	0	4/34 (11.8%)	5
Respiratory, thoracic and mediastinal disorders
Cough	8/27 (29.6%)	11	6/34 (17.6%)	11
Dyspnoea	6/27 (22.2%)	14	7/34 (20.6%)	10
Nasal congestion	3/27 (11.1%)	4	3/34 (8.8%)	4
Oropharyngeal	4/27 (14.8%)	4	1/34 (2.9%)	3
Pneumonitis	3/27 (11.1%)	3	2/34 (5.9%)	3
Productive cough	3/27 (11.1%)	3	2/34 (5.9%)	3
Upper-airway cough syndrome	3/27 (11.1%)	3	2/34 (5.9%)	3
Nasal dryness	4/27 (14.8%)	4	0/34 (0%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular	6/27 (22.2%)	13	7/34 (20.6%)	12
Dry skin	1/27 (3.7%)	1	5/34 (14.7%)	7
Rash erythematous	4/27 (14.8%)	4	2/34 (5.9%)	2
Ecchymosis	1/27 (3.7%)	1	3/34 (8.8%)	3
Erythema	1/27 (3.7%)	1	3/34 (8.8%)	3
Vascular disorders
Hypertension	2/27 (7.4%)	6	3/34 (8.8%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.