Trial Outcomes & Findings for A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Lymphomas (NCT NCT02401048)

Last Updated: 2019-06-27

Results Overview

The response criteria is measured based on the revised criteria for malignant lymphoma described by the International Working Group for NHL (Cheson 2014).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

61 participants

Primary outcome timeframe

From the date of first study treatment until progressive disease

Results posted on

2019-06-27

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	27	34
Overall Study COMPLETED	5	4
Overall Study NOT COMPLETED	22	30

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1b/2: Follicular Lymphoma Expansion Cohort: n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/2: Diffuse Large B-cell Lymphoma Expansion Cohort: n=34 Participants All participants who received at least one dose of study treatment.	Total n=61 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants	15 Participants n=7 Participants	34 Participants n=5 Participants
Age, Categorical >=65 years	8 Participants n=5 Participants	19 Participants n=7 Participants	27 Participants n=5 Participants
Age, Continuous	57 years STANDARD_DEVIATION 11.88 • n=5 Participants	61.2 years STANDARD_DEVIATION 15.15 • n=7 Participants	59.3 years STANDARD_DEVIATION 13.85 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	13 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	21 Participants n=7 Participants	38 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	23 Participants n=5 Participants	32 Participants n=7 Participants	55 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	27 participants n=5 Participants	34 participants n=7 Participants	61 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

The response criteria is measured based on the revised criteria for malignant lymphoma described by the International Working Group for NHL (Cheson 2014).

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=34 Participants All participants who received at least one dose of study treatment.
Phase 1b/2 : Overall Response Rate of Number of Participants	7 Participants	8 Participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=7 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=8 Participants All participants who received at least one dose of study treatment.
Phase 1b/ 2: Duration of Response	11.3 Months Interval 8.3 to The 95% Confidence Interval is not applicable because the median Duration of Response was estimated based on time to event data. The 95% Confidence limit cannot be estimated.	NA Months Interval 2.5 to The median Duration of Response was not reached. The 95% Confidence limit cannot be estimated.

SECONDARY outcome

Timeframe: first dose date of study drug (ibrutinib or MEDI4736) to the first documentation of disease progression

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=34 Participants All participants who received at least one dose of study treatment.
Phase 1b/ 2: Progression-free Survival (PFS)	10.2 Months Interval 4.7 to 13.1	2.6 Months Interval 1.5 to 4.4

SECONDARY outcome

Timeframe: First dose date of study drug (ibrutinib or MEDI4736) to the date of death due to any cause

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=34 Participants All participants who received at least one dose of study treatment.
Phase 1b/2: Overall Survival	NA Months Interval 23.6 to The median Overall Survival was not reached. The 95% Confidence limit cannot be estimated.	5.1 Months Interval 3.7 to 10.1

SECONDARY outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=28 Participants All participants who received at least one dose of study treatment.
Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib Lead-In Day 6/7	196 ng/mL Standard Deviation 245	140 ng/mL Standard Deviation 117
Phamacokinetics: Mean Maximum Observed Plasma Concentration (Cmax) for Ibrutinib Cycle 3 Day 1	155 ng/mL Standard Deviation 102	183 ng/mL Standard Deviation 101

SECONDARY outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=28 Participants All participants who received at least one dose of study treatment.
Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib Lead-In Day 6/7	1.95 hour Interval 0.75 to 4.0	2.01 hour Interval 0.93 to 6.0
Pharmacokinetics: Mean Time to Maximum Observed Plasma Concentration (Tmax) for Ibrutinib Cycle 3 Day 1	2.00 hour Interval 1.0 to 6.05	2.07 hour Interval 1.0 to 4.97

SECONDARY outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=28 Participants All participants who received at least one dose of study treatment.
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	936 ng*h/mL Standard Deviation 691
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	1606 ng*h/mL Standard Deviation 901

SECONDARY outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=27 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=28 Participants All participants who received at least one dose of study treatment.
Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib Lead-In Day 6/7	5.35 hour Standard Deviation 2.16	6.43 hour Standard Deviation 1.92
Pharmacokinetics: Mean Terminal Elimination Half-Life (t1/2,Term) for Ibrutinib Cycle 3 Day 1	6.14 hour Standard Deviation 1.96	5.27 hour Standard Deviation 1.21

SECONDARY outcome

Timeframe: 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.

Peak plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=17 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort All participants who received at least one dose of study treatment.
Pharmacokinetics: Mean Peak Plasma Concentration (Cmax) for MEDI4736	388 ug/mL Geometric Coefficient of Variation 14.1	—

SECONDARY outcome

Timeframe: Cycle 6 Day 1 (predose)

Trough plasma concentration of MEDI4736 on Cycle 6 Day 1 (ibrutinib + MEDI)

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=20 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort All participants who received at least one dose of study treatment.
Pharmacokinetics: Mean Trough Plasma Concentration (Ctrough) for MEDI4736	207 ug/mL Geometric Coefficient of Variation 12.8	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=17 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort All participants who received at least one dose of study treatment.
Pharmacokinetics: MEDI4736 Accumulation Ratio for Cmax	1.90 ratio Standard Deviation 0.51	—

SECONDARY outcome

Timeframe: Cycle 6 Day 1 (predose)

Accumulation ratio from Cycle 6 Day 1 to Cycle 1 Day 1 for Ctrough for MEDI4736

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=19 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort All participants who received at least one dose of study treatment.
Pharmacokinetics: MEDI4736 Accumulation Ratio for Ctrough	3.31 ratio Standard Deviation 0.8	—

SECONDARY outcome

Timeframe: 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.

BTK occupancy

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=18 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=22 Participants All participants who received at least one dose of study treatment.
Bruton Tyrosine Kinase (BTK) Occupancy	77.6 BTK % occupancy Standard Error 8.4	91.2 BTK % occupancy Standard Error 3.4

SECONDARY outcome

Timeframe: Cycle 3 Day 1 Pre-dose

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

BTK occupancy

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=14 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=6 Participants All participants who received at least one dose of study treatment.
Pharmacodynamics of Ibrutinib in Subjects With Relapsed or Refractory Lymphomas	83.1 BTK % occupancy Standard Error 9.4	94.4 BTK % occupancy Standard Error 3.1

SECONDARY outcome

Timeframe: 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.

Detectable Free Serum PD-L1 level

Outcome measures

Outcome measures
Measure	Phase 1b/ 2: Follicular Lymphoma Expansion Cohort n=8 Participants All participants who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort n=6 Participants All participants who received at least one dose of study treatment.
Pharmacodynamics of MEDI4736 in Subjects With Relapsed or Refractory Lymphomas	18.4 pg/mL	NA pg/mL NA means the data is not evaluable

Adverse Events

Phase 1b/2: Follicular Lymphoma Expansion Cohort:

Serious events: 10 serious events

Other events: 27 other events

Deaths: 6 deaths

Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort:

Serious events: 23 serious events

Other events: 33 other events

Deaths: 24 deaths

Serious adverse events

Other adverse events

Additional Information

Emily Liu

Pharmacyclics

Phone: (669) 224-1899

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Phase 1b/2: Follicular Lymphoma Expansion Cohort: n=27 participants at risk All subjects who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort: n=34 participants at risk All subjects who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Dermatitis acneiform	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Skin and subcutaneous tissue disorders Rash generalised	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Vascular disorders Deep vein thrombosis	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Blood and lymphatic system disorders Neutropenia	3.7% 1/27 • Number of events 2 • 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.	2.9% 1/34 • Number of events 1 • 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.
Blood and lymphatic system disorders Febrile Neutropenia	3.7% 1/27 • Number of events 2 • 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.	0.00% 0/34 • 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.
Cardiac disorders Atrial Fibrillation	3.7% 1/27 • Number of events 3 • 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.	8.8% 3/34 • Number of events 4 • 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.
Cardiac disorders Left Ventricular Failure	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Endocrine disorders Hypercalcaemia of malignancy	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Gastrointestinal disorders Oesophagitis	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
General disorders Oedema peripheral	3.7% 1/27 • Number of events 1 • 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.	2.9% 1/34 • Number of events 1 • 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.
General disorders Pyrexia	0.00% 0/27 • 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.	5.9% 2/34 • Number of events 2 • 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.
General disorders Fatigue	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Hepatobiliary disorders Autoimmune hepatitis	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 2 • 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.
Infections and infestations Cellulitis	3.7% 1/27 • Number of events 1 • 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.	2.9% 1/34 • Number of events 1 • 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.
Infections and infestations Pneumonia	0.00% 0/27 • 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.	5.9% 2/34 • Number of events 2 • 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.
Infections and infestations Urinary tract infection	0.00% 0/27 • 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.	5.9% 2/34 • Number of events 2 • 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.
Infections and infestations Bronchopulmonary aspergillosis	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Investigations Alanine aminotransferase increased	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Investigations Blood creatinine increased	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Investigations Electrocardiogram QT prolonged	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/27 • 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.	5.9% 2/34 • Number of events 2 • 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.
Metabolism and nutrition disorders Dehydration	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 2 • 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.
Metabolism and nutrition disorders Electrolyte imbalance	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Metabolism and nutrition disorders Failure to thrive	3.7% 1/27 • Number of events 2 • 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.	0.00% 0/34 • 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.
Musculoskeletal and connective tissue disorders Muscular weakness	7.4% 2/27 • Number of events 2 • 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.	0.00% 0/34 • 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.
Musculoskeletal and connective tissue disorders Back pain	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.00% 0/27 • 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.	17.6% 6/34 • Number of events 7 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphoma	0.00% 0/27 • 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.	8.8% 3/34 • Number of events 3 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B-cell lymphoma	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour rupture	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Nervous system disorders Syncope	3.7% 1/27 • Number of events 1 • 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.	2.9% 1/34 • Number of events 1 • 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.
Nervous system disorders Dizziness	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Nervous system disorders Tremor	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Psychiatric disorders Mental status changes	3.7% 1/27 • Number of events 2 • 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.	0.00% 0/34 • 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.
Renal and urinary disorders Acute kidney injury	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Renal and urinary disorders Ureteric obstruction	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Renal and urinary disorders Urinary retention	0.00% 0/27 • 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.	2.9% 1/34 • Number of events 1 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.7% 1/27 • Number of events 1 • 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.	2.9% 1/34 • Number of events 1 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.
Respiratory, thoracic and mediastinal disorders Pneumonitis	3.7% 1/27 • Number of events 1 • 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.	0.00% 0/34 • 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.

Other adverse events
Measure	Phase 1b/2: Follicular Lymphoma Expansion Cohort: n=27 participants at risk All subjects who received at least one dose of study treatment.	Phase 1b/ 2: Diffuse Large B-cell Lymphoma Expansion Cohort: n=34 participants at risk All subjects who received at least one dose of study treatment.
Blood and lymphatic system disorders Neutropenia	22.2% 6/27 • Number of events 13 • 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.	32.4% 11/34 • Number of events 21 • 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.
Blood and lymphatic system disorders Thrombocytopenia	14.8% 4/27 • Number of events 4 • 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.	17.6% 6/34 • Number of events 11 • 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.
Blood and lymphatic system disorders Increased tendancy to bruise	18.5% 5/27 • Number of events 7 • 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.	11.8% 4/34 • Number of events 5 • 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.
Blood and lymphatic system disorders Anaemia	0.00% 0/27 • 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.	17.6% 6/34 • Number of events 8 • 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.
Blood and lymphatic system disorders Leukopenia	0.00% 0/27 • 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.	11.8% 4/34 • Number of events 7 • 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.
Blood and lymphatic system disorders Lymphadenopathy	14.8% 4/27 • Number of events 5 • 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.	0.00% 0/34 • 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.
Eye disorders Cataract	3.7% 1/27 • Number of events 1 • 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.	8.8% 3/34 • Number of events 3 • 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.
Eye disorders Dry eye	11.1% 3/27 • Number of events 3 • 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.	2.9% 1/34 • Number of events 1 • 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.
Gastrointestinal disorders Diarrhoea	59.3% 16/27 • Number of events 23 • 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.	47.1% 16/34 • Number of events 27 • 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.
Gastrointestinal disorders Nausea	33.3% 9/27 • Number of events 9 • 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.	35.3% 12/34 • Number of events 15 • 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.
Gastrointestinal disorders Constipation	11.1% 3/27 • Number of events 3 • 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.	20.6% 7/34 • Number of events 7 • 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.
Gastrointestinal disorders Dry mouth	14.8% 4/27 • Number of events 5 • 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.	17.6% 6/34 • Number of events 6 • 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.
Gastrointestinal disorders Abdominal distension	7.4% 2/27 • Number of events 2 • 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.	17.6% 6/34 • Number of events 8 • 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.
Gastrointestinal disorders Gastrooesophageal reflux disease	11.1% 3/27 • Number of events 3 • 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.	8.8% 3/34 • Number of events 3 • 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.
Gastrointestinal disorders Stomatitis	14.8% 4/27 • Number of events 5 • 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.	5.9% 2/34 • Number of events 2 • 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.
Gastrointestinal disorders Abdominal pain	3.7% 1/27 • Number of events 1 • 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.	11.8% 4/34 • Number of events 4 • 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.
Gastrointestinal disorders Dyspepsia	18.5% 5/27 • Number of events 6 • 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.	0.00% 0/34 • 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.
Gastrointestinal disorders Dysphagia	3.7% 1/27 • Number of events 1 • 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.	11.8% 4/34 • Number of events 5 • 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.
General disorders Fatigue	44.4% 12/27 • Number of events 13 • 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.	47.1% 16/34 • Number of events 19 • 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.
General disorders Oedema peripheral	25.9% 7/27 • Number of events 10 • 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.	38.2% 13/34 • Number of events 22 • 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.
General disorders Pyrexia	11.1% 3/27 • Number of events 3 • 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.	17.6% 6/34 • Number of events 7 • 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.
General disorders Peripheral swelling	7.4% 2/27 • Number of events 2 • 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.	5.9% 2/34 • Number of events 4 • 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.
Infections and infestations Upper respiratory tract infection	44.4% 12/27 • Number of events 19 • 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.	8.8% 3/34 • Number of events 4 • 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.
Infections and infestations Urinary tract infection	11.1% 3/27 • Number of events 5 • 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.	8.8% 3/34 • Number of events 4 • 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.
Injury, poisoning and procedural complications Contusion	11.1% 3/27 • Number of events 4 • 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.	8.8% 3/34 • Number of events 6 • 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.
Injury, poisoning and procedural complications Fall	7.4% 2/27 • Number of events 3 • 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.	11.8% 4/34 • Number of events 6 • 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.
Investigations Blood creatinine increased	3.7% 1/27 • Number of events 2 • 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.	8.8% 3/34 • Number of events 9 • 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.
Investigations Weight decreased	7.4% 2/27 • Number of events 2 • 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.	5.9% 2/34 • Number of events 3 • 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.
Investigations Weight increased	0.00% 0/27 • 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.	11.8% 4/34 • Number of events 7 • 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.
Metabolism and nutrition disorders Decreased appetite	29.6% 8/27 • Number of events 8 • 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.	32.4% 11/34 • Number of events 11 • 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.
Metabolism and nutrition disorders Hyperuricaemia	18.5% 5/27 • Number of events 6 • 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.	14.7% 5/34 • Number of events 8 • 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.
Metabolism and nutrition disorders Hyponatraemia	7.4% 2/27 • Number of events 4 • 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.	14.7% 5/34 • Number of events 8 • 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.
Metabolism and nutrition disorders Hypercalcaemia	7.4% 2/27 • Number of events 6 • 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.	11.8% 4/34 • Number of events 6 • 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.
Metabolism and nutrition disorders Hypokalaemia	11.1% 3/27 • Number of events 4 • 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.	8.8% 3/34 • Number of events 3 • 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.
Metabolism and nutrition disorders Dehydration	7.4% 2/27 • Number of events 2 • 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.	8.8% 3/34 • Number of events 3 • 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.
Metabolism and nutrition disorders Hypomagnesaemia	11.1% 3/27 • Number of events 3 • 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.	5.9% 2/34 • Number of events 2 • 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.
Metabolism and nutrition disorders Hypophosphataemia	3.7% 1/27 • Number of events 1 • 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.	11.8% 4/34 • Number of events 4 • 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.
Musculoskeletal and connective tissue disorders Back pain	18.5% 5/27 • Number of events 9 • 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.	14.7% 5/34 • Number of events 7 • 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.
Musculoskeletal and connective tissue disorders Muscle spasms	22.2% 6/27 • Number of events 8 • 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.	8.8% 3/34 • Number of events 3 • 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.
Musculoskeletal and connective tissue disorders Arthralgia	14.8% 4/27 • Number of events 9 • 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.	5.9% 2/34 • Number of events 3 • 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.