Clinical trial NCT02401048
Conditions: Diffuse Large B-Cell Lymphoma Follicular Lymphoma
Sponsor: Pharmacyclics LLC.
Start date: 2015-05-01; Completion date: 2017-11-01
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: FACTORIAL

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

Detailed description:

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Ibrutinib intervention 2: MEDI4736
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
IMBRUVICA® (ibrutinib) 
PCYC-1136-CA, Amendment 1 
20 February 2015 
Final 
 
 
 
 
 
 
PROTOCOL 
 
 
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 
PROTOCOL NUMBER: 
PCYC-1136-CA 
STUDY DRUG(S): 
Ibrutinib and MEDI4736 
IND NUMBER: 
102,688 
SPONSOR MEDICAL 
MONITOR: 
Alvina Chu, MD 
Pharmacyclics, Inc. 
Phone: +1 (408) 215-3027 
Fax: 
+1 (408) 215-3684 
Email: achu@pcyc.com 
SPONSOR: 
Pharmacyclics, Incorporated  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
29 December 2014 
AMENDMENT 1 FINAL: 
20 February 2015 
 
 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics, Inc. that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee. This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics, Inc. 
 
 
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PCYC-1136-CA, Amendment 1 
20 February 2015 
Final 
 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF IN-TEXT TABLES .......................................................................................................8 
LIST OF APPENDICES ...............................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................21 
1. 
BACKGROUND ...................................................................................................................24 
1.1 
Diffuse Large B-cell Lymphoma .......................................................................................24 
1.2 
Follicular Lymphoma.........................................................................................................25 
1.3 
Ibrutinib..............................................................................................................................26 
1.3.1 
Summary of Nonclinical Data .....................................................................................27 
1.3.1.1. 
Pharmacology ........................................................................................................27 
1.3.1.2. 
Toxicology .............................................................................................................27 
1.3.1.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................28 
1.3.1.4. 
Summary of Nonclinical Data (ibrutinib and MEDI4736 Combination) ..............28 
1.3.2 
Summary of Clinical Data ...........................................................................................28 
1.3.2.1. 
Pharmacokinetics and Product Metabolism ...........................................................28 
1.3.3 
Summary of Clinical Safety .........................................................................................29 
1.3.3.1. 
Monotherapy Studies in Hematologic Malignancies .............................................29 
1.3.4 
Risks .............................................................................................................................30 
1.3.4.1. 
Bleeding-related Events .........................................................................................30 
1.3.4.2. 
Cardiac Events .......................................................................................................30 
1.3.4.3. 
Cytopenias..............................................................................................................30 
1.3.4.4. 
Diarrhea..................................................................................................................30 
1.3.4.5. 
Infections................................................................................................................30 
1.3.4.6. 
Other Malignancies ................................................................................................31 
1.3.4.7. 
Rash........................................................................................................................31 
1.3.4.8. 
Tumor Lysis Syndrome..........................................................................................31 
1.3.5 
Summary of Clinical Data (ibrutinib and MEDI4736 combination) ...........................31 
1.4 
MEDI4736 .........................................................................................................................31 
1.4.1 
Summary of Nonclinical Data .....................................................................................32 
1.4.2 
Summary of Clinical Data ...........................................................................................33 
1.4.3 
Summary of Clinical Safety .........................................................................................34 
1.4.4 
Summary of Clinical Efficacy .....................................................................................35 
1.5. 
Study Rationale ..................................................................................................................35 
1.6 
Dosing Rationale ................................................................................................................37 
1.6.1 
Ibrutinib Dose ..............................................................................................................37 
1.6.2 
MEDI4736 Dose ..........................................................................................................37 
1.6.3 
Ibrutinib and MEDI4736 Doses in Combination .........................................................38 
2. 
STUDY OBJECTIVES ........................................................................................................40 
2.1 
Primary Objectives.............................................................................................................40 
2.2 
Secondary Objectives.........................................................................................................40 
2.3 
Exploratory Objectives ......................................................................................................40 
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3. 
STUDY DESIGN ..................................................................................................................42 
3.1 
Overview of Study Design .................................................................................................42 
3.1.1 
Phase 1b .......................................................................................................................42 
3.1.2 
Phase 2 .........................................................................................................................44 
3.2 
Study Schema.....................................................................................................................46 
4. 
SUBJECT SELECTION ......................................................................................................47 
4.1 
Inclusion Criteria ...............................................................................................................47 
4.2 
Exclusion Criteria ..............................................................................................................49 
5. 
TREATMENT OF SUBJECTS ...........................................................................................52 
5.1 
Treatment Allocation .........................................................................................................52 
5.2 
Phase 1b Dose De-escalation and Stopping Rules .............................................................52 
5.3 
Definition of Dose-Limiting Toxicity (DLT) ....................................................................53 
5.4 
Replacement of Subjects ....................................................................................................54 
5.5 
Study Treatment .................................................................................................................54 
5.5.1 
Phase 1b .......................................................................................................................55 
5.5.2 
Phase 2 .........................................................................................................................55 
5.6 
Study Medication ...............................................................................................................55 
5.6.1 
Ibrutinib........................................................................................................................55 
5.6.1.1. 
Formulation/Packaging/Storage .............................................................................55 
5.6.1.2. 
Dose and Administration .......................................................................................56 
5.6.1.3. 
Overdose ................................................................................................................56 
5.6.1.4. 
Dose Modification for Adverse Reactions .............................................................56 
5.6.2 
MEDI4736 ...................................................................................................................57 
5.6.2.1. 
Formulation/Packaging/Storage .............................................................................57 
5.6.2.2. 
Dose and Administration .......................................................................................58 
5.6.2.3. 
Overdose ................................................................................................................59 
5.6.2.4. 
Immune-related Adverse Events (irAEs) ...............................................................59 
5.6.2.5. 
Dose Modification for Adverse Reactions .............................................................59 
5.7 
Criteria for Permanent Discontinuation of Study Drug .....................................................70 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES ......................................................71 
6.1 
Permitted Concomitant Medications ..................................................................................71 
6.2 
Medications to Be Used with Caution ...............................................................................71 
6.2.1 
CYP3A-inhibitors/Inducers .........................................................................................71 
6.2.2 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib .................72 
6.2.3 
Antiplatelet Agents and Anticoagulants ......................................................................72 
6.3 
Prohibited Concomitant Medications ................................................................................72 
6.4 
Guidelines for Ibrutinib Management with Surgeries or Procedures ................................73 
6.4.1 
Minor Surgical Procedures ..........................................................................................73 
6.4.2 
Major Surgical Procedures ...........................................................................................73 
6.4.3 
Emergency Procedures.................................................................................................73 
7. 
STUDY EVALUATIONS ....................................................................................................74 
7.1 
Description of Procedures ..................................................................................................74 
7.1.1 
Assessments .................................................................................................................74 
7.1.1.1. 
ICF .........................................................................................................................74 
7.1.1.2. 
Confirm Eligibility .................................................................................................74 
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7.1.1.3. 
Medical History and Demographics ......................................................................74 
7.1.1.4. 
Prior and Concomitant Medications ......................................................................74 
7.1.1.5. 
Adverse Events ......................................................................................................75 
7.1.1.6. 
Physical Examination.............................................................................................75 
7.1.1.7. 
ECOG Performance Status ....................................................................................75 
7.1.1.8. 
Vital Signs ..............................................................................................................75 
7.1.2 
Laboratory ....................................................................................................................76 
7.1.2.1. 
Hematology ............................................................................................................76 
7.1.2.2. 
Chemistry (Serum) .................................................................................................76 
7.1.2.3. 
Thyroid Stimulating Hormone ...............................................................................76 
7.1.2.4. 
Coagulation Studies ...............................................................................................76 
7.1.2.5. 
Creatinine Clearance ..............................................................................................76 
7.1.2.6. 
Hepatitis Serologies and Human Immunodeficiency Virus (HIV) ........................76 
7.1.2.7. 
Urinalysis ...............................................................................................................77 
7.1.2.8. 
Pregnancy Test .......................................................................................................77 
7.1.3 
Diagnostics/Procedures ................................................................................................77 
7.1.3.1. 
ECG........................................................................................................................77 
7.1.3.2. 
CT/MRI and PET Scans.........................................................................................77 
7.1.3.3. 
Bone Marrow Aspirate and Biopsy ........................................................................78 
7.1.3.4. 
Tumor Tissue Biopsy .............................................................................................78 
7.1.4 
Pharmacokinetics/Pharmacodynamics/Biomarkers .....................................................79 
7.1.4.1. 
Pharmacokinetics ...................................................................................................79 
7.1.4.2. 
Biomarkers and Pharmacodynamics Studies .........................................................80 
7.2 
Response Evaluations ........................................................................................................81 
7.3 
Sample Collection and Handling .......................................................................................81 
8. 
STUDY PROCEDURES ......................................................................................................82 
8.1 
Screening Phase .................................................................................................................82 
8.1.1 
Screening/Consenting Visit .........................................................................................82 
8.2 
Treatment Phase .................................................................................................................83 
8.2.1 
Ibrutinib Lead-in Day 1 (baseline) ...............................................................................83 
8.2.2 
Ibrutinib Lead-in Day 2 ...............................................................................................84 
8.2.3 
Ibrutinib Lead-in Day 6 or 7 ........................................................................................84 
8.2.4 
Cycle 1 Day 1 (C1D1) .................................................................................................84 
8.2.5 
Cycle 1 Day 8 (C1D8) .................................................................................................85 
8.2.6 
Cycle 1 Day 15 (C1D15) .............................................................................................86 
8.2.7 
Cycle 1 Day 22 (C1D22) .............................................................................................86 
8.2.8 
Cycle 2 Day 1 (C2D1) .................................................................................................87 
8.2.9 
Cycle 2 Day 15 (C2D15) .............................................................................................87 
8.2.10 
Cycle 3 Day 1 (C3D1) .................................................................................................88 
8.2.11 
Cycle 3 Day 15 (C3D15) .............................................................................................89 
8.2.12 
Cycle 4 Day 1 (C4D1) .................................................................................................90 
8.2.13 
Cycle 4 Day 15 (C4D15) .............................................................................................91 
8.2.14 
Cycle 5 Day 1 (C5D1) .................................................................................................91 
8.2.15 
Cycle 5 Day 15 (C5D15) .............................................................................................92 
8.2.16 
Cycle 6 Day 1 (C6D1) .................................................................................................92 
8.2.17 
Cycle 6 Day 15 (C6D15) .............................................................................................93 
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8.2.18 
Day 1 of Each Subsequent Cycle .................................................................................94 
8.2.19 
Day 15 of Each Subsequent Cycle ...............................................................................95 
8.2.20 
Response Evaluations ..................................................................................................95 
8.2.21 
Treatment Termination (Optional Visit) ......................................................................96 
8.3 
Follow-up Phase.................................................................................................................96 
8.3.1 
End-of-Treatment Visit for Ibrutinib ...........................................................................96 
8.3.2 
End-of-Treatment Visit for MEDI4736 .......................................................................97 
8.3.3 
Response Follow-up.....................................................................................................98 
8.3.4 
Survival Follow-up ......................................................................................................98 
8.4 
Missed Evaluations ............................................................................................................98 
9. 
SUBJECT COMPLETION AND WITHDRAWAL .........................................................99 
9.1 
Completion .........................................................................................................................99 
9.2 
Withdrawal from Study Treatment ....................................................................................99 
9.3 
Withdrawal from Study......................................................................................................99 
10. STATISTICAL METHODS AND ANALYSIS ...............................................................101 
10.1 
Analysis Populations ........................................................................................................101 
10.1.1 
Treated Population .....................................................................................................101 
10.1.2 
Safety Population .......................................................................................................101 
10.1.3 
Response-evaluable Population .................................................................................101 
10.1.4 
Additional Analysis Populations................................................................................101 
10.1.5 
Replacement of Subjects ............................................................................................101 
10.2 
Endpoints for Phase 1b ....................................................................................................101 
10.2.1 
Primary Endpoints .....................................................................................................101 
10.2.2 
Secondary Endpoints .................................................................................................102 
10.3 
Endpoints for Phase 2 ......................................................................................................102 
10.3.1 
Primary Endpoint .......................................................................................................102 
10.3.2 
Secondary Endpoints .................................................................................................102 
10.3.3 
Exploratory Endpoints ...............................................................................................102 
10.4 
Sample Size Determination..............................................................................................102 
10.4.1 
Phase 1b .....................................................................................................................102 
10.4.2 
Phase 2 .......................................................................................................................103 
10.5 
Subject Information .........................................................................................................104 
10.6 
Analysis Methods.............................................................................................................104 
10.6.1 
Phase 1b Analyses......................................................................................................104 
10.6.2 
Phase 2 Analyses........................................................................................................104 
10.6.2.1. 
Primary Efficacy Analysis ...................................................................................104 
10.6.2.2. 
Secondary Efficacy Analyses ..............................................................................105 
10.6.2.3. 
Exploratory Efficacy Analyses ............................................................................105 
10.6.2.4. 
Subgroup Analyses ..............................................................................................105 
10.7 
Safety Analysis ................................................................................................................105 
10.7.1 
Adverse Events ..........................................................................................................106 
10.7.2 
Clinical Laboratory Tests ...........................................................................................106 
10.8 
Dose Level Review Committee .......................................................................................107 
10.9 
Pharmacokinetic Analysis (Ibrutinib) ..............................................................................107 
10.10 Pharmacokinetic Analysis (MEDI4736) ..........................................................................107 
10.11 Immunogenicity Analyses ...............................................................................................107 
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10.12 Pharmacodynamic Analyses ............................................................................................108 
10.13 Biomarker Analyses .........................................................................................................108 
11. ADVERSE EVENT REPORTING ...................................................................................109 
11.1 
Definitions........................................................................................................................109 
11.1.1 
Adverse Events (AE) .................................................................................................109 
11.1.2 
Serious Adverse Events .............................................................................................110 
11.1.3 
Severity Criteria (Grade 1-5) .....................................................................................110 
11.1.4 
Causality (Attribution) ...............................................................................................111 
11.2 
Unexpected Adverse Events ............................................................................................111 
11.3 
Special Reporting Situations ............................................................................................112 
11.4 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators .....................................................................................................................112 
11.4.1 
Assessment of Adverse Events ..................................................................................112 
11.4.2 
Adverse Event Reporting Period ...............................................................................112 
11.4.3 
Expediting Reporting Requirements for Serious Adverse Events .............................113 
11.4.4 
Pregnancy ...................................................................................................................114 
11.4.5 
Other Malignancies ....................................................................................................115 
11.4.6 
Adverse Events of Special Interest (AESI) ................................................................115 
11.4.6.1. 
Major Hemorrhage ...............................................................................................115 
11.4.6.2. 
Pneumonitis..........................................................................................................115 
11.4.6.3. 
Hypersensitivity Reactions ..................................................................................115 
11.4.6.4. 
Hepatic Function Abnormalities (Hepatotoxicity)...............................................116 
12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ....................117 
12.1 
Regulatory and Ethical Compliance ................................................................................117 
12.2 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval...................................................................................117 
12.3 
Informed Consent.............................................................................................................117 
12.4 
Quality Control and Quality Assurance ...........................................................................118 
12.5 
Protected Subject Health Information Authorization ......................................................118 
12.6 
Study Files and Record Retention....................................................................................118 
12.7 
Case Report Forms and Record Maintenance ..................................................................119 
12.8 
Investigational Study Drug Accountability .....................................................................120 
12.9 
Study Monitoring/Audit Requirements............................................................................120 
12.10 Investigator Responsibilities ............................................................................................121 
12.11 Sponsor Responsibilities ..................................................................................................121 
12.12 Financial Disclosure.........................................................................................................122 
12.13 Liability and Clinical Trial Insurance ..............................................................................122 
12.14 Protocol Amendments ......................................................................................................122 
12.15 Publication of Study Results ............................................................................................123 
12.16 Study Discontinuation ......................................................................................................123 
13. REFERENCES ...................................................................................................................124 
14. APPENDICES .....................................................................................................................129 
 
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20 February 2015 
Final 
 
LIST OF IN-TEXT TABLES  
Table 1. 
Overview of Ongoing Clinical Studies of MEDI4736 in Which Subjects Have 
Been Treated ......................................................................................................... 33 
Table 2. 
Phase 1b Dosing Levels ........................................................................................ 43 
Table 3. 
Ibrutinib Dose Modifications ................................................................................ 57 
Table 4. 
Dose Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated MEDI4736-related Adverse 
Reactions ............................................................................................................... 59 
LIST OF APPENDICES 
Appendix 1. 
Schedule of Assessments for Phase 1b and Phase 2 ........................................... 130 
Appendix 2.  Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, and 
Biomarkers: Phase 1b and Phase 2 ..................................................................... 132 
Appendix 3. 
ECOG Performance Status Scores ...................................................................... 134 
Appendix 4. 
Inhibitors and Inducers of CYP3A ..................................................................... 135 
Appendix 5. 
Revised Criteria for Response Assessment of Malignant Lymphoma 
(Cheson 2014) ..................................................................................................... 136 
Appendix 6. 
New York Heart Association (NYHA) Functional Classification ...................... 139 
Appendix 7. 
Contraception Requirements for MEDI4736 ...................................................... 140 
 
 
 
 
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IMBRUVICA® (ibrutinib) 
PCYC-1136-CA, Amendment 1 
20 February 2015 
Final 
 
SYNOPSIS 
Study 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 
Protocol Number: 
PCYC-1136-CA 
Study Phase: 
1b/2 
Study Duration: 
Estimated to be approximately 3 years 
Number of Subjects: 
Approximately 109 subjects will be enrolled throughout the study (up to 
36 subjects in Phase 1b and approximately 73 subjects in Phase 2) 
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
MEDI4736 will be supplied in glass vials containing 500 mg of liquid 
solution at a concentration of 50 mg/mL for intravenous (IV) 
administration. 
Objectives: 
Phase 1b: 
Primary Objectives: 
• 
To determine the recommended Phase 2 dose (RP2D) of ibrutinib in 
combination with MEDI4736 in subjects with relapsed or refractory 
lymphomas 
• 
To determine the safety and tolerability of ibrutinib in combination 
with MEDI4736 in subjects with relapsed or refractory lymphomas 
 
Secondary Objectives: 
• 
To evaluate the efficacy of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory lymphomas by assessing the 
overall response rate (ORR)  
• 
To evaluate the efficacy of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory lymphomas by assessing the 
duration of response (DOR)  
• 
To determine the pharmacokinetics (PK) and pharmacodynamics of 
both ibrutinib and MEDI4736 in subjects with relapsed or refractory 
lymphomas 
 
Phase 2: 
Primary Objective: 
• 
To evaluate the efficacy of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory lymphomas by assessing the ORR 
 
Secondary Objectives: 
• 
To determine the efficacy of ibrutinib in combination with MEDI4736 
in subjects with relapsed or refractory lymphomas by assessing the 
DOR, progression-free survival (PFS), and overall survival (OS) 
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• 
To determine the safety and tolerability of ibrutinib in combination 
with MEDI4736 in subjects with relapsed and refractory lymphomas 
• 
To determine the PK and pharmacodynamics of both ibrutinib and 
MEDI4736 in subjects with relapsed or refractory lymphomas 
 
Exploratory Objectives: 
• 
To evaluate immune cell subsets after treatment with ibrutinib in 
combination with MEDI4736 
• 
To evaluate non-BTK related pharmacodynamics (ie, interleukin-2-
inducible T-cell kinase [ITK]) after treatment with ibrutinib in 
combination with MEDI4736 
• 
To evaluate chemokine/cytokine levels after treatment with ibrutinib in 
combination with MEDI4736 
• 
To identify genes and proteins associated with sensitivity or resistance 
to ibrutinib and/or MEDI4736 combination (ie, PD-1 ligand [PD-L1]) 
• 
To evaluate the efficacy of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory lymphomas by assessing the rate 
and duration of minimal residual disease (MRD) negativity 
Study Design: 
This is a Phase 1b/2, open-label multi-center study to assess the safety and 
efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas. A 6+3 de-escalation design will be 
employed in Phase 1b to assess doses of ibrutinib in combination with 
MEDI4736 to determine the RP2D for this study.  
 
Phase 1b: 
In the safety portion of the study, a starting dose of 560 mg of ibrutinib and 
10 mg/kg of MEDI4736 will be explored in Cohort 1 and will follow a 6+3 
dose de-escalation design including a sentinel subject with at least a 3-day 
observation period in each Phase 1b dosing cohort prior to dosing 
additional subjects to monitor for any unexpected acute or overlapping 
toxicities. Subjects with one of the following two tumor types will be 
eligible for enrollment in Phase 1b: 
• Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• Diffuse large B cell lymphoma (DLBCL) 
In cohort 1, ibrutinib will be administered orally (PO) daily in 6 subjects at 
a dose of 560 mg in combination with MEDI4736 at a dose of 10 mg/kg 
intravenously (IV) every 2 weeks in 28-day cycles for 12 months or until 
unacceptable toxicity or disease progression occurs.  
 
As a lead-in to the first cycle, ibrutinib will be given for 7 days prior to 
starting MEDI4736 in order to obtain single agent PK and biomarker 
samples that can be compared to combination therapy.  
 
If the subject incidence of dose-limiting toxicities (DLTs) from Day 1 of 
Cycle 1 of combination therapy to the laboratory evaluations on Day 1 of 
Cycle 2 is <33.3% (ie, ≤1 of 6 or ≤2 of 9 subjects with a DLT), this dose 
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level will be considered safe to proceed to Phase 2, and will be defined as 
the RP2D. If 2 subjects within the initial cohort of 6 subjects experience a 
DLT, an additional 3 subjects will be enrolled at the same dose level. If 3 
or more of 69 subjects experience a DLT, dose de-escalation will occur. 
A similar 6+3 cohort design will be utilized in the de-escalation cohorts. 
De-escalation cohorts -1A and -1B will be opened simultaneously to 
determine which dosing schedule is most appropriate for the phase 2 
portion of the study (for cohort definitions, see synopsis section: Study 
Treatment). Determination will be based on the safety profile of the 
2 treatment regimens. If necessary, the dose de-escalation cohort -2 will be 
enrolled thereafter.  
 
The Phase 1b DLT observation period will occur from Day 1 of Cycle 1 of 
ibrutinib in combination with MEDI4736 treatment until the laboratory 
evaluations on Day 1 of Cycle 2 which will occur before the MEDI4736 
infusion on Day 1 of Cycle 2. A DLT is an AE at least possibly related to 
study drug(s) defined as: 
 
Any Grade 3 or higher non-hematologic AE (with additional clarifications 
below) 
 
Grade 3 or higher nausea, vomiting, or diarrhea (non-colitis-related) 
that is uncontrolled by maximal supportive care and persists for 
>7 days would be considered a DLT 
 
Grade 3 fatigue that persists for >7 days would be considered a DLT 
 
Any Grade 3 immune related adverse event (irAE) that does not 
downgrade to Grade ≤2 within 3 days after onset of the event despite 
maximal supportive care including systemic corticosteroids, or does 
not downgrade to Grade ≤1 or baseline within 14 days would be 
considered a DLT 
 
Any Grade ≥2 pneumonitis that does not resolve to Grade ≤1 within 
3 days of the initiation of maximal supportive care would be 
considered a DLT. 
 
The DLT definition excludes the following conditions: 
o Grade 3 endocrinopathy that is managed with or without systemic 
corticosteroid therapy and/or hormone replacement therapy and 
the subject is asymptomatic 
o Grade 3 inflammatory reaction attributed to a local antitumor 
response (eg, inflammatory reaction at sites of metastatic disease, 
lymph nodes, etc)  
o Vitiligo or alopecia of any AE grade would not be considered a 
DLT 
2)  Clinically relevant hematologic AE such as: 
 
Grade 3 or 4 neutropenia (ANC<1,000/ mm3) lasting >7 days 
 
Febrile neutropenia (Grade 3 or 4 neutropenia with fever ≥38.3ºC) 
 
Grade 3 or 4 thrombocytopenia (<25,000/ mm3) lasting >7 days  or 


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requiring transfusion or associated with Grade ≥2 bleeding 
• Any other Grade 4 hematologic AE, except lymphopenia 
During the Phase 1b DLT observation period of ibrutinib in combination 
with MEDI4736, subjects will be replaced for any of the following 
reasons: 
• Missed ≥5 consecutive doses of ibrutinib or missed 7 total doses (not 
due to DLT) 
• Missed dose of MEDI4736 or received the MEDI4736 dose outside of 
the protocol-allowed window (±2 days) (not due to DLT) 
• Study drug discontinuation for any reason other than DLT  
After the RP2D of ibrutinib in combination with MEDI4736 is defined, 
enrollment in Phase 2 will commence. 
 
Phase 2: 
Two tumor types will be enrolled in separate cohorts as part of this 
protocol: 
• Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• Diffuse large B cell lymphoma (DLBCL) 
For FL: n = 39 
The FL cohort will enroll 39 response-evaluable subjects. An interim 
analysis will be performed after 19 subjects are evaluable for tumor 
response after completing at least 2 response assessments. If only 6 or 
fewer responders (≤6/19) are observed, the Sponsor may consider 
discontinuation of this cohort; however, assessment of biomarkers (that 
may aid in prospective enrichment of responders) or tumor measurements 
(showing clinically relevant tumor reductions, ie, 40%, that fit the criteria 
for SD) may support continued enrollment (see Section 12.11).    
 
For DLBCL: n = 34 
Subjects with germinal center B-cell (GCB) and non-GCB subtypes will be 
enrolled at a 1:1 ratio approximately. The DLBCL cohort will enroll 
34 response-evaluable subjects. An interim analysis will be performed after 
9 subjects are evaluable for tumor response after completing at least 
2 response assessments. If only 1 or fewer responder (≤1/9) is observed, 
the Sponsor may consider discontinuation of this cohort; however, 
assessment of biomarkers (that may aid in prospective enrichment of 
responders) or tumor measurements (showing clinically relevant tumor 
reductions, ie, 40%, that fit the criteria for SD) may support continued 
enrollment (see Section 12.11).  
 
In the DLBCL cohort, additional prospectively identified non-GCB 
subjects may be enrolled if a 22% ORR (2/9) is not achieved at the interim 
analysis in the unselected DLBCL population so that at least a total of 
16 subjects with the non-GCB subtype are evaluated.  
Note: The Phase 2 subjects include all of those subjects treated at R2PD in 
Phase 1b but with tumor type as defined for Phase 2. 
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During the Phase 2 portion of the study, if a subject discontinues study 
drug prior to the first tumor response assessment for reasons other than 
progressive disease, the subject may be replaced. 
The primary analysis will occur at least 12 months after the last FL subject 
is enrolled and at least 9 months after the last DLBCL subject is enrolled. 
Dosing of ibrutinib in combination with MEDI4736 will continue for a 
total of 12 cycles of therapy if the subject is deriving clinical benefit (CR, 
PR, or SD) and the subject is not experiencing unacceptable toxicity. After 
12 cycles, dosing of ibrutinib alone will continue as long as clinical benefit 
is seen without safety concerns or disease progression.  Response 
evaluations will occur on Day 1 of Cycle 3 and then after every 3rd cycle 
through the 1st year and after every 6th cycle thereafter. Assessment will 
follow the Revised Criteria for Response Assessment of Malignant 
Lymphoma (Cheson 2014).  
In order to accommodate the potential for immune flare 
(pseudoprogression), treatment with MEDI4736 and ibrutinib may 
continue between the initial assessment of suspected progression and 
confirmation of progression. Subjects with presumed progressive disease 
(PD) who, in the Investigator’s opinion, continue to receive clinical benefit 
from their treatment may continue to receive MEDI4736 and ibrutinib as 
dictated in the protocol after consultation with the Sponsor and at the 
Investigator’s discretion (see Section 12.11). In the absence of clinically 
significant deterioration, a CT scan or biopsy may be performed at least 
4 weeks later to confirm PD. If PD is confirmed at the later time point, PD 
should be assigned to the prior time point at which PD criteria were also 
met. MEDI4736 and ibrutinib should be discontinued if there is confirmed 
PD per Revised Criteria for Response Assessment of Malignant 
Lymphoma (Cheson 2014) or other clinical data suggest clear evidence of 
progression.  
Subjects are required to undergo a pre-treatment tumor biopsy for all 
phases of this study; a post-progression biopsy is recommended but will be 
optional. 
Population: 
Subjects with relapsed or refractory: 
 
Follicular lymphoma (FL) (grade 1, 2, or 3A) 
 
Diffuse large B cell lymphoma (DLBCL) 
Centers: 
Multi-center, United States (US) only 
Inclusion Criteria: 
1. Men and women ≥ 18 years of age 
2. Pathologically confirmed:  
A. Phase 1b: diffuse large B-cell lymphoma or follicular lymphoma 
(grade 1, 2, or 3A) according to World Health Organization 
(WHO) criteria 
B. Phase 2: diffuse large B-cell lymphoma or follicular lymphoma 
(grade 1, 2, or 3A) according to WHO criteria without clinical or 
pathological evidence of transformation 
3. Provision of a fresh tumor biopsy or an available archival tumor 
sample processed as formalin-fixed, paraffin-embedded (FFPE) taken 
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(Note: Earlier archived tumor tissue from all enrolled subjects will also 
be requested.)      
4. Relapsed or refractory disease: 
A. DLBCL 
1) Relapsed or refractory disease, defined as:  
a) Recurrence of disease after a complete response (CR) 
OR 
b) Partial response (PR), stable disease (SD) or progressive 
disease (PD) at completion of the treatment regimen 
preceding entry to the study (residual disease) 
2) Subjects who have not already had a stem cell transplant must 
not be considered a candidate for high dose chemotherapy with 
stem cell transplant (HDT/SCT) and must meet at least one of 
the following criteria: 
a) Age ≥70 years 
b) Diffuse lung capacity for carbon monoxide <50% by 
pulmonary function test 
c) Left ventricular ejection fraction <50% by multiple gated 
acquisition /echocardiogram 
d) Other organ dysfunction or co-morbidities precluding the 
use of HDT/SCT on the basis of unacceptable risk of 
treatment-related morbidity 
e) Failure to achieve PR or CR with salvage therapy 
f) Subject refusal of HDT/SCT 
B. FL 
1) Previously received at least one appropriate 
chemoimmunotherapy regimen and have relapsed or refractory 
disease 
5. Measurable disease:  One or more measurable disease sites on CT scan 
(>1.5 cm in longest dimension) is required. Lesions in anatomical 
locations (such as extremities or soft tissue lesions) that are not well 
visualized by CT may be measured by MRI instead. 
6. Adequate hematologic function independent of transfusion support for 
at least 7 days prior to screening and independent of growth factor 
support for at least 14 days prior to screening, defined as:  
• Absolute neutrophil count >1500 cells/mm3 (1.50 x 109/L) 
• Platelet count >50,000 cells/mm3 (50 x 109/L) unless there is 
documented bone marrow involvement 
• Hemoglobin >8.0 g/dL 
7. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤ 2.5 x upper limit of normal (ULN) 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome such that bilirubin ≤3.0 x ULN or is of non-hepatic 
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origin) 
• Estimated Creatinine Clearance ≥40 mL/min (Cockcroft-Gault)  
8. Prothrombin time (PT) <1.5 x ULN and activated partial 
thromboplastin time (aPTT ) <1.5 x ULN 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 
10. Female subjects must either be of non-reproductive potential (ie, post-
menopausal by history: ≥60 years old and no menses for ≥1 year 
without an alternative medical cause; OR history of hysterectomy, OR 
history of bilateral tubal ligation, OR history of bilateral 
oophorectomy) or must have a negative serum pregnancy test upon 
study entry.  
11. Male subjects who are not sterilized and who are sexually active with a 
female partner of childbearing potential and female subjects of 
childbearing potential who are sexually active with a nonsterilized 
male partner must agree to use 2 highly effective methods of birth 
control (eg, condoms, implants, injectables, combined oral 
contraceptives, or intrauterine devices [IUDs]) during the period of 
therapy and for 3 months after the last dose of study drug (see 
Appendix 7). 
12. Male subjects must agree to not donate sperm, and female subjects 
must agree to not donate eggs (ova, oocytes) for the purposes of 
assisted reproduction during or for 3 months after the last dose of 
either study drug. 
Exclusion Criteria: 
1. Anti-tumor therapy (chemotherapy, antibody therapy, immunotherapy, 
biologic-based therapy, or investigational agent) within 14 days of 
study Day 1 (or 6 weeks for nitrosureas or mitomycin C); Enrollment 
of subjects that have received molecularly-targeted small molecule 
inhibitors less than 28 days prior to study Day 1 will be permitted if 
more than 14 days and at least 5 drug half-lives have passed prior to 
receiving the first dose of ibrutinib.  
2. Prior therapy with ibrutinib or other BTK inhibitor and/or anti-PD1, 
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte 
associated antigen 4 (CTLA-4) antibody 
3. Unresolved toxicities from prior anti-cancer therapy, defined as having 
not resolved to Common Terminology Criteria for Adverse Event 
(CTCAE, version 4.03) grade 0 or 1, or to the levels dictated in the 
inclusion/exclusion criteria with the exception of stable neuropathy, 
vitiligo, alopecia, or other irreversible toxicity not reasonably expected 
to be exacerbated by study treatment (eg, hearing loss)  
4. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see 
Appendix 4) 
5. Vaccinated with live, attenuated vaccines within 4 weeks of first dose 
of study drug (Note: Subjects, if enrolled, should not receive live 
vaccines during the study and until 30 days after the last dose of study 
drug) 
6. Current or prior use of immunosuppressive medication within 14 days 
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before the first dose of MEDI4736. The following are exceptions to 
this criterion: 
• Intranasal, inhaled, topical corticosteroids, or local corticosteroid 
injections (eg, intra-articular injection) 
• Systemic corticosteroids at doses not to exceed 10 mg/day of 
prednisone or its equivalent 
• Corticosteroids as pre-medication for hypersensitivity reactions (eg, 
CT scan pre-medication) 
7. History of allogeneic organ transplant or <100 days after autologous 
transplant 
8. Primary central nervous system (CNS) lymphoma or evidence of CNS 
involvement by lymphoma 
9. Any uncontrolled active systemic infection, or recent infection 
requiring intravenous antibiotic treatment that was completed ≤14 days 
before the first dose of study drug 
10. Known history of previous clinical diagnosis of active tuberculosis 
11. Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia) 
12. History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment  
13. Major surgery within 4 weeks of first dose of study drug 
14. Concomitant use of warfarin or other Vitamin K antagonists 
15. History of primary immunodeficiency 
16. Known history of human immunodeficiency virus (HIV) or current 
chronic/active infection with hepatitis C virus (HCV) or hepatitis B 
virus (HBV) 
• Subjects with chronic or active hepatitis B as diagnosed by 
serologic tests are excluded from the study. In equivocal cases, 
hepatitis B or C polymerase chain reaction (PCR) may be 
performed and must be negative for enrollment. 
17. Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as 
defined by the New York Heart Association Functional Classification 
(see Appendix 6); or a history of myocardial infarction, uncontrolled 
hypertension or cardiac arrhythmia, unstable angina, or acute coronary 
syndrome within 6 months prior to enrollment 
18. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated 
from 3 electrocardiograms (ECGs) using Fridericia formula 
19. Unable to swallow capsules or malabsorption syndrome, disease or 
condition significantly affecting gastrointestinal function, or resection 
of the stomach or small bowel, or partial or complete bowel 
obstruction 
20. Lactating women, men planning to father a child, or women planning 
pregnancy while taking study drug or within 3 months after the last 
dose of study drug 
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21. Known allergy or hypersensitivity to ibrutinib or MEDI4736 or any 
excipient 
22. Active or prior documented autoimmune or inflammatory disorders 
including but not limited to inflammatory bowel disease (eg, colitis, 
Crohn’s disease), diverticulitis with the exception of a prior resolved 
episode or diverticulosis, celiac disease, irritable bowel disease, or 
other serious gastrointestinal chronic conditions associated with 
diarrhea, type I diabetes mellitus, multiple sclerosis, systemic lupus 
erythematosus, Wegener’s granulomatosis (granulomatosis with 
polyangiitis), myasthenia gravis, Graves’ disease, rheumatoid arthritis, 
pneumonitis, interstitial lung disease, hypophysitis, or uveitis within 
the past 3 years prior to the start of treatment. The following are 
exceptions to this criterion: 
• Subjects with vitiligo or alopecia 
• Subjects with hypothyroidism (eg, following Hashimoto syndrome) 
stable on hormone replacement or psoriasis not requiring systemic 
treatment 
23. History of other malignancies, except 
• Malignancy treated with curative intent and with no known active 
disease present for ≥5 years before the first dose of study drug and 
felt to be at low risk for recurrence by the treating physician 
• Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease 
• Adequately treated carcinoma in situ without evidence of disease 
24. Unwilling or unable to participate in all required study evaluations and 
procedures 
25. Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise the 
subject’s safety or put the study outcomes at undue risk, eg, psychiatric 
illness/social situations that would limit compliance with study 
requirement or compromise the ability of the subject to give written 
informed consent 
26. Unable to understand the purpose and risks of the study and to provide 
a signed and dated informed consent form (ICF) and authorization to 
use protected health information (in accordance with national and local 
subject privacy regulations) 
27. Concurrent enrollment in another clinical study, unless in a follow-up 
period or in an observational study 
Study Treatment: 
One cycle of treatment is 28 days in duration and consists of daily 
administration of ibrutinib PO with MEDI4736 IV every 2 weeks. As a 
lead-in to the first cycle, ibrutinib will be given for 7 days prior to starting 
MEDI4736 in order to obtain single agent PK and biomarker samples that 
can be compared to the PK when ibrutinib is administered in combination 
with MEDI4736. Dosing of ibrutinib in combination with MEDI4736 will 
continue for a total of 12 cycles of therapy if the subject is deriving clinical 
benefit (CR, PR, or SD) and the subject is not experiencing unacceptable 
toxicity. Re-treatment with MEDI4736 will not be allowed following 
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completion of 12 cycles of treatment, regardless of any dose delays, missed 
doses, or following permanent discontinuation for any reason. After 12 
cycles, dosing of ibrutinib alone will continue as long as clinical benefit is 
seen without safety concerns or disease progression. 
Phase 1b (including de-escalation cohorts): 
Cohort  1 
ibrutinib 560 mg PO qd, MEDI4736 10 mg/kg IV q2 weeks 
Cohort -1A ibrutinib 420 mg PO qd, MEDI4736 10 mg/kg IV q2 weeks 
Cohort -1B 
ibrutinib 560 mg PO qd, MEDI4736 3 mg/kg IV q2 weeks 
Cohort -2 
ibrutinib 420 mg PO qd, MEDI4736 3 mg/kg IV q2 weeks 
 
Phase 2: 
RP2D established in Phase 1b (420 mg or 560 mg PO ibrutinib daily and 
3 mg/kg or 10 mg/kg IV MEDI4736 q2 weeks) given continuously in 
28-day cycles in the following two cohorts: 
• Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• Diffuse large B cell lymphoma (DLBCL) 
Safety Monitoring: 
 
AEs and serious adverse events (SAEs) will be reviewed by the Sponsor on 
an ongoing basis to identify safety concerns. A Dose Level Review 
Committee will evaluate the safety data from the 1b portion of the trial. 
Members of this committee will include participating investigators or 
designee as well as the Sponsor (invitees include: the Medical Monitor or 
designee, the clinical lead, a Drug Safety representative and a 
Biostatistician) (see Section 12.11). 
Statistical Methods and 
Data Analysis: 
Tumor response assessment will follow the Revised Criteria for Response 
Assessment of Malignant Lymphoma (Cheson 2014).  
 
Phase 1b: 
Phase 1b is based on a 6+3 de-escalation design described in the Study 
Design Section to determine the RP2D. 
A primary objective is to evaluate safety and tolerability of ibrutinib in 
combination with MEDI4736. AEs including DLTs, laboratory values, and 
dosing data will be listed and summarized by tumor type and dose cohort. 
Secondary objectives are to evaluate efficacy and PK and 
pharmacodynamics in subjects receiving the combination regimen. ORR 
and DOR will be calculated and summarized by tumor type and dose 
cohort descriptively. PK and pharmacodynamics (ie, BTK) data will be 
evaluated by tumor type and dose cohort. 
 
Phase 2: 
Phase 2 will use the RP2D ascertained in Phase 1b to treat approximately 
73 subjects (39 FL and 34 DLBCL subjects). For Phase 2 the following 
analyses will be undertaken: 
 
Primary Efficacy Endpoint: 
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The primary efficacy endpoint is the ORR in each of the two cohorts. The 
observed ORR along with its 95% confidence interval will be calculated 
for each tumor type.  
Secondary Efficacy Endpoints: 
• DOR will be calculated and summarized by descriptive statistics for 
responders by tumor type. The Kaplan-Meier estimate will be provided 
for DOR if a sufficient number of responders are observed.  
• PFS and OS will be evaluated by tumor type with Kaplan-Meier 
estimates. 
• PK and pharmacodynamics profiles will also be evaluated by tumor 
type. 
 
Exploratory Efficacy Analysis: 
The exploratory efficacy variables will be summarized descriptively and 
include the following: 
• Immune cell subsets 
• Non-BTK related pharmacodynamics (ie, ITK) 
• Chemokine/cytokine levels  
• Genes and proteins associated with sensitivity or resistance to ibrutinib 
and/or MEDI4736 (ie, PD-L1) 
• Rate and duration of MRD negativity 
For each cohort, a subgroup analysis will be conducted to calculate ORR 
and its 95% confidence interval based on PD-1 ligand expression (positive 
versus negative). For the DLBCL cohort, a subgroup analysis will also be 
conducted based on subjects with GCB and non-GCB subtype, 
respectively. 
 
Safety Analysis: 
AEs, SAEs, laboratory data, vital signs, other relevant safety data, and 
dosing data will be listed and summarized by cohort. 
Sample Size 
Determination: 
Phase 1b:  
6-36 subjects for DLT assessment (6-9 subjects in up to 4 dose de-
escalation cohorts, regardless of tumor type) 
Phase 2:  
Approximately 73 response-evaluable subjects (including those subjects 
treated at the RP2D in Phase 1b but with tumor type as defined for Phase 2). 
 
For FL: 
A maximum of 39 response-evaluable subjects (including those subjects 
treated at the RP2D in Phase 1b and with tumor type of FL) will be 
enrolled. An interim analysis will be performed after 19 subjects are 
evaluable for tumor response after completing at least 2 response 
assessments. If only 6 or fewer responders (≤6/19) are observed, the 
Sponsor may consider discontinuation of this cohort (see Section 12.11).  
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The null hypothesis that the true ORR is 30% will be tested against a one-
sided alternative that the ORR is 50%. The null hypothesis will be rejected 
if 17 or more responses are observed in the 39 subjects. This design yields 
a 1-sided type I error rate of 0.05 and power of 80% when the true ORR is 
50%. This statistical design including number of subjects and number of 
responders follows the statistical framework of Simon’s minimax two-
stage design (Simon, 1989). Enrollment will continue while the interim 
analysis is performed. 
 
For DLBCL: 
A maximum of 34 response-evaluable subjects with GCB and non-GCB 
(inclusive of subjects treated at the RP2D in Phase 1b in the unselected 
DLBCL population) will be enrolled at a 1:1 ratio approximately.  
An interim analysis will be performed after 9 subjects are evaluable for 
tumor response after completing at least 2 response assessments. If only 
1 or fewer responder (≤1/9) is observed, the Sponsor may consider 
discontinuation of this cohort (see Section 12.11).   
The null hypothesis that the true ORR is 15% will be tested against a one-
sided alternative that the ORR is 35%. The null hypothesis will be rejected 
if 9 or more responses are observed in the 34 subjects. This design yields a 
1-sided type I error rate of 0.05 and power of 80% when the true ORR is 
35%. This statistical design including number of subjects and number of 
responders follows the statistical framework of Simon’s optimal two-stage 
design (Simon 1989). Enrollment will continue while the interim analysis 
is performed. 
 
 
 
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ABBREVIATIONS 
ABC 
activated B cell 
ADA 
antidrug antibody  
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE  
adverse event  
AESI 
Adverse Events of Special Interest 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
ASCO 
American Society of Clinical Oncology 
AST  
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
AUC0-14 
area under the curve from zero to 14 days 
AUC0-24  
area under the curve from zero to 24 hours  
BCR  
B-cell receptor  
BMI 
body mass index 
BR 
bendamustine and rituximab 
BTK  
Bruton’s tyrosine kinase  
CD 
cluster of differentiation 
CDC 
complement-dependent cytotoxicity 
CEOP 
cyclophosphamide, etoposide, vincristine, prednisone 
CEPP 
cyclophosphamide, etoposide, prednisone, procarbazine 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL 
systemic clearance 
CLL 
chronic lymphocytic leukemia  
CNS  
central nervous system  
CR  
complete response  
CTCAE 
Common Terminology Criteria for Adverse Events  
CTLA-4 
cytotoxic T-lymphocyte-associated antigen 4 
CYP  
cytochrome P450 
DA-EPOCH 
dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone 
DLBCL 
diffuse large B-cell lymphoma 
DLRC 
Dose Level Review Committee 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group performance status 
ECG 
Electrocardiogram 
FCR 
fludarabine/cyclophosphamide/rituximab 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FL 
follicular lymphoma 
G-CSF 
granulocyte-colony stimulating factor 
GCB 
germinal center B cell 
GCP 
Good Clinical Practice 
GDP 
gemcitabine, dexamethasone, cisplatin 
GemOx 
gemcitabine, oxaliplatin 
GGT 
gamma-glutamyltransferase 
GLP 
good laboratory practices 
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HBV 
hepatitis B virus 
HCV  
hepatitis C virus 
HDT/SCT 
high dose chemotherapy with stem cell transplant 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator's Brochure 
IC50  
concentration that inhibits a process by 50% 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
Ig 
immunoglobulin 
ILD 
interstitial lung disease 
INR 
International normalized ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible T-cell kinase  
JC 
John Cunningham 
Km 
Michaelis constant 
LD 
longest diameter  
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantitation 
mAb 
monoclonal antibody 
MCL 
mantle cell lymphoma 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimum residual disease 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NF-κB 
nuclear factor kappa light chain enhancer of activated B cells 
NHL 
non-Hodgkin lymphoma 
NOAEL 
no-observed-adverse-effect level 
NONMEM 
nonlinear mixed-effects modeling 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
Overall survival 
PBMC 
peripheral blood mononuclear cells 
PBML 
primary mediastinal 
PCR 
Polymerase Chain Reaction 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death-ligand 1 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (oral) 
PR  
partial response  
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time  
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QTc  
QT interval corrected for heart  rate 
Q2W 
every 2 weeks  
R-CHOP 
rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone 
R-CVP 
rituximab, cyclophosphamide, vincristine, prednisone 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE  
serious adverse event 
SD 
stable disease  
SEER 
Surveillance, Epidemiology, and End Results 
SJS 
Stevens-Johnson Syndrome 
sPD-L1 
soluble PD-L1 
t1/2 
half-life 
Th 
helper T cell 
Tmax 
time to maximum plasma concentration  
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 
 
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1. 
BACKGROUND 
1.1 
Diffuse Large B-cell Lymphoma  
Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas 
(NHLs) in the United States, with an annual incidence that has been rising gradually since the 
1990s (Fisher 2004). The estimated 2010 prevalence of NHL in the US was approximately 
509,000 individuals, with over 200,000 of these cases in individuals over the age of 70 years 
(SEER 2010). It is estimated that 30−40% of NHL cases are of the DLBCL category 
(Hans 2004). According to the current Surveillance, Epidemiology, and End Results (SEER) 
data, the median age at diagnosis is 67 years (SEER 2010). A very aggressive malignancy in its 
untreated natural history, DLBCL is a potentially curable disease, with a significant proportion 
of patients cured with modern chemoimmunotherapy. Nonetheless, for those patients not cured 
by standard initial therapy, the prognosis remains generally poor (Gisselbrecht 2010) and 
DLBCL still accounts for the highest number of deaths per year of all the NHL histologies. 
DLBCL gene expression profiling reveals 3 molecular subtypes: activated B cell (ABC), 
germinal center B cell (GCB) and primary mediastinal (PMBL). The ABC subtype accounts for 
~30% of cases of DLBCL and has an inferior prognosis. Chronic active B-cell receptor (BCR) 
signaling is a pathogenic mechanism in ABC DLBCL and this chronic activation engages the 
classic nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. In 
contrast, GCB DLBCL pathogenesis is independent of the NF-κB pathway (Lenz 2010). This 
difference in the molecular mechanism of pathogenesis may explain why the ABC subtype is 
less sensitive to chemotherapy and remains less curable than the GCB subtype. Thus, new 
strategies for the ABC subtype are needed.    
Treatment for relapsed and refractory DLBCL remains challenging. Following initial therapy, 
the approach of re-induction chemotherapy followed by high-dose chemotherapy with stem cell 
transplant (HDT/SCT) for responding patients remains the current standard of care. For patients 
that are not eligible for stem cell therapy, per National Comprehensive Cancer Network (NCCN) 
guidelines, a variety of therapies are recommended for second line treatment. These include DA-
EPOCH (dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone)  
+/- rituximab (Jermann 2004; Wilson 2008), CEPP (cyclophosphamide, etoposide, prednisone, 
procarbazine) +/- rituximab (Chao 1990), CEOP (cyclophosphamide, etoposide, vincristine, 
prednisone) +/- rituximab (Bartlett 2001; Moccia 2009), GDP (gemcitabine, dexamethasone, 
cisplatin) +/- rituximab (Crump 2004), GemOx (gemcitabine, oxaliplatin) +/- rituximab 
(Lopez 2008; Corazzelli 2009; El Gnaoui 2007), Bendamustine +/- rituximab (Ohmachi 2013; 
Weidmann 2002; Rigacci 2012), Lenalidomide +/- rituximab (Wiernik 2008; Witzig 2011) and 
rituximab single-agent therapy (Robach 2002). These therapeutic options are largely 
chemotherapy-based and offer a poor prognosis in non-GCB subjects including the ABC 
subtype. Recurrent or resistant DLBCL in patients ineligible for transplantation is particularly 
difficult to treat and is associated with a markedly reduced survival (Thieblemont 2007; 
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Jabbour 2004). Treatment options are also limited for those who have failed stem cell transplant 
or salvage chemotherapy-based strategies (Martelli 2013). 
Treatment of patients with relapsed or refractory DLBCL with chemotherapy-free regimens such 
as ibrutinib and MEDI4736 may be an attractive treatment option if found to be well tolerated 
and have significant anti-tumor activity. Alternative treatment options with a favorable safety 
profile for recurrent or relapsed disease in a heavily pretreated patient population are still needed. 
1.2 
Follicular Lymphoma  
Follicular lymphoma (FL) is the second most common NHL accounting for approximately 22% 
of cases (NHL Classification Project 1997). The overall incidence of FL is 3.18 new cases per 
100,000 persons each year in the United States (US) (Morton 2006). FL is characterized by an 
indolent clinical course, typical morphology, and the presence of a chromosomal translocation, 
t(14;18)(q32;q21) or variant in 85% of patients (Relander 2010). The neoplastic lymphocytes in 
FL express pan-B markers CD19, CD20, CD22, and CD79a; as well as antigens of the germinal 
center (including CD10 and Bcl-6). Histologically, the follicular form of NHL is composed 
mainly of centrocytes with an admixture of centroblasts. Grading is based on the number of large 
transformed cells in 10 malignant follicles viewed at high power (Martinez 2007). FL is 
generally subdivided into 3 grades (NHL Classification Project 2007). However, Grade 3 is often 
further divided into 2 subgroups, 3a and 3b; with 3b considered more aggressive (Hans 2003). 
Importantly, primary FL cells have been found to maintain enhanced signaling from the BCR 
compared to normal B cells (Irish 2006). Treatment often depends on the stage of the disease, 
symptoms, patient age, and comorbidities. 
Alkylating agents such as cyclophosphamide or bendamustine, in combination with rituximab, 
constitute the mainstay of combination therapy. The most commonly used alkylator-based 
regimens include BR (bendamustine and rituximab), R-CHOP (rituximab, cyclophosphamide, 
vincristine, doxorubicin, and prednisone), or R-CVP (rituximab, cyclophosphamide, vincristine, 
and prednisone) (Lymphoma Research Foundation, 2011). Response rates in excess of 85% are 
observed with many different combinations in the first-line setting (Peterson 2003, 
Hiddeman 2005, Czuczman 2005, Rummel 2005); however, most patients treated will eventually 
relapse, and subsequent responses become increasingly shorter in duration and less frequent. 
Patients who become resistant to chemoimmunotherapy, clinically defined as relapsed within 
12 months, have no good treatment options (Fisher 1979, Sehn 2012). In these patients, toxicity 
commonly outweighs the benefit of treatment with chemotherapy (Fisher 1979, Tinmouth 2001). 
Investigational agents (eg, ofatumumab, lenalidomide, bortezomib) have been used with 
response rates of 10% to 27%. 
Due to the toxicity seen with standard combination treatment regimens in patients who are 
elderly, and for patients that have moderate tumor burdens and non-life threatening disease, a 
chemotherapy-free regimen such as ibrutinib and MEDI4736 may be an attractive treatment 
option if found to be well tolerated and have significant anti-tumor activity. Treatment options 
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with a favorable safety profile for recurrent disease in a heavily pretreated patient population are 
still needed.  
1.3 
Ibrutinib  
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK). Inhibition of BTK blocks downstream BCR signaling pathways and thus 
prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and selected members of 
the kinase family with 10-fold specificity compared with non-BTK kinases. Ibrutinib 
(IMBRUVICA®) is approved by the U.S. Food and Drug Administration (FDA) for the treatment 
of: 1) mantle cell lymphoma (MCL) in patients who have received at least one prior therapy 
based on overall response rate, 2) chronic lymphocytic leukemia (CLL) in patients who have 
received at least one prior therapy, 3) CLL in patients with 17p deletion, and 4) Waldenstrom’s 
Macroglobulinemia. Ibrutinib is currently under investigation in various indications.  
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release. B cells express cell surface 
immunoglobulins comprising the BCR, which is activated by binding to antigen. Antigen 
binding induces receptor aggregation and the clustering and activation of multiple tyrosine 
kinases, which in turn activate further downstream signaling pathways (Bishop 2003).  
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated. It is thought that B-cell lymphomas and CLL result from mutations 
and translocations acquired during normal B-cell development (Shaffer 2002). Several lines of 
evidence suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies.  
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease 
X-linked immunodeficiency, both caused by a mutation in the BTK gene. These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B cells. The BTK 
protein is expressed in most hematopoietic cells with the exception of T cells and natural killer 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells (Satterthwaite 2000).  
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from 
the plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain 
maximal pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg. In Study 
PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 
560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration. 
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Sixteen subjects enrolled in the dose-escalation phase of Study PCYC-04753 had a diagnosis of 
FL (Fowler 2012). Eleven subjects received ibrutinib at doses that achieved full BTK occupancy 
(ie, 2.5 mg/kg or higher). The median time on ibrutinib was 7 months (0 to 29 months) and time 
to response was 4.6 months. Overall, the response rate was 55% (3 CRs, 3 PRs; 95% confidence 
interval [CI]=[23%, 83%])(Fowler 2012) and the responses were durable (median response 
duration: 12.3 months) (Fowler 2012). Three patients had chemorefractory disease, and 2 of 
these patients responded (1 CR, 1 PR). The median PFS at study completion for subjects with FL 
was 13.4 months (Study PCYC-04753 CSR). 
Ibrutinib has also demonstrated single agent activity in the treatment of relapsed or refractory de 
novo DLBCL in Study PCYC-1106-CA. Study PCYC-1106-CA is an ongoing Phase 2, open-
label, nonrandomized, multicenter study in patients with relapsed or refractory de novo DLBCL 
receiving 560 mg/day of ibrutinib. Data are currently available on 70 patients from this trial who 
have relapsed or refractory disease with 29 ABC subtype, 20 GCB subtype, 16 Type 3 subtype 
and 5 subjects subtype unknown. The ORR in these 70 patients was 25% (17/70) with 9% of 
patients achieving a complete response (CR) and 16% of patients achieving a partial response 
(PR). Patients with ABC subtype appeared to be the most sensitive with an ORR of 41% (12/29) 
with 17% CR and 24% PR (de Vos 2013). 
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure (IB). 
1.3.1 
Summary of Nonclinical Data  
1.3.1.1. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of BTK (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of BTK activity (concentration that inhibits by 50% [IC50] = 
0.39 nM). The irreversible binding of ibrutinib to cysteine-481 in the active site of BTK results 
in sustained inhibition of BTK catalytic activity and enhanced selectivity over other kinases that 
do not contain a cysteine at this position. When added directly to human whole blood, ibrutinib 
inhibits signal transduction from the B-cell receptor and blocks primary B-cell activation (IC50 = 
80 nM) as assayed by anti-IgM stimulation followed by cluster of differentiation (CD)69 
expression (Herman 2011).  
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB. 
1.3.1.2. 
Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system or respiratory system in rats at any dose tested. Further, no treatment-related 
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corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs.  
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).  
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic. In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in subjects administered the dose of 560 mg daily, respectively.    
1.3.1.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
1.3.1.4. 
Summary of Nonclinical Data (ibrutinib and MEDI4736 Combination) 
This is an exploratory study and there are no nonclinical data on the combination of ibrutinib and 
MEDI4736. 
1.3.2 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the IB.  
1.3.2.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased with substantial intersubject variability. The mean half life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours. Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
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overnight fasting with median time to Tmax delayed from 2 to 4 hours. Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with 
approximately 15 times lower inhibitory potency compared to ibrutinib. The metabolite-to-parent 
AUC ratio ranged from 0.7 to 3.4. Steady-state exposure of ibrutinib and PCI-45227 was less 
than 2-fold of first dose exposure. 
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces. Subjects with mild and moderate renal 
insufficiency (creatinine clearance >30 mL/min) were eligible to enroll in Study PCYC-1102-CA 
in which pharmacokinetic (PK) assessments were included. No dose adjustment is needed for 
mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There is no 
data in patients with severe renal impairment or patients on dialysis. The study of ibrutinib in 
hepatic impaired subjects is currently in progress. 
1.3.3 
Summary of Clinical Safety  
1.3.3.1. 
Monotherapy Studies in Hematologic Malignancies 
Pooled safety data for subjects treated with ibrutinib monotherapy in 11 nonrandomized 
studies (PCYC-1102-CA, PCYC-1117-CA, PCYC-1112-CA [crossover only], PCYC-1104-CA, 
PCI-32765MCL2001, PCI-32765MCL4001, PCYC-1106-CA, PCYC-1111-CA, 
PCI-32765FLR2002, PCYC-04753, and PCI-32765-JPN-101) has been evaluated (ibrutinib IB, 
version 8.0).   
The most frequently reported treatment-emergent adverse events (AEs) in more than 10% of 
subjects receiving ibrutinib as monotherapy in nonrandomized studies (N=1061) were diarrhea 
(35.9%), fatigue (28.6%), nausea (20.2%), cough (17.5%), and anemia (15.2%). The most 
commonly reported Grade 3 or 4 AEs that were hematologic in nature were neutropenia (10.7%), 
thrombocytopenia (6.2%), and anemia (5.5%). Pneumonia (5.7%), fatigue (2.9%), hypertension 
(2.7%), and atrial fibrillation (2.6%) were the most frequently reported nonhematologic Grade 3 
or 4 AEs.  
The incidence of treatment-emergent serious adverse events (SAEs) reported was 41.3% 
(N=1061); pneumonia (7.0%), atrial fibrillation (2.8%), and febrile neutropenia (2.3%) were the 
most commonly reported treatment-emergent SAEs.  
In a randomized Phase 3 study in subjects with CLL/small lymphocytic lymphoma (SLL) 
(PCYC-1112-CA), the most frequently reported treatment-emergent AEs in the ibrutinib arm 
were diarrhea (47.7%), fatigue (27.7%), nausea (26.2%), pyrexia (23.6%), anemia (22.6%), and 
neutropenia (21.5%). AEs reported at a higher incidence (>10% difference) in the ibrutinib arm 
than in the ofatumumab arm included diarrhea (ibrutinib: 47.7%, ofatumumab: 17.8%), 
arthralgia (17.4%, 6.8%), and petechiae (13.8%, 1.0%).  
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The most commonly reported Grade 3 or 4 AEs in more than 2% of ibrutinib treated subjects that 
were hematologic in nature were neutropenia (16.4%), thrombocytopenia (5.6%), and anemia 
(4.6%). Pneumonia (6.7%) was the most frequently reported nonhematologic event. The most 
frequently reported SAEs in ibrutinib subjects were pneumonia (8.7%), atrial fibrillation (3.1%), 
pyrexia (3.1%), lung infection (2.6%), lower respiratory tract infection (2.1%) and urinary tract 
infection (2.1%).  
The above information is reported based on available data from the ibrutinib IB, version 8.0, and 
is subject to change with more current updates. For more detailed information please refer to the 
current version of the IB. 
1.3.4 
Risks 
1.3.4.1. 
Bleeding-related Events  
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include primarily minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria.  
1.3.4.2. 
Cardiac Events 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly 
in subjects with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. In 
particular subjects with a history of cardiac arrhythmias should be monitored closely. 
1.3.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
1.3.4.4. 
Diarrhea  
Approximately one-third of subjects treated with ibrutinib monotherapy and two-thirds treated with 
combination therapy reported diarrhea. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe, with only a small number  
(0.1–1.5%) of Grade 3 events, and no Grade 4 events reported to date.  
1.3.4.5. 
Infections  
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per Common 
Terminology Criteria for Adverse Events (CTCAE). The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis. Isolated cases of John 
Cunningham (JC) virus reactivation resulting in progressive multifocal leukoencephalopathy 
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(PML) have been observed and resulted in death. Two cases in relapsed CLL subjects have been 
reported. One case occurred after multiple prior rituximab regimens and less than one year after 
the last dose of rituximab and high dose steroid administration. The second case occurred during 
concomitant administration of rituximab, bendamustine and ibrutinib. 
1.3.4.6. 
Other Malignancies 
Other malignancies, most frequently skin cancers, have occurred in subjects treated with 
ibrutinib. Across the MCL (PCYC-1104-CA) and CLL/SLL studies (PCYC-1112-CA and 
PCYC-1102-CA), non-melanoma skin cancers and non-skin cancers were reported in 5.0% 
(18/357) and 2.5% (9/357) of subjects who received ibrutinib, respectively. 
1.3.4.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to 
moderate in severity. One case of Stevens-Johnson Syndrome (SJS), with a fatal outcome, was 
reported in a subject with CLL. The subject received ibrutinib (420 mg/day) and was also 
receiving various antibiotics and antigout medication (allopurinol) known to be associated with 
SJS.  
1.3.4.8. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single 
agent ibrutinib or in combination with chemotherapy. Subjects at risk of tumor lysis syndrome 
are those with comorbidities and/or risk factors such as high tumor burden prior to treatment, 
increased uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre‐existing 
kidney abnormalities. 
1.3.5 
Summary of Clinical Data (ibrutinib and MEDI4736 combination)  
This is an exploratory study and there are no clinical data on the use of the combination of 
ibrutinib and MEDI4736 in FL or DLBCL. 
1.4 
MEDI4736 
AstraZeneca and MedImmune are pursuing development of MEDI4736 as a potential anticancer 
therapy for patients with advanced malignancies. In addition to the information provided here, 
please refer to the MEDI4736 IB (Edition 7.0). 
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 
[B7-H1], CD274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). MEDI4736 is 
composed of 2 identical heavy chains and 2 identical light chains, with an overall molecular 
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weight of approximately 149 kDa. MEDI4736 contains a triple mutation in the constant domain 
of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q and 
the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function 
(MEDI4736 IB).  
1.4.1 
Summary of Nonclinical Data 
MEDI4736 binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that MEDI4736 antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release of 
interferon gamma (IFN-γ). Additionally, MEDI4736 demonstrated a lack of antibody-dependent 
cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. In vivo studies show that MEDI4736 inhibits tumor growth in a xenograft 
model via a T-cell dependent mechanism. Moreover, an anti-mouse PD-L1 antibody 
demonstrated improved survival in a syngeneic tumor model when given as monotherapy and 
resulted in complete tumor regression in >50% of treated mice when given in combination with 
chemotherapy. Combination therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-
associated antigen 4 [CTLA-4]) resulted in tumor regression in a mouse model of colorectal 
cancer.  
Cynomolgus monkeys were selected as the only relevant species for evaluation of the PK, 
pharmacodynamics, and potential toxicity of MEDI4736. Following intravenous (IV) 
administration, the PK of MEDI4736 in cynomolgus monkeys was nonlinear. Systemic clearance 
(CL) decreased and concentration half-life (t1/2) increased with increasing doses, suggesting 
saturable target binding-mediated clearance of MEDI4736. No apparent gender differences in PK 
profiles were observed for MEDI4736.  
In general, treatment of cynomolgus monkeys with MEDI4736 was not associated with any 
MEDI4736-related adverse effects that were considered to be of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) PK, pharmacodynamics, and dose range-
finding study, and a GLP 4-week repeat-dose toxicity study were consistent with antidrug 
antibody (ADA)-associated morbidity and mortality in individual animals. The death of a single 
animal in the non-GLP, PK, pharmacodynamics, and dose range-finding study was consistent 
with an ADA-associated acute anaphylactic reaction. The spectrum of findings, especially the 
clinical signs and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose 
study was also consistent with ADA immune complex deposition, and ADA:MEDI4736 immune 
complexes were identified in a subsequent non-GLP, investigative immunohistochemistry study. 
Similar observations were reported in cynomolgus monkeys administered human mAbs 
unrelated to MEDI4736. Given that immunogenicity of human mAbs in nonclinical species is 
generally not predictive of responses in humans, the ADA-associated morbidity and mortality 
were not considered for the determination of the no-observed-adverse-effect level (NOAEL) of 
MEDI4736. Finally, data from the pivotal 3-month GLP toxicity study with MEDI4736 in 
cynomolgus monkeys showed that subchronic dosing of MEDI4736 was not associated with any 
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adverse effects. Therefore, the NOAEL of MEDI4736 in all the general toxicity studies was 
considered to be 100 mg/kg, the highest dose tested in these studies. In addition to the in vivo 
toxicology data, no unexpected membrane binding of MEDI4736 to human or cynomolgus 
monkey tissues was observed in GLP tissue cross-reactivity studies using normal human and 
cynomolgus monkey tissues (MEDI4736 IB). 
1.4.2 
Summary of Clinical Data  
As of the data cutoff date of 14 July 2014, a total of 509 subjects have been enrolled and treated 
with MEDI4736 in 10 ongoing clinical studies: 5 employing MEDI4736 as monotherapy and 5 
as combination therapy (Table 1). No studies have yet been completed. The majority of the 
clinical data are from Study CD-ON-MEDI4736-1108, which has treated the largest number of 
subjects (N = 414). 
Table 1. Overview of Ongoing Clinical Studies of MEDI4736 in Which Subjects Have 
Been Treated  
Study Number (Phase) 
Study Population 
Treatment Regimen 
Subjects 
Treated 
Monotherapy Studies (N = 449)  
CD-ON-MEDI4736-1108 (Phase 1/2)  
Advanced solid tumors  
MEDI4736 Q2W or Q3W  
414 
D4190C00002 (Phase 1)  
Advanced solid tumors  
MEDI4736 Q2W or Q3W  
18 
D4190C00007 (Phase 1)  
MDS  
MEDI4736 Q2W  
2 
D4190C00003 (ATLANTIC) (Phase 2)  
NSCLC  
MEDI4736 Q2W  
14 
D4190C00001 (PACIFIC) (Phase 3)  
NSCLC  
MEDI4736 Q2W or placebo  
1 
Combination Therapy Studies (N = 60)  
CD-ON-MEDI4736-1161 (Phase 1)  
Melanoma  
MEDI4736 Q2W + 
trametinib ± dabrafenib  
18 
D4190C00006 (Phase 1b)  
NSCLC  
MEDI4736 Q2W or Q4W + 
tremelimumab Q4W  
18 
D791PC00001 (Phase 1)  
NSCLC  
MEDI4736 Q2W + gefitinib  
10 
D6020C00001 (Phase 1)  
Advanced malignancies  MEDI4736 Q2W + 
MEDI0680 (AMP-514) 
Q2W or Q4W  
4 
LUD2013-003 (Phase 1)a  
Advanced solid tumors  
MEDI4736 Q2W + 
tremelimumab Q4W  
10 
MDS = myelodysplastic syndrome; NSCLC = non-small cell lung cancer; Q2W = every 2 weeks; Q3W = every 3 weeks;  
Q4W = every 4 weeks.  
a. All studies in this table are sponsored by AstraZeneca/MedImmune, except LUD2013-003, which is sponsored 
by the Ludwig Institute for Cancer Research.  
 
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Pharmacokinetics and Product Metabolism  
MEDI4736 monotherapy exhibited nonlinear (dose-dependent) PK. The area under the 
concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-
proportional manner over the dose range of 0.1 to 15 mg/kg and approached linearity at 
≥3 mg/kg, suggesting that the nonlinear PK of MEDI4736 is likely due to saturable target-
mediated clearance. Exposures following multiple doses (currently up to a maximum of 
26 doses) demonstrated accumulation consistent with PK parameters estimated from the first 
dose.  
Suppression of free soluble PD-L1 (sPD-L1) was correlated with MEDI4736 PK concentrations. 
Following administration of MEDI4736 monotherapy, free sPD-L1 levels were below the lower 
limit of quantitation (LLOQ) in the majority of subjects with available data (n = 38) at all 
timepoints following IV doses ≥1 mg/kg every 2 weeks (Q2W). Overall, a low incidence of 
ADA was observed. Of the 220 subjects who received MEDI4736 monotherapy and for whom 
PK/ADA data were available, 5 were detected ADA positive, with an impact on PK and 
pharmacodynamics reported in 1 subject. None of the 16 subjects who received MEDI4736 in 
combination with tremelimumab were ADA positive (MEDI4736 IB).  
1.4.3 
Summary of Clinical Safety  
As of 14 July 2014, no identified risks are clearly associated with the use of MEDI4736 
(MEDI IB, Edition 7.0). Important potential risks based on the mechanism of action of 
MEDI4736 and its related molecules include immune-mediated reactions such as enterocolitis, 
dermatitis, hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, and neuropathy. Additional 
important potential risks include infusion-related reactions, hypersensitivity, serious allergic 
reactions, serious infections, and immune complex disease.  
The majority of the safety data are from the monotherapy study, CD-ON-MEDI4736-1108, 
specifically the 10 mg/kg Q2W cohort (N = 393). In this cohort, the most frequently reported 
(≥5% of subjects) AEs (all grades, regardless of causality) were fatigue (29.8%), nausea (20.1%), 
dyspnea (19.6%), decreased appetite (19.1%), constipation (14.0%), diarrhea and vomiting 
(12.5% each), cough (11.5%), pyrexia and back pain (10.4% each), rash (10.2%), headache 
(8.1%), dizziness (7.9%), anemia and pruritus (7.4 each), arthralgia (7.1%), myalgia and 
increased aspartate aminotransferase (AST) (6.6% each), peripheral edema and increased 
gamma-glutamyltransferase (GGT) (5.9% each), chills (5.3%), and increased alanine 
aminotransferase (AST) and musculoskeletal chest pain (5.1% each). In approximately half of 
the subjects, the highest AE severity was Grade 1 (25.2% of subjects) or Grade 2 (22.9% of 
subjects). Most of these events were managed clinically without the need for dose modifications 
or delays. Grade 3 or higher AEs that occurred in >1% of subjects were dyspnea (5.1%), 
increased GGT (3.3%), fatigue, general physical health deterioration, increased AST, and back 
pain (2.3% each), anemia and dehydration (1.8% each), and abdominal pain, vomiting, sepsis, 
syncope, and hypotension (1.3% each). Adverse events (all grades) considered by the 
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investigator to be related to MEDI4736 in >5% of subjects were fatigue (13.5%), nausea (8.4%), 
and diarrhea, rash, and decreased appetite (5.3% each). Treatment-related Grade 3 AEs in 2 or 
more subjects were fatigue (4 subjects), increased GGT (3 subjects), and vomiting, increased 
ALT, increased AST, and arthralgia (2 subjects each). There were 2 subjects with treatment-
related Grade 4 events (hypercalcemia, fatigue) and 1 subject with a treatment-related Grade 5 
event (angiopathy). In general, Grade 3 or 4 AEs were manageable with standard toxicity 
management guidelines.  
SAEs and other significant AEs occurred in fewer than one-third of subjects treated with 
MEDI4736 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108. The most frequently reported 
SAEs (regardless of causality; >5 subjects) were dyspnea (3.6%), general physical health 
deterioration (2.2%), pyrexia (1.9%), back pain and abdominal pain (1.7% each), and 
dehydration and pleural effusion (1.4% each). One subject (with Stage IV lung cancer and a 
history of cardiac disease) died due to angiopathy considered by the investigator as related to 
MEDI4736. AEs that resulted in permanent discontinuation of MEDI4736 in ≥2 subjects were 
dyspnea (7 subjects), general physical health deterioration (5 subjects), and death, increased 
transaminases (AST and ALT), pulmonary embolism, and respiratory failure (2 subjects each).  
Overall, the AE profile of MEDI4736 was consistent with the pharmacology of the target. No 
tumor types appeared to be associated with unique AEs (MEDI4736 IB).  
1.4.4 
Summary of Clinical Efficacy 
As of 14 July 2014, partial efficacy data are available for 2 monotherapy studies (CD-ON-
MEDI4736-1108 and D4190C00002) and 1 combination therapy study (D4190C00006, 
MEDI4736 and tremelimumab). Tumor assessments were based on Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 criteria (Eisenhauer 2009). Clinical activity was observed 
across the 3 studies in solid tumors which include subjects with non-small-cell lung cancer 
(NSCLC), squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma 
(HCC), cutaneous melanoma, gastroesophageal cancer, and pancreatic adenocarcinoma. 
1.5. 
Study Rationale 
PD-L1 helps regulate normal immune responses by controlling T-cell activation and is utilized 
by tumors to help evade detection and elimination by the host immune system tumor response. In 
the lymph nodes, PD-L1 on antigen-presenting cells binds to PD1 or CD80 on activated T cells 
and delivers an inhibitory signal to the T cell (Keir 2008; Park 2010). By binding to PD-L1, 
MEDI4736 inhibits PD-L1-dependent immunosuppressive effects and allows T cells to 
recognize and kill tumor cells (MedImmune/AstraZeneca, Data on file). 
PD-L1 is expressed by DLBCL cells and PD-1 by DLBCL tumor-associated T cells 
(Rosenwald 2003, Xerri 2008). PD-L1 has been found to be highly expressed by 
immunohistochemistry in Epstein-Barr virus-positive DLBCL, which is correlated with an 
aggressive clinical course (Chen 2013). In a study of 288 DLBCL patients, those with an 
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elevated soluble PD-L1 level in plasma of at least 1.52 ng/mL experienced a poorer prognosis 
with a 3-year OS of 76% versus 89% (p<0.001) (Rossille 2014). Treatment of patients with 
DLBCL with pidilizumab, an anti-PD1 monoclonal antibody, showed an ORR of 51% with a CR 
rate of 34% (Armand 2013). PFS at 16 months was 72%, comparing favorably to other 
contemporaneously published clinical trials in a similar patient population (Gisselbrecht 2010, 
Vose 2011). Recently, a phase I study with nivolumab, another anti-PD monoclonal antibody, in 
heavily pretreated DLBCL patients showed an ORR of 36% (including 9% CR). 
(Lesokhin 2014) 
In subjects with FL, PD1 is highly expressed on intratumoral and peripheral blood T cells and is 
associated with impaired T-cell function (Yang 2006, Myklebust 2013). In a phase 2 study 
testing pidilizumab in combination with rituximab in 32 subjects with relapsed FL, an objective 
response was reported in 66% of subjects with a 52% CR rate which is higher than expected for 
rituximab monotherapy in this patient population (Westin 2014). In addition, nivolumab has 
shown a 30% PR rate and 10% CR rate in heavily pretreated patients with FL that were included 
in a phase I trial (Lesokhin 2014). Therefore, targeting of the PD1/PD-L1 pathway might 
enhance endogenous antitumor responses in FL (Westin 2014).  
Ibrutinib has demonstrated antitumor activity in DLBCL and FL (see Section 1.3). Treatment of 
subjects with DLBCL with ibrutinib has shown greatest benefit in the ABC subtype 
(de Vos 2013) which historically had been linked to a poorer prognosis compared to other 
subtypes. In addition to BTK inhibition, ibrutinib is an irreversible inhibitor of ITK (interleukin-
2-inducible kinase) (Iwaki 2005, Dubovsky 2013). ITK is a member of the TEC family of 
kinases and retains close homology with the BTK active site including conservation of the 
cysteine residue which ibrutinib binds to covalently. ITK inhibition reduces helper T-cell (Th)2-
dominant immune responses and potentiates Th1-based responses (Dubovsky 2013). This shift in 
the Th1/Th2 ratio may not only directly potentiate anti-tumor activity, but it may also augment 
anti-tumor immune activation triggered by MEDI4736. 
Animal models of lymphoma have demonstrated activity when BTK and PD-L1 inhibitors are 
combined. BALB/c mice implanted with the syngeneic A20 B-cell lymphoma have been widely 
used to study immunotherapy for DLBCL and FL (Donnou 2012). A20 cells express BTK but 
are insensitive to ibrutinib in vitro and in vivo. In this model, a PD-L1 blocking antibody had 
modest effect on tumor growth whereas the tumor cells remained insensitive to ibrutinib. On 
combining the two antagonists, however, a complete tumor regression in 50% of treated animals 
was observed. Mechanistic studies implicated T cells as responsible for the tumor eradication. 
Mice treated with the combination therapy, but not with either single agent, mounted a robust 
and tumor-specific T-cell response. The superior efficacy of the ibrutinib/anti-PD-L1 
combination was reproduced in a second model using the J558 plasmacytoma cells, which are 
also insensitive to ibrutinib. The results strongly suggest that ibrutinib has an immune-
modulating property that enhances the anti-tumor effect of PD-L1 blockade (manuscript 
submitted). 
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Taken together, these data support testing the combination of ibrutinib and MEDI4736 for 
treatment of DLBCL and FL with the potential for synergistic anti-tumor activity. 
1.6 
Dosing Rationale 
1.6.1 
Ibrutinib Dose 
Ibrutinib has been FDA-approved for previously treated MCL at a dose of 560 mg and for 
previously treated CLL and CLL with del17p at a dose of 420 mg daily. In 2 studies in subjects 
with B-cell malignancies, the pharmacodynamics of ibrutinib were determined by monitoring the 
BTK active-site occupancy in subjects’ peripheral blood mononuclear cells (PBMC) before and 
after ibrutinib treatment (ibrutinib IB, version 8.0). Doses tested in the first-in-human ascending-
dose study were 1.25, 2.5, 5.0, 8.3 and 12.5 mg/kg ibrutinib PO given non-continuously in 
35-day cycles (28 days on, 7 days off) as well as 8.3 mg/kg and 560 mg ibrutinib PO given 
continuously (Advani 2013). No maximum tolerated dose (MTD) was identified. Subjects 
administered drug at doses of 2.5 mg/kg/day or higher achieved BTK occupancy at or above 
90% at 4 and 24 hours after drug administration (Advani 2013). Absolute doses in the 2.5 and 
5 mg/kg cohort ranged from 40 to 320 mg/day and from 280 to 600 mg/day, respectively. The 
highest dose administered was 1,400 mg of ibrutinib. Based on these data, fixed dose levels of 
>280 mg are expected to be necessary to ensure achievement of the full pharmacodynamic effect 
in the vast majority of patients. The sustained pharmacodynamic effect despite a relatively rapid 
elimination of ibrutinib is secondary to irreversible inhibition of BTK in subjects’ PBMCs 
(ibrutinib IB, version 8.0). Consistent with this, once-a-day oral dosing resulted in 24-hour 
sustained target inhibition in these trials.  
Ibrutinib has been tested in combination with R-CHOP in subjects with treatment-naïve DLBCL 
or FL in a Phase 1b study in which the recommended Phase 2 dose for ibrutinib was 560 mg per 
day (Younes 2014). The study demonstrated clinical activity across all dose cohorts in the all-
treated population, with an ORR of 100% in evaluable DLBCL patients at the recommended 
dose (Younes 2014, Chaturvedi 2014). A Phase 3 trial of ibrutinib in combination with R-CHOP 
for frontline treatment of subjects with DLBCL at the 560 mg daily dose is ongoing. 
Due to the extensive clinical experience with the 560 mg dose in terms of safety and efficacy, a 
dose of 560 mg/day has been chosen for the initial cohort in this study. 
1.6.2 
MEDI4736 Dose 
In a phase I study, MEDI4736 has shown an acceptable safety profile using different doses and 
dosing schedules. Every-other-week doses of 0.1, 0.3, 1, 3, and 10 mg/kg MEDI4736 IV and one 
every-3-week dose of 15 mg/kg MEDI4736 IV were explored in a 12-month treatment period 
(Segal 2014). The highest individual dose delivered was 15 mg/kg; however, since this dose was 
given every 3 weeks, the highest total exposure was with 10 mg/kg MEDI4736 every 2 weeks 
(Segal 2014). 
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The majority of the safety data are from the monotherapy study, CD-ON-MEDI4736-1108, 
specifically the 10 mg/kg Q2W cohort (N = 393) (MEDI4736 IB). With respect to safety, no 
DLTs were reported in the dose-escalation portion of this trial and no MTD was identified.  In 
approximately 50% of subjects, the highest AE severity was Grade 1 or Grade 2. Most of these 
events were clinically manageable without the need for dose modifications or dose delays. 
Serious adverse events (SAEs) and other significant AEs occurred in fewer than one-third of 
subjects treated with 10 mg/kg MEDI4736 given every other week. Across the currently ongoing 
MEDI4736 clinical studies, the incidence of infusion-related reactions has been low (0.8%; 4 of 
509 subjects). In the monotherapy study, CD-ON-MEDI4736-1108, 5 infusion-related reactions 
were reported in 3 of 414 subjects (0.7%) treated with MEDI4736 every 2 or every 3 weeks. One 
subject had 3 Grade 2 events and the remaining 2 subjects had a Grade 2 and Grade 3 event, 
respectively. All events resolved, were nonserious, and considered related to MEDI4736 
(MEDI4736 IB). Refer to Section 1.4.3 for additional details. 
Consistent with the nonclinical studies, MEDI4736 exhibited nonlinear (dose-dependent) PK by 
peak concentration and AUC-time curve from 0 to 14 days over the dose range of 0.1 to 
15 mg/kg, likely due to saturable target-mediated clearance. Near complete target saturation 
(membrane bound and sPD-L1) is expected with a ≥3 mg/kg dose of MEDI4736 given every 
2 weeks. Exposures following multiple doses (currently data available up to a maximum of 
26 doses) demonstrated accumulation that was consistent with PK parameters estimated from the 
first dose (MEDI4736 IB). Refer to Section 1.4.2 for additional details.  
Preliminary population-PK modeling was performed using a nonlinear mixed-effects modeling 
approach (NONMEM, Version 7.1, ICON Development Solution, Elliott City, MD) using data 
from a total of 38 subjects. Based on the mean Michaelis constant (Km) value, >99% target 
saturation (both soluble and membrane bound) is expected at a concentration of MEDI4736 of 
≥40 μg/mL. Hence, this concentration was identified as target trough concentration during dose 
selection. PK simulations indicate that following a 10 mg/kg dose of MEDI4736 given every 
2 weeks, >90% of subjects are expected to maintain a PK exposure of ≥40 μg/mL throughout the 
dosing interval (MEDI4736 IB). 
In multiple tumor types, early and durable clinical activity measured by tumor reduction was 
observed at multiple doses as early as 6 weeks and was maintained through 67+ weeks and off 
active therapy. The dose of 10 mg/kg every 2 weeks for 12 months was selected for further 
clinical development (Lutzky 2014).  
Based on the data above, a dose of 10 mg/kg every 2 weeks for 12 months was chosen for the 
initial cohort in this study.   
1.6.3 
Ibrutinib and MEDI4736 Doses in Combination  
Based on the above findings which describe the safety and PK profiles of ibrutinib and 
MEDI4736, the low discontinuation rate due to AEs, the low dose reduction rate, and the low 
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rate of high grade AEs, a dose of 560 mg ibrutinib PO daily continuously combined with a dose 
of 10 mg/kg MEDI4736 IV every 2 weeks for 12 months was chosen as the starting dose. (For 
MEDI4736 given every other week, the maximum number of doses is 24). As a lead-in to the 
first cycle, ibrutinib will be given for 7 days prior to starting MEDI4736 in order to obtain single 
agent PK and biomarker samples that can be compared to combination therapy. A dose de-
escalation design will be employed and in each cohort a sentinel subject will have a 3-day 
observation period prior to dosing of subsequent subjects to monitor for unexpected acute or 
overlapping toxicities.    
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2. 
STUDY OBJECTIVES  
2.1 
Primary Objectives 
Phase 1b:  
• To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with 
MEDI4736 in subjects with relapsed or refractory lymphomas 
• To determine the safety and tolerability of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory lymphomas  
Phase 2:  
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas by assessing the ORR 
2.2 
Secondary Objectives 
Phase 1b:  
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas by assessing the ORR 
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas by assessing the DOR 
• To determine the PK and pharmacodynamics (ie, BTK) of both ibrutinib and MEDI4736 
in subjects with relapsed or refractory lymphomas 
 
Phase 2:  
• To determine the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas by assessing the DOR, PFS, and OS 
• To determine the safety and tolerability of ibrutinib in combination with MEDI4736 in 
subjects with relapsed and refractory lymphomas 
• To determine the PK and pharmacodynamics (ie, BTK) of both ibrutinib and MEDI4736 
in subjects with relapsed or refractory lymphomas  
2.3 
Exploratory Objectives  
• To evaluate immune cell subsets after treatment with ibrutinib in combination with 
MEDI4736 
• To evaluate non-BTK related pharmacodynamics (ie ITK) after treatment with ibrutinib 
in combination with MEDI4736  
• To evaluate chemokine/cytokine levels after treatment with ibrutinib in combination with 
MEDI4736 
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• To identify genes and proteins associated with sensitivity or resistance to ibrutinib and/or 
MEDI4736 (ie, PD-L1) 
• To evaluate the efficacy of ibrutnib in combination with MEDI4736 in subjects with 
relapsed or refractory lymphomas by assessing the rate and duration of minimal residual 
disease (MRD) negativity 
 
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3. 
STUDY DESIGN  
3.1 
Overview of Study Design 
This is a Phase 1b/2, open-label multi-center study to assess the safety and efficacy of ibrutinib 
in combination with MEDI4736 in subjects with relapsed or refractory lymphomas. A 6+3 de-
escalation design will be employed in Phase 1b to assess doses of ibrutinib in combination with 
MEDI4736 to determine the RP2D for this study.  
3.1.1 
Phase 1b 
In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg 
of MEDI4736 will be explored in cohort 1 and will follow a 6+3 dose de-escalation design. 
Subjects will be enrolled in up to 4 dose cohorts (1, -1A, -1B, or -2) (for dose levels see Table 2). 
There is no requirement for a specific distribution of subjects with FL or DLBCL. The first 
subject in each dose cohort will be dosed as a sentinel subject with at least a 3-day observation 
period until the next subject in the cohort is dosed to monitor for any unexpected acute or 
overlapping toxicities. 
Subjects with one of the following two tumor types will be eligible for enrollment: 
• Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• Diffuse large B-cell lymphoma (DLBCL) 
In cohort 1, ibrutinib will be administered orally (PO) daily in 6 subjects at a dose of 560 mg 
until unacceptable toxicity or disease progression occurs. As a lead-in to the first cycle, ibrutinib 
will be given for 7 days prior to starting MEDI4736 in order to obtain single agent PK and 
biomarker samples that can be compared to combination therapy. MEDI4736 will be 
administered at a dose of 10 mg/kg IV every 2 weeks in 28-day cycles for 12 months, or until 
unacceptable toxicity or disease progression occurs.  
DLT assessment will occur from Day 1 of Cycle 1 of the combination therapy until the 
laboratory evaluations on Day 1 of Cycle 2 which will occur before the MEDI4736 infusion on 
Day 1 of Cycle 2. If subject incidence of DLTs within the DLT assessment period (with ibrutinib 
in combination with MEDI4736) is <33.3% (ie, ≤1 of 6 or ≤2 of 9), this dose level will be 
considered safe to proceed to Phase 2, and will be defined as the RP2D. If 2 subjects within the 
initial cohort of 6 subjects experience a DLT, an additional 3 subjects will be enrolled at the 
same dose level. If 3 or more of 6-9 subjects experience a DLT, a dose de-escalation will occur. 
A similar 6+3 cohort design will be utilized in the dose de-escalation cohorts (see Table 2 and 
Section 5.2). De-escalation cohorts -1A and -1B will be opened simultaneously to determine 
which dosing schedule is most appropriate for the Phase 2 portion of the study. Determination 
will be based on the safety profile of the 2 treatment regimens, as evaluated by the Sponsor and 
enrolling investigators, potentially taking PK and pharmacodynamic aspects into consideration 
(see Section 12.11). If necessary, the dose de-escalation cohort -2 will be enrolled thereafter. The 
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process for dose level determination in Phase 1b to proceed to Phase 2 is summarized in Figure 1 
(see also Section 5.2). 
Table 2. Phase 1b Dosing Levels 
28-Day Dosing Cycle  
Ibrutiniba 
MEDI4736b 
Cohort 1 
560 mg once daily PO 
10 mg/kg IV 
Cohort -1 Ac 
420 mg once daily PO 
10 mg/kg IV 
Cohort -1 Bc 
560 mg once daily PO 
3 mg/kg IV 
Cohort -2 
420 mg once daily PO 
3 mg/kg IV 
a. 
Ibrutinib will be administered PO daily beginning in the ibrutinib lead-in phase, then in combination with MEDI4736 
starting Cycle 1 Day 1 
b. 
MEDI4736  will be administered IV on Day 1 and Day 15 of each 28-day cycle 
c. 
Cohorts -1A and -1B are 2 parallel cohorts and will be enrolled concurrently in the sequence of -1A followed by -1B 
 
DLTs are defined in Section 5.3. 
Replacement of subjects during the DLT observation period is defined in Section 5.4. 
After the RP2D is defined, enrollment in Phase 2 will commence. Subjects who were not treated 
at the RP2D in Phase 1b will continue to be treated at the assigned dose and will be followed for 
response and overall survival. 
Figure 1 Phase 1b Dose Level Determination 
 
≥3 subjects with DLT?
YES
NO
Cycle 1: 560 mg ibrutinib po daily + MEDI4736 10 mg/kg IV q2 wks
Dose de-escalation #1: (Simultaneous enrollment)
Cohort -1A (n = 6): ibrutinib 420 mg daily, MEDI4736 10 mg/kg IV q2 wks
Cohort -1B (n = 6): ibrutinib 560 mg daily, MEDI4736 3 mg/kg IV q2 wks
Dose de-escalation #2: (following de-escalation #1)
Cohort -2 (n = 6): ibrutinib 420 mg daily, MEDI4736 3 mg/kg IV q2 wks
Enroll 3 more subjects at same dose level
≥ 1 more subject with DLT?
2 subjects with DLT?
DLT period = 28 days after combo first dose
YES
NO
YES
Proceed to Ph 2
Proceed to Ph 2
Ibrutinib lead-in period: 560 mg ibrutinib po x 7 days (n = 6)
NO
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3.1.2 
Phase 2 
Subjects will be treated at the RP2D as determined in Phase 1b.  
Two tumor types will be enrolled in separate cohorts as part of this protocol: 
• Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• Diffuse large B-cell lymphoma (DLBCL) 
FL: n = 39 
The FL cohort will be enrolled prospectively without further subclassification. An interim 
analysis will be performed after 19 subjects are evaluable for tumor response after completing at 
least 2 response assessments (≥Cycle 6 Day 1). If only 6 or fewer responders (≤6/19) are 
observed, the Sponsor may consider discontinuation of this cohort; however, assessment of 
biomarkers (that may aid in prospective enrichment of responders) or tumor measurements 
(showing clinically relevant tumor reductions, ie, 40%, that fit the criteria for SD) may support 
continued enrollment (see Section 12.11). If a subject discontinues prior to the first tumor 
response assessment for reasons other than progressive disease, the subject will be replaced (see 
Section 5.4). 
DLBCL: n = 34 
Subjects with GCB and non-GCB subtypes will be enrolled at a 1:1 ratio approximately. An 
interim analysis will be performed after 9 subjects are evaluable for tumor response after 
completing at least 2 response assessments (≥Cycle 6 Day 1). If only 1 or fewer responder (≤1/9) 
is observed, the Sponsor may consider discontinuation of this cohort; however, assessment of 
biomarkers (that may aid in prospective enrichment of responders) or tumor measurements 
(showing clinically relevant tumor reductions, ie, 40%, that fit the criteria for SD) may support 
continued enrollment (see Section 12.11). If a subject discontinues prior to the first tumor 
response assessment for reasons other than progressive disease, the subject will be replaced (see 
Section 5.4). 
In the DLBCL cohort, additional prospectively identified non-GCB subjects may be enrolled if a 
22% ORR (2/9) is not achieved at the interim analysis in the unselected DLBCL population so 
that at least a total of 16 subjects with the non-GCB subtype are evaluated.  
Note: The Phase 2 subjects include all of those subjects treated at R2PD in Phase 1b that have 
the tumor type as defined for Phase 2. 
The primary analysis will occur at least 12 months after the last FL subject is enrolled and at 
least 9 months after the last DLBCL subject is enrolled. 
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Dosing of ibrutinib in combination with MEDI4736 will continue for a total of 12 cycles of 
therapy if the subject is deriving clinical benefit (CR, PR, or SD) and the subject is not 
experiencing unacceptable toxicity. After 12 cycles, dosing of ibrutinib alone will continue as 
long as clinical benefit is seen without safety concerns or disease progression. 
Response evaluations will occur on Cycle 3 Day 1, Cycle 6 Day 1, Cycle 9 Day 1, Cycle 12 Day 
1, and every 6 cycles thereafter. Assessment will follow the Revised Criteria for Response 
Assessment of Malignant Lymphoma (Cheson 2014).  
In order to accommodate the potential for immune flare (pseudoprogression), treatment with 
MEDI4736 and ibrutinib may continue between the initial assessment of progression and 
confirmation for progression. Subjects with presumed PD who, in the Investigator’s opinion, 
continue to receive clinical benefit from their treatment may continue to receive MEDI4736 and 
ibrutinib as dictated in the protocol after consultation with the Sponsor and at the Investigator’s 
discretion (see Section 12.11). In the absence of clinically significant deterioration, a CT scan or 
biopsy may be performed at least 4 weeks later to confirm PD. If PD is confirmed at the later 
time point, PD should be assigned to the prior time point at which PD criteria were also met. 
MEDI4736 and ibrutinib should be discontinued if there is confirmed PD per Revised Criteria 
for Response Assessment of Malignant Lymphoma (Cheson 2014) or other clinical data suggest 
clear evidence of progression. 
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3.2 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Phase 
(within 28 days of first dose of  study drug) 
Assess Eligibility Criteria- obtain Sponsor approval to enroll 
Enrollment 
Treatment Discontinuation 
Complete Treatment Termination Visit 
Follow-up Phase 
(until death, lost-to-follow up, consent withdrawal, or 
study end, whichever occurs first) 
 
Complete End-of-Treatment Visits: 
30 days after the last dose of ibrutinib and 
90 days after the last dose of MEDI4736, 
or prior to subsequent anticancer therapy 
 
Prior to disease progression (if applicable):  
• 
Continue disease evaluations until PD 
 
Following disease progression:  
• 
Survival and subsequent anticancer therapy 
Treatment Phase 
Ibrutinib at 560 or 420 mg/day PO qd (includes 7-day lead-in) 
MEDI4736 at 10 mg/kg or 3 mg/kg IV Q2W for 12 months  
Treatment until disease progression or unacceptable toxicity 
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4. 
SUBJECT SELECTION  
4.1 
Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria: 
1. Men and women ≥ 18 years of age 
2. Pathologically confirmed:  
a) Phase 1b: diffuse large B-cell lymphoma or follicular lymphoma (grade 1, 2, or 3A) 
according to World Health Organization (WHO) criteria 
b) Phase 2: diffuse large B-cell lymphoma or follicular lymphoma (grade 1, 2, or 3A) 
according to WHO criteria without clinical or pathological evidence of transformation 
3. Provision of a fresh tumor biopsy or an available archival tumor sample processed as 
formalin-fixed, paraffin-embedded (FFPE) taken within 3 months of screening, and after the 
most recent treatment (Note: Earlier archived tumor tissue from all enrolled subjects will also 
be requested.) 
4. Relapsed or refractory disease: 
A. DLBCL 
1)  Relapsed or refractory disease, defined as:  
a) Recurrence of disease after a complete response (CR),  
OR 
b) Partial response (PR), stable disease (SD) or progressive disease (PD) at 
completion of the treatment regimen preceding entry to the study (residual 
disease) 
2) Subjects who have not already had a stem cell transplant must not be considered a 
candidate for high dose chemotherapy with stem cell transplant (HDT/SCT) and must 
meet at least one of the following criteria: 
a) Age ≥70 years 
b) Diffuse lung capacity for carbon monoxide <50% by pulmonary function test 
c) Left ventricular ejection fraction <50% by multiple gated acquisition / 
echocardiogram 
d) Other organ dysfunction or co-morbidities precluding the use of HDT/SCT on the 
basis of unacceptable risk of treatment-related morbidity 
e) Failure to achieve PR or CR with salvage therapy 
f) Subject refusal of HDT/SCT 
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B. FL 
1) Previously received at least one appropriate chemoimmunotherapy regimen and have 
relapsed or refractory disease 
5. Measurable disease:  One or more measurable disease sites on CT scan (>1.5 cm in longest 
dimension) is required. Lesions in anatomical locations (such as extremities or soft tissue 
lesions) that are not well visualized by CT may be measured by MRI instead. 
6. Adequate hematologic function independent of transfusion support for at least 7 days prior to 
screening and independent of growth factor support for at least 14 days prior to screening, 
defined as:  
• Absolute neutrophil count >1500 cells/mm3 (1.50 x 109/L) 
• Platelet count >50,000 cells/mm3 (50 x 109/L) unless there is documented bone marrow 
involvement 
• Hemoglobin >8.0 g/dL 
7. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤2.5 x upper limit of 
normal (ULN) 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome such that 
bilirubin ≤3 x ULN or is of non-hepatic origin) 
• Estimated Creatinine Clearance ≥40 mL/min (Cockcroft-Gault)  
8. Prothrombin time (PT) <1.5 x ULN and activated partial thromboplastin time (aPTT) 
<1.5 x ULN 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
10. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: 
≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of 
hysterectomy, OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) or 
must have a negative serum pregnancy test upon study entry. 
11. Male subjects who are not sterilized and who are sexually active with a female partner of 
childbearing potential, and female subjects of childbearing potential who are sexually active 
with a nonsterilized male partner must agree to use 2 highly effective methods of birth 
control (eg, condoms, implants, injectables, combined oral contraceptives, or intrauterine 
devices [IUDs]) during the period of therapy and for 3 months after the last dose of study 
drug (see Appendix 7). 
12. Male subjects must agree to not donate sperm, and female subjects must agree to not donate 
eggs (ova, oocytes) for the purposes of assisted reproduction during or for 3 months after the 
last dose of either study drug. 
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4.2 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Anti-tumor therapy (chemotherapy, antibody therapy, immunotherapy, biologic-based 
therapy, or investigational agent) within 14 days of study Day 1 (or six weeks for nitrosureas 
or mitomycin C); Enrollment of subjects that have received molecularly-targeted small 
molecule inhibitors less than 28 days prior to study Day 1 will be permitted if more than 
14 days and at least 5 drug half-lives have passed prior to receiving the first dose of ibrutinib.  
2. Prior therapy with ibrutinib or other BTK inhibitor and/or anti-PD1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody 
3. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03) grade 0 or 1, or to 
the levels dictated in the inclusion/exclusion criteria with the exception of stable neuropathy, 
vitiligo, alopecia, or other irreversible toxicity not reasonably expected to be exacerbated by 
study treatment (eg, hearing loss)  
4. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 4) 
5. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug (Note: 
Subjects, if enrolled, should not receive live vaccines during the study and until 30 days after 
the last dose of study drug) 
6. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
MEDI4736. The following are exceptions to this criterion: 
• Intranasal, inhaled, topical corticosteroids, or local corticosteroid injections (eg, intra-
articular injection) 
• Systemic corticosteroids at doses not to exceed 10 mg/day of prednisone or its equivalent 
• Corticosteroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-
medication) 
7. History of allogeneic organ transplant or <100 days after autologous transplant 
8. Primary CNS lymphoma or evidence of CNS involvement by lymphoma 
9. Any uncontrolled active systemic infection, or recent infection requiring intravenous 
antibiotic treatment that was completed ≤14 days before the first dose of study drug 
10. Known history of previous clinical diagnosis of active tuberculosis 
11. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia) 
12. History of stroke or intracranial hemorrhage within 6 months prior to enrollment  
13. Major surgery within 4 weeks of first dose of study drug 
14. Concomitant use of warfarin or other Vitamin K antagonists 
15. History of primary immunodeficiency 
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16. Known history of human immunodeficiency virus (HIV) or current chronic/active infection 
with hepatitis C virus (HCV) or hepatitis B virus (HBV) 
• Subjects with chronic or active hepatitis B as diagnosed by serologic tests are excluded 
from the study. In equivocal cases, hepatitis B or C polymerase chain reaction (PCR) may 
be performed and must be negative for enrollment. 
17. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification (see Appendix 6); or a history of myocardial infarction, 
uncontrolled hypertension or cardiac arrhythmia, unstable angina, or acute coronary 
syndrome within 6 months prior to enrollment  
18. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia formula 
19. Unable to swallow capsules or malabsorption syndrome, disease or condition significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, or partial or 
complete bowel obstruction 
20. Lactating women, men planning to father a child, or women planning pregnancy while taking 
study drug or within 3 months after the last dose of study drug 
21. Known allergy or hypersensitivity to ibrutinib or MEDI4736 or any excipient 
22. Active or prior documented autoimmune or inflammatory disorders including but not limited 
to inflammatory bowel disease (eg, colitis, Crohn’s disease), diverticulitis with the exception 
of a prior resolved episode or diverticulosis, celiac disease, irritable bowel disease, or other 
serious gastrointestinal chronic conditions associated with diarrhea, type I diabetes mellitus, 
multiple sclerosis, systemic lupus erythematosus, Wegener’s granulomatosis (granulomatosis 
with polyangiitis), myasthenia gravis, Graves’ disease, rheumatoid arthritis, pneumonitis, 
interstitial lung disease, hypophysitis, or uveitis within the past 3 years prior to the start of 
treatment. The following are exceptions to this criterion: 
• Subjects with vitiligo or alopecia 
• Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone 
replacement or psoriasis not requiring systemic treatment 
23. History of other malignancies, except 
• Malignancy treated with curative intent and with no known active disease present for 
≥5 years before the first dose of study drug and felt to be at low risk for recurrence by the 
treating physician 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
• Adequately treated carcinoma in situ without evidence of disease 
24. Unwilling or unable to participate in all required study evaluations and procedures 
25. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
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undue risk, eg, psychiatric illness/social situations that would limit compliance with study 
requirement or compromise the ability of the subject to give written informed consent 
26. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations) 
27. Concurrent enrollment in another clinical study, unless in a follow-up period or in an 
observational study 
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5. 
TREATMENT OF SUBJECTS 
5.1 
Treatment Allocation  
This is an open-label study (both Phase 1b and Phase 2). After the subject has completed all 
baseline (screening) procedures and meets the inclusion and none of the exclusion criteria, study 
site personnel can enroll the subject. All enrolled subjects will receive open-label ibrutinib 
capsules and MEDI4736 intravenous infusions.  
In Phase 1b, two dose levels of ibrutinib (560 or 420 mg/day) and MEDI4736 (10 or 3 mg/kg IV 
every 2 weeks) may be tested (Table 2). The starting dose will be 560 mg of ibrutinib PO daily 
and 10 mg/kg of MEDI4736 IV every 2 weeks. The dose may be modified based on the number 
of DLTs observed. In each cohort, a sentinel subject will have a 3-day observation period prior to 
dosing of subsequent subjects to monitor for unexpected toxicities. In Phase 2, subjects will be 
treated at the RP2D as determined in Phase 1b. 
5.2 
Phase 1b Dose De-escalation and Stopping Rules 
Refer to Figure 1 for a summary of the de-escalation process. 
Phase 1b will follow a 6+3 design with 6-9 subjects at each dose level. Before determining the 
RP2D, 6 subjects in any given cohort must have completed the DLT observation period which is 
defined as the assessment period from Day 1 of Cycle 1 of the combination therapy until the 
laboratory evaluations on Day 1 of Cycle 2 which will occur before the MEDI4736 infusion on 
Day 1 of Cycle 2. The dose will be selected as the RP2D if the subject incidence of DLTs during 
the DLT assessment period with combination study treatment is <33% (ie, ≤1/6 or ≤2/9 subjects 
with a DLT). If there are ≥3 subjects with a DLT in Cohort 1, then the next lower dose level 
(Cohorts -1A and -1B, see Table 2) will be enrolled.  
Cohort -1A and -1B are two parallel dose de-escalation cohorts and will be enrolled concurrently 
in a non-randomized fashion in the sequence of -1A followed by -1B. For example, the first 
available subject will go to Cohort -1A, the second subject to Cohort -1B, the third to -1A, the 
fourth to -1B, etc. However, when one dose de-escalation cohort needs an additional 3 subjects 
to evaluate DLTs, all available subjects will be assigned to this cohort first. In these cohorts, it 
will be determined which dosing schedule is most appropriate for the Phase 2 portion of the 
study. Determination will be based on the safety profile of the 2 treatment regimens, as evaluated 
by the Sponsor and enrolling investigators, potentially taking PK and pharmacodynamic aspects 
into consideration (see Section 12.11).   
If the subject incidence of DLTs within the DLT assessment period with combination study 
treatment is <33.3% (ie, ≤1 of 6 or ≤2 of 9 subjects with a DLT), this dose level will be 
considered safe to proceed to Phase 2, and thus will be defined as the RP2D.  
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Enrollment in Cohort 1 will proceed as follows: 
 If 0 or 1 DLT is observed during the DLT observation period in the initial 6 subjects in 
Cohort 1, then this dose will be the RP2D.  
 If 2 DLTs are observed in the initial 6 subjects in Cohort 1, then 3 additional subjects will 
be enrolled to this cohort.  
o If 0 DLT in the 3 additional subjects is observed, then this dose will be the RP2D.  
o If 1 or more DLT is observed, the dose will be de-escalated to Cohorts -1A and -1B 
 If 3 or more DLTs are observed in the initial 6 subjects, enrollment into Cohort 1 will be 
stopped and the dose will be de-escalated to Cohorts -1A and -1B.    
A similar 6+3 cohort design will be utilized in the dose de-escalation cohorts. If necessary, the 
dose de-escalation cohort -2 will be enrolled thereafter. 
If a subject experiences a DLT during the DLT observation period, the subject will discontinue 
treatment. However, any subject(s) tolerating the dose level through the DLT observation period 
will continue with the same dose level of study drug even if subsequently-enrolled study subjects 
receive treatment at a dose de-escalation. 
A Dose Level Review Committee (DLRC) will evaluate the safety data from each cohort of 
Phase 1b. Members of this committee will include participating investigators or designees as 
well as the Sponsor (invitees include: the Medical Monitor or designee, the clinical lead, a Drug 
Safety representative and a Biostatistician) (see Section 12.11). 
5.3 
Definition of Dose-Limiting Toxicity (DLT) 
The assessment of DLT will follow the guidelines provided in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 (accessible at the website, 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
The Phase 1b DLT observation period will occur from Day 1 of Cycle 1 of ibrutinib in 
combination with MEDI4736 treatment to the laboratory evaluations on Day 1 of Cycle 2 which 
will occur before the MEDI4736 infusion on Day 1 of Cycle 2.  
A DLT is an AE at least possibly related to study drug(s) defined as: 
1) Any Grade 3 or higher non-hematologic AE (with additional clarifications below) 
 Grade 3 or higher nausea, vomiting, or diarrhea (non-colitis-related) that is uncontrolled 
by maximal supportive care and persists for >7 days would be considered a DLT 
 Grade 3 fatigue that persists for >7 days would be considered a DLT 
 Any Grade 3 immune-related adverse event (irAE) that does not downgrade to Grade ≤2 
within 3 days after onset of the event despite maximal supportive care including systemic 
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 Any Grade ≥2 pneumonitis that does not resolve to Grade ≤1 within 3 days of the 
initiation of maximal supportive care would be considered a DLT. 
 The DLT definition excludes the following conditions: 
o Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the subject is asymptomatic 
o Grade 3 inflammatory reaction attributed to a local antitumor response 
(eg, inflammatory reaction at sites of metastatic disease, lymph nodes, etc) 
o Vitiligo or alopecia of any AE grade would not be considered a DLT  
2) Clinically relevant hematologic AE such as: 
 Grade 3 or 4 neutropenia (ANC<1,000/ mm3) lasting >7 days 
 Febrile neutropenia (Grade 3 or 4 neutropenia with fever ≥38.3ºC) 
 Grade 3 or 4 thrombocytopenia (<25,000/ mm3) lasting >7 days or requiring transfusion 
or associated with Grade ≥2 bleeding 
 Any other Grade 4 hematologic AE, except lymphopenia  
5.4 
Replacement of Subjects 
During the Phase 1b DLT observation period, subjects will be replaced for any of the following 
reasons: 
 Missed ≥5 consecutive doses of ibrutinib or missed 7 total doses (not due to DLT) 
 Missed dose of MEDI4736 or received the MEDI4736 dose outside of the protocol-
allowed window (±2 days) (not due to DLT) 
 Study drug discontinuation for any reason other than DLT  
Subjects who are replaced for missed doses may continue to receive study treatment if there is a 
clinical benefit, but they will not be part of the DLT analysis. 
During the Phase 2 portion of the study, if a subject discontinues study drug prior to the first 
tumor response assessment for reasons other than progressive disease, the subject may be 
replaced. 
5.5 
Study Treatment 
All eligible subjects will be treated with ibrutinib PO and MEDI4736 IV in 28-day cycles. Prior 
to the first cycle, ibrutinib will be given daily for 7 days in the ibrutinib lead-in period prior to 
starting MEDI4736. On infusion days where pharmacokinetic, pharmacodynamic, or biomarker 
samples are drawn post-dose, MEDI4736 IV should be given first, with administration of 
ibrutinib as soon as possible after the end of infusion.  
Missed doses of ibrutinib and MEDI4736 will not be made up. Dose modification of MEDI4736 
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Dosing of ibrutinib will continue up to 3 years as long as the subject is deriving clinical benefit 
(CR, PR, or SD) and the subject is not experiencing unacceptable toxicity. Dosing of MEDI4736 
will continue for a total of 12 cycles of therapy if clinical benefit is seen without safety concerns. 
Toxicity may result in discontinuation or hold of one study drug while the other may continue to 
be dosed. Depending on the suspected relatedness to either agent (or both), the Investigator may 
perform dose modification and/or dose delays as per Section 5.6.1.4 and/or Section 5.6.2.5 at his 
or her clinical discretion.  Re-treatment with MEDI4736 will not be allowed following 
completion of 12 cycles of treatment, regardless of any dose delays, missed doses, or following 
permanent discontinuation for any reason. 
5.5.1 
Phase 1b 
Two dose levels of ibrutinib (560 or 420 mg/day) and 2 dose levels of MEDI4736 (10 or 3 mg/kg 
IV every other week) may be tested. The starting dose will be 560 mg ibrutinib PO daily and 
MEDI4736 10 mg/kg IV every 2 weeks. Prior to the first cycle, there will be an ibrutinib lead-in 
period in which ibrutinib will be given for 7 days prior to starting MEDI4736. 
The first subject in each dose cohort will be dosed as a sentinel subject with at least a 3-day 
observation period until the next subject in the cohort is dosed to monitor for any unexpected 
acute or overlapping toxicities. 
Dose escalation of any agent (ibrutinib or MEDI4736) beyond the original assigned dose at any 
time will not be allowed.  
5.5.2 
Phase 2 
Subjects will be administered ibrutinib in combination with MEDI4736 at the RP2D determined 
during the Phase 1b portion of the study. Prior to the first cycle, there will be an ibrutinib lead-in 
period in which ibrutinib will be given for 7 days prior to starting MEDI4736. 
5.6 
Study Medication 
5.6.1 
Ibrutinib  
5.6.1.1. 
Formulation/Packaging/Storage  
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
ibrutinib Investigator's Brochure for a list of excipients.  
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. Study drug 
will be dispensed in child-resistant packaging.  
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Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.6.1.2. 
Dose and Administration 
Ibrutinib 560 mg (4 x 140-mg capsules) or 420 mg (3 x 140-mg capsules) is administered orally 
once daily. The capsules are to be taken around the same time each day with 8 ounces 
(approximately 240 mL) of water. The capsules should be swallowed intact and subjects should 
not attempt to open capsules or dissolve them in water. The use of strong CYP3A inhibitors/ 
inducers and grapefruit and Seville oranges should be avoided for the duration of the study 
(Appendix 4). 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose. 
The first dose of ibrutinib will be administered in the clinic on Day 1, after which subsequent 
dosing is typically on an outpatient basis unless otherwise specified in Section 8 and Appendix 1. 
Ibrutinib will be dispensed to subjects in bottles at appropriate visits. When new study drug is 
dispensed, unused ibrutinib dispensed during previous visits must be returned to the site and drug 
accountability records (Section 12.8) should be updated. Returned capsules must not be 
redispensed to anyone. 
5.6.1.3. 
Overdose  
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any SAE criterion must be reported as a 
SAE in the appropriate time frame and documented as clinical sequelae to an overdose. There is 
no specific antidote for ibrutinib. In the event of an overdose, subjects should be closely 
monitored and given appropriate supportive treatment. 
Refer to Section 11 for further information regarding AE reporting.  
5.6.1.4. 
Dose Modification for Adverse Reactions  
For an ibrutinib-related adverse reaction, the dose of ibrutinib should be modified according to 
the dose modification guidelines in Table 3 if any of the following toxicities occur: 
• Grade 4 neutropenia (ANC <500/µL) for more than 7 days. See Section 6.1 and 6.3 for 
instructions regarding the use of growth factor support.  
• Grade 3 thrombocytopenia (platelet count <50,000/mm3 (50 x 109/L) in the presence of 
grade 2 or greater bleeding events. 
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• Grade 4 thrombocytopenia (platelet count <25,000/mm3 (25 x 109/L). 
• Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy.  
• Any other Grade 4 or unmanageable Grade 3 toxicity. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anti-coagulants or anti-
platelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 6.2.3).  
Table 3. 
Ibrutinib Dose Modifications  
Occurrence Action to be Taken  
First 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original dose 
level 
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 420 mg/day for original 560 mg/day dose; 280 mg/day for original 
420 mg/day dose) 
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 280 mg/day for original 560 mg/day dose) or discontinue for original 
420 mg/day dose  
Fourth 
Discontinue study drug 
 
After a dose reduction, dose escalations of ibrutinib to the previous higher dose may be 
considered after consultation with the Medical Monitor if the event does not recur after at least 
one cycle of the lower dose. 
If tumor lysis syndrome is diagnosed, follow the institutional guidelines for management. 
Study treatment should be discontinued in the event of an ibrutinib toxicity lasting more than 
28 days, unless reviewed and approved by the Medical Monitor. 
Study treatment interruptions, dose reductions or modifications, or any other changes in study 
drug administration should be recorded in the clinical database. 
5.6.2 
MEDI4736  
5.6.2.1. 
Formulation/Packaging/Storage  
Liquid Drug Product  
MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. The investigational product is supplied as a 
vialed liquid solution in clear 10R glass vials closed with an elastomeric stopper and a flip-off 
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cap overseal. Each vial contains 500 mg (nominal) of active investigational product at a 
concentration of 50 mg/mL. The solution will be diluted with 0.9% saline for IV infusion.  
Unopened vials of MEDI4736 liquid Drug Product must be stored at 2°C to 8°C (36°F to 46°F).  
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.6.2.2. 
Dose and Administration 
The liquid product is to be diluted with 0.9% saline for IV infusion. 
The first dose will be administered in the clinic on Cycle 1 Day 1 and then every 2 weeks 
thereafter. 
MEDI4736 will be administered as an IV infusion approximately 1 hour in duration.  
Following preparation of MEDI4736, the entire contents of the IV bag should be administered as 
an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm in-line filter. The IV 
line should be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line 
was not flushed. Since the compatibility of MEDI4736 with other IV medications and solutions, 
other than normal saline (0.9% [weight/volume] sodium chloride for injection), is not known, the 
MEDI4736 solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessments (see Appendix 1). In the event of a Grade ≤2 
infusion-related reaction, the infusion rate of study drug may be decreased by 50% or interrupted 
until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until 
completion of the infusion. For subjects with a Grade ≤2 infusion-related reaction, subsequent 
infusions may be administered at 50% of the initial rate (see Table 4 for toxicity management). 
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or premedication per institutional 
standard may be administered at the discretion of the investigator. If the infusion-related reaction 
is Grade ≥3 in severity, study drug will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
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5.6.2.3. 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose. Signs and symptoms of an overdose that meet any SAE criterion must be reported as a 
SAE in the appropriate time frame and documented as clinical sequelae to an overdose. In the 
event of an overdose, subjects should be closely monitored and given appropriate supportive 
treatment. 
Refer to Section 11 for further information regarding AE reporting.  
5.6.2.4. 
Immune-related Adverse Events (irAEs) 
Because MEDI4736 leads to T-cell activation and proliferation, there is the possibility of 
observing irAEs during the conduct of this study. Potential irAEs may be similar to those seen 
with the use of ipilimumab and MDX-1106 including immune-mediated enterocolitis, dermatitis, 
hepatitis, and endocrinopathies (Brahmer 2010, Hodi 2010). Subjects should be monitored for 
signs and symptoms of irAEs. In the absence of an alternate etiology (eg, infection and PD), 
signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be 
considered to be immune-related. 
5.6.2.5. 
Dose Modification for Adverse Reactions 
For MEDI4736-related adverse reactions, please refer to the Table 4 below.  It is important to 
note that these guidelines prepared by the Sponsor are to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated MEDI4736-related Adverse 
Reactions 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management) 
Drug administration modifications of 
study drug/study regimen will be made to 
manage potential immune-related AEs 
based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
It is recommended that management of irAEs follow 
the guidelines presented in this table 
- 
Subjects should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression, concomitant medications, 
infections, etc.) 
- 
In the absence of a clear alternative etiology, all 
events should be considered potentially 
immune related. 
- 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events  
- 
Systemic corticosteroids (eg, prednisone or IV 
equivalent) should be considered for persistent 
 
Grade 1 
No dose modification 
 
Grade 2 
Hold study drug/study 
regimen dose until Grade 2 
resolution to Grade ≤1 
• If toxicity worsens then 
treat as Grade 3 or Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
 
Grade 3 
Depending on the individual 
toxicity, may permanently 
discontinue study drug/study 
regimen. Please refer to 
guidelines below 
low-grade or severe (Grade ≥3) events 
- 
If symptoms recur or worsen during 
corticosteroid tapering, increase the 
corticosteroid dose until stabilization or 
improvement of symptoms, then resume 
corticosteroid tapering at a slower rate  
- 
More potent immunosuppressives – TNF 
antagonist class (eg, infliximab), 
mycophenolate, etc. should be considered for 
events not responding to systemic steroids after 
discussion with study physician 
- 
Discontinuation of study drug is not mandated 
for Grade 3/Grade 4 inflammatory reactions 
attributed to local tumour response (eg, 
inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.) 
 
Grade 4 
Permanently discontinue 
study drug/study regimen  
Infusion- related 
reactions 
 
Any Grade 
- 
Management per institutional standard at the 
discretion of investigator 
- 
Monitor subjects for signs and symptoms of 
infusion-related reactions (eg, fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, skin rashes etc.) 
and anaphylaxis (eg, generalized urticaria, 
angioedema, wheezing, hypotension, 
tachycardia, etc.) 
 
Grade 1 
The infusion rate of study 
drug/study regimen may be 
decreased by 50% or 
temporarily interrupted until 
resolution of the event 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator  
- 
Consider premedication per institutional 
standard prior to subsequent doses 
 
Grade 2 
The infusion rate of study 
drug/study regimen may be 
decreased 50%  or 
temporarily interrupted until 
resolution of the event (up to 
4 hours) 
Subsequent infusions may be 
given at 50% of the initial 
infusion rate 
 
Grade 3/4 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4: 
- 
Manage severe infusion-related reactions per 
institutional standards (eg, IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid) 
Pneumonitis/ 
Interstitial lung 
disease (ILD) 
 
Any Grade 
- 
Monitor subjects for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough). Subjects should 
be evaluated with imaging and pulmonary 
function tests including other diagnostic 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
procedures as described below 
- 
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up and 
high-resolution CT scan  
 
Grade 1 
No dose modification 
required. However, consider 
holding study drug/study 
regimen dosing as clinically 
appropriate and during 
diagnostic work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only): 
- 
Monitor and closely follow up in 2-4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion) and laboratory work-up and then as 
clinically indicated 
- 
Consider pulmonary and infectious disease 
consult  
 
Grade 2 
Hold study drug/study 
regimen dose until Grade 2 
resolution to Grade ≤1 
• If toxicity worsens then 
treat as Grade 3 or 
Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
For Grade 2 (Mild to Moderate New Symptoms):  
- 
Monitor symptoms daily and consider 
hospitalization 
- 
Discuss with study physician and consider 
systemic steroids (eg, prednisone 1-2mg/kg/day 
or IV equivalent)  
- 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional 
workup and treatment with IV 
methylprednisolone 2-4mg/kg/day should be 
considered 
- 
If no improvement within 3-5 days, further 
immunosuppressive therapy (eg, infliximab) 
should be considered. 
- 
Once improving, gradually taper steroids over 
≥4 weeks and consider prophylactic antibiotics 
- 
Consider pulmonary and infectious disease 
consult 
 
Grade 3 or 
4 
Permanently discontinue 
study drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life threatening):  
- 
Discuss with study physician 
- 
Pulmonary and infectious disease consult 
- 
Hospitalize the subject 
- 
Supportive Care (oxygen, etc.) 
- 
Initiate empiric IV corticosteroids (eg, 
methylprednisolone or equivalent) at 1 to 
4 mg/kg/day  
- 
If no improvement within 3-5 days, additional 
workup and treatment with additional 
immunosuppressive therapy (eg, infliximab) 
should be considered 
- 
Once improving, gradually taper steroids over 
≥4 weeks and consider prophylactic antibiotics 
Diarrhea/ 
Enterocolitis 
 
Any Grade 
- 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits)  
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
- 
Subjects should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression, infections, etc.) 
- 
Steroids should be considered if an alternative 
etiology is not determined, even for low grade 
events, in order to prevent potential progression 
to higher grade event 
- 
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis 
 
Grade 1 
No dose modification 
For Grade 1:  
- 
Close monitoring for worsening symptoms 
- 
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (eg, American Dietetic Association 
colitis diet), and loperamide 
 
Grade 2 
Hold study drug/study 
regimen until resolution to  
Grade ≤1 
• If toxicity worsens then 
treat as Grade 3 or  
Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
For Grade 2:  
- 
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (eg, American Dietetic Association 
colitis diet), and loperamide and/or budesonide  
- 
If event is persistent (>3-5 days) or worsens, 
consider  prednisone 0.5 to 1 mg/kg/day or IV 
equivalent 
- 
If not responsive within 3-5 days, consider IV 
corticosteroids (eg, methylprednisolone IV or 
equivalent) at 1 to 2 mg/kg/day 
- 
If event is not responsive within 3-5 days or 
worsens, additional workup and treatment with  
IV methylprednisolone 2-4 mg/kg/day should 
be considered  
- 
If no improvement within 3-5 days, further 
immunosuppressives (eg, infliximab) should be 
considered 
- 
Consult study physician if no resolution to 
Grade ≤1 in 3-4 days 
- 
Once improving, gradually taper steroids over 
≥4 weeks  
 
Grade 3 or 
4 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4: 
- 
Discuss with study physician 
- 
Monitor stool frequency and volume and 
maintain hydration   
- 
Urgent GI consult and imaging as appropriate 
- 
Initiate empiric IV corticosteroids (eg, 
methylprednisolone IV or equivalent) at 1 to 
4 mg/kg/day 
- 
If no improvement within 3-5 days, consider 
further immunosuppressives (eg, infliximab) 
- 
Caution: Ensure GI consult to rule out bowel 
perforation and refer to label before using 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
infliximab. Once improving, gradually taper 
steroids over ≥4 weeks and consider 
prophylactic antibiotics 
Hepatitis 
 
Any Grade 
- 
Monitor and evaluate liver function test: AST, 
ALT, ALP and total bilirubin  
- 
Evaluate for alternative etiologies (eg, viral 
hepatitis, disease progression, concomitant 
medications)  
 
Grade 1 
No dose modification 
If it worsens, treat as Grade 
2 event 
- 
Continue LFT monitoring per protocol 
 
Grade 2 
Hold study drug/study 
regimen dose until Grade 2 
resolution to Grade ≤1 
• If toxicity worsens then 
treat as Grade 3 or  
Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
For Grade 2:  
- 
Discuss with study physician if no resolution to 
Grade ≤1 in 1-2 days 
- 
Recheck LFTs in 1-2 days. If event is persistent 
(>3-5 days) or worsens, consider prednisone 0.5 
to 1 mg/kg/day or IV equivalent 
- 
If no improvement within 3-5 days, consider 
additional workup and treatment with IV 
methylprednisolone 2-4 mg/kg/day 
o 
If no improvement within 3-5 days, 
consider further immunosuppressives (eg, 
mycophenolate mofetil) 
o 
Once improving, gradually taper steroids 
over ≥4 weeks and consider prophylactic 
antibiotics 
 
Grade 3 
For elevations in 
transaminases ≤8 × ULN, or 
elevations in bilirubin ≤5 × 
ULN  
- Hold study drug/study 
regimen dose until 
resolution to Grade ≤1 or 
baseline   
- Resume study drug/study 
regimen administration at 
the next scheduled dose if 
elevations downgrade  
Grade ≤1 or baseline within 
14 days 
Permanently discontinue 
study drug/study regimen if 
the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days  
For elevations in 
transaminases >8 × ULN or 
elevations in bilirubin >5 × 
ULN, discontinue study 
For Grade 3 or 4: 
- 
Discuss with the study physician  
- 
Initiate empiric IV corticosteroids (eg, 
methylprednisolone IV or equivalent) at 1 to 
4 mg/kg/day  
o 
If no improvement within 3-5 days, 
consider further immunosuppressive 
therapy (eg, mycophenolate mofetil) 
o 
If still no further improvement within 
3-5 days, consider other 
immunosuppressive therapy per local 
guidelines 
- 
Hepatology consult, abdominal workup, and 
imaging as appropriate 
o 
Once improving, gradually taper steroids 
over ≥4 weeks and consider prophylactic 
antibiotics 
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Final 
 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
drug/study regimen  
Permanently discontinue 
study drug/study regimen for 
any case meeting Hy’s law 
criteria 
Grade 4 
Permanently discontinue 
study drug/study regimen  
Rash (excluding 
Bullous skin 
formations) 
 
Any Grade 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, 
THE STUDY PHYSICIAN SHOULD BE 
CONTACTED** 
 
Grade 1 
No dose modification 
For Grade 1: 
- 
Consider symptomatic treatment including oral 
antipruritics (eg, diphenhydramine or 
hydroxyzine) and topical therapy (eg, urea 
cream) 
 
Grade 2 
For persistent (>1-2 weeks) 
Grade 2 events, hold 
scheduled study drug/study 
regimen until resolution to 
Grade ≤1 or baseline  
• If toxicity worsens then 
treat as Grade 3 
• If toxicity improves to 
baseline then resume 
administration at next 
scheduled dose 
For Grade 2 : 
- 
Consider symptomatic treatment including oral 
antipruritics (eg, diphenhydramine or 
hydroxyzine) and topical therapy (eg, urea 
cream) 
- 
Consider moderate-strength topical steroid  
- 
If no improvement of rash/skin lesions occurs 
within 3-5 days or is worsening, discuss with 
study physician and consider systemic steroids 
prednisone 0.5 to 1 mg/kg/day or IV equivalent 
- 
Consider dermatology consult  
- 
Consider skin biopsy if persistent for 
>1-2 weeks or recurs 
Grade 3 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 or baseline 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the Grade 3 
skin rash to  Grade ≤1 or 
baseline within 30 days, then 
permanently discontinue 
study drug/study regimen  
For Grade 3 or 4: 
- 
Discuss with study physician 
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consult dermatology  
- 
Consider skin biopsy (preferably more than 1) 
as clinically feasible. 
- 
Initiate empiric IV corticosteroids (eg, 
methylprednisolone IV or equivalent) at 1 to 
4 mg/kg/day 
- 
Once improving, gradually taper steroids over 
≥4 weeks and consider prophylactic antibiotics 
Grade 4 
Permanently discontinue 
study drug/study regimen  
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
 
Any Grade 
- 
Monitor subjects for signs and symptoms of 
endocrinopathies. Non-specific symptoms 
include headache, fatigue, behavior changes, 
changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension and 
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IMBRUVICA® (ibrutinib) 
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Final 
 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
adrenal 
insufficiency, 
etc.) 
weakness. 
- 
Subjects should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression including brain metastases, 
infections, etc.) 
- 
Monitor and evaluate thyroid function tests: 
TSH, free T3 and free T4 and other relevant 
endocrine labs dependent on suspected 
endocrinopathy 
- 
If a subject experiences an AE that is thought to 
be possibly of autoimmune nature (eg, 
thyroiditis, pancreatitis, hypophysitis, diabetes 
insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody 
testing  
 
Grade 1 
No dose modification 
For Grade 1: (including those with asymptomatic 
TSH elevation) 
- 
Monitor subject with appropriate endocrine 
function tests 
- 
If TSH <0.5X LLN, or TSH >2X ULN or 
consistently out of range in 2 subsequent 
measurements, include FT4 at subsequent 
cycles as clinically indiated and consider 
endocrinology consult  
 
Grade 2  
Hold study drug/study 
regimen dose until resolution 
to Grade ≤1 
• 
If toxicity worsens then 
treat as Grade 3 or 
Grade 4 
• 
If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- 
Discuss with study physician  
- 
Initiate hormone replacement as needed for 
management 
- 
Evaluate endocrine function, and as clinically 
indicated, consider pituitary scan 
- 
For subjects with abnormal endocrine work up,  
consider short-term, high-dose corticosteroids 
(eg, methylprednisolone or IV equivalent) with 
relevant hormone replacement (eg, 
levothyroxine, hydrocortisone, or sex 
hormones)  
- 
For subjects with normal endocrine work up 
(lab or MRI scans), repeat labs/MRI as 
clinically indicated 
 
 
 
Grade 3 
Hold study drug/study 
regimen dose until 
endocrinopathy symptom(s) 
are controlled 
Resume study drug/study 
regimen administration if 
controlled at the next 
For Grade 3 or 4: 
- 
Discuss with study physician 
- 
Initiate empiric IV corticosteroids (eg, 
methylprednisolone IV or equivalent) at 1 to 
2 mg/kg/day  
- 
Administer hormone replacement therapy as 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
scheduled dose 
necessary 
- 
For adrenal crisis, severe dehydration, 
hypotension, or shock: immediately initiate 
intravenous corticosteroids with 
mineralocorticoid activity 
- 
Consult endocrinologist 
- 
Once improving, gradually taper 
immunosuppressive steroids over ≥4 weeks 
 
Grade 4 
Permanently discontinue 
study drug/study regimen  
Immune-
mediated  
Neurotoxicity 
(except 
Myasthenia 
Gravis and 
Guillian-Barre)   
 
Any Grade 
- 
Subjects should be evaluated to rule out any 
alternative etiology (eg, disease progression, 
infections, metabolic syndromes and 
medications, etc.) 
- 
Monitor subject for general symptoms 
(headache, nausea, vertigo, behavior change, or 
weakness) 
- 
Consider appropriate diagnostic testing (eg, 
electromyogram and nerve conduction 
investigations) 
- 
Symptomatic treatment with neurological 
consult as appropriate 
 
Grade 1 
No dose modifications 
-- 
 
Grade 2 
For acute motor 
neuropathies or  
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade ≤1 
For sensory neuropathy/ 
neuropathic pain, consider 
holding study drug/study 
regimen dose until resolution 
to Grade ≤1. 
• If toxicity worsens then 
treat as Grade 3 or  
Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
- 
Discuss with study physician  
- 
Consider Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (eg, 
gabapentin, duloxetine, etc.) 
- 
Consider systemic steroids prednisone 
1-2 mg/kg/day or IV equivalent at 0.5 to 
1 mg/kg/day 
- 
If no improvement within 3-5 days, consider 
additional workup and treatment with 
additional immunosuppressive therapy (eg, 
IVIgG) 
 
 
 
 
 
Grade 3 
Hold study drug/study 
regimen dose until resolution 
to Grade ≤1 
Permanently discontinue 
study drug/study regimen if 
Grade 3 irAE does not 
resolve to Grade ≤1 within 
30 days 
For Grade 3 or Grade 4: 
- 
Discuss with study physician 
- 
Consult Neurology Consult 
- 
Consider hospitalization 
- 
Consider empiric IV corticosteroids (eg, 
methylprednisolone or IV equivalent) at 1 to 
2 mg/kg/day 
- 
If no improvement within 3-5 days, consider 
additional workup and treatment with 
additional immunosuppressants (eg, IVIgG) 
- 
Once stable, gradually taper steroids over 
 
Grade 4 
Permanently discontinue 
study drug/study regimen 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
≥4 weeks 
Immune-
mediated 
peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and Myasthenia 
Gravis 
 
Any Grade 
- 
The prompt diagnosis of immune-mediated 
peripheral neuromotor syndromes is important, 
since certain subjects may unpredictably 
experience acute decompensations which can 
result in substantial morbidity or in the worst 
case, death. Special care should be taken for 
certain sentinel symptoms which may predict a 
more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic 
instability 
- 
Subjects should be evaluated to rule out any 
alternative etiology (eg, disease progression, 
infections, metabolic syndromes and 
medications, etc.). It should be noted that the 
diagnosis of immune-mediated peripheral 
neuromotor syndromes can be particularly 
challenging in subjects with underlying cancer, 
due to the multiple potential confounding 
effects of cancer (and its treatments) throughout 
the neuraxis. Given the importance of prompt 
and accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological consult 
- 
Neurophysiologic diagnostic testing (eg, 
electromyogram and nerve conduction 
investigations, and  “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated 
upon suspicion of such conditions and may be 
best facilitated by means of a neurology 
consultation  
Important to consider that the use of steroids as 
the primary treatment of Guillain-Barre is not 
typically considered effective. Subjects 
requiring treatment should be considered for 
plasmapharesis (or IVIgG, as an alternative) 
 
 
Grade 1 
No dose modification 
- 
Discuss with the study physician 
- 
Care should be taken to monitor subjects for 
sentinel symptoms of a potential 
decompensation as described above 
- 
Consider a neurology consult unless the 
symptoms are very minor and stable 
 
Grade 2 
Hold study drug/study 
regimen dose until resolution 
to Grade ≤1 
Permanently discontinue 
study drug/study regimen if 
does not resolve to Grade ≤1 
within 30 days or if there are 
Grade 2 : Moderate  
- 
Discuss with the study physician  
- 
Care should be taken to monitor subjects for 
sentinel symptoms of a potential 
decompensation as described above 
- 
Obtain a Neurology Consult  
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IMBRUVICA® (ibrutinib) 
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Final 
 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
signs of respiratory 
insufficiency or autonomic 
instability 
- 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (eg, 
gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
Myasthenia Gravis. Important to consider 
that steroid therapy (especially with high 
doses) may result in transient worsening of 
myasthenia and should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Subjects unable to tolerate steroids may be 
candidates for treatment with 
plasmapharesis or IVIgG. Such decisions 
are best made in consultation with a 
neurologist, taking into account the unique 
needs of each subject. 
o 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. Subjects requiring treatment 
should be considered for plasmapharesis 
(or IVIgG, as an alternative). 
 
Grade 3 
Hold study drug/study 
regimen dose until resolution 
to Grade ≤1 
Permanently discontinue 
study drug/study regimen if 
Grade 3 irAE does not 
resolve to Grade ≤1 within 
30 days or if there are signs 
of respiratory insufficiency 
or autonomic instability 
For severe or life threatening (Grade 3 or 4) events:  
- 
Discuss with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological 
consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat 
Myasthenia Gravis. It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Subjects unable to tolerate steroids may be 
candidates for treatment with 
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IMBRUVICA® (ibrutinib) 
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Final 
 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue 
study drug/study regimen 
plasmapharesis or IVIgG. 
o 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. Subjects requiring treatment 
should be considered for plasmapharesis 
(or IVIgG, as an alternative). 
Non-immune Mediated Reactions 
CTC 
Grade/Severity 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: dose modifications are not required 
for adverse events not deemed to be 
related to study treatment (ie, events due 
to underlying disease) or for laboratory 
abnormalities not deemed to be clinically 
significant 
Treat accordingly as per institutional standard 
1 
No dose adjustment 
Treat accordingly as per institutional standard 
2 
Hold study drug/study drug regimen until 
resolution to Grade ≤1 or baseline 
Treat accordingly as per institutional standard 
3 
Hold study drug/study drug regimen until 
resolution to Grade ≤1 or baseline 
 
For AEs that downgrade to Grade ≤2 
within 7 days or resolve to Grade ≤1 or 
baseline within 14 days, resume study 
drug/study regimen administration at next 
scheduled dose. Otherwise, discontinue 
study drug/study regimen 
Treat accordingly as per institutional standard 
4 
Discontinue study drug/study regimen 
(Note: For Grade 4 labs, decision to 
discontinue would be based on 
accompanying clinical signs/symptoms 
and as per Investigator’s clinical judgment 
and in consultation with the Sponsor 
Treat accordingly as per institutional standard 
20 January 2015 version 
Abbreviations:  AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event;  
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed 
tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease;  
IM = intramuscular; irAE = immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events; PO = by mouth; TNF = tumor necrosis factor;  
TSH = thyroid stimulating hormone; ULN = upper limit of normal 
 
MEDI4736 treatment interruptions in study drug administration should be recorded in the 
clinical database. 
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IMBRUVICA® (ibrutinib) 
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Final 
 
5.7 
Criteria for Permanent Discontinuation of Study Drug 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk. For a list of criteria for permanent discontinuation of study treatment, refer to 
Section 9.2.  
Subjects who withdraw for any reason other than those specified in Sections 5.4 and 9.2 will not 
be replaced. An End-of-Treatment Visit for ibrutinib (Section 8.3.1) and an End-of-Treatment 
Visit for MEDI4736 (Section 8.3.2) are required for all subjects except for those subjects who 
have withdrawn full consent. 
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IMBRUVICA® (ibrutinib) 
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Final 
 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded from the time of ICF signing until 30 days after the last 
dose of ibrutinib and 90 days after the last dose of MEDI4736. 
6.1 
Permitted Concomitant Medications  
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 
growth factors (erythropoietin) is permitted per institutional policy and in accordance with 
American Society of Clinical Oncology (ASCO) guidelines (Smith 2006). Transfusions may be 
given in accordance with institutional policy.  
Short courses (≤14 days) of corticosteroid treatment for non-cancer related medical reasons 
considered unrelated to study treatment (eg, unrelated joint inflammation, asthma exacerbation, 
rash, antiemetic use) at doses that do not exceed 100 mg per day of prednisone or equivalent are 
permitted after discussion with the Medical Monitor.  During corticosteroid treatment with 
>10 mg per day of prednisone or equivalent, MEDI4736 should be held until event resolution to 
Grade ≤1 or baseline; thereafter, MEDI4736 administration may be resumed at the next 
scheduled dose. For MEDI4736-related adverse reactions, please follow the corticosteroid and 
dose administration guidelines in Section 5.6.2.5. 
6.2 
Medications to Be Used with Caution 
6.2.1 
CYP3A-inhibitors/Inducers  
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Co-administration 
of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased dose normalized 
exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively. The maximal 
observed ibrutinib exposure (AUC) was ≤2-fold in 37 subjects treated with mild and/or moderate 
CYP3A inhibitors when compared with the ibrutinib exposure in 76 subjects not treated 
concomitantly with CYP3A inhibitors. Clinical safety data in 66 subjects treated with moderate 
(n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in toxicities. 
Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, and nefazadone) should be avoided. If a strong 
CYP3A inhibitor must be used, consider reducing the ibrutinib dose to 140 mg or withhold 
ibrutinib temporarily. Subjects should be monitored for signs of ibrutinib toxicity. If the benefit 
outweighs the risk and a moderate CYP3A inhibitor must be used, monitor subject for toxicity 
and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during 
ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Appendix 4). 
Co-administration of ibrutinib with a strong CYP3A inducer, rifampin, in healthy subjects 
decreases ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of 
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strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and St. John’s Wort). Consider 
alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix 4; a comprehensive 
list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised and 
should be checked frequently for updates. 
6.2.2 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib  
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL). Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There is no clinical data available. Therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib.  
6.2.3 
Antiplatelet Agents and Anticoagulants  
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. For guidance on ibrutinib and 
the use of anticoagulants during procedures/surgeries see Section 6.4. 
For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, for treatment of 
atrial fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If therapeutic 
anticoagulation is clinically indicated, treatment with ibrutinib should be held and should not be 
restarted until the subject is clinically stable and has no signs of bleeding. Subjects should be 
observed closely for signs and symptoms of bleeding. No dose reduction is required when study 
drug is restarted. 
6.3 
Prohibited Concomitant Medications  
Any systemic chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy 
is prohibited while the subject is receiving ibrutinib and/or MEDI4736 treatment.  
Transfusional support is prohibited for at least 7 days prior to Screening. Growth factors are 
prohibited for at least 14 days prior to Screening. 
Immunosuppressive medications within 14 days before the first dose of MEDI4736 and 
throughout the study are prohibited. The following are exceptions to this criterion: 
• Intranasal, inhaled, topical corticosteroids, or local corticosteroid injections (eg, intra-
articular injection) 
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• Corticosteroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-
medication) 
• Corticosteroids given for prevention or treatment of infusion reactions  
• Corticosteroids given for acute toxicity managements, eg pneumonitis or other immune-
related AEs  
• For the above exceptions, short courses (≤14 days) of systemic corticosteroid treatment 
for non-cancer related medical reasons at doses that do not exceed 100 mg per day of 
prednisone or equivalent are permitted (see Section 6.1). 
Subjects should not receive live vaccines during the study and until 30 days after the last dose of 
study drug. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.4 
Guidelines for Ibrutinib Management with Surgeries or Procedures   
Ibrutinib may increase the risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   
6.4.1 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis), ibrutinib should be held for at least 3 days prior to the procedure and should not be 
restarted for at least 3 days after the procedure. For bone marrow biopsies that are performed 
while the subject is on ibrutinib, it is not necessary to hold ibrutinib. There is no need to hold 
MEDI4736 for minor surgical procedures. 
6.4.2 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention and should be held at least 7 days after the procedure 
and restarted at the discretion of the investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes. MEDI4736 has not been shown 
to affect wound healing; therefore, administration will not be impacted by major surgery. 
6.4.3 
Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure. 
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7. 
STUDY EVALUATIONS 
7.1 
Description of Procedures 
7.1.1 
Assessments  
7.1.1.1. 
ICF 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. Subjects must also grant permission to use protected health 
information per the Health Insurance Portability and Accountability Act (HIPAA). In addition, 
subjects must sign all approved ICF amendments per the site IRB/REB/IEC guidelines during 
the course of the study.  
7.1.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4). De-identified copies of 
the pathology report confirming diagnosis of FL or DLBCL (tumor biopsy and bone marrow 
biopsy), a list of prior anticancer therapies and best responses, and the radiology report from 
screening CT scan (or MRI if indicated) and positron emission tomography (PET) will need to 
be submitted to the Sponsor as part of the enrollment process. In addition, DLBCL subtype 
should be provided (IHC testing at local laboratory) at the time of eligibility verification. 
7.1.1.3. 
Medical History and Demographics 
The subject’s clinically significant medical history through review of medical records and by 
interview will be collected and recorded. Clinically significant is defined as any events, 
diagnoses or laboratory values requiring treatment, follow-up or the presence of signs or 
symptoms that require medical intervention. Concurrent medical signs and symptoms must be 
documented to establish baseline severities. A disease history, including the date of the initial 
diagnosis and a list of all prior anticancer treatments, dates administered, and responses and 
duration of response to these treatments, will also be recorded.  
7.1.1.4. 
Prior and Concomitant Medications 
All prior/concomitant medications (including over-the-counter, supplements, and herbal 
products) and procedures will be collected from date of ICF or from 14 days before the start of 
study drug, throughout the End-of-Treatment Visit for ibrutinib, End-of-Treatment Visit for 
MEDI4736, or initiation of alternative cancer therapy, whichever is longer. After a subject 
discontinues study treatment, receipt of all subsequent anticancer therapies will be collected until 
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death, subject withdrawal of full consent, loss to follow-up, or study termination by the Sponsor, 
whichever comes first. 
7.1.1.5. 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 11.1. All medical 
occurrences that meet the AE definition must be recorded from the time the ICF is signed until 
30 days after the last dose of ibrutinib and until 90 days after the last dose of MEDI4736 or until 
initiation of alternative cancer therapy. AEs will be recorded in the eCRFs from the 
administration of the first dose of the study drug and will continue to be recorded until 30 days 
after the last dose of ibrutinib and until 90 days after the last dose of MEDI4736 or until 
initiation of alternative cancer therapy. Laboratory abnormalities designated clinically significant 
by the Investigator will also be recorded as AEs. A clinical laboratory abnormality should be 
documented as an adverse event if any one of the following conditions is met:  
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests  
• the abnormality is of a degree that requires active management; eg, change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
• results in study withdrawal 
• is associated with a serious adverse event 
• is considered by the Investigator to be of clinical significance  
Additional important requirements for AE and SAE reporting are explained in Section 11.4. 
7.1.1.6. 
Physical Examination 
Physical examination will be performed at Screening, Day 1 of each Cycle, End-of-Treatment 
visit for ibrutinib and End-of-Treatment Visit for MEDI4736. The physical examination will 
include, at a minimum, the general appearance of the subject, height (screening only) and weight, 
and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, nervous system, and lymphatic system.  
A limited symptom-directed physical examination is required at all other visits.   
7.1.1.7. 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 3. 
7.1.1.8. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and will 
be assessed after the subject has been resting in the sitting position for at least 3 minutes.  
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Vital signs will be measured repeatedly on MEDI4736 infusion days as outlined in Section 8. 
Additional measurements may be taken if a subject experiences an infusion reaction: 30 minutes, 
60 minutes, and 2 hours post end of infusion.  
7.1.2 
Laboratory 
Local laboratories will be used except for certain biomarker assays and in cases where a 
specialized laboratory is needed. 
7.1.2.1. 
Hematology 
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils 
and bands (if reported). These should be performed at the site’s local laboratory. 
7.1.2.2. 
Chemistry (Serum) 
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, 
total bilirubin, lactate dehydrogenase (LDH), phosphate,  uric acid, magnesium and bicarbonate. 
These should be performed at the site’s local laboratory.  
7.1.2.3. 
Thyroid Stimulating Hormone 
Thyroid stimulating hormone (TSH) will be tested at the site’s local laboratory. If TSH is 
abnormal, additional tests such as free thyroxine (T4) and triiodothyronine (T3) levels should be 
performed as clinically indicated. 
7.1.2.4. 
Coagulation Studies 
Measurement of prothrombin time (PT)/international normalized ratio (INR), and activated 
partial thromboplastin time (aPTT) will be performed at the site’s local laboratory. 
7.1.2.5. 
Creatinine Clearance 
Creatinine clearance will be measured and calculated using the Cockcroft-Gault method or 
determined by 24-hour creatinine clearance collection. This should be performed in conjunction 
with the site’s local laboratory. 
7.1.2.6. 
Hepatitis Serologies and Human Immunodeficiency Virus (HIV) 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
surface antibody, and Hepatitis B core antibody, and HIV-1 antibody will be evaluated. Subjects 
with chronic or active hepatitis B or C as diagnosed by serologic tests are excluded from the 
study. In equivocal cases, hepatitis B or C polymerase chain reaction (PCR) for viral load may be 
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performed and must be negative for enrollment. Subjects with a positive HIV screen and 
confirmatory test are excluded. These should be performed at the site’s local laboratory. 
7.1.2.7. 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. The use 
of urine dipstick is permitted; however, if the dipstick demonstrates any abnormal parameters, 
microscopic examination of urine should be performed. This should be performed at the site’s 
local laboratory. Urinalysis will be performed at Screening and throughout the MEDI4736 
treatment period as outlined in Section 8. 
7.1.2.8. 
Pregnancy Test 
A serum pregnancy test will be required at Screening by local laboratory only for women of 
childbearing potential, as defined in the inclusion criteria. A urine pregnancy test will also be 
performed on Day 1 prior to the first dose of study drugs. If positive, pregnancy must be ruled 
out by ultrasound to be eligible. This test will be performed routinely during and after study 
treatment and may be performed more frequently if required by local regulatory authorities. 
7.1.3 
Diagnostics/Procedures 
7.1.3.1. 
ECG 
Twelve-lead ECGs should be performed in triplicate with a 2- to 5-minute time lag between each 
measurement at Screening and for assessments throughout treatment as outlined in Section 8. 
ECGs should be performed at other times if clinically indicated. 
Abnormalities noted at Screening should be included in the medical history. During visits in 
which both ECGs and blood draws are performed, ECGs are recommended to be performed first. 
Additionally, triplicate 12-lead ECGs should be performed at the Investigator’s discretion, 
particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new-
onset dyspnea. 
7.1.3.2. 
CT/MRI and PET Scans 
A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any 
other disease sites is needed for each response evaluation.  
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the chest and neck without contrast. In this case, neck nodes 
cannot be used as target lesions. 
NOTE:  PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
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parameters, and includes the use of IV contrast. Also, in the event that the Sponsor requests 
submission of imaging, the CT images must be separated from the PET data prior to submitting 
the data, and cannot be transmitted as fused CT/PET images.  
If using a hybrid machine to acquire both PET and CT, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results.  
If independent CT and PET scanners are used, and the subject is receiving both scans on the 
same day, the PET must be performed prior to the CT with IV contrast. 
The same radiographic technique used for a subject’s pretreatment tumor assessment should be 
used throughout the course of the study and should be mentioned in each radiology report. 
The same imaging equipment should be used for all scans, whenever possible. 
Following the pretreatment tumor assessments, CT/MRI should be performed as per schedule of 
assessments in Appendix 1 (or more often if clinically indicated) and repeat PET scanning will 
only be required to confirm CR and will be performed only if it was positive at Screening. 
Subjects who refuse CT/MRI scans and miss more than one scan will be removed from the 
study. 
De-identified copies of all scans and radiology reports (including those from screening and any 
unscheduled scans) may be requested to be provided to the Sponsor or designee. At the 
Sponsor’s discretion, the Sponsor or its designee may conduct an independent review of the 
Investigator responses. 
7.1.3.3. 
Bone Marrow Aspirate and Biopsy 
A unilateral bone marrow aspirate and biopsy will be done at Screening or up to 28 days before 
the first dose of study drug. Thereafter, bone marrow aspirate and biopsy will only be required to 
confirm CR if it was positive at Screening. 
Standard clinical testing will be performed at the study center’s local laboratory or other clinical 
laboratory listed on the Investigator’s form FDA 1572. Additional samples will be collected for 
biomarkers and other exploratory evaluations such as for evidence of minimal residual disease 
(MRD) if methods are available. 
All bone marrow (BM) samples obtained at Screening and to confirm CR should be submitted to 
the Sponsor if available. 
7.1.3.4. 
Tumor Tissue Biopsy 
Subjects are required to undergo a pre-treatment tumor biopsy which will be submitted to the 
Sponsor (unless archived formalin-fixed, paraffin-embedded [FFPE] tissue obtained within the 
last 3 months and after the last systemic anticancer treatment is available to submit to the 
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Sponsor) (“recent biopsy”). Earlier archived FFPE tissue for enrolled subjects will also be 
submitted to the Sponsor if available (“historical biopsy”). An optional biopsy will be collected 
at disease progression (see Section 6.4 for management of ibrutinib with invasive procedures).  
Note the following guidelines for tumor biopsy sampling: 
• If feasible, 4 core needle (at least 18-gauge) tumor biopsy samples are requested, with a 
minimum of at least 3 core samples. The first and third core samples will be placed in 
formalin and processed, while the second and fourth core samples (fourth sample, if 
available) will be immediately frozen and processed (see Laboratory Manual).   
• An archived tumor tissue block (FFPE) where such samples exist in a quantity sufficient 
to allow for analysis will be requested for all enrolled subjects. If an archived tumor 
block cannot be provided, at least 10 newly cut unstained slides with tissue sections of 
4 microns thick may be provided instead (see Laboratory Manual). Archived tumor tissue 
may be submitted from tumor biopsies starting from diagnosis. 
Tumor biopsies may be evaluated for key target expression (eg, PD-L1) via IHC, and genomic 
analyses may be performed if there is sufficient material; other biomarkers that predict 
sensitivity or resistance to the drug combination may also be explored. At minimum, biopsy 
samples obtained at baseline (including archived slides) will be collected for FL and DLBCL 
subjects and used to determine GCB and non-GCB subtypes for subjects with DLBCL.  
7.1.4 
Pharmacokinetics/Pharmacodynamics/Biomarkers  
Refer to the Laboratory Manual for instructions on collecting and processing these samples. On 
days of sampling visits, the clinical staff will instruct the subject to not take a dose before arrival 
at the clinic. Study drug intake will be observed by clinic staff. The actual time (versus requested 
time) that each sample is drawn must be recorded using a 24-hour format. The same clock should 
be used for recording the time of dosing. All predose collections should be performed prior to 
receiving any study drug (ibrutinib or MEDI4736). All post-dose collection times are calculated 
from the time that ibrutinib is dosed, unless subjects have discontinued ibrutinib and continue 
MEDI4736. If ibrutinib is discontinued, post-dose collection times will be calculated from the 
end of the MEDI4736 infusion. 
7.1.4.1. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and serum concentrations of MEDI4736 will be determined 
using a validated analytical method. Other potential metabolites of ibrutinib may be explored. 
For collection timepoints, refer to the Schedule of Assessments for Pharmacokinetics, 
Pharmacodynamics, and Biomarkers (Appendix 2). 
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7.1.4.2. 
Biomarkers and Pharmacodynamics Studies 
Samples collected may be used for pharmacodynamic and biomarker assessments to monitor 
both ibrutinib and MEDI4736 activity when co-administered. Biomarkers of interest include 
BTK, ITK, and other kinase activity and signaling, soluble PD-L1, anti-drug antibody 
immunogenicity, drug occupancy, expression analysis, genomic sequencing, flow cytometry and 
secreted protein analyses (ie, chemokines, cytokines). Fluids including blood collected during the 
course of the study may be used for, but not limited to, pharmacodynamic and biomarker 
assessments as noted below. In addition, analyses of samples may be re-prioritized and other 
markers may also be investigated if new research emerges. 
Cytokines, chemokines, cell surface markers and genomic markers may be tested in peripheral 
blood, tumor tissue and buccal swabs. If skin biopsies or other specimens are available, they may 
also be evaluated.  
For molecular profiling of tumor samples, DNA/RNA may be extracted for gene expression and 
genomic testing including mutational analysis. 
Immune cell subsets in peripheral blood may be evaluated by immunophenotyping, including 
T/B/NK cell counts and other markers.  
Samples may be tested to evaluate potential biomarkers related to disease and treatment 
response, investigate potential mechanisms of treatment resistance, and assess the physiological 
effects of ibrutinib and MEDI4736.. These efforts may identify biomarkers that could assist with 
future development of this combination.  
Immunogenicity analyses of anti-drug antibodies (ADA) will be performed before and after 
treatment with ibrutinib in combination with MEDI4736 to identify evidence of an anti-
MEDI4736 response. 
For collection timepoints, refer to the Schedule of Assessments for Pharmacokinetics, 
Pharmacodynamics, and Biomarkers (Appendix 2). 
7.1.4.2.1. 
Minimal Residual Disease (MRD) Analysis 
Current data indicate that there may be a survival advantage in lymphoma patients who attain an 
MRD negative status at the completion of therapy (Mitterbauer-Hohendanner 2004, Liu 2012, 
Galimberti 2014). Results from several lymphoma studies including both indolent and malignant 
lymphomas have demonstrated such a trend. While not a part of the response criteria, collection 
of MRD will enhance the understanding of the depth of response achieved and may predict for 
impending relapse. 
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Baseline assessment for tumor burden (using the selected MRD assessment method) will be 
performed using tumor tissue biopsy, peripheral blood, and/or bone marrow aspirate collected at 
baseline. 
Peripheral blood samples for MRD evaluation will be obtained at screening and throughout the 
study every 8 weeks until CR is achieved. For biomarker collection timepoints (including MRD 
evaluation), refer to the Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, and 
Biomarkers (Appendix 2).  
Subjects with CR should have peripheral blood DNA samples obtained at the first time CR is 
suspected and every 3 cycles thereafter for evaluating MRD unless the subject withdraws 
consent or develops PD. Peripheral blood for MRD will be assessed every 3 cycles for 1 year. 
In addition, BM aspirate samples obtained for CR confirmation may be assessed for MRD 
analysis unless the subject withdraws consent or develops PD. Instructions for 
collecting/submitting samples for MRD analyses are provided the Laboratory Manual. 
7.2 
Response Evaluations 
Response assessments will be completed by the Investigator. The response criteria are based on 
the revised criteria for malignant lymphoma described by the International Working Group for 
NHL (Cheson 2014). At Screening, up to six target lesions will be selected and will be followed 
for the duration of the study until confirmed progressive disease.  
For subjects with PET-positive tumors at baseline, response evaluations will largely be based on 
the CT scan; however PET will be required to confirm a complete response (CR). 
Lesions in anatomical locations that are not well visualized by CT may be measured by 
MRI instead. 
Refer to Appendix 5 for response criteria. 
7.3 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form. Refer to the Schedule of Assessments 
(Appendix 1 and Appendix 2) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 
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8. 
STUDY PROCEDURES  
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments. Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated. The 
Schedules of Assessments for Phase 1b and Phase 2 are provided in Appendix 1 with PK, 
pharmacodynamics, and biomarker collection details in Appendix 2.  
8.1 
Screening Phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified. 
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed. After signing the ICF, completing all 
screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study. 
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the 28-day screening window. The pre-
treatment tumor tissue biopsy may be within 3 months. 
8.1.1 
Screening/Consenting Visit 
The following procedures will be performed during Screening: 
• Informed Consent 
• Review of eligibility criteria (Inclusion/Exclusion criteria) 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vital signs, weight and height  
• Triplicate 12-lead ECG (2-5 minutes apart) 
• Bone marrow aspirate and biopsy 
• Tumor biopsy (see Section 7.1.3.4) 
• Review of prior and concomitant medications  
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT) 
• PET scan (in addition to CT scan) 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Coagulation (PT, PTT, INR) 
o Creatinine Clearance 
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o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies and HIV 
o Urinalysis 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
8.2 
Treatment Phase 
8.2.1 
Ibrutinib Lead-in Day 1 (baseline) 
Screening laboratory assessments performed within 48 hours of Ibrutinib Lead-in Day 1 may be 
used as pre-dose ibrutinib Lead-in Day 1 laboratory assessments and are not required to be 
repeated. 
Pre-dose 
• Confirmation of eligibility 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Triplicate 12-lead ECG (2-5 minutes apart) 
• Buccal swab 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples collected pre-dose for: 
o Ibrutinib pharmacokinetics 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib 
Post-dose 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o Ibrutinib pharmacokinetics 
o Ibrutinib biomarkers and pharmacodynamics 
• Triplicate 12-lead ECG (2-5 minutes apart) at approximately 2 hours post ibrutinib dose 
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• Review of AEs and concomitant medications 
8.2.2 
Ibrutinib Lead-in Day 2  
Pre-dose 
• Research laboratory blood samples collected pre-dose for: 
o Ibrutinib pharmacokinetics (24-hour time point from Day 1) 
o Ibrutinib biomarkers and pharmacodynamics (24-hour time point from Day 1) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of ibrutinib 
8.2.3 
Ibrutinib Lead-in Day 6 or 7  
Pre-dose 
• Research laboratory blood samples collected pre-dose for: 
o Ibrutinib pharmacokinetics  
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of ibrutinib 
Post-dose 
• Research laboratory blood samples (See Appendix 2 for collection schedule): 
o Ibrutinib pharmacokinetics 
• Review of AEs and concomitant medications 
8.2.4 
Cycle 1 Day 1 (C1D1)  
Pre-dose 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Triplicate 12-lead ECG (2-5 minutes apart) 30-60 minutes prior to MEDI4736 infusion 
start 
• Clinical laboratory tests for: 
o Hematology 
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o Serum chemistry 
o TSH 
o Urinalysis 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples collected pre-dose for: 
o Ibrutinib biomarkers and pharmacodynamics 
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoints: 
o End of MEDI4736 infusion (+5 minutes) 
o 30 minutes (±5 minutes) post end of MEDI4736 infusion 
o 60 minutes (±5 minutes) post end of MEDI4736 infusion 
o 2 hours (±15 minutes) post end of MEDI4736 infusion 
• Triplicate 12-lead ECG (2-5 minutes apart) within 3 hours after the end of the MEDI4736 
infusion 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics (to be collected after ibrutinib dose is taken) 
• Review of AEs and concomitant medications 
8.2.5 
Cycle 1 Day 8 (C1D8)  
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
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o Serum chemistry 
• Review of AEs and concomitant medications 
8.2.6 
Cycle 1 Day 15 (C1D15) 
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
8.2.7 
Cycle 1 Day 22 (C1D22)  
• Physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
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o Serum chemistry 
• Review of AEs and concomitant medications 
8.2.8 
Cycle 2 Day 1 (C2D1) 
Pre-dose 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o MEDI4736 pharmacokinetics 
• Review of AEs and concomitant medications 
8.2.9 
Cycle 2 Day 15 (C2D15)  
Pre-dose 
• Physical exam 
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• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.10 
Cycle 3 Day 1 (C3D1)  
Pre-dose 
• Complete physical exam 
• Response Assessment  
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT) – can be performed within 7 days prior to C3D1 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Triplicate 12-lead ECG (2-5 minutes apart) 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples: 
o Ibrutinib pharmacokinetics 
o Ibrutinib biomarkers and pharmacodynamics 
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o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o Ibrutinib pharmacokinetics 
o MEDI4736 pharmacokinetics 
• Triplicate 12-lead ECG (2-5 minutes apart) at approximately 2 hours post ibrutinib dose 
• Review of AEs and concomitant medications 
8.2.11 
Cycle 3 Day 15 (C3D15) 
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
 
Note: After Cycle 3, Day 15 hematology and chemistry laboratories can be obtained if 
clinically indicated. 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
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• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoints: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.12 
Cycle 4 Day 1 (C4D1) 
Pre-dose 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Urinalysis 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
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8.2.13 
Cycle 4 Day 15 (C4D15)  
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoints: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.14 
Cycle 5 Day 1 (C5D1) 
Pre-dose 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Triplicate 12-lead ECG (2-5 minutes apart) 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
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• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoints: 
o End of MEDI4736 infusion (+5 minutes) 
• Triplicate 12-lead ECG (2-5 minutes apart) 30-60 minutes within 3 hours after the end of 
MEDI4736 infusion 
• Review of AEs and concomitant medications 
8.2.15 
Cycle 5 Day 15 (C5D15) 
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.16 
Cycle 6 Day 1 (C6D1) 
Pre-dose 
• Complete physical exam 
• Response Assessment 
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT) – can be performed within 7 days prior to C6D1 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
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o Serum chemistry 
o TSH 
o Urine pregnancy test (for women of childbearing potential only) 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics  
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
• Research laboratory blood samples (see Appendix 2 for collection schedule): 
o MEDI4736 pharmacokinetics 
8.2.17 
Cycle 6 Day 15 (C6D15) 
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
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o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.18 
Day 1 of Each Subsequent Cycle 
Subjects will continue to come in on Day 1 of each cycle for the first 12 months. After this time, 
subjects will come in on Day 1 of every third cycle. The following procedures will be performed 
unless otherwise specified. 
Pre-dose 
• Complete physical exam 
• Response Assessment 
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT) should be performed every 3 cycles (Cycle 9, Cycle 12 and every 6 cycles thereafter)  
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology (every cycle through Cycle 12, then at every 3 cycles thereafter) 
o Serum chemistry (every cycle through Cycle 12, then at every 3 cycles 
thereafter) 
o TSH (every cycle through Cycle 12, then at every 3 cycles thereafter) 
o Urinalysis (on Cycle 7 and Cycle 10) 
o Urine pregnancy test (for women of childbearing potential only) (every cycle 
through Cycle 12, then at every 3 cycles thereafter) 
• Research laboratory blood samples (on Cycle 7 and every 2 cycles thereafter, until CR 
achieved, then every 3 cycles thereafter): 
o Ibrutinib biomarkers and pharmacodynamics 
• Research laboratory blood samples (on Cycle 9 and every 3 cycles thereafter): 
o Ibrutinib biomarkers and pharmacodynamics 
o MEDI4736 pharmacokinetics  
o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (±5 minutes) during MEDI4736 infusion 
• Dispense ibrutinib and diary card (every cycle through Cycle 12, then at every 3 cycles 
thereafter) 
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• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Research laboratory blood samples (on Cycle 9 and every 3 cycles thereafter; see 
Appendix 2 for collection schedule): 
o MEDI4736 pharmacokinetics  
• Review of AEs and concomitant medications 
8.2.19 
Day 15 of Each Subsequent Cycle  
The Day 15 visits can be discontinued at the end of treatment with MEDI4736. 
Pre-dose 
• Physical exam 
• ECOG Performance Status 
• Vital signs (within 30 minutes of MEDI4736 infusion start) and weight 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 30 minutes (± 5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (approximately within 15 minutes of end of 
MEDI4736 infusion) 
Post-dose 
• Vital signs at the following timepoint: 
o End of MEDI4736 infusion (+5 minutes) 
• Review of AEs and concomitant medications 
8.2.20 
Response Evaluations 
Response evaluations will be performed per the schedule outlined in Appendix 1. Imaging 
should be performed in the 7 days prior to the first dose of the next cycle. The following 
procedures will be performed in conjunction with standard visits as follows: 
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT)  
• Response Assessment  
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• To be completed to confirm CR: 
o PET scan (in addition to CT scan) 
o Bone marrow aspirate and biopsy 
o Ibrutinib biomarkers and pharmacodynamics (unless already obtained within the 
last 7 days) 
8.2.21 
Treatment Termination (Optional Visit) 
At the time of disease progression, an optional Treatment Termination visit may occur. The 
purpose of this visit is to allow an opportunity to collect biomarker samples and subject 
information at the time of disease progression prior to treatment discontinuation. If possible, the 
visit should be performed within 4 to 24 hours after the subject’s previous dose. An optional 
tumor tissue biopsy may be collected at disease progression. In conjunction with this optional 
visit, CT or MRI and/or PET scans may be done per Investigator discretion to assess for PD. 
The following procedures will be performed: 
• Physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• CT scan of neck, chest, abdomen, pelvis (if needed per Investigator discretion) 
• PET scan (if needed per Investigator discretion) 
• Response Assessment 
• Tumor biopsy (if feasible) (see Section 7.1.3.4) 
• Research laboratory blood samples: 
o Ibrutinib biomarkers and pharmacodynamics 
o MEDI4736 pharmacokinetics 
o MEDI4736 pharmacodynamics 
8.3 
Follow-up Phase 
Once a subject has completed the Treatment Phase, they will enter the Post-treatment Phase. 
Subjects that withdraw from treatment for reasons other than progressive disease will participate 
in ongoing response follow-up discussed in Section 8.3.3. 
8.3.1 
End-of-Treatment Visit for Ibrutinib 
An End-of-Treatment visit should occur 30 days (±7 days) after the last dose of ibrutinib or prior 
to the start of a new anticancer treatment. This visit may occur as a standard study visit if the 
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subject continues treatment with MEDI4736 alone. An optional tumor tissue biopsy may be 
collected if treatment was discontinued due to disease progression. If the subject starts a new 
anticancer treatment less than 7 days after the Treatment Termination visit, only those 
procedures not conducted at the Treatment Termination visit should be performed at the End-of-
Treatment visit.  
Subjects who withdraw consent to treatment may still participate in End-of-Treatment visit. The 
following procedures will be performed at the End-of-Treatment visit: 
• Complete physical exam  
• ECOG Performance Status 
• Vital signs and weight 
• Triplicate 12-lead ECG (2-5 minutes apart) 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Research laboratory blood samples collected: 
o Ibrutinib biomarkers and pharmacodynamics (unless already obtained within the 
last 7 days) 
• Review of AEs and concomitant medications 
8.3.2 
End-of-Treatment Visit for MEDI4736 
An End-of-Treatment visit should occur 90 days (±7 days) after the last dose of MEDI4736 or 
prior to the start of a new anticancer treatment. This visit may occur as a standard Day 1 cycle 
study visit if the subject continues treatment with ibrutinib alone. Subjects who withdraw consent 
to treatment may still participate in the End-of-Treatment visit. The following procedures will be 
performed: 
• Complete physical exam  
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Urinalysis 
o Review of AEs and concomitant medications 
• Research laboratory blood samples: 
o MEDI4736 pharmacokinetics 
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o MEDI4736 pharmacodynamics (includes anti-drug antibodies) 
8.3.3 
Response Follow-up 
Subjects who discontinue the study treatments (both ibrutinib and MEDI4736) for reasons other 
than progressive disease will be followed every 12 weeks (±7 days) until progressive disease or 
death, up to 3 years after the first dose of the last subject enrolled. The following procedures will 
be performed: 
• Physical examination 
• CT scan of neck, chest, abdomen, pelvis (and/or MRI for lesions not well-visualized by 
CT) at the end of Cycle 2 (within 7 days prior to starting Cycle 3) and then again every 
third cycle (within 7 days prior to starting the next cycle) 
• PET scan (if needed to confirm PD per Investigator discretion) 
• Response assessment 
8.3.4 
Survival Follow-up 
Once subjects progress or start use of alternative anticancer therapy (for subjects who have not 
withdrawn consent), they will be contacted approximately every 12 weeks (±7 days) from the 
last dose by clinic visit or telephone to assess survival and the use of alternative anticancer 
therapy, up to 3 years after the last dose of the last subject enrolled. Subjects will be contacted 
until death, subject withdrawal, lost to follow-up, or study termination by the Sponsor, 
whichever occurs first. 
8.4 
Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled date 
as possible. An exception is made when rescheduling becomes, in the Investigator’s opinion, 
medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation. 
In that case, the missed evaluation should be abandoned. 
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9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.  
9.2 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• Progressive disease 
• Unacceptable toxicity: an AE that prevents further administration of ibrutinib and 
MEDI4736 (including a DLT) 
• Withdrawal of consent for treatment by subject 
• Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• Study termination by Sponsor 
• Subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo an End-of-
Treatment Visit and be followed for progression and survival.  
The Investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
and/or MEDI4736 treatment due to disease progression or a DLT and should provide redacted 
documentation of disease progression for review by the Sponsor’s Medical Monitor. If a subject 
shows signs of disease progression on physical examination or laboratory assessment, the subject 
may continue study treatment until disease progression is confirmed. These subjects should stay 
in the study to be followed for survival.  
9.3 
Withdrawal from Study 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• Withdrawal of consent for follow-up observation by the subject 
• Lost to follow-up 
• Study termination by Sponsor 
• Death 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. The measures taken to follow up should be documented. 
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When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
• Reason for withdrawal; 
• Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits)  
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10. STATISTICAL METHODS AND ANALYSIS  
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).  
10.1 
Analysis Populations 
10.1.1 
Treated Population 
The treated population will include subjects who have enrolled in the study and received at least 
1 dose of any of the study treatments (either ibrutinib or MEDI4536). This population will be 
used for analysis of efficacy.  
10.1.2 
Safety Population 
The safety population will consist of all enrolled subjects who received at least one dose of any 
study treatment. The safety population will be used for the analysis of safety data.  
10.1.3 
Response-evaluable Population 
The response-evaluable population is defined as all enrolled subjects who received at least one 
dose of study treatment (ibrutinib or MEDI4736) and provided at least one post-baseline 
response (or disease) assessment. The response-evaluable population will be used as the primary 
population for analyses based on overall response. 
10.1.4 
Additional Analysis Populations 
Additional analysis populations, which may be used in sensitivity analyses for primary and 
secondary efficacy objectives and for analyses of exploratory objectives, will be defined in the 
statistical analysis plan. 
10.1.5 
Replacement of Subjects 
Subjects who were enrolled but not dosed or had missing doses as described in Section 5.4 will 
be replaced. For replacement of subjects in the DLT observation period please refer to 
Section 5.4. 
10.2 
Endpoints for Phase 1b 
10.2.1 
Primary Endpoints 
• Recommended Phase 2 Dose (RP2D) of ibrutinib in combination with MEDI4736 
• Safety and tolerability of ibrutinib in combination with MEDI4736 
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10.2.2 
Secondary Endpoints 
• Overall response rate (ORR) 
• Duration of response (DOR) 
• Pharmacokinetics (PK) and pharmacodynamics profiles 
10.3 
Endpoints for Phase 2 
10.3.1 
Primary Endpoint 
• ORR 
10.3.2 
Secondary Endpoints 
• DOR  
• Progression-free survival (PFS) 
• Overall survival (OS) 
• PK and pharmacodynamics (ie, BTK) profiles 
10.3.3 
Exploratory Endpoints 
• Immune cell subsets 
• Non-BTK-related pharmacodynamics (ie, ITK) 
• Plasma chemokine/cytokine levels 
• Genes and/or proteins (within the tumor or other collected specimens) associated with 
sensitivity or resistance to ibrutinib and/or MEDI4736 
• Rate and duration of MRD negativity 
10.4 
Sample Size Determination 
This study is not powered for comparison of treatment arms. Approximately 109 subjects will be 
enrolled throughout the study (up to 36 subjects in Phase 1b and approximately 73 subjects in 
Phase 2). 
10.4.1 
Phase 1b 
Dose de-escalation will follow the 6+3 design described in Section 3.1 and up to 4 cohorts 
including 3 dose de-escalation cohorts (1, -1A, -1B, and -2) will be enrolled if needed to 
determine the RP2D for the combination therapy. 
A total of 6-36 subjects eligible for DLT assessment will be enrolled into Phase 1b of the study 
with 6-9 DLT-evaluable subjects (regardless of tumor type) per dose cohort. Subjects are 
considered DLT-evaluable if they receive the assigned dose of study treatment (both ibrutnib and 
MEDI4736) and complete the safety follow-up through the DLT-observation period. 
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Cohorts -1A and -1B are two parallel dose de-escalation cohorts. Subjects will be enrolled 
concurrently in the sequence of -1A followed by -1B. For example, the first available subject 
goes to -1A, the second to -1B, the third to -1A, the fourth to -1B, etc. However, when one dose 
de-escalation cohort needs an additional 3 subjects to evaluate DLTs, all available subjects will 
be assigned to this cohort first. 
Subjects in Phase 1b who were dosed at the RP2D may also be included in the Phase 2 analysis. 
10.4.2 
Phase 2 
Approximately 73 response-evaluable subjects (including those subjects treated at the RP2D in 
Phase 1b but with tumor type as defined for Phase 2) will be enrolled. 
For FL: 
A maximum of 39 response-evaluable subjects (including those subjects treated at the RP2D in 
Phase 1b but with tumor type of FL) will be enrolled. An interim analysis will be performed after 
19 subjects are evaluable for tumor response after completing at least 2 response assessments. If 
only 6 or fewer responders (≤6/19) are observed, the Sponsor may consider discontinuation of 
this cohort (see Section 12.11). 
The null hypothesis that the true ORR is 30% will be tested against a one-sided alternative that 
the ORR is 50%. The null hypothesis will be rejected if 17 or more responses are observed in 
39 subjects. This design yields a 1-sided type I error rate of 0.05 and power of 80% when the 
true ORR is 50%. This statistical design including number of subjects and number of responders 
follows the statistical framework of Simon’s minimax two-stage design (Simon, 1989). 
Enrollment will continue while the interim analysis is performed.  
For DLBCL: 
A maximum of 34 subjects with GCB and non-GCB subtypes (including those subjects treated at 
the RP2D in Phase 1b but with tumor type of GCB and non-GCB DLBCL) will be enrolled at a 
1:1 ratio approximately.  
An interim analysis will be performed after 9 subjects are evaluable for tumor response after 
completing at least 2 response assessments. If only 1 or fewer responder (≤1/9) is observed, the 
Sponsor may consider discontinuation of this cohort (see Section 12.11).  
The null hypothesis that the true ORR is 15% will be tested against a one-sided alternative that 
the ORR is 35%. The null hypothesis will be rejected if 9 or more responses are observed in the 
34 subjects. This design yields a 1-sided type I error rate of 0.05 and power of 80% when the 
true ORR is 35%. The statistical design including number of subjects and number of responders 
follows the statistical framework of Simon’s optimal two-stage design (Simon, 1989). 
Enrollment will continue while the interim analysis is performed. 
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10.5 
Subject Information 
The distribution of subjects for each of the analysis populations will be provided. The number of 
subjects enrolled by each investigative site and country, dosed, and discontinued will be 
summarized. Treatment discontinuation will be summarized according to the reasons for 
discontinuation. Demographic and baseline variables will be summarized. Baseline disease 
characteristics will also be summarized. 
10.6 
Analysis Methods 
Tumor response and disease progression will be based on tumor response assessment per the 
Investigator using the Revised Criteria for Response Assessment of Malignant Lymphoma 
(Cheson 2014). Criteria are summarized in Appendix 5. 
10.6.1 
Phase 1b Analyses 
The primary objective of Phase 1b is to determine the RP2D and to evaluate safety and 
tolerability of ibrutinib in combination with MEDI4736. An algorithm-based 6+3 dose de-
escalation design is used to find the RP2D of the combination regimen and to characterize the 
most frequent adverse events and DLTs. DLTs will be evaluated and will include all adverse 
events experienced through Phase 1b. Study-drug exposure and laboratory data will be evaluated 
and summarized by dose cohort. 
The secondary objectives are to evaluate efficacy, PK, and pharmacodynamics in subjects 
receiving ibrutinib in combination with MEDI4736. The observed ORR along with the 
corresponding 95% confidence interval based on exact binomial distribution and duration of 
response (DOR) will be calculated and summarized with descriptive statistics by dose cohort and 
tumor type. PK and pharmacodynamics (ie, BTK) data will be summarized by dose cohort and 
tumor type. 
10.6.2 
Phase 2 Analyses  
10.6.2.1. Primary Efficacy Analysis 
The primary efficacy analysis will occur at least 12 months after the last FL subject is enrolled 
and at least 9 months after the last DLBCL subject is enrolled. The primary efficacy analysis will 
be based on ORR using the response-evaluable population in each of the two tumor cohorts. 
ORR is the proportion of response-evaluable subjects who achieved a complete response (CR) or 
a partial response (PR). The observed ORR along with its 95% confidence interval based on 
exact binomial distribution will be calculated and summarized for each tumor cohort. 
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10.6.2.2. Secondary Efficacy Analyses 
Duration of response (DOR) is defined as duration of 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, and will 
be calculated and summarized with descriptive statistics for responders by tumor type cohort. 
The Kaplan-Meier estimate will be provided for DOR, if a sufficient number of responders are 
observed. The censoring rules for DOR will be provided in the SAP. 
Progression-free survival (PFS) and overall survival (OS) will be evaluated by tumor type cohort 
with Kaplan-Meier estimates using the Safety Population. PFS is defined as duration of time 
from the first dose date of study drug (ibrutinib or MEDI4736) to the first documentation of 
disease progression per Investigator per Revised Criteria for Response Assessment of Malignant 
Lymphoma (Cheson 2014) or the date of death due to any cause, whichever occurs first. OS is 
defined as duration of time from the first dose date of study drug (ibrutinib or MEDI4736) to the 
date of death due to any cause. Censoring rules for PFS and OS will be described in the SAP. 
Pharmacokinetics (PK) and pharmacodynamics (ie, BTK) profiles will be evaluated by tumor 
type cohort and overall. 
10.6.2.3. Exploratory Efficacy Analyses 
The exploratory efficacy variables will be summarized descriptively and may include the 
following: 
• Immune cell subsets 
• Non-BTK-related pharmacodynamics (ie, ITK) 
• Plasma chemokine/cytokine levels  
• Genes and/or proteins (within the tumor or other collected specimens) associated with 
sensitivity or resistance to ibrutinib 
• Rate and duration of MRD negativity 
10.6.2.4. Subgroup Analyses 
For each tumor type cohort, a subgroup analysis will be conducted to calculate ORR and its 95% 
CI based on PD-1 ligand expression (positive versus negative).  
For the DLBCL cohort, a subgroup analysis will also be conducted to calculate ORR and its 95% 
CI for GCB and non-GCB DLBCL types. 
10.7 
Safety Analysis 
Analysis of safety data will be conducted on the safety population. The baseline value is defined 
as the last value collected on or prior to the first dose date of study drug (ibrutinib or MEDI4736, 
whichever comes first). 
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The safety variables to be analyzed include exposure of study drug, AEs, clinical laboratory test 
results (hematology and chemistry), ECOG performance, physical examination and vital sign 
measurements. Exposure of study treatment and reasons for discontinuation from study treatment 
will be tabulated. In general, continuous variables will be summarized using descriptive statistics 
(n, mean, median, standard deviation, and range). Categorical variables will be summarized 
using frequencies and percentages. No formal statistical testing is planned.  
10.7.1 
Adverse Events 
AE parameters to be evaluated are the type, incidence, and intensity of AEs; the relationship of 
AEs to study treatment; and the action taken with respect to study treatment due to AEs. 
The verbatim terms used in the CRF by Investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events (TEAEs) are those AEs occurring after the first dose of study treatment and within 
30 days following the last dose of ibrutinib or within 90 days following the last dose of 
MEDI4736 (whichever date is later) OR will be collected until the start date of a new anticancer 
therapy that falls within this AE collection period; any AE that is considered study drug-related 
regardless of the start date of the event; or any AE that is present at baseline but worsens in 
severity or frequency after the first administration of study treatment or an AE that is 
subsequently considered drug-related by the Investigator. All TEAEs will be included in the 
analysis. For each AE, the number and percentage of subjects who experience at least one 
occurrence of the given event will be summarized. The number and percent of subjects with 
TEAEs will be summarized according to intensity (NCI CTCAE, Version 4.03) and drug 
relationship, as well as categorized by system organ class and preferred term. Summaries, 
listings, datasets, or subject narratives may be provided, as appropriate, for those subjects who 
die, who discontinue treatment due to an AE, or who experience a severe or a serious AE. 
10.7.2 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry. Local 
laboratory results will be converted based on the normal ranges and standardized using the SI 
unit. Selected hematology and chemistry laboratory parameters are detailed in Section 7.1.2. 
Laboratory values will be graded using the NCI CTCAE Version 4.03.  
Descriptive statistics will be provided for the values of selected clinical laboratory tests at each 
scheduled on-treatment evaluation including the final value. Percent change from baseline to 
each scheduled on-treatment evaluation and to the final value will also be summarized. 
For selected variables, the mean value and mean percent change over time will be presented 
graphically. 
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided. The worst toxicity grade 
during the study will be tabulated. 
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10.8 
Dose Level Review Committee 
A Dose Level Review Committee will be established to evaluate the safety data from each cohort 
of the Phase 1b on an ongoing basis. Members of this committee will include participating 
Investigators or designees as well as the Sponsor (invitees include: the Medical Monitor or 
designee, the clinical lead, a Drug Safety representative, and a statistician) (see Section 12.11).  
10.9 
Pharmacokinetic Analysis (Ibrutinib)  
Ibrutinib and PCI-45227 bioanalytical data will be used in noncompartmental PK analysis. 
Plasma concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the PK summary. 
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point and PK parameters of ibrutinib and PCI-45227 (including but not limited 
to): Cmax, Tmax, AUClast, and t1/2. 
Mean plasma ibrutinib and PCI-45227 concentration time profiles will be plotted. 
Ibrutinib data from this study may also be combined with data from other studies performed with 
ibrutinib in subjects with hematologic malignancies as part of a population-PK analysis using 
nonlinear mixed effects models. For the population-PK analysis, covariates that could potentially 
correlate with plasma PK parameters will be evaluated. The results of the population-PK 
analyses (if performed) will be presented in a separate report. 
10.10 
Pharmacokinetic Analysis (MEDI4736)  
Individual MEDI4736 concentrations will be tabulated by dose cohort along with descriptive 
statistics. Individual and mean concentration-time profiles will be generated and included in the 
report. Pharmacokinetic parameters will be determined using standard non-compartmental 
methods. The following PK parameters will be determined after the first or steady-state dose: 
peak concentration (Cmax), trough concentration (Ctrough), time to peak concentration (Tmax) and 
area under the curve (AUC), as data allow. Accumulation to steady state will be assessed as the 
ratio of Cmax,ss:Cmax and Ctrough,ss:Ctrough. Descriptive statistics of non-compartmental PK 
parameters will be provided. 
10.11 
Immunogenicity Analyses 
Immunogenicity analyses will be performed by determining the anti-MEDI4736 response before 
and after after treatment with ibrutinib in combination with MEDI4736 at the time points 
outlined in Appendix 2.  
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10.12 
Pharmacodynamic Analyses  
Pharmacodynamic studies will be conducted to monitor both ibrutinib and MEDI4736 activity 
when co-administered. Blood samples will be collected at baseline and at selected time points 
outlined in Appendix 2. Pharmacodynamics assays for ibrutinib may include occupancy assays 
of BTK, ITK, or other targets in the blood or other relevant assays such as pITK/pPLCgamma in 
PBMCs. To monitor the activity of MEDI4736 after ibrutinib treatment, sPD-L1 will be 
evaluated at selected time points. 
10.13 
Biomarker Analyses  
Clinically relevant biomarkers may be associated with clinical responses. Changes in phenotypic, 
genetic/genomic and molecular biomarkers may be evaluated over the course of ibrutinib and 
MEDI4736 treatment and will be summarized by treatment cohort. Association between baseline 
levels and changes from baseline in selected biomarkers and their response to treatment will be 
explored. 
• Immune cell subsets in peripheral blood will be evaluated by immunophenotyping. 
• Secreted protein levels (ie, chemokines, cytokines) in serum or plasma will be evaluated. 
• Tumor biopsies will be evaluated for key target expression (eg, PD-L1) via IHC, and 
genomic analyses may be performed if there is sufficient material; other biomarkers that 
predict sensitivity or resistance to the drug combination may also be explored, including 
mutational analysis.   
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11. ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. 
11.1 
Definitions  
11.1.1 
Adverse Events (AE) 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
AEs may include, but are not limited to: 
• Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period.  
• Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• Pre-existing condition:  A pre-existing condition (documented on the medical history 
CRF) is not considered an AE, unless the severity, frequency, or character of the event 
worsens during the study period. 
• Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention. 
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However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE. 
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level. 
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances, are also not SAEs. 
• Diagnostic Testing and Procedures:  Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
11.1.2 
Serious Adverse Events 
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
• Results in death (ie, the AE actually causes or leads to death). 
• Is life-threatening. Life-threatening is defined as an AE in which the subject was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the Investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject or the 
subject may require intervention to prevent one of the other outcomes listed in this 
definition. Examples of such events are intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not result 
in hospitalization; or development of drug dependency or drug abuse. 
Given that the Investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the Investigator believes that 
the event is serious, the event will be considered serious. 
11.1.3 
Severity Criteria (Grade 1-5) 
Definitions found in the CTCAE v4.03 will be used for grading the severity (intensity) of AEs. 
The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for 
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each referenced AE. Should a subject experience any AE not listed in the CTCAE v4.03, the 
following grading system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
• Grade 5 (Death related to AE) – experiences which result in subject death 
11.1.4 
Causality (Attribution)  
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures. Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
11.2 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed. For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents. "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
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anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation. 
11.3 
Special Reporting Situations 
Special reporting situations on a Sponsor study that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• Overdose of any study drug 
• Suspected abuse/misuse of a study drug 
• Inadvertent or accidental exposure to a study drug 
• Medication error involving a product (with or without subject exposure to the study drug, 
eg, name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE 
is considered serious, it should be recorded on the AEs eCRF as serious and should be reported 
on the Serious Adverse Event Report Form. The SAE Report Form should be sent via email or 
fax to Pharmacyclics Drug Safety or designee within 24 hours of awareness. 
11.4 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
11.4.1 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 
laboratory test, or other means, will be recorded in the subject’s medical record and on the 
Adverse Event CRF and, when applicable, on the Serious Adverse Event Report Form. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken. 
11.4.2 
Adverse Event Reporting Period 
All AEs, whether serious or non-serious, will be 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. SAEs will be reported to the Sponsor from the 
time of ICF signing. Non-serious AEs will be recorded in the eCRF from the first dose of study 
drug until 30 days after the last dose of ibrutinib and 90 days following the last dose of 
MEDI4736. If both study drugs were discontinued at the same time, an SAE after 30 days and up 
to 90 days from the last dose of study drugs should indicate the causality for MEDI4736 only 
and N/A for ibrutinib (unless there is a causal relationship to ibrutinib).  
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SAEs reported after 30 days following the last dose of ibrutinib and 90 days following the last 
dose of MEDI4736 should also be reported if considered related to study drug. Resolution 
information after 30 days following the last dose of ibrutinib and 90 days following the last dose 
of MEDI4736 should be provided.  
Subjects who discontinued investigational product for unacceptable AEs will be followed until 
there is a return to the subject’s baseline condition, or until the Investigator considers that a 
clinically satisfactory resolution is achieved. Subjects will also be contacted to document any 
new onset AEs and follow any AEs that were ongoing at the time of investigational product 
discontinuation. 
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported (see Section 11.1.1). 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, the Investigator’s evaluation of its relationship to the study drug, and the event outcome. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to Sponsor 
instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of ibrutinib or 90 days after the last dose of 
MEDI4736, the death must be reported to the Sponsor as an SAE.  
11.4.3 
Expediting Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, within 
24 hours of the discovery of the event or information. Pharmacyclics may request follow-up and 
other additional information from the Investigator (eg, hospital admission/discharge notes and 
laboratory results). The contact information (phone, email and fax) for Pharmacyclics Drug 
Safety can be found on the Serious Adverse Event Report Form and instructions. 
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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to local regulations.  
The Investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.4.4 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 90 days after 
the last dose of study drug. Any female subjects receiving study drug(s) who become pregnant 
must immediately discontinue study drug. The Investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the fetus.  
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a subject or subject’s partner from the time of consent to 90 days 
after the last dose of study drug. Any occurrence of pregnancy must be recorded on the 
Pregnancy Report Form Part I and sent via email or fax to Pharmacyclics Drug Safety, or 
designee, within 24 hours of learning of the event. All pregnancies will be followed for outcome, 
which is defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus. 
For pregnancies with an outcome of live birth, the newborn infant will be followed until 30 days 
old by completing the Pregnancy Report Form Part II. Any congenital anomaly/birth defect 
noted in the infant must be reported as an SAE. 
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11.4.5 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall survival. Other 
malignancies will only be reported as an SAE if the event meets any serious adverse event 
reporting requirement listed under section “Serious Adverse Event” (otherwise captured as an 
AE in the eCRF). 
11.4.6 
Adverse Events of Special Interest (AESI) 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, 
within 24 hours of awareness.  
11.4.6.1. Major Hemorrhage 
Major hemorrhage is defined as: 
• Any Treatment-emergent hemorrhagic adverse event of Grade 3 or higher.*   
• Any Treatment-emergent serious adverse event of bleeding of any grade.  
• Any Treatment-emergent central nervous system hemorrhage/hematoma of any grade. 
* All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 
or higher AE per CTCAE. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.6 above. 
11.4.6.2. Pneumonitis 
Pneumonitis has been reported in association with use of anti-PD-L1/anti-PD-1 antibodies 
(Brahmer 2012). Initial work-up should include a high-resolution CT scan, ruling out infection, 
and pulse oximetry. Additional assessments are to include pulmonary function tests and blood 
gases. Pulmonary consultation is recommended.  
For Grade 2 pneumonitis that does not resolve to <Grade 1 within 3 days of maximal supportive 
care (including corticosteroids) or ≥Grade 3 pneumonitis, permanently discontinue MEDI4736. 
11.4.6.3. Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti PD-
L1 and anti-PD-1 antibodies (Brahmer 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of monoclonal antibodies can be 
caused by various mechanisms, including acute anaphylactic (IgE-mediated) and anaphylactoid 
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reactions against the monoclonal antibody, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include hypotension, 
dyspnoea, cyanosis, respiratory failure, urticaria, pruritis, angioedema, hypotonia, urticaria, 
arthralgia, bronchospasm, wheezing, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness. 
11.4.6.4. Hepatic Function Abnormalities (Hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer 2012). Inflammatory hepatitis has been reported in 3% to 9% of patients 
treated with anti CTLA-4 monoclonal antibodies (eg, ipilimumab). The clinical manifestations of 
ipilimumab-treated patients included general weakness, fatigue, nausea and/or mild fever and 
increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin. 
Cases where a subject shows AST or ALT ≥3 x ULN or total bilirubin ≥2 x ULN may need to be 
reported as SAEs. These cases should be reported as SAEs if after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. For potential Hy’s Law and Hy’s Law to be met, the elevation in transaminases must 
precede or be coincident with (ie, on the same day) the elevation in total bilirubin, but there is no 
specified time frame within which the elevations in transaminases and total bilirubin must occur.  
Criteria for Hy’s Law (FDA Guidance 2009): 
• The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo  
• Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of serum 
total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase)  
• No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; 
or another drug capable of causing the observed injury. 
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12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS  
12.1 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.  
12.2 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation. Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF.  
12.3 
Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as 
country-specific national regulations and/or local laws. The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.  
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail. This process must be documented in the subject’s source record. Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed. The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time. A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
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12.4 
Quality Control and Quality Assurance 
The Sponsor shall implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements. This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2008) and 
all revisions thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 
312, Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on 
GCP (ICH E6).  
12.5 
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 12.3), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific HIPAA consent may be used). The Investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Pharmacyclics and its 
designees, regulatory agencies, and IRBs/REBs/IECs. As the study Sponsor, Pharmacyclics will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization. It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject. If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be 
collected from the subject. Any data collected on the subject before withdrawal will be used in 
the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6 
Study Files and Record Retention 
The Investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study. For those subjects subsequently excluded 
from enrollment, the reason(s) for exclusion is to be recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 
transmitted to Pharmacyclics and notification of SAEs and related reports, source 
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documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time. Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics. Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party. If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
12.7 
Case Report Forms and Record Maintenance 
CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents). Authorized study site personnel (ie, listed on the Delegation of 
Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided. The Investigator will ensure that the CRFs are accurate, 
complete, legible, and completed within a reasonable period of time. At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The CRFs exist within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics or its authorized representative for this study. Study staff will be appropriately 
trained in the use of CRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system. Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail. The Investigator attests that the information contained in the CRFs is true 
by providing an electronic signature within the EDC system. After database lock, the 
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Investigator will receive a copy of the subject data (eg, paper, CD, or other appropriate media) 
for archiving the data at the study site. 
12.8 
Investigational Study Drug Accountability 
Ibrutinib and MEDI4736 used must be kept in a locked limited access room. The study drug 
must not be used outside the context of the protocol. Under no circumstances should the 
Investigator or other site personnel supply ibrutinib or comparator to other Investigators, 
subjects, or clinics, or allow supplies to be used other than as directed by this protocol without 
prior authorization from Pharmacyclics. 
Accountability records for ibrutinib and MEDI4736 must be maintained and be readily available 
for inspection by representatives of Pharmacyclics and are open to inspections by regulatory 
authorities at any time.  
An Investigational Drug Accountability Log must be used for drug accountability. For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study: 
1. Study identification number (PCYC-1136-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib dispensed and MEDI4736 administered for that subject 
4. Date and quantity of drug dispensed or administered 
5. Any unused ibrutinib returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements. If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative for return of unused 
investigational product. Before disposal/destruction, final drug accountability and reconciliation 
must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
12.9 
Study Monitoring/Audit Requirements 
Representatives of Pharmacyclics or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. 
The purpose of monitoring is to ensure that the study is conducted in compliance with the 
protocol, standard operating procedures (SOPs), and other written instructions and regulatory 
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guidelines, and to ensure the quality and integrity of the data. This study is also subject to 
reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study. However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics, its designated agents and 
authorized employees of the appropriate Regulatory Authority to inspect the facilities used in 
this study and, for purposes of verification, allow direct access to the hospital or clinic records of 
all subjects enrolled into this study. A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. 
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation. 
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
12.10 
Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical trial research agreement 
and the Statement of Investigator Form FDA 1572, both of which are signed by the Investigator 
before commencement of the study. In summary, the Investigator will conduct the study 
according to the current protocol; will read and understand the IB; will obtain IRB/REB/IEC 
approval to conduct the study; will obtain informed consent from each study participant; will 
maintain and supply to the Sponsor or designee, auditors and regulatory agencies adequate and 
accurate records of study activity and drug accountability for study-related monitoring, audits, 
IRB/REB/IEC reviews and regulatory inspections; will report SAEs to the Sponsor or designee 
and IRB/ REB/IEC according to the specifics outlined in this protocol; will personally conduct or 
supervise the study; and will ensure that colleagues participating in the study are informed about 
their obligations in meeting the above commitments. 
12.11 
Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulations of the country in which the research is conducted. In summary, 
the Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
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Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug. 
The study is being conducted by Pharmacyclics, Inc. in collaboration with partner companies, 
AstraZeneca and Janssen Research & Development, LLC (JRD), involved and informed in the 
execution of the study. When the Sponsor is engaged in making decisions  regarding the 
combination of ibrutinib and MEDI4736 (eg, dose level selection, patient safety), the partner 
company AstraZeneca will have access to the data and actively participate in those decisions. 
12.12 
Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each Investigator and Subinvestigator (as designated on the Form FDA1572) will 
provide a personally signed Financial Disclosure Form in accordance with § 21 CFR 54. Each 
Investigator will notify Pharmacyclics or its authorized representative of any relevant changes in 
financial disclosure information during the conduct of the study and for 1 year after the study has 
been completed. 
12.13 
Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, Pharmacyclics 
will reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury which is not covered by the subject’s medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the Investigator/ 
study staff. The ICF will include a description of this reimbursement policy, incorporating 
country-specific national regulations and/or local laws. Financial compensation for lost wages, 
disability or discomfort due to the study is not available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
12.14 
Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document. 
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF. Written documentation of IRB/REB/IEC and required site approval must be received 
by Pharmacyclics before the amendment may take effect at each site. Additionally under this 
circumstance, information on any change in risk and/or change in scope must be provided to 
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subjects already actively participating in the study, and they must read, understand and sign each 
revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and 
Pharmacyclics. 
12.15 
Publication of Study Results 
Pharmacyclics may use the results of this clinical study in registration documents for Regulatory 
Authorities in the US or abroad. The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an Investigator. In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient time to 
make appropriate comments before submission for publication. 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results. The Medical Monitor, study 
director and/or lead statistician may also be included in the list of authors. This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions. 
12.16 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, both 
the Sponsor and the Investigator will arrange discontinuation procedures. In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
 
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relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Annals of 
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44. Martinez AE, Lin L, Dunphy CH. Grading of follicular lymphoma: comparison of routine histology 
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in indolent follicular lymphomas: a study of the cancer and leukemia group Br J Clin Oncol. 
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of heavily pretreated non-Hodgkin's lymphoma patients : A multicenter retrospective study on behalf 
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(Bexxar)/carmustine, etoposide, cytarabine, melphalan (BEAM) vs rituximab/BEAM and autologous 
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80. Younes A, Thieblemont C, Morschhauser F, et al. Combination of ibrutinib with rituximab, 
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14. APPENDICES 
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Appendix 1. Schedule of Assessments for Phase 1b and Phase 2 
Study Visits 
Screening 
Treatment Phase (1 Cycle = 28 Days) 
Post-treatment Phase 
 
 
Ibrutinib 
Lead-in 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluation 
Treatment 
Termination
(optional) 
End-of-Treatment 
Response 
FU  
(Until PD) 
Survival 
FU  
(Post-PD) 
ibrutinib 
MEDI4736 
 
 
D1 
Base-
line 
D2 D6 
or 
D7 
D1 D8 D15 D22 
 
D1 D15 D1 D15 D1 
D15 
At C3D1, 
C6D1, 
C9D1, 
C12D1 
& q6 cycles 
thereafter 
At time 
of PD, 
ideally 
4-24 h 
post last 
dose  
30 d from 
last ibr 
dose or 
before 
next 
therapy 
90 d from 
last MEDI 
dose or 
before next 
therapy  
 Q12 
weeks 
from last 
CT/MRI 
 Q12 
weeks 
from last 
dose 
Visit Window -28 days 
NA 
±2 days 
-2d 
±2 days 
-7 days 
NA 
±7 days 
±7 days 
±7 d 
±7 d 
Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
(Inclusion/exclusion criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
Xb 
 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
Xb 
 
X 
X 
X 
 
 
Vital signsa and weight (height 
only at screening)  
X 
X 
 
 
X 
X X 
X 
X 
X 
X 
X 
X 
Xb 
 
X 
X 
X 
 
 
Buccal swab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate and biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required 
for CR 
 
 
Tumor Biopsy i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional at progression 
 
12-lead ECG (triplicate) – See 
Section 7.1.3.1 for details 
X 
Xj 
 
 
Xc 
 
 
 
 
 
Xj 
 
C5D1 
onlyc 
 
 
 
X 
 
 
 
Prior and concomitant 
medications 
Continuous from ICF or 14 days prior the first dose of study drug (whichever is greater) 
 to 30 days after last dose of ibrutinib/90 days after last dose of MEDI4736 
 
 
Adverse events 
 
Continuous from ICF to 30 days after last dose of ibrutinib and 90 days after last dose of MEDI4736 
 
 
Hematology 
X 
X 
 
 
X 
X X 
X 
X 
X 
X 
Xd 
Xg 
 
 
X 
X 
X 
 
 
Serum chemistry 
X 
X 
 
 
X 
X X 
X 
X 
X 
X 
Xd 
Xg 
 
 
X 
X 
X 
 
 
TSH (see Section 7.1.2.3 if abnl) 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Xg 
 
 
 
 
X 
 
 
Coagulation (PT, PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologies, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum at 
screening, urine at f/u) 
X 
X 
 
 
For women of childbearing potential 
Q4 weeks from C1D1- C12D1, then Q3 cycles (±2 days) 
 
 
 
 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
 
 
 
 
Xf 
 
 
 
 
X 
 
 
PET scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
To confirm 
CR 
X (if 
needed) 
 
 
X (if 
needed) 
 
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Study Visits 
Screening 
Treatment Phase (1 Cycle = 28 Days) 
Post-treatment Phase 
 
 
Ibrutinib 
Lead-in 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluation 
Treatment 
Termination
(optional) 
End-of-Treatment 
Response 
FU  
(Until PD) 
Survival 
FU  
(Post-PD) 
ibrutinib 
MEDI4736 
 
 
D1 
Base-
line 
D2 D6 
or 
D7 
D1 D8 D15 D22 
 
D1 D15 D1 D15 D1 
D15 
At C3D1, 
C6D1, 
C9D1, 
C12D1 
& q6 cycles 
thereafter 
At time 
of PD, 
ideally 
4-24 h 
post last 
dose  
30 d from 
last ibr 
dose or 
before 
next 
therapy 
90 d from 
last MEDI 
dose or 
before next 
therapy  
 Q12 
weeks 
from last 
CT/MRI 
 Q12 
weeks 
from last 
dose 
Visit Window -28 days 
NA 
±2 days 
-2d 
±2 days 
-7 days 
NA 
±7 days 
±7 days 
±7 d 
±7 d 
CT/MRI scan, also as clinically 
indicated 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X (if 
needed) 
 
 
X 
 
Response assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
Survival status and subsequent 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ibrutinib PK  
 
See Appendix 2 for schedule 
 
 
 
 
 
 
Ibrutinib biomarkers and 
pharmacodynamics 
X 
 
See Appendix 2 for schedule 
At CR 
and/or 
progression 
X 
X 
 
 
 
MEDI4736 PK and 
pharmacodynamics 
 
 
 
 
See Appendix 2 for schedule 
 
X 
 
X 
 
 
Study Drug Administration 
In-clinic administration of 
MEDI4736 (give prior to 
ibrutinib daily dose) 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Xe 
Xe 
 
 
 
Dispense ibrutinib & diary card 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
Xg 
 
 
 
 
In-clinic administration of 
ibrutinib 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Xg 
Xe 
 
 
 
abnl = abnormal, C = cycle, CR = complete response, CT = computed tomography, D or d = day(s), d/c = discontinuation, ECG = electrocardiogram, FU = follow-up, ibr = ibrutinib,  
h = hours, ICF = informed consent form, INR = international normalized ratio, MRI = magnetic resonance imaging, NA = not applicable, PD = progressive disease;  
PK = pharmacokinetics, PT = prothrombin time, PTT = partial thromboplastin time, TSH = thyroid stimulating hormone 
Footnotes: 
a. Vital signs: On MEDI4736 infusion days, vital signs will be measured within 30 minutes prior to the start of MEDI4736 infusion, every 30 minutes (±5 minutes) during MEDI4736 
infusion, and at the end-of- infusion of MEDI4736 (+5 minutes). On C1D1, vital signs will also be measured at 30 minutes (±5 minutes), 60 minutes (±5 minutes), and 2 hours 
(± 15 minutes) post end-of- infusion of MEDI4736. On C1D1, an additional 2-hour (±15 minutes) post MEDI4736 end-of-infusion ECG will be performed. 
b. And at Day 1 and Day 15 for every cycle thereafter. The Day 15 visits can be discontinued at the end of treatment with MEDI4736.  
c. To be performed within 30 minutes prior to start of MEDI4736 infusion and within 3 hours after end of MEDI4736 infusion 
d. After Cycle 3, Day 15 hematology and chemistry laboratories can be obtained if clinically indicated 
e. And at every cycle to Cycle 12 as long as MEDI4736 is administered 
f. And at every 3 cycles through Cycle 12 
g. And at every cycle through Cycle 12, then at every 3 cycles thereafter 
h. And at every cycle thereafter in the Treatment phase 
i. Earlier archived tumor tissue from all enrolled subjects will also be requested.  
j. Triplicate ECGs to be performed predose and at approximately 2 hours post ibrutinib dose
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Appendix 2.  Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, and 
Biomarkers: Phase 1b and Phase 2 
Timepointa 
Ibrutinib 
PK 
Ibrutinib 
Biomarker/ 
Pharmacodynamics f 
MEDI4736 
PK 
MEDI4736 
Pharmacodynamics 
Screening 
 
X 
 
 
Ibrutinib 
Lead-in 
Day 1 
Predose 
Xg 
X 
 
 
1 hr post dose (±15 min) 
X 
 
 
 
2 hr post dose (±15 min) 
Xg 
 
 
 
4 hr post dose (±30 min) 
X 
X 
 
 
6 hr post dose (±1 hr) 
X 
 
 
 
Day 2 
Predose 
Xb 
Xb 
 
 
Day 6 
or 7 
Predose 
Xc 
Xc 
 
 
1 hr post dose (±15 min) 
X 
 
 
 
2 hr post dose (±15 min) 
X 
 
 
 
4 hr post dose (±30 min) 
X 
 
 
 
6 hr post dose (±1 hr) 
X 
 
 
 
Cycle 1 
Day 1 
Predose 
 
X 
X 
X (includes ADA) 
10 min (±5 min) after 
end of infusion 
 
 
X 
X (Collected after 
ibrutinib dose 
taken) 
Day 
15 
Predose 
 
X 
X 
X 
4 hr post ibrutinib dose 
(± 30 min) 
 
X 
 
 
Cycle 2 
Day 1 
Predose 
 
X 
X 
X (includes ADA) 
10 min (±5 min) after 
end of MEDI infusion 
 
 
X 
 
Day 
15 
Predose 
 
X 
 
 
 
Cycle 3 
Day 1 
Predose  
Xe, g 
Xe 
X 
X (includes ADA) 
10 min (±5 min) after 
end of MEDI infusion 
 
 
X 
 
1 hr post ibrutinib dose 
(±15 min) 
X 
 
 
 
2 hr post ibrutinib dose 
(±15 min) 
Xg 
 
 
 
4 hr post ibrutinib dose 
(±30 min) 
X 
 
 
 
6 hr post ibrutinib dose 
(±1 hr) 
X 
 
 
 
Day 15 Predose 
 
X 
 
 
Cycle 4 
Day 1 
Predose 
 
X 
 
 
 
 
Cycle 5 
Day 1 
Predose 
 
X 
 
 
 
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Timepointa 
Ibrutinib 
PK 
Ibrutinib 
Biomarker/ 
Pharmacodynamics f 
MEDI4736 
PK 
MEDI4736 
Pharmacodynamics 
Cycle 6 
Day 1 
Predose 
 
X 
X 
X (includes ADA) 
10 min (±5 min) after 
end of infusion 
 
 
X 
 
Cycle 7 and 
then q2 
cycles until 
CR, then q3 
cycles 
thereafter 
Day 1 
Predose 
 
X 
 
 
Cycle 9 and 
q3 cycles 
thereafter 
Day 1 
Predose 
 
X 
X 
X (includes ADA) 
10 min (±5 min) after 
end of infusion 
 
 
X 
 
Treatment 
Termination 
(optional) 
 
At time of PD prior to 
treatment d/c 
 
X 
X 
X 
End-of-
Treatment: 
after last 
ibrutinib 
dose 
30 
days 
post 
dose 
±7 days 
 
X (unless if already 
obtained within last 
7 days) 
 
 
End-of-
Treatment: 
after last 
MEDI 4736 
dose 
90 
days 
post  
dose 
±7 days 
 
 
X 
X (includes ADA) 
Abbreviations: ADA = anti-drug antibodies; d/c = discontinuation; ibr = ibrutinib; CR = complete response; PD = 
progressive disease; PK = pharmacokinetics 
 
 
Footnotes: 
a. Record actual time of sample collection. 
b. Sample collected 24 hours (±2 hours) after the ibrutinib lead-in Day 1 dose and prior to ibrutinib dosing on Day 2 
c. Sample collected 24 hours (±2 hours) after the ibrutinib lead-in Day 5 dose and prior to ibrutinib dosing on Day 6, OR after the 
Day 6 dose and prior to ibrutinib dosing on Day 7, whichever is the PK collection day 
d. Sample collected 24 hours (±2 hours) after the Cycle 1 Day 7 (C1D7) dose and prior to ibrutinib dosing on C1D8 
e. Sample collected 24 hours (±2 hours) after the C2D28 dose and prior to ibrutinib dosing on C3D1 
f. Includes MRD evaluation 
g. Perform triplicate ECGs at predose and approximately 2 hours post ibrutinib dose to correspond with the ibrutinib PK blood 
draws (see Appendix 1) 
 
 
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Appendix 3. ECOG Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html. Accessed January 4, 2008. 
 
 
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Appendix 4. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. A comprehensive list of inhibitors can 
be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed below. 
Refer to Section 6.2.1 on instructions for concomitant use of CYP3A inhibitors and inducers with 
ibrutinib. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
INDINAVIR 
Efavirenz 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Aprepitant 
St. John’s Wort 
Erythromycin 
Troglitazone 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 
NOT azithromycin 
 
Chloramphenicol 
 
Boceprevir 
 
Ciprofloxacin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
star fruit 
 
Telaprevir 
 
Troleandomycin 
 
Voriconazole 
 
Source: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
 
 
 
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Appendix 5. Revised Criteria for Response Assessment of Malignant Lymphoma 
(Cheson 2014) 
The following table provides a summary of response criteria for malignant lymphoma according 
to Cheson (2014). Please refer to published international guidelines for the most recent and 
complete details. 
 
Table 6.1: 
Criteria for Response Assessment of Non-Hodgkin’s Lymphoma 
Response 
Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Response 
(CR) 
Lymph nodes 
and 
extralymphatic 
sites 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
Score 1, 2, or 3a, b with or without a residual 
mass on 5PSb 
 
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, complete 
metabolic response may be inferred if uptake 
at sites of initial involvement is no greater 
than surrounding normal tissue even if the 
tissue has high physiologic uptake 
Target nodes/nodal masses 
must regress to ≤1.5 cm in LDi 
 
No extralymphatic sites of 
disease 
Non measured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
determinate, IHC negative 
Partial 
Response 
(PR) 
Lymph nodes 
and 
extralymphatic 
sites 
Partial metabolic response 
Partial remission (all of the 
following) 
Score 4 or 5b with reduced uptake compared 
with baseline and residual mass(es) of any 
size 
 
At interim, these findings suggest 
responding disease 
 
At end of treatment, these findings indicate 
residual disease 
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
 
When a lesion is too small to 
measure on CT, assign 5 mm × 
5 mm as the default value 
 
When no longer visible, 0 × 0 
mm 
For a node >5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured 
lesion 
Not applicable 
Absent/normal, regressed, but 
no increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by 
>50% in length beyond normal 
New lesions 
None 
None 
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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
No response 
or  
stable disease 
(SD) 
Lymph nodes 
and 
extralymphatic 
sites 
No metabolic response 
Stable disease 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment 
<50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Non measured 
lesion 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease (PD) 
Individual target 
nodes/nodal 
masses 
Progressive metabolic disease 
Progressive disease requires at 
least 1 of the following. 
 
PPD progression: 
An individual node/lesion must 
be abnormal with: 
• 
LDi >1.5 cm AND 
• 
Increase by ≥50% from 
PPD nadir AND 
• 
An increase in LDi or SDi 
from nadir: 
       0.5 cm for lesions ≤2 cm; 
       1.0 cm for lesions >2 cm 
In the setting of splenomegaly, 
the splenic length must increase 
by >50% of the extent of its 
prior increase beyond baseline 
(eg, a 15-cm spleen must 
increase to >16 cm). If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline 
New or recurrent splenomegaly 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or meets criteria 
below for new FDG-avid foci 
Extranodal 
lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
Non measured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured 
lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously 
resolved lesions 
A new node >1.5 cm in any 
axis 
A new extranodal site >1.0 cm 
in any axis; if <1.0 cm in any 
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Response 
Site 
PET-CT-Based Response 
CT-Based Response 
axis, its presence must be 
unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.  
 
 
Footnotes: 
a: A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be 
no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or 
myeloid growth factors).  
 
b: PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
 
 
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Appendix 6. New York Heart Association (NYHA) Functional Classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort increases. 
 
Reference:  
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256. 
 
 
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Appendix 7. Contraception Requirements for MEDI4736 
• Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use 2 methods of effective contraception from screening, and must agree to 
continue using such precautions for 90 days after the final dose of investigational 
product; cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. 
• Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as ≥60 years old and no menses for ≥1 year without an 
alternative medical cause). 
• Subjects must use 2 acceptable methods of effective contraception as described in the 
table below. 
• Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see Table below) 
from Day 1 and for 90 days after receipt of the final dose of investigational product. 
 
 
Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus 
spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone T 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) 
Combined pill 
Minipill 
Patch 
 
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SAP_001.pdf: 
 
PCYC-1136-CA 
Statistical Analysis Plan 
Page 1 of 18 
 
Version 1.0   Proprietary and Confidential                                                                       10 January 2018 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
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 
 
Protocol PCYC-1136-CA; Phase 1b/2 
 
Prepared by:  Shanhong Guan 
 
10 January 2018 
Version 1.0 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed 
consent, or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed 
that this information is privileged and confidential and that it should not be further disclosed. 
 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................3 
1. 
INTRODUCTION ..................................................................................................................5 
1.1. 
Study Design ..................................................................................................................5 
1.2. 
Endpoints .......................................................................................................................8 
1.3. 
Statistical Hypotheses ....................................................................................................9 
1.4. 
Sample Size Determination............................................................................................9 
1.5. 
Planned Analyses .........................................................................................................10 
1.5.1. Phase 1b Analyses ..........................................................................................10 
1.5.2. Phase 2 Analyses ............................................................................................10 
1.6. 
Testing Procedure and Level of Significance ..............................................................11 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................11 
2.1. 
Analysis Sets ................................................................................................................11 
2.2. 
Definition of Subgroups ...............................................................................................12 
3. 
SUBJECT INFORMATION................................................................................................12 
3.1. 
Subject Disposition ......................................................................................................12 
3.2. 
Demographics and Baseline Characteristics ................................................................12 
3.3. 
Prior and Concomitant Medications ............................................................................12 
3.4. 
Extent of Exposure to Study Treatment .......................................................................13 
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies ......................13 
4. 
EFFICACY AND SAFETY ANALYSES ...........................................................................13 
4.1. 
Efficacy Analyses ........................................................................................................13 
4.2. 
Safety Analyses ............................................................................................................15 
5. 
MODIFICATION OF ANALYSIS TO THE PROTOCOL .............................................17 
6. 
REFERENCES .....................................................................................................................17 
 
 
LIST OF TABLES 
Table 1 Summary of Efficacy Analyses ........................................................................................14 
Table 2 Summary of Safety Analyses  ...........................................................................................16 
 


 
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LIST OF ABBREVIATIONS 
ABC 
Activated B-cell  
AE(s) 
adverse event(s) 
BTK 
Bruton’s tyrosine kinase 
CNS 
central nervous system 
CR 
complete remission (response) 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity  
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FL 
follicular lymphoma 
GCB 
germinal center B cell-like 
GCP 
Good Clinical Practice 
GEP 
gene expression profile 
HDT/ASCT 
high-dose chemotherapy with autologous stem cell support 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
Ig 
Immunoglobulin 
IHC 
immunohistochemisty  
IND 
Investigational New Drug 
INR 
international normalized ratio 
IV 
Intravenous 
LLN 
low limit of normal 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEDI4736 
durvalumab 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 


 
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MTD 
maximum tolerated dose 
NHL 
non-Hodgkin’s lymphoma 
Non-GCB 
Non-Germinal Center B-cell like 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
Progression-free survival 
 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
RP2D 
partial remission (response) 
recommended phase 2 dose 
PT 
prothrombin time 
QTc 
corrected QT interval 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
standard international units 
SOC 
system organ class 
ULN 
upper limit of normal 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) lays out key elements including definitions and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1136-CA study. 
Analyses of pharmacokinetics data and biomarkers will be addressed in separate documents.  
1.1. 
Stud y Design 
This is a Phase 1b/2, open-label multi-center study to assess the safety and efficacy of ibrutinib 
in combination with MEDI4736 in subjects with relapsed or refractory lymphomas. A 6+3 de-
escalation design will be employed in Phase 1b to assess doses of ibrutinib in combination with 
MEDI4736 to determine the recommended Phase 2 dose (RP2D) for this study.  
Phase 1b: 
In the safety portion of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of 
MEDI4736 will be explored in Cohort 1 and will follow a 6+3 dose de-escalation design 
including a sentinel subject with at least a 3-day observation period in each Phase 1b dosing 
cohort prior to dosing additional subjects to monitor for any unexpected acute or overlapping 
toxicities.  
Subjects with one of the following two tumor types will be eligible for enrollment in Phase 1b: 
• 
Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• 
Diffuse large B cell lymphoma (DLBCL) 
In cohort 1, ibrutinib will be administered orally (PO) daily in 6 subjects at a dose of 560 mg in 
combination with MEDI4736 at a dose of 10 mg/kg intravenously (IV) every 2 weeks in 28-day 
cycles for 12 months or until unacceptable toxicity or disease progression occurs.  
As a lead-in to the first cycle, ibrutinib will be given for 7 days prior to starting MEDI4736 in 
order to obtain single agent PK and biomarker samples that will be compared to combination 
therapy. Per the protocol, the 7-day lead-in period of ibrutinib is not part of the dose-limiting 
toxicity (DLT) evaluation period. The DLT assessment will occur from Day 1 of Cycle 1 of the 
combination therapy until the laboratory evaluations on Day 1 of Cycle 2 (28 days). If the 
subject incidence of DLTs from Day 1 of Cycle 1 of combination therapy to the laboratory 
evaluations on Day 1 of Cycle 2 is <33.3% (ie, ≤1 of 6 or ≤2 of 9 subjects with a DLT), this dose 
level will be considered safe to proceed to Phase 2, and will be defined as the RP2D. If 2 
subjects within the initial cohort of 6 subjects experience a DLT, an additional 3 subjects will be 
enrolled at the same dose level. If 3 or more of 6-9 subjects experience a DLT, dose de-
escalation will occur. A similar 6+3 cohort design will be utilized in the de-escalation cohorts. 
De-escalation cohorts -1A and -1B will be opened simultaneously to determine which dosing 
schedule is most appropriate for the Phase 2 portion of the study (for cohort definitions, see 


 
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section 4.2: Study Treatment). Determination will be based on the safety profile of the 2 
treatment regimens. If necessary, the dose de-escalation cohort -2 will be enrolled thereafter.  
The Phase 1b DLT observation period will occur from Day 1 of Cycle 1 of ibrutinib in 
combination with MEDI4736 treatment until the laboratory evaluations on Day 1 of Cycle 2 
which will occur before the MEDI4736 infusion on Day 1 of Cycle 2. A DLT is an AE at least 
possibly related to study drug(s) defined as: 
Any Grade 3 or higher non-hematologic AE (with additional clarifications below) 
• 
Grade 3 or higher nausea, vomiting, or diarrhea (non-colitis-related) that is uncontrolled by 
maximal supportive care and persists for >7 days would be considered a DLT 
• 
Grade 3 fatigue that persists for >7 days would be considered a DLT 
• 
Any Grade 3-immune related adverse event (irAE) that does not downgrade to Grade ≤2 
within 3 days after onset of the event despite maximal supportive care including systemic 
corticosteroids, or does not downgrade to Grade ≤1 or baseline within 14 days would be 
considered a DLT 
• 
Any Grade ≥2 pneumonitis that does not resolve to Grade ≤1 within 3 days of the initiation 
of maximal supportive care would be considered a DLT. 
• 
The DLT definition excludes the following conditions: 
o Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the subject is asymptomatic 
o Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.)  
o Vitiligo or alopecia of any AE grade would not be considered a DLT 
Clinically relevant hematologic AE such as: 
• 
Grade 3 or 4 neutropenia (ANC<1,000/ mm3) lasting >7 days 
• 
Febrile neutropenia (Grade 3 or 4 neutropenia with fever ≥38.3ºC) 
• 
Grade 3 or 4 thrombocytopenia (<25,000/ mm3) lasting >7 days or requiring transfusion or 
associated with Grade ≥2 bleeding 
• 
Any other Grade 4 hematologic AE, except lymphopenia 
During the Phase 1b DLT observation period of ibrutinib in combination with MEDI4736, 
subjects will be replaced for any of the following reasons: 
• 
Missed 5 consecutive doses of ibrutinib or missed 7 total doses (not due to DLT) 
• 
Missed dose of MEDI4736 or received the MEDI4736 dose outside of the protocol-allowed 
window (±2 days) (not due to DLT) 
• 
Study drug discontinuation for any reason other than DLT  


 
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After the RP2D of ibrutinib in combination with MEDI4736 is defined, enrollment in Phase 2 
will commence. 
Phase 2: 
Two tumor types will be enrolled in separate cohorts as part of this protocol: 
• 
Follicular lymphoma (FL) (grade 1, 2, or 3A) 
• 
Diffuse large B cell lymphoma (DLBCL) 
For FL: n = 39 
The FL cohort will enroll 39 response-evaluable subjects. An interim analysis will be performed 
after 19 subjects are evaluable for tumor response after completing at least 1 response 
assessment. If only 6 or fewer responders (≤6/19) are observed, the Sponsor may consider 
discontinuation of this cohort; however, assessment of biomarkers (that may aid in prospective 
enrichment of responders) or tumor measurements (showing clinically relevant tumor reductions, 
ie, 40%, that fit the criteria for SD) may support continued enrollment.   
For DLBCL: n = 34 
Subjects with germinal center B-cell (GCB) and non-GCB subtypes will be enrolled at a 1:1 ratio 
approximately. The DLBCL cohort will enroll 34 response-evaluable subjects. An interim 
analysis will be performed after 9 subjects are evaluable for tumor response after completing at 
least 1 response assessment. If only 1 or fewer responder (≤1/9) is observed, the Sponsor may 
consider discontinuation of this cohort; however, assessment of biomarkers (that may aid in 
prospective enrichment of responders) or tumor measurements (showing clinically relevant 
tumor reductions, ie, 40%, that fit the criteria for SD) may support continued enrollment. 
In the DLBCL cohort, additional prospectively identified non-GCB subjects may be enrolled if a 
22% ORR (2/9) is not achieved at the interim analysis in the unselected DLBCL population so 
that at least a total of 16 subjects with the non-GCB subtype are evaluated.  
Note: The Phase 2 subjects include all of those response-evaluable subjects treated at R2PD in 
Phase 1b but with tumor type as defined for Phase 2. 
During the Phase 2 portion of the study, if a subject discontinues study drug prior to the first 
tumor response assessment for reasons other than progressive disease, the subject may be 
replaced. 
The primary analysis will occur at least 12 months after the last FL subject is enrolled and at 
least 9 months after the last DLBCL subject is enrolled. 
Dosing of ibrutinib in combination with MEDI4736 will continue for a total of 12 cycles of 
therapy if the subject is deriving clinical benefit (CR, PR, or SD) and the subject is not 
experiencing unacceptable toxicity. After 12 cycles, dosing of ibrutinib alone will continue as 


 
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long as clinical benefit is seen without safety concerns or disease progression. Response 
evaluations will occur on Day 1 of Cycle 3 and then after every 3rd cycle through the 1st year 
and after every 6th cycle thereafter. Assessment will follow the Revised Criteria for Response 
Assessment of Malignant Lymphoma (Cheson 2014) using CT criteria.  
In order to accommodate the potential for immune flare (pseudoprogression), treatment with 
MEDI4736 and ibrutinib may continue between the initial assessment of suspected progression 
and confirmation of progression. Subjects with presumed progressive disease (PD) who, in the 
Investigator’s opinion, continue to receive clinical benefit from their treatment may continue to 
receive MEDI4736 and ibrutinib as dictated in the protocol after consultation with the Sponsor 
and at the Investigator’s discretion. In the absence of clinically significant deterioration, a CT 
scan or biopsy may be performed at least 4 weeks later to confirm PD. If PD is confirmed at the 
later time point, PD should be assigned to the prior time point at which PD criteria were also 
met. MEDI4736 and ibrutinib should be discontinued if there is confirmed PD per Revised 
Criteria for Response Assessment of Malignant Lymphoma (Cheson 2014) or other clinical data 
suggest clear evidence of progression.  
Subjects are required to undergo a pre-treatment tumor biopsy for all phases of this study; a post-
progression biopsy is recommended but will be optional. 
  
1.2. 
Endpoints 
Primary Endpoints 
Phase 1b: 
• 
Recommended Phase 2 Dose (RP2D) of ibrutinib in combination with MEDI4736 
• 
Safety and tolerability of ibrutinib in combination with MEDI4736   
Phase 2: 
• Overall Response Rate (ORR) 
 
Secondary Endpoints 
Phase 1b: 
• 
Overall response rate (ORR) 
• 
Duration of response (DOR) 
 


 
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Phase 2:  
• 
DOR  
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
 
Safety Assessments  
Safety and tolerability assessments include adverse events, clinical laboratory tests, and vital 
signs.  
 
1.3. 
Stat istical Hyp otheses 
There is no hypothesis testing for Phase1b. The primary objective of Phase 2 is to evaluate overall 
response rate (ORR) for the combination therapy at RP2D. Hypothesis testing will be conducted 
to address this objective as follows: 
Null hypothesis (H0):            P <= x%; where P denotes overall response rate. 
Alternative hypothesis (Ha): P >= y%; where P denotes overall response rate. 
For FL cohort, a true response rate of 30% (H0) versus 50% (Ha) will be tested. For DLBCL 
cohort, a true response rate of 15% (H0) versus 35% (Ha) will be tested.  
1.4. 
Sample Size Determination  
Phase 1b: 
6-36 subjects for DLT assessment (6-9 subjects in up to 4 dose de-escalation cohorts, regardless 
of tumor type). 
Phase 2:  
Approximately 73 response-evaluable subjects (including those subjects treated at the RP2D in 
Phase 1b but with tumor type as defined for Phase 2). 
For FL: 
A maximum of 39 response-evaluable subjects (including those subjects treated at the RP2D in 
Phase 1b and with tumor type of FL) will be enrolled. An interim analysis will be performed 
after 19 subjects are evaluable for tumor response after completing at least 1 response 
assessment. If only 6 or fewer responders (≤6/19) are observed, the Sponsor may consider 
discontinuation of this cohort.  


 
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The null hypothesis that the true ORR is 30% will be tested against a one-sided alternative that 
the ORR is 50%. The null hypothesis will be rejected if 17 or more responses are observed in the 
39 subjects. This design yields a 1-sided type I error rate of 0.05 and power of 80% when the 
true ORR is 50%. This statistical design including number of subjects and number of responders 
follows the statistical framework of Simon’s minimax two-stage design (Simon, 1989). 
Enrollment will continue while the interim analysis is performed. 
For DLBCL: 
A maximum of 34 response-evaluable subjects with GCB and non-GCB (inclusive of subjects 
treated at the RP2D in Phase 1b in the unselected DLBCL population) will be enrolled at a 1:1 
ratio approximately.  
An interim analysis will be performed after 9 subjects are evaluable for tumor response after 
completing at least 1 response assessment. If only 1 or fewer responder (≤1/9) is observed, the 
Sponsor may consider discontinuation of this cohort.   
The null hypothesis that the true ORR is 15% will be tested against a one-sided alternative that 
the ORR is 35%. The null hypothesis will be rejected if 9 or more responses are observed in the 
34 subjects. This design yields a 1-sided type I error rate of 0.05 and power of 80% when the 
true ORR is 35%. This statistical design including number of subjects and number of responders 
follows the statistical framework of Simon’s optimal two-stage design (Simon 1989). Enrollment 
will continue while the interim analysis is performed. 
  
1.5. 
Planned Analyses 
1.5.1. 
Phase 1b Analyses 
A Dose Level Review Committee will be established to evaluate the safety data from each cohort 
of the Phase 1b on an ongoing basis. Dose de-escalation will follow the 6+3 design described in 
Section 3.1.1 and up to 4 cohorts including 3 dose de-escalation cohorts (1, -1A, -1B, and -2) 
will be enrolled if needed to determine the RP2D for the combination therapy. 
1.5.2. 
Phase 2 Analyses 
An interim analysis is planned for each tumor type:  
An interim analysis for FL will be performed after 19 subjects are evaluable for tumor response 
after completing at least 1 response assessment. If only 6 or fewer responders (≤6/19) are 
observed, the Sponsor may consider discontinuation of this cohort; however, assessment of 
biomarkers (that may aid in prospective enrichment of responders) or tumor measurements 
(showing clinically relevant tumor reductions, ie, 40%, that fit the criteria for SD) may support 
continued enrollment. 


 
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An interim analysis for DLBCL will be performed after 9 subjects are evaluable for tumor 
response after completing at least 1 response assessment. If only 1 or fewer responder (≤1/9) is 
observed, the Sponsor may consider discontinuation of this cohort; however, assessment of 
biomarkers (that may aid in prospective enrichment of responders) or tumor measurements 
(showing clinically relevant tumor reductions, ie, 40%, that fit the criteria for SD) may support 
continued enrollment. 
The primary efficacy analysis will occur at least 12 months after the last FL subject is enrolled 
and at least 9 months after the last DLBCL subject is enrolled. 
1.6. 
Testing Procedure and Level of Significance 
The 2-sided significance level for the final analysis of primary endpoint (ORR) will be 0.05.  
Analyses of secondary endpoints will be performed using the same significance level.  
2. GENERAL ANALYSIS CONSIDERATION 
Time to event or duration of event endpoints will be based on the actual event date (or censoring 
date) rather than visit number or visit label. Missing efficacy or safety data will not be imputed 
unless otherwise specified. 
In general, the baseline value is defined as the last valid measurement on or prior to the first dose 
of study treatment. For by-visit analysis, visit windows will be used to associate assessment with 
a scheduled visit and will be created in reference to the date of first dose of study treatment to 
assign visit number based on assessment date. 
2.1. 
Analysis Sets 
Response-evaluable Population 
The Response-evaluable Population is defined as all enrolled subjects who received at least one 
dose of study treatment (ibrutinib or MEDI4736) and provided at least one post-baseline 
response assessment. This population includes all the qualified subjects from both Phase 1b and 
Phase 2. The Response-evaluable Population will be used as the primary population for analyses 
based on overall response rate. In the analysis, subjects who had clinical progression per 
investigator will be included in the response-evaluable population.  
 
Safety Population (Treated Population) 
Safety population (Treated Population) includes all subjects who were enrolled in the study and 
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be used to summarize the safety (including dosing) data and for the analysis of PFS, OS and 
ORR sensitivity analysis.   
DLT Evaluable Population for Phase 1b 
DLT evaluable population includes Phase 1b subjects who received study treatment and did not 
meet the criteria for subject replacement during the DLT observation period. 
2.2. 
Definition of Subgroups 
For the DLBCL cohort, a subgroup analysis will also be conducted to calculate ORR and its 95% 
CI for  
• GCB and non-GCB DLBCL types per IHC test. 
• GCB, ABC and Unclassified DLBCL types per GEP test. 
3. SUBJECT INFORMATION 
3.1. 
Subject Disposition 
Subject disposition will be summarized by each tumor type cohort. Subject enrollment will be 
summarized by region, country, and investigator.  
Time on study is defined in the same way as overall survival with reversed censoring, i.e., 
subjects who died will be censored at death date. The Kaplan-Meier method will be used to 
estimate the median time on study. 
3.2. 
Demographics and  Baseline Charac teristics 
Baseline characteristics and demographic information at baseline will be summarized with 
descriptive statistics by tumor type cohort.  
3.3. 
Pr ior and  Concom itant M edications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class per the World Health Organization (WHO) drug dictionary. Concomitant medications will 
be summarized by therapeutic class and preferred term and by tumor type cohort. Concomitant 
medications are defined as medications that were taken at any time on treatment (i.e. from the 
date of the first dose of study treatment through the date of the last dose of study treatment). The 
following concomitant medications will be summarized separately: growth factors, blood 
supportive products and immunoglobulin, CYP3A inhibitors/inducers, anticoagulants and/or 
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3.4. 
Extent of Exposure to Stud y Treatment 
Exposure to study treatment will be summarized by tumor type cohort. Descriptive statistics will 
be provided for treatment duration and dosing information (e.g. total cumulative dose 
administered, relative dose intensity, dose reduction due to adverse events) for all study 
treatments.  
3.5. 
Pr evious Treatment Histor y and Subsequent Antineoplastic Th erapies 
Previous treatment history and subsequent antineoplastic agents will be summarized separately. 
4. EFFICACY AND SAFETY ANALYSES 
4.1. 
Efficacy Analyses 
Efficacy endpoints and analysis methods are summarized in Table 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 1: Summary of Efficacy Analyses 
 
Endpoint 
Definition 
Analysis Method 
Primary Endpoint 
 
Overall 
Response Rate 
(ORR) 
Proportion of subjects 
achieving the best overall 
responses of complete 
response (CR) or partial 
response (PR) with 
confirmation per the 
investigator using the Revised 
Criteria for Response 
Assessment of Malignant 
Lymphoma (Cheson 2014) 
Primary (Response-evaluable population) 
• Proportion and 2-sided 95% CI based 
on exact Binomial distribution 
(Clopper-Pearson) 
Sensitivity (Treated population) 
• Proportion and 2-sided 95% CI based 
on exact Binomial distribution 
(Clopper-Pearson) 
• Waterfall plot of best change from 
baseline of tumor load from target 
lesion(s) 
Subgroup (Response-evaluable and treated 
population): For the DLBCL cohort, a 
subgroup analysis will also be conducted to 
calculate ORR and its 95% CI for  
• GCB and non-GCB DLBCL types per 
IHC test 
• GCB, ABC and Unclassified DLBCL 
types per GEP test 
 
 
Secondary Endpoints 
 
Duration of 
Response 
(DOR) 
Duration of 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 
Primary (Response-evaluable population) 
• Kaplan-Meier estimate 
 
Progression 
Free Survival 
(PFS) 
Duration of time from the first 
dose date of study treatment 
(ibrutinib or MEDI4736) to 
the first documentation of 
disease progression or death 
Primary (Treated population) 
• All PD and death considered as events 
regardless of any anticancer therapy prior 
to PD 
• Kaplan-Meier curve 


 
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Endpoint 
Definition 
Analysis Method 
from any cause, whichever 
occurs first. 
 
Overall 
Survival (OS) 
Duration of time from the first 
dose date of study treatment 
(ibrutinib or MEDI4736) to 
the date of death due to any 
cause 
Primary (Treated population) 
• All death considered as events regardless 
any anticancer therapy prior to death 
• Kaplan-Meier curve 
 
 
4.2. 
Safety Analyses 
Safety data will be summarized by tumor type cohorts. Table 2 summarizes the safety analyses to 
be performed for all tumor type cohorts. 
Adverse events (AEs) will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA). Severity of AEs will be graded by the investigator according the NCI-
CTCAE v4.03.   
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE v4.03. 
Unless otherwise specified, only baseline and post-baseline values collected during the 
treatment-emergent period will be included in the safety analysis. A treatment-emergent adverse 
event is defined as any event that begins or worsens in either intensity or frequency on or after 
the first dose of study treatment (either ibrutinib or MEDI4736). Only treatment-emergent 
adverse events (TEAEs) occurring and reported during the study period will be included in the 
adverse event summaries.  The TEAEs will be derived as those events that 1) occur after the first 
dose of study drug (either ibrutinib or MEDI4736), through the 30 days following the last dose 
of ibrutinib or 90 days following the last dose of MEDI4736 (whichever date is later); 2) any 
event with missing onset date and its resolution date during the treatment phase; 3) any event that 
is considered study drug-related regardless of the start date of the event; or 4) any event that is 
present at baseline but worsens in severity, seriousness, or becomes subsequently considered 
drug-related by the investigator.  
 
 
 
 
 
 
 


 
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Table 2: Summary of Safety Analyses  
 
Safety 
Assessment 
Definition 
Analysis Methods 
 
Safety and 
tolerability 
 
AE: TEAEs, SAEs, grade 3 or 
worse TEAEs, related TEAEs, 
TEAEs leading to treatment 
discontinuation, TEAEs leading to 
dose reduction, TEAEs leading to 
death, protocol- defined events of 
special interest, and other safety 
observations  
 
Worst post-baseline toxicity grade 
for selected lab tests: Worst post-
baseline toxicity grade, Hgb, 
creatinine clearance, abnormal 
uric acid, liver function 
abnormalities 
 
Vital signs (blood pressure, heart 
rate, temperature, respiratory 
rate), and weight 
Descriptive summary statistics and/or 
listings 
AE: adverse event; SAE: serious adverse event; TEAE: treatment-emergent adverse event 
 


 
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5. MODIFICATION OF ANALYSIS TO THE PROTOCOL 
Below is the major change made to the analyses in the protocol: 
• The timing of interim analysis for the FL cohort is changed from “An interim analysis 
will be performed after 19 subjects are evaluable for tumor response after completing 
at least 2 response assessments” to “An interim analysis will be performed after 
19 subjects are evaluable for tumor response after completing at least 1 response 
assessment” due to the number of early treatment discontinuations prior to 2 response 
assessments. 
• The timing of the interim analysis for the DLBCL cohort is changed from “An 
interim analysis will be performed after 9 subjects are evaluable for tumor response 
after completing at least 2 response assessments.” to “An interim analysis will be 
performed after 9 subjects are evaluable for tumor response after completing at least 1 
response assessment. 
• Because of the substantial number of subjects who discontinued treatment due to PD 
after one post-baseline tumor assessment, the sponsors (Pharmacyclics and 
AstraZeneca) decided to hold the enrolment during the interim analysis.  
• The terminology ‘Safety Assessments’ instead of ‘Safety Endpoints’ is used in 
Section 1.2 safety analysis part. 
    
6. REFERENCES 
Brookmeyer R., and Crowley J., A Confidence Interval for the Median Survival Time.  
Biometrics, March 1982: 29-41. 
 
Cheson B.D, Pfistner B, Juweid ME, et al.  Revised Response Criteria for Malignant Lymphoma, 
Journal of Clinical Oncology 2007; 25: 579-586. 
 
Collett D. Modeling Survival Data in Medical Research, 2nd Edition, Chapman & Hall CRC, 
2003 
 
European Commission, Detailed Guidance on the Collection, Verification, and Presentation of 
Adverse Event/Reaction Reports Arising From Clinical Trials on Medicinal Products for Human 
Use, Official Journal of the European Union, C 172, 6 November 2011. 
 
Fleiss J.L, et al., Statistical Methods for Rates and Proportions.  Wiley Inter-science, Third 
Edition, 2003. 


 
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US Food & Drug Administration: Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007.