Clinical trial NCT02403271
Conditions: Non-Small Cell Lung Cancer Breast Cancer Pancreatic Cancer
Keywords: Pharmacyclics PCYC Ibrutinib Durvalumab (MEDI4736) Relapsed Refractory Solid Tumor Non-Small Cell Lung Cancer NSCLC Squamous Squamous NSCLC Squamous Non-Small Cell Lung Cancer Immunotherapy IMBRUVICA® Tumor Immunotherapy Anti-PD-L1 Lung Cancer Breast Cancer Triple Negative HER2 Positive HER2 + Breast Cancer Pancreatic Cancer
Sponsor: Pharmacyclics LLC.
Start date: 2015-03-01; Completion date: 2017-08-01
Enrollment: 124 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors.

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 will be explored and will follow a 6+3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma). arm 2: Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results.
Interventions: intervention 1: Ibrutinib intervention 2: Durvalumab
Intervention descriptions: intervention 1: BTK Inhibitor intervention 2: Anti PDL-1

Protocol documents:
Prot_001.pdf: 
IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
 
 
 
 
PROTOCOL 
 
 
TITLE: 
A Multi-Center Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, 
Ibrutinib, in Combination with Durvalumab (MEDI4736), in Subjects 
with Relapsed or Refractory Solid Tumors 
PROTOCOL NUMBER: 
PCYC-1135-CA 
STUDY DRUG: 
Ibrutinib 
IND NUMBER: 
124674 
SPONSOR MEDICAL 
MONITOR: 
 
Pharmacyclics LLC 
Phone: 
 
Fax: 
 
Email: 
 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
11 December 2014 
AMENDMENT 1 DATE: 
05 February 2015 
AMENDMENT 2 DATE: 
26 June 2015 
AMENDMENT 3 DATE: 
18 December 2015 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC 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 LLC. 
 
 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3 
PROTOCOL APPROVAL PAGE 
18 December 2015 
FINAL 
Study Title: A Multi-Center Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, 
Ibrutinib, in Combination with Durvalumab (MEDI4736), in Subjects with 
Relapsed or Refractory Solid Tumors 
Study Number: PCYC-1135-CA 
Amendment 1 Date 05 February 2015 
Amendment 2 Date 26 June 2015 
Amendment 3 Date 
18 December 20 15 
I have carefully read Protocol PCYC-1135-CA entitled "A Multi-Center Study of the Bruton's 
Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Durvalumab (MEDI4736), in 
Subjects with Relapsed or Refractory Solid Tumors". I agree to conduct this study as outlined 
herein and in compliance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements. Furthermore, I understand that the Sponsor, Pharmacyclics, and the Institutional 
Review Board/Research Ethics Board/Independent Ethics Committee (IRB/REBIIEC) must 
approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
ofPharmacyclics. All data pertaining to this study will be provided to Pharmacyclics. The policy 
ofPhatmacyclics LLC requires that any presentation or publication of study data by clinical 
Investigators be reviewed by Pharmacyclics, before release, as specified in the protocol. 
Principal Investigator's Signature 
Date 
Print Natne 
The following Pharmacyclics LLC representative is authorized to sign the protocol and any 
atnendments: 
--~~~~~~~~s 
Date 
 
Clinical Development, Pharmacyclics LLC 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
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TABLE OF CONTENT 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENT .................................................................................................................3 
LIST OF IN-TEXT TABLES .......................................................................................................8 
LIST OF APPENDICES ...............................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................21 
1. 
BACKGROUND .........................................................................................................24 
1.1. 
Non-Small Cell Lung Cancer ........................................................................................24 
1.2. 
Breast Cancer ................................................................................................................24 
1.2.1. 
HER-2-positive Breast Cancer ......................................................................................26 
1.2.2. 
Triple-negative Breast Cancer.......................................................................................27 
1.3. 
Pancreatic Adenocarcinoma ..........................................................................................28 
1.4. 
Ibrutinib Overview ........................................................................................................29 
1.4.1. 
Summary of Nonclinical Data .......................................................................................30 
1.4.1.1. 
Pharmacology ................................................................................................................30 
1.4.1.2. 
Safety Pharmacology and Toxicology ..........................................................................30 
1.4.2. 
Summary of Clinical Data .............................................................................................31 
1.4.2.1. 
Pharmacokinetics and Product Metabolism ..................................................................31 
1.4.3. 
Summary of Clinical Safety ..........................................................................................31 
1.4.3.1. 
Monotherapy Studies in Hematologic Malignancies ....................................................31 
1.4.3.2. 
Combination Studies .....................................................................................................32 
1.4.4. 
Risks ..............................................................................................................................32 
1.4.4.1. 
Bleeding-related Events ................................................................................................32 
1.4.4.2. 
 Atrial fibrillation ..........................................................................................................33 
1.4.4.3. 
Cytopenias .....................................................................................................................33 
1.4.4.4. 
Diarrhea .........................................................................................................................33 
1.4.4.5. 
Infections .......................................................................................................................33 
1.4.4.6. 
Other Malignancies .......................................................................................................33 
1.4.4.7. 
Rash ...............................................................................................................................33 
1.4.4.8. 
Tumor Lysis Syndrome .................................................................................................34 
1.4.5. 
Summary of Clinical Data .............................................................................................34 
1.5. 
Durvalumab (MEDI4736) Overview ............................................................................34 
1.5.1. 
Summary of Nonclinical Data .......................................................................................34 
1.5.2. 
Summary of Clinical Data .............................................................................................35 
1.5.3. 
Summary of Clinical Safety ..........................................................................................36 
1.5.4. 
Summary of Clinical Efficacy .......................................................................................38 
1.6. 
Study Rationale .............................................................................................................38 
1.6.1. 
MEDI4736 ....................................................................................................................39 
1.6.1.1. 
Tumor Immunotherapy and Programmed Death-Ligand 1 (PD-L1) ............................39 
1.6.2. 
Ibrutinib .........................................................................................................................40 
1.6.2.1. 
Direct Tumor Effects-ErbB Family Kinase Inhibition by Ibrutinib .............................40 
1.6.2.2. 
BTK-mediated Microenvironment Modulation ............................................................41 
1.6.2.3. 
ITK (Interleukin-2-inducible Kinase)-mediated T-Cell Polarization ...........................41 


IMBRUVICA® (ibrutinib) 
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1.7. 
Study Rationale in Specific Solid Tumors ....................................................................41 
1.7.1. 
Non-small Cell Lung Cancer (NSCLC) ........................................................................41 
1.7.2. 
Breast Cancer ................................................................................................................42 
1.7.2.1. 
HER2-positive Breast Cancer .......................................................................................42 
1.7.2.2. 
Triple-Negative Breast Cancer ......................................................................................43 
1.7.3. 
Pancreatic Adenocarcinoma ..........................................................................................43 
1.8. 
Dosing Rationale ...........................................................................................................44 
1.8.1. 
Ibrutinib Dose ...............................................................................................................44 
1.8.2. 
Durvalumab (MEDI4736) Dose ....................................................................................45 
1.8.3. 
Ibrutinib and MEDI4736 in Combination .....................................................................46 
2. 
STUDY OBJECTIVE .................................................................................................46 
2.1. 
Primary Objective .........................................................................................................46 
2.2. 
Secondary Objective(s) .................................................................................................46 
2.3. 
Exploratory Objective(s) ...............................................................................................47 
3. 
STUDY DESIGN .........................................................................................................47 
3.1. 
Overview of Study Design ............................................................................................47 
3.1.1. 
Study Schema ................................................................................................................51 
4. 
SUBJECT SELECTION ............................................................................................51 
4.1. 
Inclusion Criteria ...........................................................................................................51 
4.2. 
Exclusion Criteria..........................................................................................................53 
5. 
TREATMENT OF SUBJECTS .................................................................................55 
5.1. 
Treatment Allocation ....................................................................................................55 
5.2. 
Phase 1b Dose De-escalation and Stopping Rules ........................................................56 
5.3. 
Definition of Dose-Limiting Toxicity (DLT) ...............................................................57 
5.4. 
Study Treatment ............................................................................................................58 
5.4.1. 
Phase 1b ........................................................................................................................58 
5.4.2. 
Phase 2 ..........................................................................................................................58 
5.5. 
Study Medication ..........................................................................................................58 
5.5.1. 
Ibrutinib .........................................................................................................................58 
5.5.1.1. 
Formulation/Packaging/Storage ....................................................................................58 
5.5.1.2. 
Dose and Administration...............................................................................................59 
5.5.1.3. 
Overdose .......................................................................................................................59 
5.5.1.4. 
Dose Modification for Adverse Reactions ....................................................................59 
5.5.1.5. 
Dose Modification for Hepatic Impaired Subjects .......................................................60 
5.5.2. 
Durvalumab (MEDI4736) .............................................................................................61 
5.5.2.1. 
Formulation/Packaging/Storage ....................................................................................61 
5.5.2.2. 
Dose and Administration...............................................................................................61 
5.5.2.3. 
Overdose .......................................................................................................................62 
5.5.2.4. 
Dose Modification for Adverse Reactions ....................................................................62 
5.6. 
Criteria for Permanent Discontinuation of Study Drug ................................................78 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .............................................78 
6.1. 
Permitted Concomitant Medications .............................................................................78 
6.2. 
Medications to Be Used with Caution ..........................................................................79 
6.2.1. 
CYP3A-inhibitors/Inducers ..........................................................................................79 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ..................79 
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6.2.3. 
Antiplatelet Agents and Anticoagulants........................................................................79 
6.3. 
Prohibited Concomitant Medications ............................................................................80 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures............................80 
6.4.1. 
Minor Surgical Procedures ............................................................................................80 
6.4.2. 
Major Surgical Procedures ............................................................................................81 
6.4.3. 
Emergency Procedures ..................................................................................................81 
7. 
STUDY EVALUATIONS ...........................................................................................81 
7.1. 
Description of Procedures .............................................................................................81 
7.1.1. 
Assessments ..................................................................................................................81 
7.1.1.1. 
ICF ................................................................................................................................81 
7.1.1.2. 
Confirm Eligibility ........................................................................................................81 
7.1.1.3. 
Medical History, Risk Factors and Demographics .......................................................81 
7.1.1.4. 
Prior and Concomitant Medications..............................................................................82 
7.1.1.5. 
Adverse Events..............................................................................................................82 
7.1.1.6. 
Routine Physical Examination ......................................................................................82 
7.1.1.7. 
ECOG Performance Status ............................................................................................82 
7.1.1.8. 
Vital Signs .....................................................................................................................82 
7.1.2. 
Laboratory .....................................................................................................................83 
7.1.2.1. 
Hematology ...................................................................................................................83 
7.1.2.2. 
Chemistry (Serum) ........................................................................................................83 
7.1.2.3. 
Thyroid Stimulating Hormone (TSH) ...........................................................................83 
7.1.2.4. 
Coagulation Studies ......................................................................................................83 
7.1.2.5. 
Tumor Markers..............................................................................................................83 
7.1.2.6. 
Creatinine Clearance .....................................................................................................83 
7.1.2.7. 
Hepatitis Serologies ......................................................................................................84 
7.1.2.8. 
Urinalysis ......................................................................................................................84 
7.1.2.9. 
Pregnancy Test ..............................................................................................................84 
7.1.3. 
Diagnostics/Procedures .................................................................................................84 
7.1.3.1. 
ECG ...............................................................................................................................84 
7.1.3.2. 
Tumor Measurements....................................................................................................84 
7.1.3.2.1. CT/MRI .........................................................................................................................84 
7.1.3.2.2. Tumor Assessment by Physical Examination ...............................................................85 
7.1.3.3. 
Tumor Tissue Biopsy ....................................................................................................85 
7.1.3.4. 
Pharmacokinetics/Pharmacodynamics/Biomarkers ......................................................86 
7.1.3.5. 
Pharmacokinetics ..........................................................................................................86 
7.1.3.6. 
Biomarkers and Pharmacodynamics Studies ................................................................86 
7.1.3.6.1. T/B/NK Counts .............................................................................................................87 
7.1.3.6.2. Flow Cytometry-based Whole Blood Assays ...............................................................87 
7.1.3.6.3. Molecular Markers ........................................................................................................87 
7.2. 
Efficacy Evaluations .....................................................................................................87 
7.2.1. 
Definitions .....................................................................................................................87 
7.2.1.1. 
Measurable Disease .......................................................................................................88 
7.2.1.2. 
Non-measurable Disease ...............................................................................................88 
7.2.1.3. 
Target Lesions ...............................................................................................................89 
7.2.1.4. 
Non-target Lesions ........................................................................................................89 
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7.2.1.5. 
New Lesions ..................................................................................................................89 
7.2.2. 
Guidelines for Evaluation of Measurable Disease ........................................................89 
7.2.3. 
Response Criteria ..........................................................................................................91 
7.2.3.1. 
Evaluation of Target Lesions ........................................................................................91 
7.2.3.2. 
Evaluation of Non-target Lesions .................................................................................91 
7.2.3.3. 
Evaluation of Best Overall Response ............................................................................92 
7.2.3.4. 
Missing Assessments or Inevaluable Lesions ...............................................................92 
7.2.4. 
Confirmatory Measurement ..........................................................................................92 
7.2.4.1. 
Confirmation .................................................................................................................92 
7.3. 
Sample Collection and Handling ..................................................................................93 
8. 
STUDY PROCEDURES .............................................................................................93 
8.1. 
Screening Phase ............................................................................................................93 
8.1.1. 
Screening/Consenting Visit ...........................................................................................93 
8.2. 
Treatment Phase ............................................................................................................94 
8.2.1. 
Treatment Visits ............................................................................................................94 
8.2.1.1. 
Cycle 1 Day 1 (C1D1)...................................................................................................94 
8.2.1.2. 
Cycle 1 Day 2 (C1D2)...................................................................................................95 
8.2.1.3. 
Cycle 1 Day 8 (C1D8) (for Phase 1b only) ...................................................................96 
8.2.1.4. 
Cycle 1 Day 15 (C1D15)...............................................................................................96 
8.2.1.5. 
Cycle 1 Day 22 (C1D22) (for Phase 1b only) ...............................................................97 
8.2.1.6. 
Day 1 of Each Subsequent Cycle ..................................................................................97 
8.2.1.7. 
Day 15 of Each Subsequent Cycle ................................................................................98 
8.2.2. 
Response Evaluations....................................................................................................99 
8.2.3. 
Treatment Termination Visit (Optional Visit) ..............................................................99 
8.3. 
Follow-up Phase ..........................................................................................................100 
8.3.1. 
End-of-Treatment Visit for Ibrutinib ..........................................................................100 
8.3.2. 
90-day Follow-Up Visit for MEDI4736 .....................................................................101 
8.3.3. 
Response Follow-up ....................................................................................................101 
8.3.4. 
Survival Follow-up .....................................................................................................101 
8.4. 
Missed Evaluations .....................................................................................................102 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..............................................102 
9.1. 
Completion ..................................................................................................................102 
9.2. 
Withdrawal from Study Treatment .............................................................................102 
9.3. 
Withdrawal from Study ...............................................................................................103 
10. 
STATISTICAL METHODS AND ANALYSIS .....................................................103 
10.1. 
Analysis Populations ...................................................................................................103 
10.1.1. 
Enrolled Population .....................................................................................................103 
10.1.2. 
Response-evaluable Population ..................................................................................103 
10.1.3. 
Safety Population ........................................................................................................104 
10.1.4. 
Additional Analysis Populations .................................................................................104 
10.1.5. 
Replacement of Subjects .............................................................................................104 
10.2. 
Endpoints for Phase 1 .................................................................................................104 
10.2.1. 
Primary Endpoints .......................................................................................................104 
10.2.2. 
Secondary Endpoints ...................................................................................................104 
10.2.3. 
Exploratory Endpoints ................................................................................................104 
10.3. 
Endpoints for Phase 2 .................................................................................................105 
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10.3.1. 
Primary Endpoint ........................................................................................................105 
10.3.2. 
Secondary Endpoints ...................................................................................................105 
10.3.3. 
Exploratory Endpoints ................................................................................................105 
10.4. 
Sample Size Determination .........................................................................................105 
10.4.1. 
Phase 1b ......................................................................................................................105 
10.4.2. 
Phase 2 ........................................................................................................................106 
10.5. 
Subject Information .....................................................................................................107 
10.6. 
Analysis Methods ........................................................................................................107 
10.6.1. 
Phase 1b Analyses .......................................................................................................107 
10.6.2. 
Phase 2 Analyses .........................................................................................................108 
10.6.2.1. Primary Efficacy Analysis ..........................................................................................108 
10.6.2.2. Secondary Efficacy Analyses ......................................................................................108 
10.6.2.3. Exploratory Efficacy Analyses ...................................................................................109 
10.7. 
Safety Analysis ...........................................................................................................109 
10.7.1. 
Adverse Events............................................................................................................110 
10.7.2. 
Clinical Laboratory Tests ............................................................................................110 
10.8. 
Dose Level Review Committee ..................................................................................111 
10.9. 
Pharmacokinetic Analysis (Ibrutinib, Combination of Ibrutinib and MEDI4736) .....111 
10.10. 
Pharmacokinetic Analysis (MEDI4736) .....................................................................111 
10.11. 
Immunogenicity Analyses ...........................................................................................112 
10.12. 
Pharmacodynamic Analyses .......................................................................................112 
10.13. 
Biomarker Analyses ....................................................................................................112 
11. 
ADVERSE EVENT REPORTING ..........................................................................112 
11.1. 
Definitions ...................................................................................................................113 
11.1.1. 
Adverse Events (AE)...................................................................................................113 
11.1.2. 
Serious Adverse Events...............................................................................................114 
11.1.3. 
Severity Criteria (Grade 1-5) ......................................................................................114 
11.1.4. 
Causality (Attribution) ................................................................................................115 
11.2. 
Unexpected Adverse Events .......................................................................................115 
11.3. 
Special Reporting Situations .......................................................................................115 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ................................................................................................................116 
11.4.1. 
Assessment of Adverse Events ...................................................................................116 
11.4.2. 
Adverse Event Reporting Period .................................................................................116 
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events ..............................117 
11.4.4. 
Pregnancy ....................................................................................................................118 
11.4.5. 
Other Malignancies .....................................................................................................118 
11.4.6. 
Adverse Events of Special Interest (AESI) .................................................................118 
11.4.6.1. Major Hemorrhage ......................................................................................................119 
11.4.6.2. Pneumonitis .................................................................................................................119 
11.4.6.3. Hypersensitivity Reactions .........................................................................................119 
11.4.6.4. Hepatic Function Abnormalities (Hepatotoxicity) ......................................................120 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ..........120 
12.1. 
Regulatory and Ethical Compliance ...........................................................................120 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ..............................................................................121 
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12.3. 
Informed Consent ........................................................................................................121 
12.4. 
Quality Control and Quality Assurance ......................................................................121 
12.5. 
Protected Subject Health Information Authorization ..................................................122 
12.6. 
Study Files and Record Retention ...............................................................................122 
12.7. 
Case Report Forms and Record Maintenance .............................................................123 
12.8. 
Investigational Study Drug Accountability .................................................................123 
12.9. 
Study Monitoring/Audit Requirements .......................................................................124 
12.10. 
Investigator Responsibilities .......................................................................................125 
12.11. 
Sponsor Responsibilities .............................................................................................125 
12.12. 
Financial Disclosure ....................................................................................................125 
12.13. 
Liability and Clinical Trial Insurance .........................................................................126 
12.14. 
Protocol Amendments .................................................................................................126 
12.15. 
Publication of Study Results .......................................................................................126 
12.16. 
Study Discontinuation .................................................................................................127 
13. 
REFERENCES ..........................................................................................................128 
14. 
APPENDICES ...........................................................................................................135 
 
LIST OF IN-TEXT TABLES  
Table 1. 
Phase 1b Dosing Levels ...............................................................................................48 
Table 2. 
Ibrutinib Dose Modifications .......................................................................................60 
Table 3. 
Time Point Response: Subjects with Target (+/– Non-target) Disease .......................92 
Table 4. 
Effective Methods of Contraception  .........................................................................146 
LIST OF APPENDICES 
Appendix 1. 
Schedule of Assessments for Phase 1b ................................................................136 
Appendix 2. 
Schedule of Assessments for Phase 2 ..................................................................138 
Appendix 3. 
Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, and 
Biomarkers* .........................................................................................................140 
Appendix 4. 
ECOG Performance Status Scores .......................................................................141 
Appendix 5. 
Inhibitors and Inducers of CYP3A ......................................................................142 
Appendix 6. 
New York Heart Association (NYHA) Functional Classification .......................143 
Appendix 7. 
Hepatitis Serology Chart ......................................................................................144 
Appendix 8. 
Contraception Requirements for MEDI4736 .......................................................145 
Appendix 9. 
Child-Pugh Score for Subjects with Liver Impairment .......................................147 
 
 
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SYNOPSIS 
Study Title: 
A Multi-Center Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor 
Ibrutinib, in Combination with Durvalumab (MEDI4736) in Subjects with 
Relapsed or Refractory Solid Tumors 
Protocol Number: 
PCYC-1135-CA 
Study Phase: 
1b/2 
Study Duration: 
Estimated to be 3 years after the first dose of the last subject enrolled 
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) or 
maximum tolerated dose (MTD) of ibrutinib in combination with 
MEDI4736 in subjects with relapsed or refractory solid tumors 
• To determine the safety and tolerability of ibrutinib in combination 
with MEDI4736 in subjects with relapsed or refractory solid tumors  
Secondary Objectives: 
• To evaluate the efficacy of ibrutinib in combination with 
MEDI4736 by assessing the overall response rate (ORR) in subjects 
with relapsed or refractory solid tumors 
• To evaluate the efficacy of ibrutinib in combination with 
MEDI4736 by assessing the disease control rate (DCR) at Week 20 
(Cycle 5) 
• To evaluate the efficacy of ibrutinib in combination with 
MEDI4736 by assessing the duration of response (DOR)  
• To determine the pharmacokinetics and pharmacodynamics of 
ibrutinib in combination with MEDI4736 in subjects with relapsed 
or refractory solid tumors  
Phase 2: 
Primary Objectives: 
• To evaluate the efficacy of ibrutinib in combination with 
MEDI4736 in subjects with relapsed or refractory solid tumors by 
assessing the ORR 
Secondary Objectives: 
• To determine the efficacy of ibrutinib in combination with 
MEDI4736 in subjects with relapsed or refractory solid tumors by 
assessing the DCR at Week 20 (Cycle 5), DOR, progression-free 
survival (PFS), and overall survival (OS) 
• To determine the safety and tolerability of ibrutinib in combination 
with MEDI4736 in subjects with relapsed or refractory solid tumors 
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• To determine the pharmacokinetics and pharmacodynamics of 
ibrutinib in combination with MEDI4736 in subjects with relapsed 
or refractory solid tumors  
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 kinase [ITK], Epidermal Growth Factor Receptor  
[EGFR]) 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/or proteins (within the tumor or other 
collected specimens) associated with sensitivity or resistance to 
ibrutinib and/or MEDI4736 (ie, PD-Ligand-1) 
Study Design: 
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of 
ibrutinib in combination with MEDI4736 in subjects with relapsed or 
refractory solid tumors. 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) or MTD for this study.  
Phase 1b: 
In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of 
ibrutinib in combination with MEDI4736 will be explored in cohort 1 and 
will follow a 6+3 dose de-escalation design and will include a sentinel 
subject which will have a 3-day observation period prior to dosing of 
subsequent subjects. Subjects with one of the following three solid tumor 
types in Stage III/IV will be eligible for enrollment: 
• Non-small cell lung cancer (NSCLC) (adenocarcinoma or 
squamous-cell carcinoma) 
• Breast cancer (human epidermal growth factor receptor family 
member 2 [HER2] positive or triple negative) 
• Pancreatic cancer (adenocarcinoma) 
In cohort 1, (6 subjects, regardless of how many are of each tumor type), 
ibrutinib will be administered PO at a dose of 560 mg daily in combination 
with MEDI4736 at a dose of 10 mg/kg IV every 2 weeks in 28-day cycles 
until dose-limiting toxicity (DLT) or disease progression occurs. The DLT 
observation period includes Cycle 1 and laboratory assessments on Day 1 
of Cycle 2 which will occur before the MEDI4736 infusion on Day 1 of 
Cycle 2.  
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 subjects experience a DLT, dose de-escalation will occur. If subject 
incidence of DLTs during the first 28 days (Cycle 1=28 days and including 
laboratory assessments on Day 1 Cycle 2) of study treatment is <33.3% (ie, 
≤1 of 6 or ≤2 of 9), this dose level will be considered safe to proceed to 
Phase 2, and defined as the RP2D.  
A similar 6+3 cohort design will be utilized in the dose de-escalation 
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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. Determination of the RP2D will be based on the 
safety profile of the 2 treatment regimens. If necessary, the dose de-
escalation cohort -2 will be enrolled thereafter. 
A DLT is defined as any Grade 3 or higher non-hematologic or Grade 4 
hematologic adverse event (AE) possibly related to study drug(s) occurring 
during the DLT observation period with the following clarifications for the 
toxicities below: 
• Grade 4 vomiting or Grade 3 nausea and vomiting despite 
maximum medical supportive care and persisting >3 days 
• Grade 3 or 4 diarrhea despite maximum medical supportive care 
and persisting >7 days 
• Grade 3 fatigue persisting >7 days 
• Grade 3 neutropenia lasting >7 days or with fever 
• Grade 3 infusion reaction that does NOT resolve with appropriate 
clinical management 
Subjects who discontinued study drug within Cycle 1 due to reasons other 
than DLT will be replaced for DLT assessment. 
After the RP2D is defined, enrollment in Phase 2 will commence. 
Phase 2: 
Subjects with one of three solid tumor types (Stage III/IV) will be enrolled 
in separate cohorts in the Phase 2 portion of this protocol: 
• NSCLC (adenocarcinoma and squamous-cell carcinoma at an 
approximate 2:1 ratio with at least 15 subjects with squamous-cell 
carcinoma) 
• Breast cancer (triple-negative and HER2-positive cancer) at an 
approximate 2:1 ratio with at least 15 subjects with the triple-
negative breast cancer) 
• Pancreatic cancer (adenocarcinoma) 
For each of the above three cohorts, an interim analysis will be performed 
to evaluate the response and the safety profile. A cohort may be 
discontinued based on the interim efficacy and/or safety results. The 
decisions based on the results of the interim analysis are independent in the 
3 individual disease cohorts. 
NSCLC and breast cancer:  
Interim analysis: n=18 per tumor type  
Primary analysis: n=43 per tumor type 
The NSCLC and breast cancer cohorts will enroll 18 subjects per tumor 
type for the interim analysis and 25 additional subjects per tumor type for 
the primary analysis (total n=43). An interim analysis will be performed 
after 18 subjects are evaluable for tumor response. If a subject discontinues 
prior to the first tumor response assessment for reasons other than 
progressive disease, the subject will be replaced. If 2 or fewer responders 
are observed among the 18 evaluable subjects in a cohort, the Sponsor may 
consider discontinuation of this cohort; however, assessment of biomarkers 
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(that may aid in prospective enrichment for responders) or tumor 
measurements (showing clinically relevant tumor reductions, ie, <30%, 
that fit the criteria for stable disease [SD]) may support continued 
enrollment.  
Pancreatic cancer: 
Interim analysis: n=17   
Primary analysis: n=44  
For the interim analysis, 17 subjects will be enrolled, and 27 additional 
subjects will be enrolled for the primary analysis (total n=44). An interim 
analysis will be performed after 17 subjects are evaluable for tumor 
response. If a subject discontinues prior to the first tumor response 
assessment for reasons other than progressive disease, the subject will be 
replaced. If 1 or no responder is observed among the 17 evaluable subjects, 
the Sponsor may consider discontinuation of this cohort; however, 
assessment of biomarkers (that may aid in prospective enrichment for 
responders) or tumor measurements (showing clinically relevant tumor 
reductions, ie, <30%, that fit the criteria for SD) may support continued 
enrollment.  
Subjects will receive ibrutinib and MEDI4736 continuously in 28-day 
cycles until progressive disease or unacceptable toxicity. Dosing of 
ibrutinib will continue as long as the subject is deriving clinical benefit 
(complete response [CR], partial response [PR], or SD) and the subject is 
not experiencing unacceptable toxicity. Dosing of MEDI4736 will 
continue for a total of 12 months of therapy if clinical benefit is seen 
without safety concerns.   
Assessment for response will occur at the end of Cycle 2 (Cycle 2 Day 28 
[–7 days]) and then after every 3rd cycle (Cycle x Day 28 [–7 days]). 
Assessments will include computer tomography [CT]/magnetic resonance 
imaging [MRI] scans or physical examination (if the lesion is not 
assessable by CT/MRI) for the relevant tumor type and will follow 
RECIST 1.1 guidelines. 
In order to accommodate the potential for immune flare 
(pseudoprogression), treatment with ibrutinib and MEDI4736 may 
continue between the initial assessment of suspected progression and 
confirmation of progression. Subjects with suspected progressive disease 
who, in the Investigator’s opinion, continue to receive clinical benefit from 
their treatment may continue to receive ibrutinib and MEDI4736 as 
dictated in the protocol after consultation with the Sponsor and at the 
Investigator’s discretion. In the absence of symptomatic deterioration, a 
biopsy (if lesion is assessable) should be performed at the time of 
suspected tumor flare (in order to rule out tumor necrosis and/or an 
inflammatory reaction) or the investigator may continue dosing and a 
CT/MRI scan or physical examination (if the lesion is not assessable by 
CT/MRI) should 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 met. Ibrutinib and MEDI4736 should be 
discontinued if there is confirmed PD per RECIST 1.1 guidelines or other 
clinical data suggest clear evidence of progression (symptomatic 
deterioration).   
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Population: 
Subjects with one of the following relapsed or refractory Stage III/IV solid 
tumors: 
• NSCLC (adenocarcinoma or squamous-cell carcinoma) or 
• Breast cancer (HER2 positive or triple negative) or 
• Pancreatic cancer (adenocarcinoma) 
Subjects with NSCLC or pancreatic cancer must have failed at least 1 prior 
first-line systemic therapy. Subjects with breast cancer must have failed at 
least 2 prior lines of systemic therapy. 
Centers: 
Multi-center, US only 
Inclusion Criteria: 
1. Pathologically confirmed: 
• Non-small cell lung cancer (NSCLC, adenocarcinoma or 
squamous-cell carcinoma) or 
• Breast cancer (HER2-positive by fluorescent in situ hybridization 
(FISH) or immunochemistry (IHC) [See Section 1.2 for definition] 
or triple negative ) or 
• Pancreatic cancer (adenocarcinoma) 
2. For Phase 2 only: Provision of a fresh tumor biopsy or an available 
archival tumor sample processed as FFPE (formalin-fixed paraffin 
embedded) taken within 3 months, and after the most recent treatment 
with the following exception:   
• For locally advanced pancreatic cancer, a fresh biopsy is not 
required if the tumor is inaccessible or the procedure places the 
subject at a safety risk.  
•  No more than 10 subjects with locally advanced pancreatic cancer 
will be enrolled in the study without a biopsy. 
3. Radiographically or clinically documented relapsed or refractory 
disease (Stage III or IV): Subjects with NSCLC or pancreatic cancer 
must have relapsed or refractory disease and must have failed at least 
1 prior appropriate systemic first-line treatment regimen. Subjects with 
epidermal growth factor receptor (EGFR) mutation-positive NSCLC 
must have received an EGFR inhibitor and subjects with NSCLC that 
is anaplastic lymphoma kinase (ALK)-positive must have received an 
ALK inhibitor. Subjects with breast cancer must have relapsed or 
refractory disease and must have failed at least 2 prior appropriate 
systemic regimens. 
4. One or more disease lesion on CT/MRI scan or by physical 
examination (if the lesion is not assessable by CT/MRI) that is 
measurable (ie, superficial soft tissue lesions, skin lesions, etc.) per 
RECIST 1.1 guidelines. 
5. Adequate hematologic function independent of transfusion and growth 
factor support for at least 7 days prior to screening, with the exception 
of pegylated Granulocyte-colony stimulating factor (G-CSF) 
(pegfilgrastim) and darbepoetin which require discontinuation at least 
14 days prior to screening defined as:  
• Absolute neutrophil count >1500 cells/mm3 (1.50 x 109/L) 
• Platelet count >100,000 cells/mm3 (100 x 109/L)  
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• Hemoglobin >9.0 g/dL 
6. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤2.5 x upper limit of normal (ULN) for subjects without liver 
metastases and ≤3.5 x ULN for subjects with liver metastases  
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin) 
• Creatinine ≤2.0 x ULN and Creatinine Clearance ≥40 mL/min 
(Cockcroft-Gault or 24-hour creatinine clearance collection) 
7. Prothrombin time (PT)/International normalized ratio (INR) <1.5 x 
upper limit of normal (ULN) and partial thromboplastin time (PTT)/ 
activated partial thromboplastin time (aPTT) <1.5 x ULN 
8. Men and women ≥18 years of age 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 
10. Female subjects of reproductive potential must either be of non-
reproductive potential (ie, post-menopausal by history: ≥60 years old 
and no menses for ≥1 year; 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 and female subjects of reproductive potential who agree to use 
highly effective methods of birth control (eg, condoms, implants, 
injectables, combined oral contraceptives, some intrauterine devices 
[IUDs], complete abstinence 1, or sterilized partner) during the period 
of therapy and for 90 days after the last dose of study drug (see 
Appendix 8). 
12. Men must agree to not donate sperm and a woman 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 drug. 
1 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 
 
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Exclusion Criteria: 
1. Subjects with tumors of mixed small cell and NSCLC histology 
2. Any history of central nervous system (CNS) involvement of disease 
except as follows:  Subjects with previously treated CNS metastases 
that are adequately treated with whole brain radiotherapy (+/- surgery), 
that are neurologically stable, and do not require corticosteroids (of any 
dose) for symptomatic management for at least 14 days prior to first 
dose of MEDI4736 plus ibrutinib. In addition, there must be no clear 
evidence of radiographically active disease for at least 90 days prior to 
study enrollment. 
3. Anti-tumor therapy (chemotherapy, antibody therapy, immunotherapy, 
biologic-based therapy, molecularly-targeted therapy, radiation therapy 
or investigational agent) within 21 days of study Day 1 (six weeks for 
nitrosureas, mitomycin C, or antibody or molecular targeted agents 
with half-life (t1/2) >10 days; 10 weeks for radio- or toxin-
immunoconjugates); concurrent use of hormone deprivation therapy 
including but not limited to anastrozole, letrozole, or tamoxifen citrate 
for breast cancer and hormonal replacement therapy for non-cancer-
related conditions is permitted.  
Enrollment of subjects that have received molecularly-targeted small 
molecule inhibitors less than 21 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.  
4. Prior treatment with ibrutinib or other BTK inhibitor anti-CD137 or 
anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody. 
The following are exceptions to this criterion: 
• Subjects previously treated with an anti-PD1, anti-PD-L1, or anti-
PD-L2 antibody  
5. Known allergy or hypersensitivity to ibrutinib or MEDI4736 or any 
excipient 
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. 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 1 diabetes mellitus; multiple sclerosis; systemic lupus 
erythematosus; Wegener's granulomatosis; myasthenia gravis; Graves’ 
disease; rheumatoid arthritis; hypophysitis; uveitis; etc) within the past 
3 years prior to the start of treatment. The following are exceptions to 
this criterion: 
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• Subjects with vitiligo or alopecia  
• Subjects with hypothyroidism (eg, following Hashimoto's 
thyroiditis) stable on hormone replacement therapy or psoriasis not 
requiring systemic treatment 
8. History of allogeneic organ transplant 
9. 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 
10. 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 and alopecia or other irreversible toxicity not reasonably 
expected to be exacerbated by study treatment (eg, hearing loss) 
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. Vaccinated with live, attenuated vaccines within 4 weeks of the first 
dose of study drug (Note: Subjects, if enrolled, should not receive live 
vaccines during the study and until 180 days after the last dose of study 
drugs) 
14. Recent infection requiring systemic treatment that was completed 
≤14 days before the first dose of study drug 
15. Known history of human immunodeficiency virus (HIV) or active 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). 
Subjects who are positive for hepatitis B core antibody, hepatitis B 
surface antigen, or hepatitis C antibody must have a negative 
polymerase chain reaction (PCR) result before enrollment. Those who 
are PCR positive will be excluded.   
16. History of primary immunodeficiency 
17. Known history of previous clinical diagnosis of tuberculosis 
18. Any uncontrolled active systemic infection or pneumonitis or 
interstitial lung disease 
19. Major surgery within 4 weeks of the first dose of study drug 
20. 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. 
21. 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 
(Appendix 7); or a history of myocardial infarction, uncontrolled 
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hypertension or cardiac arrhythmia, unstable angina, or acute coronary 
syndrome within 6 months prior to enrollment 
22. Unable to swallow capsules or active malabsorption syndrome not 
controlled by medication, disease or conditions significantly affecting 
gastrointestinal function, or complete resection of the stomach, or 
complete resection of small bowel, or partial or complete bowel 
obstruction.  
23. Concomitant use of warfarin or other Vitamin K antagonists 
24. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor  
25. Pregnant or lactating female; men planning to father a child or women 
planning a pregnancy while taking study drug or within 3 months after 
the last dose of study drug 
26. Concurrent enrollment in another clinical study, unless in a follow-up 
period or it is an observational study. 
27. Unwilling or unable to participate in all required study evaluations and 
procedures 
28. 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)  
Study Treatment: 
One cycle of treatment is 28 days in duration and consists of daily 
administration of ibrutinib PO in combination with MEDI4736 IV every 
2 weeks. Dosing of MEDI4736 will continue for a total of 12 months if 
clinical benefit is seen without safety concerns. Re-treatment with 
MEDI4736 will not be allowed following completion of 12 months of 
treatment, regardless of any dose delays, missed doses, or following 
permanent discontinuation for any reason. Dosing of ibrutinib will 
continue as long as the subject is deriving clinical benefit (CR, PR, or SD) 
and the subject is not experiencing unacceptable toxicity.  
Phase 1b: 
Subjects in one cohort may all be of the same tumor type in Phase 1b. 
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 
*Cohorts -1A and -1B are two parallel cohorts. Subjects will be enrolled into those 
two cohorts concurrently. 
Phase 2: 
Recommended Phase 2 Dose (RP2D) established in Phase 1b (ibrutinib 
420 mg or 560 mg PO daily, and MEDI4736 3 mg/kg or 10 mg/kg IV 
every 2 weeks) given in 28-day cycles in the three tumor type cohorts. 
Safety Plan: 
This study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Procedures. Adverse events (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 (DLRC) will 
evaluate the safety data from each cohort of the Phase 1b. Members of this 
committee will include participating investigators or designees as well as 
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the Sponsor (at a minimum: the Medical Monitor or designee, a Drug 
Safety representative and a Biostatistician). The safety profile will also be 
evaluated at the interim analysis in the Phase 2 portion of the study. 
Statistical Methods and 
Data Analysis: 
Tumor response will be evaluated per RECIST 1.1 guidelines for all three 
tumor type cohorts.  
Phase 1b: 
Phase 1b is based on a 6+3 de-escalation design described in the Study 
Design Section.  
The primary objectives are to establish a RP2D or MTD and to evaluate 
safety and tolerability of ibrutinib in combination with MEDI4736. 
Adverse events (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, pharmacokinetics and 
pharmacodynamics in subjects receiving the combination regimen. Overall 
response rate (ORR), DCR at Week 20 (Cycle 5), and DOR will be 
calculated and summarized by tumor type and dose cohort descriptively. 
Pharmacokinetics and pharmacodynamics data will be evaluated by tumor 
type and dose cohort. 
Phase 2: 
Phase 2 will use the RP2D ascertained in Phase 1b. For the NSCLC and 
breast cancer cohorts, an interim analysis will be performed based on 
18 evaluable subjects and the primary analysis will be performed based on 
43 evaluable subjects per tumor type cohort. For the pancreatic cancer 
cohort, an interim analysis will be performed based on 17 evaluable 
subjects and the primary analysis will be performed based on 44 evaluable 
subjects. The primary analysis will be performed after all evaluable 
subjects have completed at least two response assessments or progressed 
prior to the second response assessment. For Phase 2, the following 
analyses will be undertaken: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the ORR per RECIST 1.1 guidelines in 
each of the three solid tumor cohorts. The observed response rate along 
with its 95% confidence interval will be calculated for each tumor type 
cohort.  
Secondary Efficacy Endpoints: 
Disease control rate (DCR) at Week 20 (Cycle 5) will be calculated and its 
95% confidence interval will be provided. Duration of response (DOR) 
will be calculated and summarized by 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.  
Progression-free survival (PFS) and OS will be evaluated by tumor type 
cohort with Kaplan-Meier estimates. 
Pharmacokinetics and pharmacodynamics profiles will be evaluated by 
tumor type cohort and overall. 
Exploratory Efficacy Analysis: 
Subgroup analysis: For each tumor type cohort, a subgroup analysis will be 
conducted to calculate the response rate and its 95% confidence interval 
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based on PD-L1 expression (positive versus negative). For the NSCLC 
cohort, a subgroup analysis will also be conducted for subjects with 
adenocarcinoma versus squamous-cell carcinoma. For the breast cancer 
cohort, a subgroup analysis will also be conducted for subjects with 
HER2-positive versus triple-negative cancers.   
Other analyses: Other exploratory efficacy variables will be summarized 
descriptively and include the following: 
• Immune-cell subsets 
• Non-BTK-related pharmacodynamics (ie, EGFR, ITK) 
• Plasma chemokine/cytokine levels  
• Genes and/or proteins including PD-L1 (within the tumor or other 
collected specimens) associated with sensitivity or resistance to 
ibrutinib 
Safety Analysis: 
Adverse events (AEs), SAEs, laboratory data, vital signs, other relevant 
safety data and dosing data will be listed and summarized by tumor type 
cohort. 
Sample Size 
Determination: 
Phase 1b:  
6-36 subjects for DLT assessment (6-9 subjects in up to 4 dose cohorts, 
regardless of tumor type) 
Phase 2:  
~130 subjects, including 6-9 subjects treated at the RP2D in Phase 1b and 
with the tumor type as defined for Phase 2. 
For NSCLC* and breast cancer**: 
• Interim analysis: 18 subjects of each of the 2 tumor types = 36 
total  
• Primary analysis: 43 subjects of each of the 2 tumor types = 86 
total 
* For the NSCLC cohort, subjects with adenocarcinoma and squamous-cell 
carcinoma will be enrolled at an approximate 2:1 ratio (ie, at least 
15 subjects with squamous-cell carcinoma will be enrolled). 
**For the breast cancer cohort, subjects with triple-negative and 
HER2-positive breast cancer will be enrolled at an approximate 2:1 ratio 
(ie, at least 15 subjects with triple-negative breast cancer will be enrolled). 
For pancreatic cancer: 
• Interim analysis: 17 subjects  
• Primary analysis: 44 subjects  
The Phase 2 portion will test a true response rate of 10% (H0) versus 25% 
(Ha) for the NSCLC and breast cancer cohorts and 5% (H0) versus 18% 
(Ha) for the pancreatic cancer cohort. The null hypothesis will be rejected 
if 8 or more responders are observed among the 43 evaluable subjects in 
the NSCLC and breast cancer cohorts. The null hypothesis will be rejected 
if 5 or more responders are observed among the 44 evaluable subjects in 
the pancreatic cancer cohort. With a 1-sided type I error rate of 0.05, each 
cohort would have 80% power based on the true response rate in the 
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alternative hypothesis. The above statistical design including number of 
subjects and number of responders for each analysis follows the statistical 
framework of Simon’s optimal 2-stage design (Simon, 1989). The 
enrollment will continue while the interim analysis is performed. 
The decision rule for consideration of discontinuation of each cohort at the 
interim analysis is described in the Study Design section above. 
 
 
 
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ABBREVIATIONS 
AC 
doxorubicin, cyclophosphamide 
ADA 
Anti-drug antibody  
AE  
adverse event  
AESI 
Adverse Events of Special Interest 
ALK 
anaplastic lymphoma kinase 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST  
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
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  
CA19-9 
carbohydrate antigen 19-9 
CEA 
carcinoembryonic antigen 
CEF 
cyclophosphamide, epirubicin, 5-fluorouracil 
CLL 
chronic lymphocytic leukemia  
CMF 
cyclophosphamide, methotrexate, 5-fluorouracil 
CNS  
central nervous system  
CR  
complete response  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP  
cytochrome P450 
Cys 
Cysteine 
DCR 
disease control rate 
DLRC 
Dose Level Review Committee 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EC 
epirubicin, cyclophosphamide 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ER 
estrogen receptor 
FAC/CAF  
5-fluorouracil, doxorubicin cyclophosphamide 
FCR 
fludarabine/cyclophosphamide/rituximab 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
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GCP 
Good Clinical Practice 
GLP 
good laboratory practices 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV  
hepatitis C virus 
HER2 
human epidermal growth factor receptor family member 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
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 
IHC 
immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible kinase  
IV 
Intravenous 
κ-Ras 
Kirsten rat sarcoma viral oncogene homolog 
LD 
longest diameter  
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
Overall survival 
PCR 
Polymerase Chain Reaction 
PD 
progressive disease 
PD-L1 
programmed death-ligand 1 
PET 
Positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (oral) 
PR  
partial response  
PT 
prothrombin time  
PTT 
partial thromboplastin time 
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Q2W 
every 2 weeks  
QTc  
QT interval corrected for heart rate  
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
REB 
research ethics board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease  
SJS 
Stevens-Johnson Syndrome 
SLL 
small lymphocytic lymphoma  
sPD-L1 
soluble PD-L1 
t1/2 
half-life 
T-DM1 
ado-trastuzumab emtansine or trastuzumab-DM1 
Th 
T-helper 
TLS 
tumor lysis syndrome 
Tmax 
time to maximum plasma concentration  
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VEGFR-2 
vascular endothelial growth factor receptor-2 
 
 
 
 
 
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1. 
BACKGROUND 
1.1. 
Non-Small Cell Lung Cancer  
Lung cancer is the leading cause of death due to cancer in the United States (US). In 2014, more 
than 110,000 new cases of lung and bronchial cancer in men and more than 100,000 new cases in 
women are expected to be diagnosed, and more than 150,000 deaths are estimated to occur due 
to lung cancer (Siegel 2014). The 5-year survival rate for lung cancer is 16.6% (Siegel 2014, 
Howlader 2009). Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancer 
cases and NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. 
NSCLC is most commonly associated with smoking tobacco or exposure to tobacco smoke or 
other pollutants but can be seen in anyone. Treatment options include combinations of surgery, 
radiation therapy, chemotherapy and molecularly-targeted therapies (eg, epidermal growth factor 
receptor [EGFR], anaplastic lymphoma kinase [ALK], mitogen-activated protein kinases 
[MAPK], phosphatidylinositide 3-kinases [PI3K] and others) (National Comprehensive Cancer 
Network [NCCN] guidelines for NSCLC). Except for very early stage disease, treatment is 
generally not curative and therapy is used to prolong survival. The presence of EGFR mutations 
within the tumor strongly predicts an improved response rate and progression-free survival 
(PFS). EGFR-targeted agents and ALK-inhibitors have been approved for use in NSCLC.  
Although many new active drugs and a multitude of chemotherapies in combination or as 
monotherapies are currently available for lung cancer, per NCCN guidelines, the reported 
second- and third-line response rates to systemic chemotherapy have generally been less than 
10% underscoring that treatment of NSCLC remains an unmet medical need. Treatment for 
relapsed or refractory NSCLC is under investigation with EGFR- and additional targeted 
therapies in clinical trials. Patients with genetic alterations (eg, mutations in EGFR, the human 
epidermal growth factor receptor family member 2 [HER2], B-Raf proto-oncogene [BRAF], and 
Kirsten rat sarcoma viral oncogene homolog [KRAS]; ALK, ROS proto-oncogene 1 [ROS1] and 
RET gene re-arrangements; MET amplification; and others) for which a targeted agent are 
available may be treated differently from patients with an absence of mutation(s). 
Thus, in the relapsed setting where patients are heavily pretreated, there remains a need for novel 
and improved therapies with improved safety profiles. 
1.2. 
Breast Cancer  
It is estimated that more than 235,000 patients in the US will be diagnosed with invasive breast 
cancer and more than 40,000 will die of the disease in 2014 (Siegel 2014). In 2013, more than 
64,000 additional cases of in situ breast cancer were diagnosed (DeSantis 2014, NCCN 
guidelines for breast cancer). Breast cancer is the most common malignancy in women in the 
US. The incidence of breast cancer has increased over the past decades, potentially due to greater 
surveillance, but the breast cancer mortality appears to be declining (Early Breast Cancer 
Trialists' Collaborative Group [EBCTCG] 2005, Berry 2005), suggesting a benefit from 
screening and improved treatment (Berry 2005). Many risk factors have been identified: female 
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gender, genetic mutations, age, family history, early menarche, late menopause, giving birth late, 
hormone replacement therapy, chest wall irradiation, benign proliferative breast disease, and 
increased breast density. Proliferative abnormalities in breast tissue are usually limited to the 
lobular and ductal epithelium and include hyperplasia, in situ carcinoma, and invasive carcinoma 
(Dupont 1985). Invasive carcinomas are ductal in origin in approximately 85%−90% of cases 
(Dupont 1985). Invasive ductal carcinomas include mucinous, adenoid cystic, and tubular 
carcinomas, which have favorable natural histories. In addition, other biologic features of the 
tumor can contribute to staging of the disease, assessment of recurrence risk, and predicting 
response to therapy, eg, expression of estrogen receptor, progesterone receptor, and the HER 
family member 2 (HER2). Estrogen and progesterone receptor status is usually determined by 
immunohistochemistry (IHC). HER2 testing can be done by assessing HER2 cell-surface 
receptors by IHC or by in situ hybridization (Wang 2000, Wolff 2013, Wolff 2014). If more 
than 10% of tumor cells are HER2 positive by IHC or the average HER2 copy number is more 
than 6.0 per cell by in situ hybridization, the tumor sample is considered positive. DNA 
microarray techniques identifying a gene expression profile can also be used to profile tumors 
(Jeffrey 2005). Hormone receptor status (estrogen and progesterone receptor) and expression of 
HER2 have significant therapeutic implications in the treatment of this disease. 
The clinical presentation is often asymptomatic and many cases are detected early in disease. 
Treatment of local breast cancer includes surgery, which may be curative in early stages, and 
radiation, or a combination of the two. Treatment of systemic breast cancer includes 
chemotherapy, endocrine therapy, and biologic therapy, or combinations of these. Adjuvant 
breast cancer therapy is used to treat lymph node disease or micrometastases. Selection of 
treatment is made based on prognostic and predictive factors, including tumor histology, clinical 
and pathological tumor characteristics, hormone receptor status, HER2 status, genetic testing, 
presence of metastatic disease, menopausal status, age, and comorbidities. Breast cancer may 
occur in men and treatment is similar to that of postmenopausal women except that when using 
aromatase inhibitors, testicular steroidogenesis needs to be suppressed (Giordano 2002a, 
Giordano 2002b). Per NCCN guidelines, breast cancer may further be divided into 
(1) noninvasive carcinomas, (2) locoregional invasive carcinoma with or without associated 
noninvasive carcinoma, (3) inoperable locoregional invasive carcinoma with or without 
associated noninvasive carcinoma, and (4) metastatic or recurrent carcinoma. In the past decade, 
many new and targeted therapies have been developed for the treatment of relapsed and 
metastatic breast cancer and have greatly improved overall survival. Many systemic therapies for 
breast cancer have an intolerable safety profile, eg frequently lead to hematologic side effects or 
neuropathy. Treatment options with a favorable safety profile for recurrent disease in a heavily 
pretreated patient population are still needed.  
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1.2.1. 
HER-2-positive Breast Cancer  
HER2 over-expression is seen in approximately 15%-30% of invasive breast cancers and is 
associated with a more aggressive tumor phenotype and a worse prognosis. Patients with HER2-
positive tumors can benefit from HER2-targeted therapies (Slamon 1989, Slamon 1987, 
Hudis 2007, Meric-Bernstam 2006, Giordano 2014, Mitri 2012). Treatment with HER2-targeted 
agents has been shown to improve survival for patients with early-stage or metastatic breast 
cancer (American Society of Clinical Oncology [ASCO]: Breast cancer. 
http://www.cancer.net/cancer-types/breastcancer; Gonzalez-Angulo 2009). The combination of 
pertuzumab, a HER-dimerization inhibitor, plus trastuzumab plus docetaxel, as compared with 
placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive 
metastatic breast cancer, significantly prolonged PFS in the randomized, double-blind, 
multinational, phase III CLEOPATRA trial (Keating 2012). Median overall survival (OS) was 
40.8 months in the placebo arm and 56.5 months in the pertuzumab arm, with a difference of 
15.7 months (ESMO abstract 3500_PR 2014). Several new agents have been approved by the US 
Food and Drug Administration (FDA) for the treatment of metastatic HER2-positive breast 
cancer since the approval of trastuzumab (Herceptin®) (Giordano 2014), but improvements for 
second and third line therapy are still needed because response rates and PFS in the relapsed 
setting are low, as expected, especially after multiple lines of prior therapy. In the EMILIA study 
(Verma 2012), 991 patients who were previously treated with trastuzumab and a taxane were 
randomly assigned to T-DM1 (ado-trastuzumab emtansine or trastuzumab-DM1 [KADCYLA®]) 
or lapatinib (TYKERB®) in combination with capecitabine (Xeloda®). Response rates were 
42.6% for the patients who received T-DM1 and 30.3% for the patients who received lapatinib in 
combination with capecitabine. Median PFS for these patients were 9.6 months and 6.4 months, 
respectively. Rates of adverse events (AEs) of grade 3 or above were higher with lapatinib plus 
capecitabine than with T-DM1 (57% vs. 41%) (Verma 2012). In a smaller study with 66 patients, 
patients with metastatic HER2-positive breast cancer who had experienced progression during 
prior trastuzumab therapy received trastuzumab and pertuzumab and the response rate was 
24.2% with a PFS of 18.5 months (Baselga 2010). 
The reported response rate in third line is yet lower. In the GSK-EGF100151 study (Geyer 2006, 
Cameron 2010), patients with HER2-positive locally advanced or metastatic breast cancer that 
had progressed after treatment with regimens that included an anthracycline, a taxane, and 
trastuzumab were randomly assigned to receive either combination therapy with lapatinib and 
capecitabine or capecitabine monotherapy. The safety profile showed no increase in serious toxic 
effects with the combination (Geyer 2006). The response rate was 22% and 14% for the two 
treatment arms, respectively (Geyer 2006). In the THERESA study, 602 patients with 
progressive HER2-positive advanced breast cancer who had received two or more HER2-
directed regimens were randomly assigned to T-DM1 or physician’s choice (404 and 
198 patients, respectively); 219 (54%) patients in the T-DM1 group and 129 (65%) of patients in 
the physician's choice group had PFS events after a median follow-up of 7.2 and 6.5 months, 
respectively. PFS was significantly improved with T-DM1 compared with physician's choice 
(median 6.2 months vs 3.3 months); a lower incidence of grade 3 or worse AEs was reported 
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with T-DM1 than with physician's choice (Krop 2014). Thus, since response rates and PFS times 
are relatively low in the relapsed setting, there remains a need for additional therapies, especially 
therapies with a tolerable safety profile for this heavily pretreated patient population. 
1.2.2. 
Triple-negative Breast Cancer  
Triple-negative breast cancer represents 10%–20% of invasive breast cancers (Boyle 2012) and 
is defined as estrogen receptor-negative, progesterone receptor-negative, and HER2-negative 
breast cancer. Triple-negative breast cancer is usually more aggressive compared to estrogen 
receptor-positive disease. Hormonal agents (eg, tamoxifen, aromatase inhibitors) that are 
commonly used in the treatment of breast cancer are ineffective, due to the absence of the 
corresponding receptors. Therapeutic options for patients with estrogen receptor-negative breast 
cancer are generally limited to a few chemotherapeutic agents.  
Several regimens have been shown to be active in patients with advanced breast cancer. Among 
combination regimens, per NCCN, the panel includes FAC/CAF (5-fluorouracil, doxorubicin 
cyclophosphamide); CEF (cyclophosphamide, epirubicin, 5-fluorouracil); AC (doxorubicin, 
cyclophosphamide); EC (epirubicin, cyclophosphamide); CMF (cyclophosphamide, 
methotrexate, 5-fluorouracil); docetaxel, capecitabine; gemcitabine, paclitaxel; and paclitaxel, 
bevacizumab.  
CAF has a response rate of 82 % versus 62% for CMF in a study where 78 patients with 
advanced metastatic breast cancer were randomized to either treatment. There was no significant 
difference in duration of response for the two arms (Bull 1978). In a study where 460 patients 
were randomized to either CEF or CMF, the overall response rate for CEF was with 57% higher 
than that for CMF with 46% (Ackland 2001). Time to progression was significantly longer with 
CEF compared to CMF (8.9 vs. 6.3 months with a 20-month follow-up time)(Ackland 2001). 
Response rates in a study comparing 105 patients who received FAC-BCG with 44 patients who 
received FAC alone were similar with 76% vs. 73%, however the duration of remission was 
longer (14 months vs. 9 months, respectively) and survival was significantly longer (24 months 
vs. 15 months, respectively) (Hortobagyi 1979). 
These listed chemotherapy regimens are used in patients with triple-negative breast cancer. The 
use of platinum-based regimens has also been explored. In a Phase 2 study of patients with 
metastatic triple-negative breast cancer, the efficacy and safety of gemcitabine and carboplatin 
with or without iniparib, a small molecule with PARP-inhibitory activity, was tested. The overall 
response rate was 52% (n=32) for the combination with iniparib and 32% (n=20) without 
iniparib (O’Shaughnessy 2011a). PFS was 5.9 and 3.6 months, respectively. The most common 
AEs were neutropenia, anemia and thrombocytopenia (O’Shaughnessy 2011a). A phase 3 trial 
testing this combination did not meet the pre-specified criteria for significance for co-primary 
endpoints of OS and PFS (O’Shaughnessy 2011b). However, in the relapsed setting combination 
chemotherapy provides higher overall response rates without a significant improvement in 
survival relative to single-agent therapy. Therefore, for patients with comorbidities or patients 
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who do not have aggressive disease, single-agent treatments with a more favorable safety profile 
are warranted. 
More recently, for patients with triple-negative relapsed and metastatic breast cancer who were 
enrolled in a Phase 3 study using ixabepilone (IXEMPRA®, an epothilone B analogue), in 
combination with capecitabine or capecitabine monotherapy, the response rates were 27% (n=91) 
for the combination and 9% (n=96) for capecitabine monotherapy (Pivot 2009). The median PFS 
was 4.1 months and 2.1 months, respectively. AEs were similar in patients with triple-negative 
breast cancer and the overall population; among the most frequent grade 3 or higher AEs were 
neutropenia, leucopenia and neuropathy (Pivot 2009). Another randomized Phase 3 study 
evaluated Halaven® (eribulin mesylate) versus capecitabine in 1,102 women with locally 
advanced or metastatic breast cancer who had up to 3 prior chemotherapy regimens. AEs were 
consistent with the known side-effect profiles of both drugs. For the subgroup with triple-
negative breast cancer, the median OS was 14.4 months compared to 9.4 months on capecitabine 
(Study 301 presented at 2012 SABCS). Also, a recent randomized phase 3 study evaluating 
adjuvant bevacizumab (Avastin®)-containing therapy in triple-negative breast cancer 
(BEATRICE study) led to the conclusion that bevacizumab cannot be recommended as adjuvant 
treatment in unselected patients with triple-negative breast cancer; an exploratory biomarker 
assessment suggested that patients with high pre-treatment plasma VEGFR-2 (vascular 
endothelial growth factor receptor-2) might benefit from the addition of bevacizumab 
(Cameron 2013), but this is not considered standard practice.  
In summary, several studies are underway attempting to improve the outcome in patients with 
triple-negative breast cancer, a subtype with limited treatment options beyond surgery, radiation 
and chemotherapy. The reported PFS for several agents is relatively short. The above data 
indicate that new agents and approaches are needed for this subset of patients.  
1.3. 
Pancreatic Adenocarcinoma  
During the year 2014 in the United States, more than 45,000 patients are estimated to be 
diagnosed with pancreatic cancer, and the majority of these patients are expected to die of their 
disease (Siegel 2014, NCCN guidelines for pancreatic cancer). After lung cancer, breast/prostate 
cancer, and colorectal cancer, pancreatic cancer is the fourth most common cause of death due to 
cancer in the US (Siegel 2014). The peak incidence of pancreatic cancer is in the seventh and 
eighth decade of life (Siegel 2014), and pancreatic cancer is thought to be more common in 
African Americans (Arnold 2009). The incidence of pancreatic cancer in the US recently 
increased, most likely due to the obesity epidemic, an aging population, and other unknown 
factors (Simard 2012, Eheman 2012, Smith 2009). Among the risk factors for pancreatic cancer 
are a genetic predisposition, increased body mass index (BMI) (Alsamarrai 2014, Larsson 2007, 
Li 2009, Patel2009), chronic pancreatitis, cigarette smoking (Anderson 2012), as well as red 
meat (Larsson 2005) and alcohol consumption (Lucenteforte 2012).  
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The best validated and most clinically used biomarker in pancreatic cancer is carbohydrate 
antigen (CA) 19-9, which is not tumor-specific, however has potential use in diagnosis, 
screening, staging, determining resectability, as a prognostic marker after surgery and as a 
predictive marker for response to chemotherapy (Morris-Stiff 2012). CA 19-9 is a poor 
biomarker for screening due to a low positive predictive value, but a good diagnostic marker 
with a sensitivity and also specificity of more than 80% (Ballehaninna 2012). A recent study 
found that normalization of CA 19-9 was associated with improved overall survival in 141 
patients with pancreatic cancer who were treated with chemotherapy, and this was the case in 
those who had surgery and in those who were treated conservatively (Tzeng 2014). 
Therapies for pancreatic adenocarcinoma include surgery, radiation, chemotherapy, and targeted 
therapies. The only curative treatment (although rare) is resection, with the best outcome as 
expected in early stages of the disease. In regards to chemotherapy, the response rate for 
pancreatic adenocarcinoma first-line treatment is approximately 20-30% (ORR 23% in 
Von Hoff 2013, Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine; 
ORR 19.1% in Cunningham 2009, Phase III randomized comparison of gemcitabine versus 
gemcitabine plus capecitabine in patients with advanced pancreatic cancer; ORR >30% in the 
ACCORD trial, Randomized phase II trial comparing folfirinox (5FU/leucovorin [LV], 
irinotecan [I] and oxaliplatin [O]) vs gemcitabine (G) as first-line treatment for metastatic 
pancreatic adenocarcinoma (MPA) (Ychou 2007). For second-line treatment with a single agent, 
the reported response rate is lower and ranges between 0% and 15% in different clinical trials 
(Walker 2014). For other second-line treatments with single-agent and combination regimens, 
the response rates vary between 0% and 30% in different clinical trials (Rahma 2013, 
Walker 2014), with the majority of trials having a response rate below 10% (Rahma 2013, 
Walker 2014). Thus, new treatment options are needed for advanced pancreatic cancer, 
especially treatment options with a tolerable safety profile for this usually very ill patient 
population.  
1.4. 
Ibrutinib Overview 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered covalentlybinding inhibitor 
of Bruton’s tyrosine kinase (BTK) by Pharmacyclics LLC for the treatment of B-cell 
malignancies. Ibrutinib has been approved in many regions, including the US and EU, for 
indications covering the treatment of patients with mantle cell lymphoma (MCL) and chronic 
lymphocytic leukemia (CLL) who have received at least one prior therapy, first-line treatment of 
patients with CLL with a deletion of the short arm of chromosome 17 (del17p) or a TP53 
mutation, and patients with Waldenström’s Macroglobulinemia. Ibrutinib is currently under 
investigation in various indications as a single agent and in combinations.  
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 B-cell receptor (BCR), which is activated by binding to 
antigen. Antigen binding induces receptor aggregation and the clustering and activation of 
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multiple tyrosine kinases, which in turn activate further downstream signaling pathways 
(Bishop 2003).  
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 (ibrutinib IB). 
1.4.1. 
Summary of Nonclinical Data  
1.4.1.1. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the Btk (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of Btk activity (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 BCR 
and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed 
by CD69 expression (Herman 2011).  
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB. 
1.4.1.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related 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 studies in pregnant rats and rabbits, ibrutinib administration was associated with 
malformations (teratogenicity) at ibrutinib doses that result in approximately 14 and 2 times the 
exposure (AUC) in patients administered the dose of 560 mg daily, respectively. Fetal loss and 
reduced fetal body weights were also seen in treated pregnant animals. Carcinogenicity studies 
have not been conducted with ibrutinib. In vitro and in vivo genetic toxicity studies showed that 
ibrutinib is not genotoxic. No effects on fertility or reproductive capacities were observed in a 
study in male and female rats. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current ibrutinib IB. 
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1.4.2. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB.  
1.4.2.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability. 
The mean half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours.  Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food. Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not considered clinically 
relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose 
exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 
patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or 
patients on dialysis have not been studied. Following single dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects 
with normal liver function. A higher proportion of Grade 3 or higher adverse reactions were 
reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.   
For the most comprehensive pharmacokinetics (PK) and product metabolism, please refer to the 
current version of the ibrutinib IB.  
1.4.3. 
Summary of Clinical Safety  
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below. For more comprehensive safety information please refer to the current version of the 
ibrutinib IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC).  
1.4.3.1. 
Monotherapy Studies in Hematologic Malignancies 
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
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Most frequently reported  
TEAEs >10%   
Most frequently reported  
Grade 3 or 4 TEAEs >2%  
Most frequently reported  
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
 
1.4.3.2. 
Combination Studies 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below. Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone).  
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 
Most frequently reported  
TEAEs >10%   
Most frequently reported  
Grade 3 or 4 TEAEs >2%  
Most frequently reported  
Serious TEAEs >1%  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
 
1.4.4. 
Risks 
1.4.4.1. 
Bleeding-related Events  
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. See Section 6.2.3 for guidance 
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on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 6.4 
for guidance on ibrutinib management with surgeries or procedures.   
1.4.4.2. 
Atrial fibrillation 
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. For atrial fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines (see Section 5.5.1.4) 
1.4.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
1.4.4.4. 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events were rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.5.1.4). 
1.4.4.5. 
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 NCI Common 
Terminology Criteria for Adverse Events (CTCAE, v4.03). The most commonly reported 
infections include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has 
not been established, cases of progressive multifocal leukoencephalopathy (PML) have occurred 
in patients treated with ibrutinib. 
1.4.4.6. 
Other Malignancies 
Other malignancies, most frequently skin cancers, have occurred in subjects treated with 
ibrutinib. Other malignancies including non-skin carcinomas have occurred in patients treated 
with ibrutinib. The most frequent second primary malignancy was non-melanoma skin cancer. 
1.4.4.7. 
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.  
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1.4.4.8. 
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 TLS are those 
with comorbidities and risk factors such as high tumor burden prior to treatment, increased uric 
acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and 
pre‐existing kidney abnormalities. 
1.4.5. 
Summary of Clinical Data  
This is an exploratory study and there is no clinical data on the use of the combination of 
ibrutinib and MEDI4736 in NSCLC (adenocarcinoma and squamous-cell carcinoma), 
HER2-positive breast cancer, triple-negative breast cancer or pancreatic adenocarcinoma. 
1.5. 
Durvalumab (MEDI4736) Overview 
AstraZeneca and MedImmune are pursuing development of durvalumab (MEDI4736) as a 
potential anticancer therapy for patients with advanced solid tumors. 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], cluster of 
differentiation [CD]274) 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 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).  
1.5.1. 
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/PD and 
potential toxicity of MEDI4736. Following intravenous (IV) administration, the PK of 
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MEDI4736 in cynomolgus monkeys was nonlinear. Systemic clearance (CL) decreased and t1/2 
increased with increasing doses, suggesting saturable target binding-mediated clearance of 
MEDI4736. No apparent gender differences in pharmacokinetics 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) pharmacokinetics and pharmacodynamics 
and dose range-finding study, and a GLP 4-week repeat-dose toxicity study were consistent with 
anti-drug antibody (ADA)-associated morbidity and mortality in individual animals. The death of 
a single animal in the non-GLP, pharmacokinetics and 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 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) 
1.5.2. 
Summary of Clinical Data  
Clinical experience with durvalumab (MEDI4736) is fully described in the current version of the 
durvalumab Investigator’s Brochure (Version 8.0). 
As of the data cut off dates (15Apr2015 to 12Jul2015, Durvalumab IB Version 8.0), a total of 
1,883 subjects have been enrolled and treated in 30 ongoing durvalumab clinical studies, 
including 20 sponsored and 10 collaborative studies. Of the 1,883 subjects, 1,279 received 
durvalumab monotherapy, 440 received durvalumab in combination with tremelimumab or other 
anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 150 have been 
treated with blinded investigational product. No studies have been completed or terminated 
prematurely due to toxicity. 
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Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 378 subjects 
in the dose-escalation and dose-expansion phases of Study CD-ON-durvalumab-1108 following 
treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks 
(Q3W). The maximum observed concentration (Cmax) increased in an approximately 
dose-proportional manner over the dose range of 0.1 to 15 mg/kg. 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 3 mg/kg and increased 
dose-proportionally at ≥3 mg/kg. These results suggest durvalumab exhibits nonlinear PK likely 
due to saturable target-mediated CL at doses <3 mg/kg and approaches linearity at doses 
≥3 mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 [sPD-L1] 
and membrane bound) is expected with durvalumab ≥3 mg/kg Q2W. Exposures after multiple 
doses showed accumulation consistent with PK parameters estimated from the first dose. In 
addition, PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, >90% of 
subjects are expected to maintain PK exposure ≥40 µg/mL throughout the dosing interval. 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 
388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg 
cohort) were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg 
cohort. 
1.5.3. 
Summary of Clinical Safety  
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important 
potential risk particularly with durvalumab and tremelimumab combination therapy. These 
events are manageable by available/established treatment guidelines as described in the study 
protocols. 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
Adverse Event Profile of durvalumab Monotherapy 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 
694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 1,279 subjects 
who have received durvalumab monotherapy (not including subjects treated with blinded 
investigational product) across the clinical development program. The majority of 
treatment-related AEs were manageable with dose delays, symptomatic treatment, and in the 
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case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity. As of 07 May2015, among the 694 subjects treated with durvalumab 
10 mg/kg Q2W in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) experienced 
a treatment-related AE, with the most frequent (occurring in ≥5% of subjects) being fatigue 
(17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 
in severity with Grade ≥3 events occurring in 65 subjects (9.4%). Treatment-related Grade ≥3 
events reported in 3 or more subjects (≥0.4%) were fatigue (12 subjects, 1.7%); increased 
aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase 
(GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and 
colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had 
treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 
event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in ≥2 subjects 
were colitis and pneumonitis (3 subjects each). A majority of the treatment-related SAEs were 
Grade ≥3 in severity and resolved with or without sequelae. AEs that resulted in permanent 
discontinuation of durvalumab were considered as treatment related in 18 subjects (2.6%), with 
colitis being the most frequent treatment-related AE resulting in discontinuation (3 subjects). 
A majority of the treatment-related AEs resulting in discontinuation of durvalumab were 
Grade ≥3 in severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in 
Study CD-ON-durvalumab-1108 is generally consistent with that of 
Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-cell 
lung cancer (NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 
303 subjects (87.1%) reported any AE in Study D4191C00003/ATLANTIC. Overall, events 
reported in ≥10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite 
(17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly 
two-thirds of the subjects experienced AEs that were Grade 1 or 2 in severity and manageable by 
general treatment guidelines as described in the current durvalumab study protocols. Grade 3 or 
higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) 
reported AEs that were considered by the investigator as related to investigational product. 
Treatment-related AEs (all grades) reported in ≥2% of subjects were decreased appetite (6.6%); 
fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting 
(2.0%). Treatment-related Grade 3 AEs reported in ≥2 subjects were pneumonitis (3 subjects) 
and increased GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four 
of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥1.0% of subjects were 
dyspnea (6.6%); pleural effusion, general physical health deterioration (2.3% each); pneumonia 
(2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, respiratory failure, 
disease progression (1.0% each). Nine subjects had an SAE considered by the investigator as 
related to durvalumab. Each treatment-related SAE occurred in 1 subject each with the exception 
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of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an 
AE (pneumonia [3 subjects]; general physical health deterioration, disease progression, 
hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary 
arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None of these events 
was considered related to durvalumab. Twenty-three of 303 subjects (7.6%) permanently 
discontinued durvalumab treatment due to AEs. Events that led to discontinuation of durvalumab 
in ≥2 subjects were dyspnea, general physical health deterioration, and pneumonia. Treatment-
related AEs that led to discontinuation were increased ALT and increased hepatic enzyme, which 
occurred in 1 subject each. 
1.5.4. 
Summary of Clinical Efficacy 
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab 
10 mg/kg Q2W were evaluable for response (defined as having ≥24 weeks follow-up, 
measurable disease at baseline, and ≥1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in bladder cancer 
(n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative 
breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status 
was known for 383 of the 456 response evaluable subjects. Across the PD-L1-positive tumors, 
ORR was highest for bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma 
(HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the 
head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-positive subset, DCR-24w was highest in 
advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 36.0%), HCC and bladder 
cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in 
Study D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among these 
subjects, the best overall responses were marrow complete remission (mCR) in 4 subjects 
(19.0%); stable disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 subjects 
(23.8%). The remaining 8 subjects (38.1%) did not meet the criteria for complete remission 
(CR), mCR, partial remission (PR), SD, or PD at the date of assessment. 
Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or unresectable melanoma 
treated with the combination of durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK 
inhibitor (MEKi; trametinib), 63 subjects were evaluable for response. A total of 35 subjects 
(55.6%) had a best overall response of confirmed or unconfirmed PR. The disease control rate 
(DCR; CR + PR [regardless of confirmation] + SD ≥12 weeks) was 79.4%.  
1.6. 
Study Rationale 
With respect to MEDI4736, PD-L1 expressed on tumor cells inhibits anti-tumor immune 
responses (Zou 2008). PD-1 is expressed on activated T cells, B cells and myeloid cells to 
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modulate immune activation or inhibition (Butte 2008). MEDI4736 is a PD-L1 inhibitor which 
binds to PD-L1 and allows T cells to recognize and kill tumor cells (MedImmune/AstraZeneca, 
Data on file). Preclinical and early clinical data suggest a benefit with PD-L1 inhibitors for 
patients with NSCLC and pancreatic adenocarcinoma. Preclinical data suggests a benefit in 
HER2-positive breast cancer models. PD-L1 is often expressed in triple-negative breast cancer, 
and patients with triple-negative breast cancer are currently enrolled in a trial with a PD-L1 
inhibitor at MedImmune/AstraZeneca (efficacy data are pending). 
With respect to the anti-tumor activity of ibrutinib, there are three potential mechanisms that may 
be operative in solid tumors: (1) direct tumor effects, eg inhibition of EGFR, HER2; (2) changes 
in the tumor microenvironment, eg inhibition of mast cell function; and (3) changes in immune 
profiles, eg alteration of Th1/Th2 polarity. 
With these distinct mechanisms of action, MEDI4736 and ibrutinib may act synergistically in 
enhancing the host anti-tumor response. 
The effects of the combination of an anti–PD-L1 antibody and ibrutinib in suppressing tumor 
growth were documented in mouse models of a variety of solid tumors, such as triple negative 
breast cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was 
accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest 
that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic 
(Sagiv-Barfi 2015). 
1.6.1. 
MEDI4736 
1.6.1.1. 
Tumor Immunotherapy and Programmed Death-Ligand 1 (PD-L1)  
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked by the host immune system. One such mechanism involves upregulation of surface 
proteins that deliver inhibitory signals to cytotoxic T cells. PD-L1 is one such protein, and is 
upregulated in a broad range of cancers with a high frequency, with up to 88% expression in 
some indications. In a number of these cancers, including lung (Mu 2011), renal 
(Thompson 2005; Thompson 2006; Krambeck 2007), pancreatic (Nomi 2007; Loos 2008; 
Wang 2010), and ovarian cancer (Hamanishi 2007), tumor cell expression of PD-L1 is associated 
with reduced survival and an unfavorable prognosis. For example, in ovarian cancer, the 5-year 
survival rate in patients with low expression of PD-L1 was 80.2% compared to 52.6% in patients 
with high expression levels of PD-L1 (Hamanishi 2007). In lung cancer, only 20% of patients 
with tumors expressing PD-L1 survived for more than 3 years compared to 49% of patients with 
tumors lacking PD-L1 expression (Mu 2011). Along with PD-L1 expression data generated at 
MedImmune/AstraZeneca, these data suggest that an antibody targeting PD-L1 may have the 
potential to affect multiple solid tumor types.  
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Programmed death-ligand 1 (PD-L1) is part of a complex system of receptors and ligands that 
are involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses 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 PD-1 or CD80 on activated T cells and delivers an inhibitory signal to 
the T cell (Keir 2008, Park 2010). This results in reduced T-cell activation and fewer activated T 
cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to 
PD-1 and CD80 on activated T cells that are reaching the tumor. The binding delivers an 
inhibitory signal to those T cells, preventing them from killing target cancer cells and protecting 
the tumor from immune elimination (Zou 2008).  
Ten clinical studies of MEDI4736 are ongoing (5 employing MEDI4736 as monotherapy and 
5 as combination therapy) across various tumor indications. Encouraging clinical activity of 
MEDI4736 combined with acceptable and manageable safety has been demonstrated across the 
monotherapy and combination therapy studies. These data provide a sound rationale for further 
development of MEDI4736 in advanced solid tumors and hematologic malignancies 
(MEDI4736 IB).  
1.6.2. 
Ibrutinib 
1.6.2.1. 
Direct Tumor Effects-ErbB Family Kinase Inhibition by Ibrutinib 
Ibrutinib binds covalently to the Cystein-481 residue which is within the active site of BTK. 
Since this residue is conserved in only 9 other kinases, such binding affords a high degree of 
selectivity with once daily dosing. The ErbB family of kinases are, however, among those 
retaining homology, and the ability of ibrutinib to target these kinases in tumors has been studied 
(Elias 2013, Chen 2014). Significant in vitro growth inhibitory activity of ibrutinib at 
concentrations within those attainable clinically was demonstrated in HER2-amplified breast 
cancer lines. Growth inhibition was further demonstrated in vivo in a mouse xenograft model at 
clinically relevant doses. Importantly, the anti-tumor activity of ibrutinib in HER2-positive 
breast cancer cell lines was superior to that of lapatinib, which is approved for this indication, 
and its enzymatic potency for HER2 (measured by IC50) was nearly three times lower.  
Ibrutinib was also found to have anti-tumor activity in a panel of EGFR-driven NSCLC cell lines 
(Gao 2014). Three cell lines were highly susceptible to ibrutinib, with IC50 between 0.002 and 
0.195 uM. Two of the cell lines tested (including erlotinib-resistant H1975 cells) harbored 
activating mutations in the EGFR gene. Ibrutinib was found to selectively inhibit growth of cells 
carrying these mutations. Importantly, the H1975 cell line was insensitive to erlotinib, but 
susceptible to ibrutinib. The effect of ibrutinib on EGFR-phosphorylation was also analyzed. 
Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, 
suggesting ibrutinib functions as an EGFR inhibitor (Gao 2014). The expression of BTK was not 
detectable in all cell lines tested, indicating that ibrutinib-induced antitumor activity in these cells 
was not mediated by BTK. An in vivo study showed that ibrutinib suppressed H1975 tumor cell 
growth and prolonged survival of the tumor-bearing mice. These results indicate that ibrutinib 
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could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant 
tumors (Gao 2014). Further, ibrutinib exhibited superior in vitro growth inhibition to erlotinib in 
a patient-derived xenograft bearing the L858R/T790M mutation and had nearly twice the 
potency compared to gefitinib against this mutant EGFR in enzyme-activity assays.  
1.6.2.2. 
BTK-mediated Microenvironment Modulation 
Several emerging lines of evidence suggest that BTK inhibition in solid tumors may be relevant 
due to modulation of the tumor microenvironment. These mechanisms may be applicable for a 
wide range of solid tumor types. Ibrutinib has been shown to inhibit in vivo tumor growth in a 
myc-driven genetically engineered pancreatic islet cell carcinoma model, and more recently in a 
k-ras driven pancreatic ductal adenocarcinoma model. This was attributed in both models to 
inhibition of mast-cell degranulation with a resulting anti-angiogenic effect (Soucek 2011, 
Masso-Valles 2013, Masso-Valles 2015). Extensive correlative evidence points to a role of 
infiltrating mast cells in progression of numerous tumor types (Dalton 2012), as does direct 
functional evidence from genetically engineered models (Soucek 2007, Chang 2011, Ma 2013). 
Bruton tyrosine kinase (BTK) is known to be essential for IgE-stimulated basophile 
degranulation (Iwaki 2005), a function which has been shown to be inhibited by ibrutinib 
(MacGlashan 2011), and which was also inhibited in mast-cell models (Soucek 2011, Masso 
2013). Ibrutinib treatment in these reports was also associated with decreases of Gr1+ infiltrating 
myelomonocytic cells which may contribute pro-angiogenic and pro-proliferative signaling. All 
described mechanisms may contribute to an anti-tumor effect.  
1.6.2.3. 
ITK (Interleukin-2-inducible Kinase)-mediated T-Cell Polarization 
Ibrutinib is an irreversible inhibitor of interleukin-2-inducible kinase (ITK) (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. Patients with CLL treated with ibrutinib have been shown to have shifts of T-helper 
(Th) polarization to a more favorable Th1 bias (Dubovsky 2013). In addition, studies of T-cell 
function in vitro and in murine neoplastic (CLL), parasitic infection (Leishmania major), and 
infectious disease (Listeria monocytogenes) models in vivo, analyses have confirmed ibrutinib as 
a clinically relevant and physiologically potent ITK inhibitor (Dubovsky 2013). ITK inhibition 
reduces Th2-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 checkpoint inhibitors such as 
PD-L1-inhibitors. 
1.7. 
Study Rationale in Specific Solid Tumors 
1.7.1. 
Non-small Cell Lung Cancer (NSCLC) 
The role of EGFR inhibition in lung cancer is well established. Responsiveness correlates 
primarily to the presence of EGFR activating mutations, with resistance often correlating with 
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development of the gatekeeper mutation T790M, and activation of other pathways involving 
MET or k-RAS, for example. Nonetheless patients progressing on (or not tolerating) one EGFR 
inhibitor may subsequently respond to another inhibitor (Wong 2010, Teng 2014, Watanabe 
2011). Importantly, ibrutinib has been found to have anti-tumor activity in both EGFR wild-type 
and mutant NSCLC cell lines. NSCLC is also being recognized as potentially more sensitive to 
immunologic mechanisms than has been suggested in the past, and evidence has suggested a role 
for mast cells in NSCLC progression (Takanami 2000, Ullah 2012). Therefore, the ability of 
ibrutinib to modulate T-cell subsets and mast cell activation could be relevant and ibrutinib may 
act synergistically with the ability of MEDI4736 to stimulate T-cell activity and augment its 
established clinical activity in NSCLC.  
With MEDI4736, in multiple tumor types including NSCLC, early and durable clinical activity 
(tumor reduction) was observed at multiple doses as early as 6 weeks, and was maintained 
through 67+ weeks and off active therapy (Lutzky 2014). Phase 3 studies in NSCLC using the 
dose of 10 mg/kg every 2 weeks for 12 months are underway.  
1.7.2. 
Breast Cancer 
In in vivo breast cancer models, ibrutinib was shown to sensitize 4T1 mammary tumor cells to 
anti-PD-L1 treatment with respect to inhibition of tumor cell growth (Sagiv-Barfi et al, 
unpublished results). Treatment with ibrutinib and a PD-L1 inhibitor was also effective in 
suppressing lung metastasis (Sagiv-Barfi et al, unpublished results).  
In light of the encouraging preclinical data showing that ibrutinib in combination with a PD-L1 
inhibitor is effective in breast cancer models, testing the combination of ibrutinib and MEDI4736 
in patients with specific subtypes of metastatic breast cancer is warranted.  
1.7.2.1. 
HER2-positive Breast Cancer 
HER2-expressing breast cancer is a well-recognized indication for HER2-targeted therapy, with 
multiple tyrosine-kinase inhibitors and monoclonal antibodies approved and in use in this setting 
(Jelovac 2013). Further, response to re-treatment with similarly targeted HER2-antagonists after 
progression does indeed occur. For example, in the EMILIA study (Verma 2012), 991 patients 
who were previously treated with trastuzumab and a taxane were randomly assigned to T-DM1 
(ado-trastuzumab emtansine or trastuzumab-DM1 [KADCYLA®]) or lapatinib (TYKERB®) in 
combination with capecitabine (Xeloda®). The overall survival was 30.9 months for the patients 
who received T-DM1 and 25.1 months for the patients who received lapatinib in combination 
with capecitabine. The response rates were 43.6% for T-DM1 and 30.8% for the combination. In 
a smaller study (Cortes 2012), 29 patients with HER2-positive breast cancer who failed prior 
trastuzumab (Herceptin®)-based therapy received pertuzumab and 17 patients continued to 
receive pertuzumab with the addition of trastuzumab. Although pertuzumab showed some 
activity in patients with HER2-positive breast cancer who failed prior trastuzumab-based 
therapy, the combination of pertuzumab and trastuzumab led to a PFS benefit (17.4 versus 
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7.1 weeks without trastuzumab). The response rates were 17.6% for the combination of 
pertuzumab and trastuzumab and 3.4% for pertuzumab monotherapy. 
Another HER2 antagonist, TYKERB® (lapatinib), is used in combination with Xeloda® 
(capecitabine) for the treatment of patients with advanced or metastatic breast cancer whose 
tumors overexpress HER2, and who have received prior therapy including an anthracycline, a 
taxane, and trastuzumab (TYKERB label). Ibrutinib was shown to have a level of enzymatic and 
cellular potency which appears to be at least comparable to that of lapatinib (Elias 2013, 
Chen 2014), and clinical testing of this indication is therefore of interest. When comparing 
ibrutinib to other ErbB inhibitors in breast-cancer cell lines, it was shown that breast cancer 
growth inhibition with ibrutinib was comparable to lapatinib, neratinib, dacomitinib, and afatinib 
in BT-474 and SK-BR3 cell lines (Chen 2014). Supported by the findings from the in vivo breast 
cancer models showing that ibrutinib has the potential to augment the activity of a PD-L1 
antagonist such as MEDI4736, HER2-positive breast cancer seems an appealing target for the 
combination.   
1.7.2.2. 
Triple-Negative Breast Cancer  
There is evidence that triple negative breast cancer tumors express PD-L1. In a recent study, 
tumor biopsies from triple negative breast cancer patients with early and advanced metastatic 
disease who underwent primary surgery and distant lesion biopsy were examined for PD-L1 
expression (Tessari 2014). PD-L1 was expressed in 100% of early triple negative breast cancer 
and in 92% of corresponding metastatic lesions. Another study using archived tumor samples 
also looked at PD-L1 expression in triple negative breast cancer (Mittendorf 2013). RNA 
sequencing showed greater expression of the PD-L1 gene in triple negative breast cancer versus 
non-triple negative breast cancer (P <0.001). Further, PD-L1 positive tumors had greater 
CD8+ T-cell infiltrates than PD-1 negative tumors (688 cells/mm vs. 263 cells/mm; P <0.0001) 
(Mittendorf 2013). Therefore, the combination of ibrutinib and MEDI4736 seems well suited for 
this subtype of breast cancer that has limited effective therapy options beyond standard 
chemotherapy.   
1.7.3. 
Pancreatic Adenocarcinoma 
Mast cells have previously been proposed as targets for cancer therapy (Soucek 2007). Soucek et 
al have shown that the oncogene myc can instruct a complex inflammatory program involving 
recruitment of mast cells, which are necessary in the tumor microenvironment for the physical 
expansion and maintenance of tumors. In a mouse pancreatic ductal adenocarcinoma model 
comprised of transgenic animals with pancreas-specific expression of κ-RasG12D (Hingorani 
2003), which is one of the most common mutations in pancreatic cancer, it was shown that 
inflammatory cells including mast cells are present in the tumor microenvironment. With 
ibrutinib treatment, general tumor size was reduced (Soucek 2012). BTK is required for mast cell 
degranulation and when given in approved doses, ibrutinib achieves nearly complete BTK 
occupancy for 24 hours. In the model, mast cells are still recruited to the tumor 
microenvironment, but are no longer degranulating (Soucek 2012). Further, ibrutinib was shown 
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to reduce tumor proliferation and tumor vasculature (Soucek 2012). Ibrutinib also reduced 
inflammatory cell infiltration and reduced collagen deposition. Mice that were treated with 
ibrutinib had a survival benefit (Soucek 2012; Masso-Valles 2015). 
The fact that pancreatic cancer has a dismal prognosis is in part related to its relative resistance 
to chemotherapy. New approaches are needed to treat this difficult disease. As reported by Segal 
et al (Segal 2014), MEDI4736 was shown to have early evidence of antitumor activity in 
pancreatic cancer patients. With the effect of ibrutinib on mast cells and other cells in the tumor 
microenvironment and the potential to augment the antitumor activity of MEDI4736, this novel 
combination provides a potential alternative approach to standard therapy for this disease. 
1.8. 
Dosing Rationale 
1.8.1. 
Ibrutinib Dose 
Ibrutinib has been FDA-approved for MCL at a dose of 560 mg and for CLL at a dose of 
420 mg. 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). 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). With respect to safety, 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 this data, fixed dose levels of >280 mg are expected to be necessary to ensure 
achievement of the full pharmacodynamics effect in the vast majority of patients. The sustained 
pharmacodynamics effect despite a relative rapid elimination of ibrutinib is secondary to 
irreversible inhibition of BTK in subjects’ PBMCs (ibrutinib IB). Consistent with this, once-a-
day oral dosing resulted in 24-hour sustained target inhibition in these trials.  
In contrast to studies in B-cell malignancies, there are multiple possible enzymatic targets whose 
inhibition could contribute to efficacy in solid tumors. In vitro and preclinical studies have 
shown that ibrutinib covalently binds to the cysteine-481 amino acid of the BTK enzyme and 
inhibits numerous processes, including ERK signaling, NF-κB DNA binding, cytosine–
phosphate–guanine (CpG)-mediated CLL-cell proliferation, and tumor-cell migration 
(ibrutinib IB). For solid tumors, the key target for mast cells and infiltrating myelomonocytic 
cells in the tumor microenvironment is BTK, whose inhibition can be reliably achieved at well 
tolerated doses. In addition, a high level of occupancy of the T-cell specific kinase ITK has been 
achieved in a study with CLL patients using ibrutinib doses of 420 mg once daily. The enzymatic 
IC50 of ibrutinib for EGFR and HER2 are higher than that for BTK, however the concentrations 
required for enzymatic inhibition in cells, and inhibition of cellular growth of sensitive cell lines 
in vitro, is similar to or only slightly higher than that required for BTK (Elias 2013; Chen 2014). 
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Growth inhibition of a breast cancer xenograft in vivo has furthermore been noted with doses that 
are effective, but not fully optimal, for BTK occupancy or for in vivo inhibition of lymphoma 
xenografts. Therefore, the approved doses of 560 or 420 mg/day may be effective in suppressing 
growth of tumors that are driven by ErbB receptors (epidermal growth factor receptor [EGFR; 
ErbB1], HER-2 [ErbB2], ErbB3, and ErbB4) (Yarden 2001, Olayioye 2000).  
Due to the extensive clinical experience with the 560 mg dose in terms of safety and efficacy, 
and due to the expected variability in the sensitivity of the solid tumors studied in this trial, a 
dose of 560 mg/day has been chosen for the initial cohort in this study. 
1.8.2. 
Durvalumab (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). 
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). The MEDI4736 10 mg/kg 
every-2-week cohort comprised subjects with nonsquamous NSCLC (n = 100), squamous 
NSCLC (n = 72), hepatocellular carcinoma (n = 20), triple-negative breast cancer (n = 26), 
pancreatic adenocarcinoma (n = 32), gastroesophageal cancer (n = 36), advanced cutaneous 
melanoma (n = 21), uveal melanoma (n = 23), squamous cell carcinoma of the head and neck 
(SCCHN, n = 59), and other (n = 4). 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. Treatment-related AEs (all grades) in 
>5% of subjects included fatigue (13.5%), nausea (8.4%), and diarrhea, rash, and decreased 
appetite (5.3% each). In general, Grade 3 or higher AEs were manageable with standard clinical 
toxicity management. Grade 3 or higher AEs that occurred in >1% of subjects were dyspnea 
(5.1%), increased gamma-glutamyltransferase (3.3%), fatigue, general physical health 
deterioration, increased aspartate aminotransferase, and back pain (2.3% each), anemia and 
dehydration (1.8% each), and abdominal pain, vomiting, sepsis, syncope, and hypotension (1.3% 
each). 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).  
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As reported at ASCO by Lutzky et al, in multiple tumor types including NSCLC, pancreatic 
cancer and triple-negative breast cancer relevant for this study protocol, 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 safety and efficacy data above, a dose of 10 mg/kg every 2 weeks for 12 months 
was chosen for the initial cohort in this study.   
1.8.3. 
Ibrutinib and MEDI4736 in Combination  
Based on the above findings which describe the safety and pharmacokinetics profiles of ibrutinib 
and MEDI4736, the low discontinuation rate due to AEs, the low dose reduction rate, and the 
low 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 26). 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.  
2. 
STUDY OBJECTIVE  
2.1. 
Primary Objective 
Phase 1b:  
• To determine the Recommended Phase 2 Dose (RP2D) or MTD of ibrutinib in 
combination with MEDI4736 in subjects with relapsed or refractory solid tumors 
• To determine the safety and tolerability of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory solid tumors  
Phase 2:  
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory solid tumors by assessing the ORR 
2.2. 
Secondary Objective(s) 
Phase 1b:  
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 by assessing the 
ORR in subjects with relapsed or refractory solid tumors 
• To evaluate the efficacy of ibrutinib in combination with MEDI4736 by assessing the 
DCR at Week 20 (Cycle 5) 
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• To evaluate the efficacy of ibrutinib in combination with MEDI4736 by assessing the 
DOR 
• To determine the pharmacokinetics and pharmacodynamics of ibrutinib in combination 
with MEDI4736 in subjects with relapsed or refractory solid tumors 
Phase 2:  
• To determine the efficacy of ibrutinib in combination with MEDI4736 in subjects with 
relapsed or refractory solid tumors by assessing the DCR at Week 20 (Cycle 5), DOR, 
PFS, and OS 
• To determine the safety and tolerability of ibrutinib in combination with MEDI4736 in 
subjects with relapsed or refractory solid tumors 
• To determine the pharmacokinetics and pharmacodynamics of ibrutinib in combination 
with MEDI4736 in subjects with relapsed or refractory solid tumors  
2.3. 
Exploratory Objective(s)  
• To evaluate immune-cell subsets after treatment with ibrutinib in combination with 
MEDI4736 
• To evaluate non-BTK-related pharmacodynamics (ie, ITK, EGFR) 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/or proteins (within the tumor or other collected specimens) 
associated with sensitivity or resistance to ibrutinib and/or MEDI4736 (ie, PD-L1) 
3. 
STUDY DESIGN  
3.1. 
Overview of Study Design 
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib and 
MEDI4736 in subjects with relapsed or refractory solid tumors. A 6+3 de-escalation design will 
be employed in Phase 1b (see Section 5.2) to assess doses of ibrutinib in combination with 
MEDI4736 to determine the RP2D or MTD for this study. In Phase 2, independent analyses will 
be performed for each tumor type cohort to evaluate the response and safety profile of the 
combination therapy. 
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 and 
will include a sentinel subject which will have a 3-day observation period prior to dosing of 
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subsequent subjects. Subjects with one of the following three tumor types will be eligible for 
enrollment: 
• NSCLC (adenocarcinoma or squamous-cell carcinoma) 
• Breast cancer (HER2 positive or triple negative) 
• Pancreatic cancer (adenocarcinoma) 
In cohort 1, 6 subjects regardless of tumor type, ibrutinib will be administered PO at a dose of 
560 mg daily in combination with MEDI4736 at a dose of 10 mg/kg IV every 2 weeks in 28-day 
cycles until DLT or disease progression occurs. Re-treatment with MEDI4736 will not be 
permitted following completion of 12 months of therapy, regardless of any dose delays, missed 
doses, or following permanent discontinuation for any reason. Dosing of ibrutinib will continue 
for 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. The DLT observation period includes Cycle 1 
and laboratory assessments on Day 1 of Cycle 2 which will occur before the MEDI4736 infusion 
on Day 1 of Cycle 2. 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 subjects experience 
a DLT, dose de-escalation will occur. If subject incidence of DLTs during the first 28 days 
(Cycle 1=28 days and including laboratory assessments on Day 1 Cycle 2) of study treatment 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.  
A similar 6+3 cohort design will be utilized in the dose de-escalation cohorts (see Table 1 and 
Section 5.2). De-escalation cohorts -(minus)1A and -1B will be opened simultaneously to 
determine which dosing schedule is most appropriate for the phase 2 portion of the study. 
Determination of the RP2D will be based on the safety profile of the 2 treatment regimens. If 
necessary, the dose de-escalation cohort -2 will be enrolled thereafter. 
Table 1. 
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 Cycle 1 Day 1. 
b. MEDI4736 will be administered IV on Day 1 and Day 15 of each 28-day cycle for a maximum of 12 months. 
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 5.3. 
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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. 
Phase 2: 
Subjects with one of three solid tumor types (Stage III/IV) will be enrolled in separate cohorts in 
the Phase 2 portion of this protocol: 
• NSCLC (adenocarcinoma and squamous-cell carcinoma at an approximate 2:1 ratio)   
• Breast cancer (triple-negative and HER2-positive breast cancer at an approximate 2:1 
ratio) 
• Pancreatic cancer (adenocarcinoma) 
For each of the above three cohorts, an interim analysis will be performed to evaluate the 
response and the safety profile. A cohort may be discontinued based on the interim efficacy 
and/or safety results. The decisions based on the results of the interim analysis are independent in 
the 3 individual disease cohorts. 
At the time of the interim safety assessment, the safety team will review and make 
recommendations for the conduct of the study. Members of the safety team will include 
participating investigators or designees as well as the Sponsor (at a minimum: the Medical 
Monitor or designee, a Drug Safety representative and a Biostatistician). The safety team may 
recommend continuing the trial unchanged, or may recommend to consider modifying in part or 
in whole, or to stop the trial due to safety concerns. 
NSCLC and breast cancer:  
• Interim analysis: n=18 per tumor type  
• Primary analysis: n=43 per tumor type 
The NSCLC and breast cancer cohorts will enroll 18 subjects per tumor type for the interim 
analysis and additional 25 subjects per tumor type for the primary analysis (total n=43). An 
interim analysis will be performed after 18 subjects are evaluable for tumor response. If a subject 
discontinues prior to the first tumor response assessment for reasons other than progressive 
disease, the subject will be replaced. If 2 or fewer responders are observed among the 
18 evaluable subjects in a cohort, the Sponsor may consider discontinuation of this cohort; 
however, assessment of biomarkers (that may aid in prospective enrichment for responders) or 
tumor measurements (showing clinically relevant tumor reductions, ie, <30%, that fit the criteria 
for SD) may support continued enrollment.  
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Pancreatic cancer: 
• Interim analysis: n=17   
• Primary analysis: n=44  
For the interim analysis, 17 subjects will be enrolled, and additional 27 subjects will be enrolled 
for the primary analysis (total n=44). An interim analysis will be performed after 17 subjects are 
evaluable for tumor response. If a subject discontinues prior to the first tumor response 
assessment for reasons other than progressive disease, the subject will be replaced. If 1 or no 
responder is observed among the 17 evaluable subjects, the Sponsor may consider 
discontinuation of this cohort; however, assessment of biomarkers (that may aid in prospective 
enrichment for responders) or tumor measurements (showing clinically relevant tumor 
reductions, ie, <30%, that fit the criteria for SD) may support continued enrollment.  
Subjects will receive ibrutinib (daily) and MEDI4736 (every 2 weeks) continuously in 28-day 
cycles until progressive disease or unacceptable toxicity. Dosing of MEDI4736 will continue for 
a total of 12 months (from initial dose) of therapy if clinical benefit is seen without safety 
concerns.  Re-treatment with MEDI4736 will not be permitted following completion of 
12 months of therapy, regardless of any dose delays, missed doses, or following permanent 
discontinuation for any reason. 
Assessment for response will occur at the end of Cycle 2 (Cycle 2 Day 28 [–7 days]) and then 
after every 3rd cycle (Cycle x Day 28 [–7 days]). Assessments will include CT/MRI scans or 
physical examination (if the lesion is not assessable by CT/MRI) for the relevant tumor type 
(ie, superficial soft tissue lesions, skin lesions, etc.) and will follow RECIST 1.1 guidelines. 
In order to accommodate the potential for immune flare (pseudoprogression), treatment with 
ibrutinib and MEDI4736 may continue between the initial assessment of suspected progression 
and confirmation of progression. Subjects with suspected progressive disease who, in the 
Investigator’s opinion, continue to receive clinical benefit from their treatment may continue to 
receive ibrutinib and MEDI4736 as dictated in the protocol after consultation with the Sponsor 
and at the Investigator’s discretion. In the absence of symptomatic deterioration, a biopsy (if 
lesion is assessable) should be performed at the time of suspected tumor flare (in order to rule 
out tumor necrosis and/or an inflammatory reaction) or the investigator may continue dosing and 
a CT /MRI scan or physical examination (if the lesion is not assessable by CT/MRI) should 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 met. Ibrutinib and 
MEDI4736 should be discontinued if there is confirmed progressive disease per RECIST 1.1 
guidelines or other clinical data suggest clear evidence of progression (symptomatic 
deterioration).  
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3.1.1. 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. Pathologically confirmed: 
• NSCLC (adenocarcinoma or squamous-cell carcinoma) or 
• Breast cancer (HER2 positive [by FISH or IHC. See Section 1.2 for definition] or triple 
negative) or 
• Pancreatic cancer (adenocarcinoma) 
Screening Phase 
(within 28 days of first study 
treatment) 
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 the following visits on specified dates or prior to subsequent anticancer therapy 
• 
End-of-Treatment Visit for ibrutinib (30 days after the last dose of ibrutinib)  
• 
90-day Follow-Up for MEDI4736 (90 days after the last dose of MEDI4736) 
Prior to disease progression (if applicable):  
• 
Continue disease evaluations 
 
Following disease progression:  
• Survival and subsequent anticancer therapy 
Treatment Phase 
Ibrutinib at 560 or 420 mg/day PO qd up to 3 years 
MEDI4736 at 10 mg/kg or 3 mg/kg IV Q2W for a maximum of 12 months   
Treatment until disease progression or unacceptable toxicity 
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2. For Phase 2 only: Provision of a fresh tumor biopsy or an available archival tumor sample 
processed as formalin-fixed paraffin embedded (FFPE) taken within 3 months, and after the 
most recent treatment with the following exception:   
• For locally advanced pancreatic cancer, a fresh biopsy is not required if the tumor is 
inaccessible or the procedure places the subject at a safety risk.  
• No more than 10 subjects with locally advanced pancreatic cancer will be enrolled in the 
study without a biopsy. 
3. Radiographically or clinically documented relapsed or refractory disease (Stage III or IV): 
Subjects with NSCLC or pancreatic cancer must have relapsed or refractory disease and must 
have failed at least 1 prior appropriate systemic first-line treatment regimen. Subjects with 
epidermal growth factor receptor (EGFR) mutation-positive NSCLC must have received an 
EGFR inhibitor and subjects with NSCLC that is anaplastic lymphoma kinase (ALK)-
positive must have received an ALK inhibitor. Subjects with breast cancer must have 
relapsed or refractory disease and must have failed at least 2 prior appropriate systemic 
regimens. 
4. One or more disease lesion on CT/MRI scan or by physical examination (if the lesion is not 
assessable by CT/MRI) that is measurable (ie, superficial soft tissue lesions, skin lesions, 
etc.) per RECIST 1.1 guidelines. 
5. Adequate hematologic function independent of transfusion and growth factor support for at 
least 7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim) and 
darbepoetin which require discontinuation at least 14 days prior to screening defined as:  
• Absolute neutrophil count (ANC) >1500 cells/mm3 (1.50 x 109/L) 
• Platelet count >100,000 cells/mm3 (100 x 109/L)  
• Hemoglobin >9.0 g/dL 
6. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤2.5 x upper limit of 
normal (ULN) for subjects without liver metastases and ≤3.5 x ULN for subjects with 
liver metastases 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin) 
• Creatinine ≤2.0 x ULN and Creatinine Clearance ≥40 mL/min (Cockcroft-Gault or 
24-hour creatinine clearance collection) 
7. Prothrombin time (PT)/International normalized ratio (INR) <1.5 x upper limit of normal 
(ULN) and partial thromboplastin time (PTT)/ activated partial thromboplastin time (aPTT) 
<1.5 x ULN 
8. Men and women ≥18 years of age 
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; OR history of hysterectomy; OR history of bilateral 
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tubal ligation; OR history of bilateral oophorectomy). Female subjects of reproductive 
potential must have a negative serum pregnancy test upon study entry. 
11. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs], complete abstinence, or sterilized partner) during the 
period of therapy and for 90 days after the last dose of study drug (see Appendix 8).  
12. Men must agree to not donate sperm and a woman 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 drug. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Subjects with tumors of mixed small cell and NSCLC histology 
2. Central nervous system (CNS) involvement of disease except as follows:  Subjects with 
previously treated CNS metastases that are adequately treated with whole brain radiotherapy 
(+/- surgery), that are neurologically stable, and do not require corticosteroids (of any dose) 
for symptomatic management for at least 14 days prior to first dose of MEDI4736 plus 
ibrutinib. In addition, there must be no clear evidence of radiographically active disease for at 
least 90 days prior to enrollment.   
3. Anti-tumor therapy (chemotherapy, antibody therapy, immunotherapy, biologic-based 
therapy, molecularly- targeted therapy, radiation therapy or investigational agent) within 
21 days of study Day 1 (six weeks for nitrosureas, mitomycin C, or antibody or molecular 
targeted agents with t1/2 >10 days; 10 weeks for radio- or toxin-immunoconjugates); 
concurrent use of hormone deprivation therapy including but not limited to anastrozole, 
letrozole, or tamoxifen citrate for breast cancer and hormonal replacement therapy for non-
cancer related conditions is permitted. Enrollment of subjects that have received molecularly-
targeted small molecule inhibitors less than 21 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.  
4. Prior treatment with ibrutinib or other BTK inhibitor, anti-CD137 or anti-cytotoxic 
T-lymphocyte associated antigen 4 (CTLA-4) antibody. The following are exceptions to this 
criterion: 
• Subjects previously treated with anti-PD1, anti-PD-L1, or anti-PD-L2 antibody  
5. Known allergy or hypersensitivity to ibrutinib or MEDI4736 or any excipients 
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) 
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• 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. 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 1 diabetes 
mellitus; multiple sclerosis; systemic lupus erythematosus; Wegener's granulomatosis; 
myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis; uveitis; etc) 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's thyroiditis) stable on hormone 
replacement therapy or psoriasis not requiring systemic treatment 
8. History of allogeneic organ transplant 
9. 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 
10. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
CTCAE (v 4.03), Grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria 
with the exception of stable neuropathy, vitiligo and alopecia or other irreversible toxicity not 
reasonably expected to be exacerbated by study treatment (eg, hearing loss) 
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. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug 
(Note: Subjects, if enrolled, should not receive live vaccines during the study and until 
180 days after the last dose of study drugs) 
14. Recent infection requiring systemic treatment that was completed ≤14 days before the first 
dose of study drug 
15. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV).  
Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or 
hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before 
enrollment. Those who are PCR positive will be excluded. 
16. History of primary immunodeficiency 
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17. Known history of previous clinical diagnosis of tuberculosis 
18. Any uncontrolled active systemic infection or pneumonitis or interstitial lung disease 
19. Major surgery within 4 weeks of the first dose of study drug 
20. 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. 
21. 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; or a history of myocardial infarction, uncontrolled 
hypertension or cardiac arrhythmia, unstable angina, or acute coronary syndrome within 
6 months prior to enrollment (Appendix 6) 
22. Unable to swallow capsules or active malabsorption syndrome not controlled by medication, 
disease or conditions significantly affecting gastrointestinal function, or complete resection 
of the stomach, or complete resection of small bowel, or partial or complete bowel 
obstruction 
23. Concomitant use of warfarin or other Vitamin K antagonists 
24. Treatment with a strong CYP3A inhibitor (Appendix 5) 
25. Pregnant or lactating female; men planning to father a child or women planning a pregnancy 
while taking study drug or within 3 months after the last dose of study drug 
26. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an 
observational study. 
27. Unwilling or unable to participate in all required study evaluations and procedures 
28. 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) 
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 met all requirements of the inclusion/exclusion criteria, 
study site personnel can enroll the subject. All enrolled subjects will receive open-label ibrutinib 
capsules and MEDI4736.  
Two dose levels of ibrutinib (560 or 420 mg/day) and MEDI4736 (10 or 3 mg/kg IV Q2 weeks) 
may be tested (Table 1). The starting dose will be 560 mg of ibrutinib PO daily and 10 mg/kg of 
MEDI4736 IV Q2 weeks. The dose may be modified based on the number of DLTs observed. 
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In each cohort, a sentinel subject will have a 3-day observation period prior to dosing of 
subsequent subjects to monitor for unexpected acute toxicities.  
Phase 1b:  
Subjects will be enrolled in up to 4 dose cohorts (1, -[minus]1A, -1B, or -2) regardless of tumor 
type (for dose levels see Table 1). Assignment of subjects to the two parallel dose de-escalation 
cohorts (-1A and -1B) will be concurrent and in the sequence of -1A followed by -1B. However, 
when one dose de-escalation cohort needs additional 3 subjects to evaluate DLTs, all available 
subjects will be assigned to this cohort first. If necessary, the dose de-escalation cohort -2 will be 
enrolled thereafter. 
Phase 2:  
Subjects will be treated at the RP2D as determined in Phase 1b. There will be no stratification of 
subjects within the pancreatic tumor type cohort. However, in the NSCLC cohort, subjects with 
adenocarcinoma or squamous-cell carcinoma will be enrolled at an approximate 2:1 ratio (ie, at 
least 15 subjects with squamous-cell carcinoma will be enrolled). In the breast cancer cohort, 
subjects with triple-negative or HER2-positive breast cancer will be enrolled at an approximate 
2:1 ratio (ie, 15 subjects with triple-negative breast cancer will be enrolled). 
5.2. 
Phase 1b Dose De-escalation and Stopping Rules 
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 first 28 days of therapy. The DLT observation period includes Cycle 1 and 
laboratory assessments 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 first 28 days (Cycle 1=28 days and including laboratory assessments on Day 1 Cycle 2) of 
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 1) will be 
enrolled.  
Cohorts -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 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, 
potentially taking pharmacokinetics and pharmacodynamics aspects into consideration. If 
necessary, the dose de-escalation cohort -2 will be enrolled thereafter. 
Enrollment in a cohort will proceed as follows: 
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• 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, then 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 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 to receive the same dose of study drugs even if a dose de-escalation occurs for 
other study subjects. 
A Dose Level Review Committee (DLRC) will evaluate the safety data from each cohort of the 
Phase 1b. Members of this committee will include participating investigators or designees as 
well as the Sponsor (at a minimum: the Medical Monitor or designee, a Drug Safety 
representative and a Biostatistician). 
5.3. 
Definition of Dose-Limiting Toxicity (DLT) 
The assessment of DLT will follow the guidelines provided in the CTCAE v 4.03. A DLT is 
defined as any Grade 3 or higher non-hematologic or Grade 4 hematologic AE possibly related 
to study drug(s) occurring during the DLT observation period with the following clarifications 
for the toxicities below: 
• Grade 4 vomiting or Grade 3 nausea and vomiting despite maximum medical supportive 
care and persisting >3 days 
• Grade 3 or 4 diarrhea despite maximum medical supportive care and persisting >7 days 
• Grade 3 fatigue persisting >7 days 
• Grade 3 neutropenia lasting >7 days or with fever 
• Grade 3 infusion reaction that does NOT resolve with appropriate clinical management 
During the Phase 1b DLT observation period, subjects will be replaced for any of the following 
reasons: 
• Missed >4 consecutive doses or missed 7 total doses of ibrutinib.  
• Missed dose of MEDI4736 or received the MEDI4736 dose outside of the protocol-
allowed window (±2 days).   
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• Study drug discontinuation for any reason other than DLT (ie, including PD).   
Subjects who are replaced for missed doses may continue to receive study treatment if there is a 
clinical benefit and will be followed for response assessment and overall survival, but they will 
not be part of the DLT analysis. 
5.4. 
Study Treatment 
All eligible subjects will be treated with ibrutinib PO and MEDI4736 IV in 28-day cycles. On 
infusion days where pharmacokinetic, pharmacodynamic or biomarker samples are taken post 
dose, MEDI4736 IV should be given first, followed by that day’s ibrutinib dose. Missed doses of 
ibrutinib and MEDI4736 will not be made up. Dose escalation of any agent (ibrutinib or 
MEDI4736) at any time will not be allowed. MEDI4736 will be given for a maximum of 
12 months. Re-treatment with MEDI4736 will not be allowed following completion of 
12 months of treatment, regardless of any dose delays or missed doses. Treatment with ibrutinib 
will continue for up to 3 years or until disease progression or unacceptable toxicity. 
5.4.1. 
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 2 week) may be tested. The starting dose will be 560 mg ibrutinib PO daily and 
MEDI4736 10 mg/kg IV every 2 weeks. 
5.4.2. 
Phase 2 
Subjects will be administered ibrutinib and MEDI4736 at the RP2D determined during the 
Phase 1b portion of the study. 
5.5. 
Study Medication 
5.5.1. 
Ibrutinib  
5.5.1.1. 
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 IB 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.  
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. 
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5.5.1.2. 
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 5). 
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 the end of the 
MEDI4736 infusion), after which subsequent dosing is typically on an outpatient basis. Subjects 
will be provided a daily drug diary to record ibrutinib doses. Ibrutinib will be dispensed to 
subjects in bottles at appropriate visits. When a new bottle 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. 
5.5.1.3. 
Overdose  
Any dose of study drug administered 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 experience in the management of ibrutinib overdose in patients. No MTD 
was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day 
(1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. One healthy 
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 
1680 mg. Subjects who ingested more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment. 
Refer to Section 11 for further information regarding AE reporting.  
5.5.1.4. 
Dose Modification for Adverse Reactions  
The dose of ibrutinib should be modified according to the dose modification guidance in Table 2 
if any of the following toxicities occur: 
• Grade 4 neutropenia (ANC <500/µL) for more than 7 days. See Sections 6.1 and 6.3 for 
instructions regarding the use of growth factor support.  
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• Grade 3 thrombocytopenia (platelet count <50,000/mm3 (50 x 109/L) in the presence of 
grade 2 or greater bleeding events. 
• 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).  
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the medical monitor to discuss for approval. 
If the dose of ibrutinib is reduced, at the Investigator’s discretion, the dose of ibrutinib may be 
re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction. Dose changes must be recorded in the Dose Administration eCRF.  
Table 2. 
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 
If TLS is diagnosed, follow the institutional guidelines for management. 
Study treatment should be discontinued in the event of a toxicity lasting more than 28 days, 
unless reviewed and approved by the Medical Monitor.  
For required dose modification for hepatic impairment refer to Section 5.5.1.5 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1. 
5.5.1.5. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child-Pugh class B or C) are excluded from study 
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participation. For subjects who develop mild liver impairment while on study (Child-Pugh 
class A), the recommended dose reduction for ibrutinib to a level of 280 mg daily (two capsules). 
For subjects who develop moderate liver impairment while on study (Child-Pugh class B), the 
recommended dose reduction is to a level of 140 mg daily (one capsule). Subjects who develop 
severe hepatic impairment (Child-Pugh class C) must hold study drug until resolved to moderate 
impairment (Child-Pugh class B) or better. Monitor subjects for signs of toxicity and follow dose 
modification guidance as needed (Refer to Appendix 9).  
5.5.2. 
Durvalumab (MEDI4736)  
5.5.2.1. 
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 
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. 
5.5.2.2. 
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 Day 1 and then every 2 weeks thereafter for 
up to 12 months, regardless of any dose delays or missed doses. 
MEDI4736 will be administered as an IV infusion approximately 1 hour in duration (including 
the IV line flush). The MEDI4736 dose will be calculated using the subject’s weight at baseline.  
This dose should be used for each MEDI4736 administration, unless there is a >10% weight 
change. In the case of a >10% weight change, the weight at the MEDI4736 dose administration 
visit should be used to calculate the dose. 
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 will 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 
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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. The ibrutinib dose should be given within 15 minutes after 
the end of the MEDI4736 infusion. 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessments. 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. Acetaminophen and/or an antihistamine (eg, 
diphenhydramine), steroids, or equivalent medications 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. 
5.5.2.3. 
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.  
5.5.2.4. 
Dose Modification for Adverse Reactions 
Refer to Section 6.1 for use of corticosteroids as concomitant medications. 
The table below outlines the MEDI4736 Toxicity Management Guidelines. 
 
 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management for 
toxicities not 
noted below) 
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. 
In addition to the criteria for permanent 
discontinuation of study drug/regimen 
based on CTC grade/severity (table 
below), permanently discontinue study 
drug/study regimen for the following 
conditions: 
• Inability to reduce corticosteroid to a 
dose of ≤10 mg of prednisone per day 
(or equivalent) within 12 weeks after 
last dose of study drug/regimen 
• Recurrence of a previously experienced 
Grade 3 treatment-related AE following 
resumption of dosing. 
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  
• For persistent (greater than 3 to 5 days) low-grade 
(Grade 2) or severe (Grade ≥3) events promptly 
start prednisone PO 1-2mg/kg/day or IV 
equivalent 
• If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [eg, up to 
2-4 mg/kg/day or IV equivalent]) until stabilization 
or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (>28 days 
of taper) 
• More potent immunosuppressives – TNF 
inhibitors (eg, infliximab) – (also refer to the 
individual sections of the immune related adverse 
event for specific type of immunosuppressive)  
should be considered for events not responding to 
systemic steroids 
• 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.). Continuation of study drug in this situation 
should be based upon a benefit/risk analysis for 
that subject. 
 
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 
• Study drug/study 
treatment can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper 
• Subjects with 
endocrinopathies who 
may require prolonged 
or continued steroid 
replacement can be 
retreated with study 
drug/study regimen on 
the following 
conditions: 1) the event 
stabilizes and is 
controlled , 2) the 
subject is clinically 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
stable as per 
Investigator or treating 
physician’s clinical 
judgment, and 3) doses 
of prednisone are at 
less than or equal to 
10mg/day or 
equivalent. 
 
Grade 3 
Depending on the 
individual toxicity, may 
permanently discontinue 
study drug/study 
regimen. Please refer to 
guidelines below 
 
Grade 4 
Permanently discontinue 
study drug/study 
regimen  
Note: For Grade 3 and 
above asymptomatic 
amylase or lipase levels 
hold study drug/regimen 
and if complete work up 
shows no evidence of 
pancreatitis, may 
continue or resume study 
drug/regimen 
Pneumonitis/ 
Interstitial lung 
disease (ILD) 
Grade of 
Pneumonitis 
(CTCAE v 
4.03) 
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 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 
(Asymptomatic
, clinical or 
diagnostic 
observations 
only, 
intervention not 
indicated) 
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 
(Symptomatic, 
medical 
intervention 
indicated, 
limiting 
instrumental 
Hold study drug/study 
regimen dose until 
Grade 2 resolution to 
Grade ≤1 
• If toxicity worsens 
then treat as Grade 3 
or Grade 4 
For Grade 2 (Mild to Moderate New Symptoms):  
• Monitor symptoms daily and consider 
hospitalization 
• Promptly start systemic steroids (e.g., prednisone 
1-2 mg/kg/day or IV equivalent) 
• Reimaging as clinically indicated 
• If no improvement within 3-5 days, additional 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
ADL) 
• If toxicity improves to 
baseline then the 
decision to reinitiate 
study drug/regimen at 
next scheduled 
treatment date will be 
based upon treating 
physician’s clinical 
judgment.  
• Study drug/study 
treatment can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
Grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper  
workup should be considered and prompt 
treatment with IV methylprednisolone 
2-4 mg/kg/day started 
• If still no improvement within 3-5 days IV 
methylprednisone at 2-4 g/kg/day, promptly start, 
immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5mg/kg every 
2 weeks). Caution: Important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab 
• Once improving, gradually taper steroids over 
≥4 weeks and consider prophylactic antibiotics, 
antifungal or anti PCP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections (Category 2B recommendation)iii  2 
• Consider pulmonary and infectious disease consult 
• Consider as necessary discussing with study 
physician 
 
Grade 3 or 4 
(Grade 3: 
Severe 
symptoms; 
limiting 
self-care ADL; 
oxygen 
indicated; 
 
Grade 4: life 
threatening 
respiratory 
compromise, 
urgent 
intervention 
indicated [e.g. 
tracheostomy 
or intubation]) 
Permanently discontinue 
study drug/study 
regimen 
 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life threatening):  
• Promptly initiate empiric IV methylprednisolone 1 
to 4 mg/kg/day or equivalent 
• Obtain pulmonary and infectious disease consult 
• Hospitalize the subject 
• Supportive Care (oxygen, etc.) 
• If no improvement within 3-5 days, additional 
workup and prompt treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5mg/kg every 2 weeks 
dose) started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab 
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and in particular, anti PCP treatment 
(please refer to current NCCN guidelines for 
treatment of cancer-related infections (Category 
2B recommendation)iii 
Diarrhea/ 
Enterocolitis 
Grade of 
Diarrhea 
(CTCAE v 
4.03) 
Any Grade 
• Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, 
or changes in bowel habits such as increased 
frequency over baseline or blood in stool) or 
related to bowel perforation (such as sepsis, 
peritoneal signs and ileus)  
• Subjects should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression, other medications, infections, 
including testing for clostridium difficile toxin 
2 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side 
Effects” 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
etc.) 
• Steroids should be considered in the absence of 
clear alternative etiology, 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 
diarrhea (stool 
frequency of 
<4 over 
baseline per 
day) 
No dose modification 
For Grade 1 diarrhea:  
• Close monitoring for worsening symptoms 
• Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (eg, American Dietetic Association colitis 
diet), and loperamide. Use of probiotics as per 
treating physician’s clinical judgment. 
 
Grade 2 
diarrhea (stool 
frequency of 4- 
6 over baseline 
per day) 
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 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
Grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper. 
For Grade 2 diarrhea:  
• Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (eg, American Dietetic Association colitis 
diet), and loperamide and/or budesonide  
• Promptly start prednisone 1 to 2 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 despite prednisone at 1-2 mg/kg/day or 
IV equivalent, GI consult should be obtained for 
consideration of further workup such as imaging 
and/or colonoscopy to confirm colitis and rule out 
perforation, and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 
• If still no improvement within 3-5 days despite 
2-4 mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as (infliximab at 
5 mg/kg once every 2 weeks23) Caution: Important 
to rule out bowel perforation and refer to 
infliximab label for general guidance before using 
infliximab 
• Consult study physician if no resolution to 
≤Grade 1 in 3-4 days 
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation])  
3 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking 
Antibody Side Effects 
 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
 
Grade 3 or 4 
diarrhea 
 
(Grade 3: stool 
frequency of ≥7 
over baseline 
per day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue 
study drug/study 
regimen 
For Grade 3 or 4 diarrhea: 
• -Promptly initiate empiric IV methylprednisolone 
2 to 4 mg/kg/day or equivalent 
• Monitor stool frequency and volume and maintain 
hydration   
• Urgent GI consult and imaging and/or 
colonoscopy as appropriate 
• If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4mg/kg/day or 
equivalent, promptly start further 
immunosuppressives (eg, infliximab at 5mg/kg 
once every 2 weeks) 
• Caution: Ensure GI consult to rule out perforation 
and refer to infliximab label for general guidance 
before using infliximab.  
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]) 
Hepatitis 
(Elevated LFTs) 
Infliximab should 
not be used for 
management of 
Immune Related 
Hepatitis 
Grade of Liver 
Function Test 
Elevation 
(CTCAE v 
4.03) 
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 
(AST or ALT 
>ULN 
to 3 times ULN 
and/or TB 
>ULN to 
1.5 times ULN) 
No dose modification 
If it worsens, treat as 
Grade 2 event 
For Grade 1 AST or ALT and/or TB elevation 
• Continue LFT monitoring per protocol 
 
Grade 2 
(AST or ALT 
>3 to 5 times 
ULN and/or 
TB >1.5-3.0 
times ULN) 
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 improves to baseline 
then treat at next 
scheduled treatment 
date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
For Grade 2 AST or ALT and or TB elevation:  
• Regular and frequent checking of LFTs (e.g. every 
1-2 days) until elevations of these are improving 
or resolved.  
• If no resolution to ≤Grade 1 in 1-2 days, discuss 
with study physician. 
• If event is persistent (>3-5 days) or worsens, 
promptly start prednisone 1-2 mg/kg/day or IV 
equivalent 
• If still no improvement within 3-5 days, despite 
1-2 mg/kg/day of prednisone or IV equivalent, 
consider additional workup and prompt treatment 
with IV methylprednisolone 2-4 mg/kg/day 
started. 
• If still no improvement within 3-5 days despite 
2-4 mg/kg/day of IV methylprednisolone, 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
event stabilizes to 
Grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper 
promptly start immunosuppressives (eg, 
mycophenolate mofetil)4. Discuss with study 
physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used.  
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, , 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]) 
 
Grade 3 (AST 
or ALT >5-20 
times ULN 
and/or TB 
>3.0-10 times 
ULN 
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 
drug/study regimen  
• Permanently 
discontinue study 
drug/study regimen for 
any case meeting Hy’s 
law criteria(ALT>3x 
ULN + bilirubin >2x 
ULN without initial 
findings of cholestasis 
(ie, elevated alkaline 
P04) and in the 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
• Promptly initiate empiric IV methylprednisolone 
at 1 to 4 mg/kg/day or equivalent  
• If still no improvement within 3-5 days despite 1 
to 4 mg/kg/day methylprednisolone IV or 
equivalent, promptly start with 
immunosuppressive therapy (mycophenolate 
mofetil) Discuss with study physician if 
mycophenolate is not available. Infliximab should 
NOT be used.  
• Hepatology consult, abdominal workup, and 
imaging as appropriate 
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]) 
4 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by 
Michael Postow MD 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
absence of any 
alternative causeiv 
Grade 4 
Permanently discontinue 
study drug/study 
regimen  
 
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine 
Grade of 
Elevated Serum 
Creatinine 
(CTCAE v 
4.03) 
 
 
 
Any Grade 
 
 
• Consult with Nephrologist 
• Monitor for signs and symptoms that may be 
related to changes in renal function (eg, routine 
urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, 
etc.) 
• Subjects should be thoroughly evaluated to rule out 
any alternative etiology (eg, disease progression, 
infections etc.) 
• Steroids should be considered in the absence of 
clear alternative etiology even for low grade 
events (Grade 2) , in order to prevent potential 
progression to higher grade event 
 
Grade 1 [Serum 
Creatinine >1-
1.5X baseline; 
>ULN to 1.5X 
ULN] 
No dose modification 
For Grade 1 elevated creatinine: 
• Monitor serum creatinine weekly and any 
accompanying symptom 
o 
If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol. 
o 
If it worsens, depending on the 
severity , treat as Grade 2 or Grade 
3 or 4 
• Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, etc. 
 
Grade 2 [Serum 
Creatinine 
>1.5-3.0 X 
baseline; 
>1.5X- 
3.0XULN] 
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 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 for 5-7 days 
have passed after 
completion of steroid 
taper 
For Grade 2 elevated creatinine: 
• Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, etc. 
• Carefully monitor serum creatinine every 2-3 days 
and as clinically warranted 
• Consult Nephrologist and consider renal biopsy if 
clinically indicated 
• If event is persistent (>3-5 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day or IV 
equivalent 
• If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day or 
IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone at 2-4 mg/kg/day started. 
• Once improving gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]). 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
• When event returns to baseline, resume study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol. 
 
Grade 3 or 4 
(Grade 3: 
Serum 
Creatinine >3.0 
X baseline; 
>3.0-6.0 X 
ULN 
Permanently discontinue 
study drug/study 
regimen 
• Carefully monitor serum creatinine on daily basis 
• Consult Nephrologist and consider renal biopsy if 
clinically indicated 
• Promptly start prednisone 1 to 2 mg/kg/day or IV 
equivalent 
• If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day or 
IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started.  
 
Grade 4: Serum 
Creatinine 
>6.0 X ULN) 
 
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation] 
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin 
Rash 
(Please refer to 
NCI CTCAE v 
4.03 for 
definition of 
severity/grade 
depending on 
type of skin 
rash) 
Any Grade 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, 
THE STUDY PHYSICIAN SHOULD BE 
CONTACTED AND STUDY DRUG 
DISCONTINUED ** 
 
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 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and 5-7 days 
have passed after 
For Grade 2 : 
• Obtain dermatology consult 
• 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 despite 
symptomatic treatment and/or use of moderate 
strength topical steroid, discuss with study 
physician and consider systemic steroids 
prednisone 0.5 to 1 mg/kg/day or IV equivalent 
• Consider skin biopsy if persistent for >1-2 weeks 
or recurs 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
completion of steroid 
taper 
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: 
• Consult dermatology 
• Promptly initiate empiric IV methylprednisolone 1 
to 4 mg/kg/day or equivalent 
• Consider hospitalization 
• Monitor extent of rash [Rule of Nines] 
• Consider skin biopsy (preferably more than 1) as 
clinically feasible. 
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]) 
• Discuss with Study Physician 
Grade 4 
Permanently discontinue 
study drug/study 
regimen  
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.) 
Any Grade 
Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
 
• Consult endocrinologist 
• 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 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 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 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 indicated and consider endocrinology 
consult  
 
Grade 2 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1 
• If toxicity worsens 
then treat as Grade 3 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
• Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids  
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
CTCAE v4.03 
for defining the 
CTC 
Grade/severity 
2) 
or Grade 4 
• If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper 
• Subjects with 
endocrinopathies who 
may require prolonged 
or continued steroid 
replacement can be 
retreated with study 
drug/study regimen on 
the following 
conditions: 1) the 
event stabilizes and is 
controlled, 2) the 
subject is clinically 
stable as per 
Investigator or treating 
physician’s clinical 
judgement, and 3) 
doses of prednisone 
are at less than or 
equal to 10 mg/day or 
equivalent. 
• 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, corticosteroids (eg, 
1-2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with 
relevant hormone replacement (eg, levothyroxine, 
hydrocortisone, or sex hormones)  
• Once improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]) 
For subjects with normal endocrine work up (lab 
or MRI scans), repeat labs/MRI as clinically 
indicated 
 
Grade 3 or 4 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v 4.03 
for defining the 
CTC 
grade/severity 3 
or 4) 
 
• For Grade 3 or 4 
endocrinopathy other 
than hypothyroidism, 
hold study drug/study 
regimen dose until 
endocrinopathy 
symptom(s) are 
controlled 
• Resume study 
drug/study regimen 
administration if 
controlled at the next 
scheduled dose 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
For Grade 3 or 4: 
• Consult endocrinologist 
• Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids 
• Promptly initiate empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent 
• Administer hormone replacement therapy as 
necessary 
• For adrenal crisis, severe dehydration, 
hypotension, or shock: immediately initiate IV 
corticosteroids with mineralocorticoid activity 
• Once improving, gradually taper 
immunosuppressive steroids over ≥4 weeks and 
consider prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer- related 
infections [Category 2B recommendation]) 
 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper 
• Discuss with study physician 
Immune-
mediated  
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillian-Barre)   
  
Grade of 
Neurotoxicity 
Depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE v 4.03 
for defining the 
CTC grade 
/severity 
 
 
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 
See “Any Grade” recommendations above. 
 
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. 
o If toxicity worsens 
then treat as Grade 3 
or Grade 4 
o If toxicity improves 
to baseline then treat 
at next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
• Discuss with study physician  
• Consider Neurology Consult  
• Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (eg, 
gabapentin, duloxetine, etc.) 
• Promptly start systemic steroids prednisone 
1-2 mg/kg/day or IV equivalent  
• If no improvement within 3-5 days, despite 
1-2 mg/kg/day prednisone or IV equivalent 
consider additional workup and promptly treat 
with additional immunosuppressive therapy (eg, 
IVIG) 
 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
18 December 2015 
FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Grade ≤1 and 5-7 days 
have passed after 
completion of steroid 
taper 
 
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 
• Obtain neurology consult 
• Consider hospitalization 
• Promptly initiate empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent 
• If no improvement within 3-5 days, consider 
additional workup and treatment with additional 
immunosuppressants (eg, IVIG) 
• Once stable, gradually taper steroids over 
≥4 weeks 
 
Grade 4 
• Permanently 
discontinue study 
drug/study regimen 
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 started with IVIG and 
followed by plasmapheresis if not responsive to 
IVIG.  
 
Grade 1 
No dose modification 
• Discuss with the study physician 
• Care should be taken to monitor subjects for 
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IMBRUVICA® (ibrutinib) 
PCYC-1135-CA Amendment 3  
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FINAL 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
sentinel symptoms of a potential decompensation 
as described above 
• Obtain 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 
signs of autonomic 
instability 
Grade 2 :  
• Discuss with the study physician  
• Care should be taken to monitor subjects for 
sentinel symptoms of a potential decompensation 
as described above 
• Obtain Neurology Consult  
• 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 
IVIG. 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 started with IVIG and 
followed by plasmapharesis if not responsive to 
IVIG. 
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Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
 
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 plasmapharesis or 
IVIG. 
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 started with IVIG and followed by 
plasmapheresis if not responsive to IVIG. 
Grade 4 
Permanently discontinue 
study drug/study 
regimen 
 
Infusion-Related Reactions 
Severity Grade 
Dose Modifications 
Toxicity Management 
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 
Subsequent infusions may be given at 50% 
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Infusion-Related Reactions 
Severity Grade 
Dose Modifications 
Toxicity Management 
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) 
 
Non-immune Mediated Reactions 
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or 
equal to Grade 2, please discuss with Study Physician” 
CTC 
Grade/Severity 
Dose Modification 
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 regimen until 
resolution to Grade ≤1 or baseline 
Treat accordingly as per institutional standard 
3 
Hold study drug/study 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 
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. 
i 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
ii NCI CTCAE v4.03 
iii ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
iv FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
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MEDI4736 treatment interruptions in study drug administration should be recorded in the 
clinical database. 
5.6. 
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 complete 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 Section 5.3 and 9.2 will not 
be replaced. A Treatment Termination Visit (Section 8.2.3) and End-of-Treatment Visit 
(Section 8.3.1) are required for all subjects except for those subjects who have withdrawn full 
consent. 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be collected from the time of ICF signing or 14 days prior to the 
first dose, whichever is greater, 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 
ASCO guidelines (Smith 2006). Transfusions may be given in accordance with institutional 
policy.  
Hormonal or bone sparing treatment are permitted with approval of the Medical Monitor. 
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 and infusion reactions) 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. Doses higher than this are permitted only for infusion 
prophylaxis/reactions or for acute toxicity management.  
If corticosteroid treatment for study drug related adverse events with >10 mg per day of 
prednisone or equivalent is needed, MEDI4736 should be held until the event resolves to 
Grade ≤1 or baseline and the Medical Monitor should be contacted. Thereafter, MEDI4736 
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administration may be resumed at the next scheduled dose (also see Section 5.5.2.4 for Dose 
Modifications for Adverse Reactions). 
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 CYP3A4 or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
• If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, 
reduce ibrutinib dose to 140 mg or withhold treatment for the duration of the inhibitor 
use. Subjects should be monitored for signs of ibrutinib toxicity.  
• If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 
ibrutinib to 140 mg for the duration of the inhibitor use. Avoid grapefruit and Seville 
oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see 
Appendix 5). 
• No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction (see Section 5.5.1.2). 
A list of common CYP3A inhibitors and inducers is provided in Appendix 5; For further 
information, please refer to the current version of the IB and examples of inhibitors, inducers, 
and substrates can 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. 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 
gastrointestinal 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. 
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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, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and 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 chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving ibrutinib treatment.  
Transfusional support is prohibited for at least 7 days prior to Screening. Pegylated G-CSF 
(pegfilgrastim) and darbepoetin 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) 
• 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 management, eg pneumonitis or other 
immune-related AEs, or non-cancer related medical reasons per guidance in Section 6.1 
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, lumbar puncture [other 
than shunt reservoir access], 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. 
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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 as soon as possible and until the surgical site 
is reasonably healed or for at least 7 days after the urgent surgical procedure, whichever is 
longer. 
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 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).  
7.1.1.3. 
Medical History, Risk Factors 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. Details of any cancer risks will be identified (to 
include family history of cancer, history of being >30 lbs overweight, radiation therapy before 
the age of 30 [specify location], alcohol ingestion, smoking/tobacco use, chronic pancreatitis, 
known genetic abnormality [eg, KRAS etc]). Concurrent medical signs and symptoms must be 
documented to establish baseline severities. A disease history, including the date of the initial 
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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 the time of ICF signing or from 14 days before 
the start of study drug, whichever is greater, through 30 days after the last dose of ibrutinib and 
90 days after the last dose of MEDI4736. After a subject discontinues study treatment, receipt of 
all subsequent anticancer therapies will be collected until 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 SAE definition must be recorded from the time the ICF is signed until 
30 days after the last dose of ibrutinib and 90 days after the last dose of MEDI4736. AEs will be 
recorded in the electronic case report forms (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 
90 days after the last dose of MEDI4736. Laboratory abnormalities designated clinically 
significant by the Investigator will also be recorded as AEs. Additional important requirements 
for AE and SAE reporting are explained in Section 11.4. 
7.1.1.6. 
Routine Physical Examination 
The Screening, Day 1 of each Cycle, Treatment Termination Visit and End-of-Treatment Visit 
for ibrutinib or the 90-Day Follow-Up Visit for MEDI4736, 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 4. 
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.  
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. 
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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 be performed at the site’s local laboratory and will include a 
complete blood count: white blood cells, red blood cells, hemoglobin, hematocrit, platelets, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils and bands (if reported).  
7.1.2.2. 
Chemistry (Serum) 
Serum chemistry parameters will be performed at the site’s local laboratory and will include 
sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total 
protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, LDH, phosphate, uric acid, 
magnesium and bicarbonate. Amylase and lipase should be obtained at Screening, and any time 
during the study if clinically indicated for evaluation of pancreatitis.  
7.1.2.3. 
Thyroid Stimulating Hormone (TSH) 
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 PT/INR, and PTT/aPTT will be performed at the site’s local laboratory.  
7.1.2.5. 
Tumor Markers 
Tumor markers specific to each tumor type, as noted below, will be performed using the site’s 
local laboratory. 
• Pancreatic Cancer - CA 19-9 
• Breast Cancer - CA 15-3 and CA 27.29 
• NSCLC - CA-125 and carcinoembryonic antigen (CEA) 
7.1.2.6. 
Creatinine Clearance 
Creatinine clearance will be measured at the site’s local laboratory and calculated using the 
Cockcroft-Gault method or determined by 24-hour creatinine clearance collection.  
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7.1.2.7. 
Hepatitis Serologies 
Hepatitis serologies will be performed the site’s local laboratory and will include hepatitis C 
antibody, hepatitis B surface antigen, and hepatitis B core antibody will be evaluated. Subjects 
with chronic or active hepatitis B or C as diagnosed by serologic tests are excluded from the 
study. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is positive, 
then PCR to quantitate hepatitis B or C DNA must be performed and must be negative for 
enrollment.  
7.1.2.8. 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose and will 
be performed at the site’s local laboratory. Urinalysis will be performed as outlined in Section 8.   
7.1.2.9. 
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 serum or urine pregnancy test will 
also be performed on Day 1 prior to the first dose of study drug. If positive, pregnancy must be 
ruled out by ultrasound to be eligible. This test may be performed more frequently if required by 
local regulatory authorities. 
7.1.3. 
Diagnostics/Procedures 
7.1.3.1. 
ECG 
12-lead ECGs should be performed in triplicate with a 1-minute time lag (within 5 min) between 
each measurement at Screening and for all 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. 
Tumor Measurements 
7.1.3.2.1. 
CT/MRI 
Documented tumor measurement is required using CT scans, positron emission tomography / 
computed tomography (PET/CT) or MRI, as appropriate, and are to be performed after 2 cycles 
of treatment and then after every 3 cycles of treatment. The same method of assessment (CT, 
PET/CT or MRI) and the same technique for acquisition of data must be used to characterize 
each identified and reported lesion at baseline and at follow-up. 
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Pretreatment tumor assessment will be performed within 28 days before the first dose of study 
drug. A CT scan (with contrast unless contraindicated) of the chest, abdomen, and pelvis and any 
other disease sites is required for the pretreatment tumor assessment. An adequate volume of 
contrast should be given to ensure metastases are well-visualized and the method of 
administration (dose and rate) should be consistent for subsequent examinations. Lesions in 
anatomical locations that are not well visualized by CT may be measured by MRI instead. 
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the neck and chest without contrast.  
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 
parameters, and includes the use of IV contrast. The PET must be performed prior to the CT with 
IV contrast as to not compromise PET results. Additionally, 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 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. 
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 (eg, central 
imaging vendor). At the Sponsor’s discretion, the Sponsor or its designee may conduct an 
independent review of the investigator responses. 
7.1.3.2.2. 
Tumor Assessment by Physical Examination  
Documented tumor measurement by physical examination (ie, superficial soft tissue lesions, skin 
lesions, etc.) is required for tumor lesions meeting RECIST 1.1 criteria but only if not assessable 
using CT scans, positron emission tomography / computed tomography (PET/CT) or MRI, as 
appropriate, and is to be performed after 2 cycles of treatment and then after every 3 cycles of 
treatment. The same method of assessment (physical examination) must be used to characterize 
each identified and reported lesion at baseline and at follow-up. 
Pretreatment tumor assessment by physical examination, as appropriate will be performed within 
28 days before the first dose of study drug.   
7.1.3.3. 
Tumor Tissue Biopsy 
Mandatory tumor biopsy (fresh or archived FFPE if within the last 3 months and after the last 
systemic anticancer treatment) unless the tumor is inaccessible or the procedure places the 
subject at a safety risk (ie, locally advanced pancreatic cancer), will be obtained before study 
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treatment in Phase 2; in Phase 1b, these are optional. Another optional biopsy will be collected at 
disease progression. 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 for analysis; other 
biomarkers that predict sensitivity or resistance to the drug combination may also be explored.  
7.1.3.4. 
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.  
7.1.3.5. 
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. 
Refer to the Schedule of Assessments (Appendix 1 and Appendix 2) and the Schedule of 
Assessments for Pharmacokinetics, Pharmacodynamics, Biomarkers in Appendix 3, and Lab 
Collection Flowsheet. 
7.1.3.6. 
Biomarkers and Pharmacodynamics Studies 
Samples collected may be used for pharmacodynamics and biomarker assessments including 
ITK and other kinase activity and signaling, soluble PD-L1, ADA immunogenicity, drug 
occupancy, expression analysis, genomic sequencing, flow cytometry and secreted protein 
analyses. Fluids including blood, ascites, or pleural fluid collected during the course of the study 
may be used for, but not limited to, pharmacodynamics 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. 
For molecular profiling of tumor samples, DNA/RNA may be extracted for expression and 
genomic profiling. 
Refer to the Schedule of Assessments (Appendix 1 and Appendix 2) and the Schedule of 
Assessments for Pharmacokinetics, Pharmacodynamics, Biomarkers in Appendix 3, and Lab 
Collection Flowsheet. 
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7.1.3.6.1. 
T/B/NK Counts 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected before dosing at the protocol-specified time points. Percentages and absolute counts of 
CD3+, CD4+, CD8+, CD19+ and CD16/56+ cells will be determined.  
7.1.3.6.2. 
Flow Cytometry-based Whole Blood Assays 
Immunophenotyping of subject’s blood before and after ibrutinib and MEDI4736 treatment will 
be performed by staining for T, B, and NK cells, monocytes and other markers. 
7.1.3.6.3. 
Molecular Markers 
Cytokines, chemokines, cell surface markers and genomic markers will be tested in peripheral 
blood, tumor tissue and buccal swabs. If skin biopsies or other specimen are available, they may 
also be evaluated. Samples will be collected from all subjects.   
Samples may also be tested to evaluate other potential biomarkers related to disease and 
treatment response and to investigate potential mechanisms of treatment resistance. These 
samples may be characterized by technologies such as gene expression profiling, targeted 
sequencing for genomic alterations, and intracellular pathway analyses. Inhibition of BTK, ITK 
and non-BTK and other related kinases may also be explored. These efforts may identify 
biomarkers that could assist with future development of this compound. Pharmacodynamics 
assays, ie, BTK and ITK occupancy, may be performed to correlate results of biomarker 
assessments to the physiological effects of ibrutinib. 
7.2. 
Efficacy Evaluations 
All subjects in the study will have their response assessed using the RECIST 1.1 guidelines 
(Eisenhauer 2009). In the event of symptomatic deterioration due to underlying disease, as 
determined by the investigator, the investigator should define the criteria for discontinuation of 
study drug (eg, if related to disease progression or other causes). Grading for best response will 
be categorized as CR, PR, SD, or PD. Additional information can be found in 
https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf  
Confirmatory scans will be obtained ≥4 weeks after the initial documentation of an objective 
response.  
7.2.1. 
Definitions 
Response and progression will be evaluated in this study using RECIST 1.1 guidelines 
(Eisenhauer 2009). In the event of symptomatic deterioration due to underlying disease, as 
determined by the investigator, the investigator should define the criteria for discontinuation of 
study drug (eg, if related to disease progression or other causes). Changes in the longest diameter 
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(unidimensional measurement) of the tumor lesions and the short axis for lymph nodes are used 
in the RECIST 1.1 guidelines.  
NOTE:  Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
7.2.1.1. 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter for tumor lesions or short axis for lymph nodes to be recorded) with 
a minimum size as follows: 
• 10 mm with CT scan with a slice thickness of no greater than 5 mm. 10 mm caliper 
measurement by clinical exam. 
• If the slice thickness is >5 mm, the minimum size for a measurable lesion is twice the 
slice thickness. 
Lymph nodes can only be considered as target lesions if they are ≥15 mm in the short axis. 
Although lymph nodes ≥10 mm is considered pathological, they cannot be categorized as target 
lesions in RECIST 1.1 guidelines.  
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
7.2.1.2. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm using 
spiral CT or MRI scan, or by physical examination if the lesion is not assessable by CT scan, or 
pathological nodes with ≥10 to <15 mm short access) as well as truly non-measurable lesions are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-
measurable disease. 
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7.2.1.3. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at the baseline/screening assessment. Target lesions should be selected on the basis of 
their size (tumor lesions with the longest diameter and lymph nodes with the short axis) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically). A 
sum of the diameters for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference by which to characterize the 
objective tumor response. Lesions that have been irradiated cannot be included in the tumor 
assessment, unless unequivocal tumor progression has been documented in these lesions after 
radiation therapy. 
7.2.1.4. 
Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at the baseline/screening assessment. Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions. Measurements of these lesions are not required, but the presence or absence 
(or in rare cases unequivocal progression) of each should be noted throughout follow-up. 
Measurements are not required and these lesions should be followed as ‘Complete Response 
(CR)’, ‘Incomplete Response/Stable Disease (SD)’, or 'Progressive Disease (PD)’. Recording 
several lesions involving the same organ as a single item is acceptable. 
7.2.1.5. 
New Lesions 
If new lesions appear and there is doubt as to whether a lesion is new or an inflammatory change, 
follow-up scans are required. If the new lesion is confirmed, as unequivocal (ie, not attributable 
to differences in scanning technique, change in imaging modality or findings thought to be 
something other than the tumor by a scan obtained at least 4 weeks after the initial scan), the date 
of progression is taken to be the date on which the new lesion was first detected. If a lesion 
reappears after disappearing in a subject with CR, PD is declared. However, if such a lesion 
behaves in this manner in a subject with SD or PR, it is the change in sum of diameters that 
defines the response or progression. 
A lesion found in a follow-up study in a region that was not scanned at baseline is still 
considered a new lesion and will indicate PD, if confirmed by a repeat scan obtained at least 
4 weeks after the initial scan. 
7.2.2. 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
Measurements need not be along the same axis (as measured at baseline), but should always be 
the longest axis of the lesion at that point in time. It does not have to be at the same slice 
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position, provided the measurement is of the same lesion. However, if the initial measurements 
are in the axial plane, all further measurements of that lesion must remain in the axial plane. 
Likewise, if the initial measurements are in the coronal plane (this is acceptable), all further 
measurements of that lesion must be in the coronal plane. 
If a lesion disappears, the measurement of that lesion is clearly 0 mm; however, if the lesion 
remains present, but is too small to measure accurately, a default measurement of 5 mm should 
be given, regardless of slice thickness. If lymph nodes decrease to <10 mm, these are considered 
to be disease free, but remain target lesions. If lesions merge, the long axis of the resulting lesion 
is measured as one lesion in place of the individual lesions. If lesions split, the long axis of each 
individual lesion is added together. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both methods 
have been used to assess the antitumor effect of a treatment. 
Nodal lesions:  If lymph nodes are chosen as target lesions and decrease to normal size 
(<10 mm), the measurement of the lesion must still be included in the sum of the target lesions. 
This means that subjects may still meet the criteria for CR even if the sum of target lesions is not 
zero.  
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (eg, skin nodules and palpable lymph nodes). In 
the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
Tumor markers:  Tumor markers alone cannot be used to assess response.  
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases (eg, residual lesions in tumor types such as germ cell tumors, where known residual benign 
tumors can remain). 
NOTE:  The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may be a 
side effect of the treatment) and PD. 
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7.2.3. 
Response Criteria 
7.2.3.1. 
Evaluation of Target Lesions 
Complete Response 
(CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in the short axis 
to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
Tumor flares:  
Delayed responses after a tumor flare have been reported in subjects who have received immune-
based therapy. Caution must be exercised not to confuse a possible tumor flare with PD. It is 
recommended that a biopsy is performed (if lesion is assessable) in order to rule out tumor 
necrosis and/or an inflammatory reaction) or the lesion is reassessed radiographically, and if 
there is continued evidence of tumor progression, the date of PD will be documented as the 
previous evaluation (See Section 3.1 for further details). 
7.2.3.2. 
Evaluation of Non-target Lesions 
Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
(PD): 
Unequivocal progression of existing non-target lesions and/or 
appearance of one or more new lesions. 
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7.2.3.3. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). The subject’s best response assignment will depend on the achievement of 
both measurement and confirmation criteria. 
Table 3. 
Time Point Response: Subjects with Target (+/– Non-target) Disease 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or 
not all evaluated 
No 
PR 
SD 
Non-PD or 
not all evaluated 
No 
SD 
not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
7.2.3.4. 
Missing Assessments or Inevaluable Lesions 
When an imaging assessment is not done or a lesion is not evaluable at a particular time point, 
usually the subject is considered not evaluable (NE) at that time point. 
7.2.4. 
Confirmatory Measurement 
7.2.4.1. 
Confirmation 
To be assigned a status of PR or CR as the best overall response, changes in tumor measurements 
must be confirmed by repeat assessments that should be performed ≥4 weeks after the criteria for 
response are first met. 
In the case of SD, measurement must have met the SD criteria at least once after study entry at a 
minimal duration of 6 weeks from Study Day 1. 
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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. 
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 and 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 if taken after most recent treatment. 
8.1.1. 
Screening/Consenting Visit 
The following procedures will be performed during Screening: 
• Informed Consent 
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight and height  
• 12-lead ECG (in triplicate, 1 minute apart (within 5 min) 
• Tumor biopsy (Optional for Phase 1b, required for Phase 2) 
• Review of prior medications  
• Imaging by CT/MRI  
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• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH 
o Coagulation (PT, PTT/aPTT, INR) 
o Disease-specific tumor markers 
o Creatinine Clearance 
o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies 
o Urinalysis 
• Research laboratory blood samples: 
o Biomarkers and pharmacodynamics  
8.2. 
Treatment Phase 
8.2.1. 
Treatment Visits 
8.2.1.1. 
Cycle 1 Day 1 (C1D1) 
Laboratory assessments performed within 48 hours of C1D1 may be used as predose C1D1 
laboratory assessments and are not required to be repeated. Predose laboratory test results for 
eligibility (*) must be reviewed to confirm eligibility prior to start of treatment. 
Predose 
• Confirmation of eligibility 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 min of MEDI4736 infusion start) and weight 
• 12-lead ECG (in triplicate, 1 minute apart (within 5 min) 30-60 minutes prior to 
MEDI4736 infusion start 
• Clinical laboratory tests for: 
o Hematology* 
o Serum chemistry* 
o TSH  
o Disease-specific tumor markers 
o Pregnancy test (for women of childbearing potential only)* 
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o Urinalysis 
• Research laboratory blood samples collected pre-dose for: 
o Pharmacokinetics  
o Biomarkers and pharmacodynamics  
o Buccal swab 
• Review of concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 15 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (within 15 minutes AFTER the end of MEDI4736 
infusion) 
Postdose 
• Vital signs at the following time points: 
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 
• 12-lead ECG (in triplicate, 1 minute apart (within 5 min) 2 h and 4 h post ibrutinib dose 
• Research laboratory blood samples (see Appendix 3 for collection schedule): 
o Pharmacokinetics  
o Biomarkers and pharmacodynamics  
• Review of AEs and concomitant medications 
• Dispense ibrutinib bottle to subject 
8.2.1.2. 
Cycle 1 Day 2 (C1D2)  
Predose 
• Research laboratory blood samples: 
o Pharmacokinetics (24 h time point from Day 1) 
o Biomarkers and pharmacodynamics (24 h time point from Day 1) 
Dosing 
• In-clinic administration of ibrutinib 
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8.2.1.3. 
Cycle 1 Day 8 (C1D8) (for Phase 1b only)  
• Brief physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Review of AEs and concomitant medications 
8.2.1.4. 
Cycle 1 Day 15 (C1D15)  
Predose 
• Brief physical exam 
• ECOG Performance Status 
• Vital signs (within 30 mins of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Research laboratory blood samples: 
o Pharmacokinetics 
o Biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 15 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (within 15 minutes AFTER the end of MEDI4736 
infusion) 
Postdose 
• Vital signs at the following time points: 
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 
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• Research laboratory blood samples (see Appendix 3 for collection schedule): 
o Pharmacodynamics  
• Review of AEs and concomitant medications 
8.2.1.5. 
Cycle 1 Day 22 (C1D22) (for Phase 1b only)  
• Brief physical exam 
• ECOG Performance Status 
• Vital signs and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
• Review of AEs and concomitant medications 
8.2.1.6. 
Day 1 of Each Subsequent Cycle 
Subjects must continue to come in on Day 1 of each cycle for the first 15 cycles. After this time, 
subjects must come in on Day 1 of every 3rd cycle.  
Predose 
• Complete physical exam 
• ECOG Performance Status 
• Vital signs (within 30 mins of MEDI4736 infusion start) and weight 
• Cycle 3 and 5 only – 12-lead ECG (in triplicate, 1 minute apart [within 5 min]) 
30−60 minutes prior to MEDI4736 infusion start 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o TSH (Day 1 each cycle while being treated with MEDI4736 until Cycle 13 and at the 
90-day follow-up visit) 
o Disease-specific tumor markers 
o Urinalysis (Beginning at Cycle 1 and then every 3 cycles, [eg, Cycle 4 Day 1, Cycle 7 
Day 1, Cycle 10 Day 1, etc] during the MEDI4736 infusion period and at the 90-day 
Follow-Up Visit) 
o Pregnancy test (if applicable) 
• Research laboratory blood samples (see Appendix 3 for collection schedule): 
o Pharmacokinetics  
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o Biomarkers and pharmacodynamics  
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 15 minutes (±5 minutes) during MEDI4736 infusion 
• Review subject dosing diary and dispense ibrutinib 
• In-clinic administration of ibrutinib (within 15 minutes AFTER the  end of MEDI4736 
infusion) 
Postdose 
• Vital signs at the following time points: 
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 
• Cycle 3 only – 12-lead ECG (in triplicate, 1 minute apart [within 5 min] 2 h and 4 h post 
ibrutinib dose 
• Cycle 5 only – 12-lead ECG (in triplicate, 1 minute apart, [within 5 min] 2 h post 
ibrutinib dose 
• Research laboratory blood samples (see Appendix 3 for collection schedule): 
o Pharmacokinetics 
o Biomarkers and pharmacodynamics  
• Review of AEs and concomitant medications 
• Dispense ibrutinib bottle to subject 
8.2.1.7. 
Day 15 of Each Subsequent Cycle 
The Day 15 visits can be discontinued at the end of treatment with MEDI4736. 
Predose 
• Brief physical exam 
• ECOG Performance Status 
• Vital signs (within 30 mins of MEDI4736 infusion start) and weight 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
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• Research laboratory blood samples (see Appendix 3 for collection schedule): 
o Biomarkers and pharmacodynamics 
• Review of AEs and concomitant medications 
Dosing 
• In-clinic administration of MEDI4736 
• Vital signs every 15 minutes (±5 minutes) during MEDI4736 infusion 
• In-clinic administration of ibrutinib (within 15 minutes AFTER the end of MEDI4736 
infusion) 
Postdose 
• 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 
• Review of AEs and concomitant medications 
8.2.2. 
Response Evaluations 
Response Evaluation visits will be performed per the schedule outlined in Appendix 1 and 
Appendix 2. The following procedures will be performed in conjunction with standard visits as 
follows: 
• Radiologic exam by CT and/or MRI at the end of Cycle 2 (Cycle 2 Day 28 [– 7 days]) 
and then after every 3rd cycle (Cycle x Day 28 [-7 days]) 
• RECIST 1.1 Response Evaluation 
• Research laboratory blood samples (when subject achieved CR and/or at PD, unless taken 
within the last 7 days): 
o Biomarkers and pharmacodynamics 
8.2.3. 
Treatment Termination Visit (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, or physical examination (if the lesion is not assessable) by 
any of these modalities may be done per investigator discretion to assess for progressive disease. 
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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 Pregnancy test 
o Disease-specific tumor markers 
• Research laboratory blood samples collected: 
o Biomarkers and pharmacodynamics 
• Optional tumor tissue biopsy (if discontinued treatment due to disease progression) 
• Review of AEs and concomitant medications 
8.3. 
Follow-up Phase 
Once a subject has completed the Treatment Termination Visit, they will enter the Follow-Up 
Phase. Subjects that withdraw from treatment for reasons other than progressive disease will 
participate in ongoing response follow-up. 
8.3.1. 
End-of-Treatment Visit for Ibrutinib 
An End-of-Treatment Visit should occur 30 days (±7 days) from the last dose of ibrutinib 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 MEDI4736 alone. An optional tumor tissue 
biopsy may be collected if treatment was discontinued due to PD.  
Subjects who withdraw consent to treatment may still have an 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 
• Clinical laboratory tests for: 
o Hematology 
o Serum chemistry 
o Disease-specific tumor markers 
o Pregnancy test 
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• Research laboratory blood samples collected: 
o Biomarkers and pharmacodynamics (unless taken within the last 7 days) 
• Review of AEs and concomitant medications 
8.3.2. 
90-day Follow-Up Visit for MEDI4736 
A 90-day Follow-Up Visit should occur approximately 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 have a 90-day Follow-Up 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 Urinalysis 
o Disease-specific tumor markers 
o TSH 
• Research laboratory blood samples collected: 
o Pharmacokinetics and pharmacodynamics  
• Review of AEs and concomitant medications 
8.3.3. 
Response Follow-up 
Subjects who discontinue the study for reasons other than PD will be followed every 12 weeks 
(±7 days) from the last CT or MRI scan until PD, up to 3 years after the first dose of the last 
subject enrolled. An optional tumor tissue biopsy may be collected at PD. During this period, it 
is preferred that disease-specific tumor markers and CT or MRI scans are obtained using 
RECIST 1.1 guidelines. 
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 follow up on survival and use of alternative anticancer 
therapy (including the response and disease progression for the therapy), up to 3 years after the 
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first 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. 
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.  
Subjects may receive treatment for up to 3 years, unless they enroll in an extension study, reach 
the time of the study closure, or discontinue from the study for any reason, whichever occurs 
first. 
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 intercurrent illness or adverse event that prevents further 
administration of ibrutinib and/or MEDI4736 
• Symptomatic deterioration 
• Dose-Limiting Toxicity  
• Withdrawal of consent for treatment by subject 
• Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• Lost to follow-up  
• Study termination by Sponsor 
• Subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo a Treatment 
Termination and an End-of-Treatment Visit and be followed for progression and survival.  
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The Investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
and/or MEDI4736 treatment due to PD, a DLT, or an AE 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. 
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)  
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. 
Enrolled Population 
This population includes all subjects who were enrolled in Phase 1b and Phase 2. 
10.1.2. 
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 
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population for analyses based on overall response rate and disease control rate at Week 20 
(Cycle 5).  
10.1.3. 
Safety Population 
The Safety Population will consist of all enrolled subjects who received at least one dose of 
study treatment. The Safety Population will be used for the analysis of safety data. This 
population will also be used for the analyses of progression-free survival and overall survival. 
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 will be replaced. For replacement of subjects in the 
DLT observation period please refer to Section 5.3. 
10.2. Endpoints for Phase 1 
10.2.1. 
Primary Endpoints 
• Recommended Phase 2 Dose (RP2D) or MTD of ibrutinib in combination with 
MEDI4736 
• Safety and tolerability of ibrutinib in combination with MEDI4736 
10.2.2. 
Secondary Endpoints 
• Overall response rate (ORR) 
• Disease control rate (DCR) at Week 20 (Cycle 5) 
• Duration of response (DOR)  
• Pharmacokinetics and pharmacodynamics profiles 
10.2.3. 
Exploratory Endpoints 
• Immune-cell subsets 
• Non-BTK-related pharmacodynamics (ie, EGFR, 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 
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10.3. Endpoints for Phase 2 
10.3.1. 
Primary Endpoint 
• Overall response rate (ORR) 
10.3.2. 
Secondary Endpoints 
• Disease control rate (DCR) at Week 20 (Cycle 5) 
• Duration of response (DOR)  
• Progression-free survival (PFS) 
• Overall survival (OS) 
• Pharmacokinetics and pharmacodynamics profiles 
10.3.3. 
Exploratory Endpoints 
• Immune-cell subsets 
• Non-BTK-related pharmacodynamics (ie, EGFR, 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 
10.4. Sample Size Determination 
This study is not powered for comparison of treatment arms. 
10.4.1. 
Phase 1b 
Dose de-escalation will follow the 6+3 design described in Section 5.2 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. Up to 4 dose 
cohorts will be tested. Subjects are considered DLT-evaluable if they receive the assigned dose 
of study treatment (both ibrutinib and MEDI4736) and complete the safety follow-up through the 
DLT-observation period. 
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 
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be assigned to this cohort first. If necessary, the dose de-escalation cohort -2 will be enrolled 
thereafter. 
Subjects in Phase 1b who were dosed at the RP2D and with a tumor type as defined for Phase 2 
may also be included in the Phase 2 analysis. 
10.4.2. 
Phase 2 
Hypothesis for the true response rate will be tested as described below for each cohort 
independently. With a 1-sided type I error rate of 0.05, each cohort would have 80% power 
based on true response rate in the alternative hypothesis. Approximately 130 subjects (including 
6-9 subjects treated at the RP2D in Phase 1b and with the tumor type as defined for Phase 2) 
across the three tumor type cohorts will be included in the Phase 2 analyses (an interim analysis 
and the primary analysis). The Phase 2 statistical design including number of subjects and 
number of responders for each analysis follows the statistical framework of Simon’s optimal 
two-stage design (Simon, 1989). The enrollment will continue while the interim analysis is 
performed. 
For each cohort, if a subject discontinues prior to the first tumor response assessment for reasons 
other than progressive disease, the subject may be replaced.  
NSCLC cohort and breast cancer cohort (n=18 for the interim analysis and n=43 for the 
primary analysis for each cohort):  
For each of the two tumor type cohorts, a true response rate of 10% (H0) versus 25% (Ha) will 
be tested and the probability of early stopping is at least 73.4% if the true response rate is ≤10% 
(H0), and no greater than 13.5% if the true response rate is ≥25% (Ha). 
An interim analysis will be performed based on the first 18 evaluable subjects (defined in 
Section 10.1.2) for each cohort independently. If 2 or fewer responders are observed among the 
18 evaluable subjects in a cohort, the enrollment may be stopped. Otherwise, enrollment will 
continue to enroll an additional 25 evaluable subjects for a total of 43 evaluable subjects for the 
primary analysis. The null hypothesis will be rejected if 8 or more responders are observed 
among the 43 evaluable subjects. 
For the NSCLC cohort, subjects with adenocarcinoma and squamous-cell carcinoma will be 
enrolled at an approximate 2:1 ratio (ie, at least 15 subjects with squamous-cell carcinoma will 
be enrolled). 
For the breast cancer cohort, subjects with triple negative or HER2-positive breast cancer will be 
enrolled at an approximate 2:1 ratio (ie, at least 15 subjects withtriple-negative breast cancer will 
be enrolled). 
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Pancreatic cancer cohort (n=17 for the interim analysis and n=44 for the primary analysis):  
A true response rate of 5% (H0) versus 18% (Ha) will be tested and the probability of early 
stopping is at least 79.2% if the true response rate is ≤5% (H0), and no greater than 16.2% if the 
true response rate is ≥18% (Ha). 
An interim analysis will be performed based on the first 17 evaluable subjects. If 1 or no 
responder is observed among the 17 evaluable subjects, the enrollment may be stopped. 
Otherwise, the enrollment will continue to enroll additional 27 evaluable subjects for a total of 
44 evaluable subjects for the primary analysis. The null hypothesis will be rejected if 5 or more 
responders are observed among the 44 evaluable subjects. 
For NSCLC, 10% was chosen based on the fact that, per NCCN guidelines, the reported second- 
and third-line response rates to systemic chemotherapy have generally been less than 10% and 
have limited clinical utility. For HER2-positive breast cancer, response rates and PFS in the 
relapsed setting are low, especially after multiple lines of prior therapy. For third line, published 
response rates were 22% and 14% in one study (Geyer 2006). For triple-negative breast cancer, 
in a Phase 3 study, the response rates were 27% and 9% (Pivot 2009). In combination with these 
response rates and given the fact that many of these therapies have intolerable side effects, 10% 
was chosen for breast cancer overall as the futility endpoint. A 25% response rate would be 
considered clinically meaningful. For pancreatic cancer, in the relapsed setting, the majority of 
trials had a response rate below 10% (Rahma 2013, Walker 2014), and also based on the fact that 
treatment options are limited for this population, 5% was chosen as the futility endpoint with 
≥18% being worth further study. 
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 RECIST 1.1 guidelines for all three tumor types. 
10.6.1. 
Phase 1b Analyses 
The primary objective of Phase 1b is to determine the RP2D or MTD 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 AEs 
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experienced through Phase 1b. Study-drug exposure and laboratory data will be evaluated and 
summarized by dose cohort and tumor type. 
The secondary objectives are to evaluate efficacy and pharmacokinetics / pharmacodynamics in 
subjects receiving the combination regimen. The ORR along with the corresponding 95% 
confidence interval based on exact binomial distribution and DOR for responders will be 
calculated and summarized with descriptive statistics by dose cohort and tumor type. Disease 
control rate (DCR) at Week 20 (Cycle 5) along with its 95% confidence interval based on exact 
binomial distribution will be provided by dose cohort and tumor type. Pharmacokinetics and 
pharmacodynamics data will be summarized by dose cohort and tumor type. 
10.6.2. 
Phase 2 Analyses  
Timing of Phase 2 Analysis: 
For each tumor type cohort, an interim analysis will be performed to evaluate safety and 
determine the response rate after the first 18 evaluable subjects for the NSCLC and breast cancer 
cohorts /17 evaluable subjects for the pancreatic cancer cohort completed at least one tumor 
response assessment or at least 3 responders in the NSCLC and breast cancer cohorts / 
2 responders in the pancreatic cancer cohort were observed, whichever occurs first. Confirmation 
of response is not required for the interim analysis.  
The primary analysis for each cohort will be performed to determine the response rate and safety 
profile after all subjects included for the Phase 2 analysis have completed at least two tumor 
response assessments or have progressed prior to the second tumor response assessment. 
Confirmation of response is required for the primary analysis. A cohort may be discontinued 
based on the interim efficacy and/or safety results.   
The final analysis will be performed at the end of the study (3 years after the first dose of the last 
subject enrolled) based on all subjects enrolled in this study. 
10.6.2.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will be based on ORR using the Response-evaluable Population in 
each of the three solid tumor cohorts. ORR is the proportion of response-evaluable subjects who 
achieved a CR or a PR with confirmation. The observed ORR along with its 95% confidence 
interval based on exact binomial distribution will be calculated and summarized for each tumor 
cohort. 
10.6.2.2. 
Secondary Efficacy Analyses 
Disease control rate (DCR) at Week 20 (Cycle 5) will be based on the Response-evaluable 
Population in each of the three solid tumor cohorts. DCR at Week 20 (Cycle 5) is the proportion 
of response-evaluable subjects who maintain disease control (CR, PR or SD) at Week 20 
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(Cycle 5). The observed DCR at Week 20 (Cycle 5) along with its 95% confidence interval 
based on exact binomial distribution will be calculated and summarized for each tumor cohort. 
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; censoring conventions for DOR will be provided in the SAP. 
Progression-free survival (PFS) and 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 using RECIST 1.1 guidelines 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 conventions for those 
two endpoints will be described in the statistical analysis plan (SAP). 
Pharmacokinetics and pharmacodynamics profiles will be evaluated by tumor type cohort and 
overall. 
10.6.2.3. 
Exploratory Efficacy Analyses 
Subgroup Analyses: For each tumor type cohort, a subgroup analysis will be conducted to 
calculate response rate and its 95% confidence interval based on PD-L1 expression (positive 
versus negative). For the NSCLC cohort, a subgroup analysis will also be conducted based on 
subjects with adenocarcinoma versus squamous-cell carcinoma. For the breast cancer cohort, a 
subgroup analysis will also be conducted based on subjects with HER2-positive versus triple-
negative breast cancer.  
Other analyses: Other exploratory efficacy variables will be summarized descriptively and may 
include the following: 
• Immune cell subsets 
• Non-BTK-related pharmacodynamics (ie, EGFR, ITK) 
• Plasma chemokine/cytokine levels  
• Genes and/or proteins (within the tumor or other collected specimens) associated with 
sensitivity or resistance to ibrutinib 
10.7. Safety Analysis 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who received at least one dose of study drug. 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, standard error and range). Categorical variables will be 
summarized using frequencies and percentages. No formal statistical testing is planned.  
10.7.1. 
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of adverse 
events; the relationship of adverse events to study treatment; and the action taken with respect to 
study treatment due to adverse events. 
The verbatim terms used in the eCRF by Investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs 
will be defined in the statistical analysis plan. 
All treatment-emergent AEs 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 treatment-emergent adverse events will be 
summarized according to intensity (CTCAE, v4.03) 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 an SAE. 
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 
International System (SI) unit. Selected hematology and chemistry laboratory parameters are 
detailed in Section 7.1.2. Laboratory values will be graded using the CTCAE v4.03.  
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 (the Medical Monitor or designee, a Drug 
Safety representative, and a statistician at a minimum).  
10.9. Pharmacokinetic Analysis (Ibrutinib, Combination of Ibrutinib and MEDI4736)  
Ibrutinib and PCI-45227 bioanalytical data will be used in noncompartmental pharmacokinetics 
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 pharmacokinetics summary. 
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point and pharmacokinetics 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-pharmacokinetics 
analysis using nonlinear mixed effects models. For the population-pharmacokinetics analysis, 
covariates that could potentially correlate with plasma pharmacokinetics parameters will be 
evaluated. The results of the population-pharmacokinetics analyses (if performed) will be 
presented in a separate report. 
For the drug combination of ibrutinib and MEDI4736, model-derived exposure parameters (PK 
parameters) may be used to explore PK/PD correlation between the exposure of ibrutinib and its 
active metabolites with relevant clinical or biomarker information to assess effectiveness and 
toxicity. 
Ibrutinib and MEDI4736 PK data in this study will be compared to observed/reported 
concentration data for ibrutinib and MEDI4736 and/or concentration estimates from the existing 
literature and/or population PK models to explore the potential for a pharmacokinetic interaction 
between ibrutinib and MEDI4736. 
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 pharmacokinetics 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 
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state will be assessed as the ratio of Cmax,ss:Cmax and Ctrough,ss:Ctrough. Descriptive statistics of 
non-compartmental pharmacokinetics parameters will be provided. 
10.11. Immunogenicity Analyses 
Immunogenicity analyses will be performed by determining the anti-MEDI4736 response before 
and/or after treatment with ibrutinib and MEDI4736 at selected time points during treatment with 
ibrutinib and MEDI4736.  
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 
during treatment with ibrutinib and/or MEDI4736. Pharmacodynamic assays for ibrutinib may 
include occupancy assays of 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 for analysis; other 
biomarkers that predict sensitivity or resistance to the drug combination may also be 
explored.   
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. 
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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 adverse event term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events 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. 
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. 
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11.1.2. 
Serious Adverse Events 
A serious adverse event 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 
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 
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• 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 
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 
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• 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 adverse event, it should be recorded on the adverse 
events eCRF. If the adverse event is considered serious, it should be recorded on the adverse 
events 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 adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
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 adverse event or serious adverse event 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 for ibrutinib 
and/or 90 days after the last dose for 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/or 90 days after 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).  
Serious adverse events reported after 30 days following the last dose of ibrutinib and/or 90 days 
after the last dose of MEDI4736 should also be reported if considered related to any of the study 
drugs.  
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). 
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All adverse events, 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 and/or 90 days after the last dose 
of MEDI4736, the death must be reported to the Sponsor as a serious adverse event.  
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events (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. 
All serious adverse events 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.  
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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 adverse event, 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 must be reported. 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 a serious adverse event. 
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 adverse events, or groups of adverse events, 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.  
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11.4.6.1. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• 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 v4.03.  
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 
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. 
In the event of a Grade ≤2 infusion-related reaction, the infusion rate of MEDI4736 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 infusion rate. 
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the infusion- 
related reaction is Grade ≥3 or higher in severity, treatment with MEDI4736 should be 
discontinued. 
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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. 
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. 
For cases in which the aminotransferase and bilirubin elevations meet the Hy’s Law criteria 
threshold, a discussion between the Investigator and the Medical Monitor should take place to 
determine the evaluation and management of the subject.   
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 
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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. 
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 
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all revisions thereof, and in accordance with the 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 of all subjects who have consented to enroll 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 
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 
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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 
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 
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Investigator or other site personnel supply ibrutinib or MEDI4736 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-1135-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib or MEDI4736 dispensed or 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 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. If access to the EMR cannot be granted to the 
monitor, the site must ensure that all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects. During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 
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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 
Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug. 
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. 
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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. 
The ICF will include a description of treatment in the event of a study related injury and 
handling of the costs associated therewith, 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 
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. 
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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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13. 
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14. 
APPENDICES 
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Appendix 1. Schedule of Assessments for Phase 1b 
Study Visits for Phase 1b 
Screening Treatment-Phase (1 cycle = 28 Days) 
Post-treatment 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluation 
Treatment 
Termination 
(optional) 
End-of-
Treatment 
for ibr 
90-day  
FU for 
MEDI4736 
Response 
FU  
(Until PD) 
Survival 
FU 
(Post-PD) 
 
 
D1 D2 D8 D15 D22 
D1 
D15 D1 D15 D1g D15h 
End of  
Cycle 2  
&  
Q3 cycles 
thereafter 
At any 
time 
during 
the study 
30 d from 
last ibr or 
before  
next 
therapy 
90 d from 
last MEDI 
4736 dose 
or before 
next 
therapy 
Q12  
weeks  
from last 
CT/MRI 
scan 
Q12 
weeks 
from last 
dose 
Visit Window 
-28 days 
NA 
± 2 days 
-2 days 
± 3 days 
-7 days 
NA 
± 7 days 
± 7 days 
± 7 days 
Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility (Inclusion/exclusion 
criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Vital signsa and weight (height only at 
screening) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Tumor Biopsy (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X At progression (optional) 
 
12-lead ECG (triplicate) 
X 
Xb 
 
 
 
 
 
 
Xb 
 
C5D1b  
 
 
 
 
Prior and concomitant medications 
Continuous from ICF or 14 days prior the first dose of study drug (whichever is greater) 
 to 30 days (ibrutinib)/90 days (MEDI4736) after last dose  
 
 
Adverse events 
 
Continuous from ICF to 30 days (ibrutinib)/90 days (MEDI4736) after last dose 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Serum chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
TSH 
X 
X 
 
 
 
 
X 
 
X 
 
Xc 
 
 
 
 
X 
 
 
Coagulation (PT, PTT/aPTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-specific tumor markers 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Creatinine clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
(serum at screening, urine at f/u) 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
X 
 
 
CT/MRI scan 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
RECIST 1.1 response evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Survival status and subsequent 
antineoplastic therapy,and disease 
progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Study Visits for Phase 1b 
Screening Treatment-Phase (1 cycle = 28 Days) 
Post-treatment 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluation 
Treatment 
Termination 
(optional) 
End-of-
Treatment 
for ibr 
90-day  
FU for 
MEDI4736 
Response 
FU  
(Until PD) 
Survival 
FU 
(Post-PD) 
 
 
D1 D2 D8 D15 D22 
D1 
D15 D1 D15 D1g D15h 
End of  
Cycle 2  
&  
Q3 cycles 
thereafter 
At any 
time 
during 
the study 
30 d from 
last ibr or 
before  
next 
therapy 
90 d from 
last MEDI 
4736 dose 
or before 
next 
therapy 
Q12  
weeks  
from last 
CT/MRI 
scan 
Q12 
weeks 
from last 
dose 
Visit Window 
-28 days 
NA 
± 2 days 
-2 days 
± 3 days 
-7 days 
NA 
± 7 days 
± 7 days 
± 7 days 
PK  
 
Refer to Appendix 3 for sampling schedule 
 
 
Biomarkers and Pharmacodynamics 
X 
Refer to Appendix 3 for sampling schedule 
 
 
Buccal swab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Dispense ibrutinib & review diary 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
In-clinic administration of ibrutinibe 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
In-clinic administration of MEDI4736 
 
X 
 
 
X 
 
X 
X 
X 
X 
Xf 
Xf 
 
 
 
 
 
 
C = cycle, CR = complete response, CT = computed tomography, D or d = day(s), ECG = electrocardiogram, FU = follow-up, ibr = ibrutinib, ICF = informed consent form,  
INR = international normalized ratio, MRI = magnetic resonance imaging, PD = progressive disease, PK = pharmacokinetics, PT = prothrombin time, PTT = partial thromboplastin time, 
aPTT = activated partial thromboplastin time, RECIST = response evaluation criteria in solid tumors, TSH = thyroid stimulating hormone 
a. 
Vital signs: On MEDI4736 infusion days, vital signs will be measured within 30 minutes prior to the start of MEDI4736 infusion, every 15 minutes (± 5 minutes) during 
MEDI4736 infusion, at the end-of- infusion of MEDI4736 (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post end-of-infusion of MEDI4736. On C1D1, C3D1 and C5D1, 
additional ECGs will be performed (see footnote b). 
b. 
To be performed within 30-60 minutes prior to start of MEDI4736 infusion. In addition, on C1D1 and C3D1, triplicate ECGs will be performed at 2 h and 4 h post ibrutinib dose; 
on C5D1, triplicate ECGs will be performed at 2 h post ibrutinib dose.         
c. 
At Day 1 each cycle while being treated with MEDI4736 and then 90 Days after the last dose of MEDI4736 
d. 
Beginning at Cycle 4 and then every 3 Cycles during the MEDI4736 infusion period and 90 days after the last dose of MEDI4736. 
e. 
In-clinic administration of ibrutinib should be done within 15 minutes after the end of the MEDI4736 infusion. 
f. 
MEDI4736 dosing should only continue for up to 12 months after the first dose. 
g. 
Subjects must continue to come in on Day 1 of each cycle for the first 15 cycles. After this time, subjects must come in on Day 1 of every 3rd cycle.  
h. 
The Day 15 visits can be discontinued at the end of treatment with MEDI4736. 
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Appendix 2. Schedule of Assessments for Phase 2  
Study Visits for Phase 2 
Screening 
Treatment-Phase (1 cycle = 28 Days) 
Post-treatment 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluations 
Treatment 
Termination 
(optional) 
End-of-
Treatment 
for ibr 
90-day FU 
for 
MEDI4736 
Response 
FU  
(Until PD) 
Survival 
FU  
(Post-PD) 
 
 
D1 
D2 
D15 
D1 
D15 D1 
D15 
D1g 
D15h 
End of  
Cycle 2  
&  
Q3 cycles 
thereafter 
At any 
time 
during the 
study 
30 d  
from last 
ibr or 
before  
next 
therapy 
90 d from 
last MEDI 
4736 dose 
or before 
next 
therapy 
Q12 
weeks 
from last 
CT/MRI 
scan 
Q12 weeks 
from last 
dose 
Visit Window 
-28 days 
NA 
± 2 days 
± 3 days 
-7 days 
NA 
± 7 days 
± 7 days 
± 7 days 
Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
(Inclusion/exclusion criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Vital signsa and weight (height only at 
screening) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Tumor Biopsy  
X 
 
 
 
 
 
 
 
 
 
 
X At progression (optional) 
 
12-lead ECG (triplicate) 
X 
Xb 
 
 
 
 
Xb 
 
C5D1b 
 
 
 
 
Prior and concomitant medications 
Continuous from ICF or 14 days prior the first dose of study drug (whichever is greater) 
 to 30 days (ibrutinib)/90 days (MEDI4736) after last dose  
 
 
Adverse events 
 
Continuous from ICF to 30 days (ibrutinib)/90 days (MEDI4736) after last dose 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Serum chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
TSH 
X 
X 
 
 
X 
 
X 
 
Xc 
 
 
 
 
X 
 
 
Coagulation (PT, PTT/aPTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease-specific tumor markers 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Creatinine clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test   
(serum at screening, urine at f/u) 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
Xd 
 
 
 
 
X 
 
 
CT/MRI scan 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
RECIST 1.1 response evaluation 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Survival status and subsequent 
anticancer therapy (including response 
and disease progression for the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Study Visits for Phase 2 
Screening 
Treatment-Phase (1 cycle = 28 Days) 
Post-treatment 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 & 
Beyond 
Response 
Evaluations 
Treatment 
Termination 
(optional) 
End-of-
Treatment 
for ibr 
90-day FU 
for 
MEDI4736 
Response 
FU  
(Until PD) 
Survival 
FU  
(Post-PD) 
 
 
D1 
D2 
D15 
D1 
D15 D1 
D15 
D1g 
D15h 
End of  
Cycle 2  
&  
Q3 cycles 
thereafter 
At any 
time 
during the 
study 
30 d  
from last 
ibr or 
before  
next 
therapy 
90 d from 
last MEDI 
4736 dose 
or before 
next 
therapy 
Q12 
weeks 
from last 
CT/MRI 
scan 
Q12 weeks 
from last 
dose 
Visit Window 
-28 days 
NA 
± 2 days 
± 3 days 
-7 days 
NA 
± 7 days 
± 7 days 
± 7 days 
therapy) 
PK  
 
Refer to Appendix 3 for sampling schedule 
 
 
Biomarkers and Pharmacodynamics 
X 
Refer to Appendix 3 for sampling schedule 
 
 
Buccal swab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Dispense ibrutinib & review diary 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
In-clinic administration of ibrutinibe 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
In-clinic administration of MEDI4736 
 
X 
 
X 
X 
X 
X 
X 
Xf 
Xf 
 
 
 
 
 
 
C = cycle, CR = complete response, CT = computed tomography, D or d = day(s), ECG = electrocardiogram, FU = follow-up, ibr = ibrutinib, ICF = informed consent form, INR = 
international normalized ratio, MRI = magnetic resonance imaging, PD = progressive disease, PK = pharmacokinetics, PT = prothrombin time, PTT = partial thromboplastin time, aPTT = 
activated partial thromboplastin time , RECIST = response evaluation criteria in solid tumors, TSH = thyroid stimulating hormone 
a. 
Vital signs: On MEDI4736 infusion days, vital signs will be measured within 30 minutes prior to the start of MEDI4736 infusion, every 15 minutes (± 5 minutes) during 
MEDI4736 infusion, at the end-of- infusion of MEDI4736 (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post end-of- infusion of MEDI4736.  
b. 
To be performed within 30-60 minutes prior to start of MEDI4736 infusion. In addition, on C1D1 and C3D1, triplicate ECGs will be performed at 2 h and 4 h post ibrutinib dose; 
on C5D1, triplicate ECGs will be performed at 2 h post ibrutinib dose.   
c. 
At Day 1 each cycle while being treated with MEDI4736 and then 90 Days after the last dose of MEDI4736. 
d. 
Beginning at Cycle 4 and then every 3 Cycles during the MEDI4736 infusion period and 90 days after the last dose of MEDI4736.  
e. 
In-clinic administration of ibrutinib should be done within 15 minutes after the end of the MEDI4736 infusion. 
f. 
MEDI4736 dosing should only continue for up to 12 months after the first dose. 
g. 
Subjects must continue to come in on Day 1 of each cycle for the first 15 cycles. After this time, subjects must come in on Day 1 of every 3rd cycle.  
h. 
The Day 15 visits can be discontinued at the end of treatment with MEDI4736. 
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Appendix 3. Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, and 
Biomarkers* 
Timepointsa 
Ibrutinib 
PK 
Ibrutinib 
Biomarker/ 
Pharmacodynamics c MEDI4736
PK 
MEDI4736 
Pharmacodynamics 
Screening 
 
X 
 
 
Cycle 1 
Day 1 
Predose b 
X 
X 
X 
X (includes ADA) 
1 hr postdose ibrutinib (± 15 min) 
X 
 
X d 
X d 
2 hr postdose ibrutinib (± 15 min) 
X 
 
 
 
4 hr postdose ibrutinib (± 30 min) 
X 
X 
 
 
Day 2 
24 hr postdose Day 1 (± 2 h)  
X 
X 
 
 
Day 15 Predose b 
 
X 
X 
X 
4 hr postdose ibrutinib (± 30 min) 
 
X 
 
 
Cycle 2 
Day 1 
Predose b  
 
X 
 
 
Day 15 Predose b 
 
X 
 
 
Cycle 3 
Day 1 
Predose b 
X 
X 
X 
X (includes ADA) 
1 hr postdose ibrutinib (± 15 min) 
X 
 
X d 
X d 
2 hr postdose ibrutinib (± 15 min) 
X 
 
 
 
4 hr postdose ibrutinib (± 30 min) 
X 
 
 
 
Day 15 Predose b 
 
X 
 
 
Cycle 4 
Day 1 
Predose b 
 
X 
 
 
Cycle 5 
Day 1 
Predose b 
 
X 
 
 
Cycle 6 
Day 1 
Predose b 
 
X 
X 
X (includes ADA) 
1 hr postdose ibrutinib (± 15 min) 
 
 
X d 
X d 
Cycles 9, 
12, 15 
Day 1 
Predose b 
 
X 
X 
X (includes ADA) 
Cycle 18 &
q3 cycles 
thereafter 
Day 1 
Predose b 
 
X 
 
 
At CR and/or Progressive Disease e 
 
X 
 
 
Treatment Termination Visit (Optional) 
 
X 
 
 
End-of-Treatment Visit for ibrutinib  
(30 Day Follow-up) e 
 
X 
 
 
90 Day Follow-up Visit for MEDI4736 e 
 
 
X 
X 
Abbreviations: ADA = anti-drug antibodies; CR = complete response; PK = pharmacokinetics 
* Please refer to the PPD Laboratory Flowchart for a complete list of lab samples to be collected at each time point 
a. 
MEDI4736 will be administered as an IV infusion approximately 1 hour in duration.  Subjects are expected to 
take ibrutinib PO within 15 minutes AFTER the end of the MEDI4736 infusion. 
b. 
Predose=predose MEDI4736 infusion and ibrutinib PO  
c. 
This column combines both ibrutinib biomarker and pharmacodynamics (ibrutinib PD CPT) collections. Please 
refer to the collection flow chart for exact timepoints of each collection. 
d. 
1-hr post dose ibrutinib is approximately 1 hr (+ up to 15 min) after the end of the MEDI4736 infusion and 
approximately 2 hr (+ up to 15 min) after the initiation of MEDI4736 infusion. Samples are to be drawn at the 
same time. 
e. 
If the visit occurs at a routine study visit where the samples are already being drawn, a separate set of samples is 
not required. 
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Appendix 4. 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 5. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.2.1 on instructions 
for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
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 
cobicistat 
boceprevir 
mibefradil 
telaprevir 
troleandomycin 
posaconazole 
rifabutin 
rifampin 
St. John’s Wort 
troglitazone 
Moderate inhibitors: 
 
aprepitant 
amprenavir 
amiodarone 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir/ritonavir 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
voriconazole 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
 
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Appendix 6. New York Heart Association (NYHA) Functional Classification 
 
 
 
From: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp  
 
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. Hepatitis Serology Chart 
Hepatitis B serologic testing involves measurement of several hepatitis B virus (HBV)-specific antigens 
and antibodies. Different serologic “markers” or combinations of markers are used to identify different 
phases of HBV infection and to determine whether a patient has acute or chronic HBV infection, is 
immune to HBV as a result of prior infection or vaccination, or is susceptible to infection. 
Interpretation of Hepatitis B Serologic Test Results 
HBsAg 
negative 
Susceptible 
anti-HBc 
negative 
anti-HBs 
negative 
HBsAg 
negative 
Immune due to natural infection 
anti-HBc 
positive 
anti-HBs 
positive 
HBsAg 
negative 
Immune due to hepatitis B vaccination 
anti-HBc 
negative 
anti-HBs 
positive 
HBsAg 
positive 
Acutely infected 
anti-HBc 
positive 
IgM anti-HBc 
positive 
anti-HBs 
negative 
HBsAg 
positive 
Chronically infected 
anti-HBc 
positive 
IgM anti-HBc 
negative 
anti-HBs 
negative 
HBsAg 
negative 
Interpretation unclear; four possibilities: 
1. Resolved infection (most common) 
2. False-positive anti-HBc, thus susceptible 
3. “Low level” chronic infection 
4. Resolving acute infection4. Resolving acute infection 
anti-HBc 
positive 
anti-HBs 
negative 
 
• 
Hepatitis B surface antigen (HBsAg): A protein on the surface of hepatitis B virus; it can be 
detected in high levels in serum during acute or chronic hepatitis B virus infection. The presence of 
HBsAg indicates that the person is infectious. The body normally produces antibodies to HBsAg as 
part of the normal immune response to infection. HBsAg is the antigen used to make hepatitis B 
vaccine. 
• 
Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs is generally interpreted as 
indicating recovery and immunity from hepatitis B virus infection. Anti-HBs also develops in a 
person who has been successfully vaccinated against hepatitis B.  
• 
Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute hepatitis B 
and persists for life. The presence of anti-HBc indicates previous or ongoing infection with hepatitis 
B virus in an undefi ned time frame.  
• 
IgM antibody to hepatitis B core antigen (IgM anti-HBc): Positivity indicates recent infection 
with hepatitis B virus (≤6 mos). Its presence indicates acute infection. 
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Appendix 8. Contraception Requirements for MEDI4736 
• Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use at least 1 highly effective method of contraception from screening, and must agree 
to continue using such precautions for 90 days after the last dose of MEDI4736 
monotherapy; cessation of birth control after this point should be discussed with a 
responsible physician. Female subjects must use a hormonal method (eg, “the pill”) in 
addition to a barrier method (ie, male condom plus spermicide), to ensure pregnancy does not 
occur.  Not engaging in sexual activity is an acceptable practice; however, periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
birth control. Female subjects should refrain from breastfeeding and egg cell donation 
throughout this period. 
• It is strongly recommended for the male partner of a female subject to also use a male 
condom plus spermicide throughout this period. 
o 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 12 months with no menses without an alternative medical 
cause) 
o The acceptable methods of contraception are described in Table 4. A highly effective 
method of contraception is defined as 1 that results in a low failure rate (ie, less than 
1% per year) when used consistently and correctly.  Not all methods of acceptable 
contraception are highly effective. 
• Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from Day 1 and for 90 days after the last 
dose of MEDI4736 monotherapy. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm donation 
throughout this period. 
It is strongly recommended for the female partner of a male subject to also use an effective 
method of contraception throughout this period. 
• All subjects: Subjects should not donate blood while participating in this study and for 
3 months following the last dose of study treatment. 
 
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Table 4. 
Effective Methods of Contraception  
Barrier/Intrauterine Method 
Hormonal Methods 
Male or female condom with or without spermicidea,b,c 
Implants 
Cap, diaphragm, or sponge with spermicidea,b,c 
Hormone shot or injection 
Copper T intrauterine device 
Combined pill 
Levonorgesterel-releasing intrauterine system (eg, Mirena®)d 
Minipillb 
 
Patch 
a. 
Female partners of male subjects must use an effective method of birth control. 
b. 
Only highly effective (<1% pregnancy rate per year) when used with additional methods of birth control. 
c. 
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
methods) are also considered acceptable, but not highly effective, birth control methods. 
d. 
This is also considered a hormonal method. 
 
 
 
 
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Appendix 9. Child-Pugh Score for Subjects with Liver Impairment 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT/INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, et al. “Transection of the oesophagus for bleeding oesophageal 
varices”.  The British journal of surgery, 1973;60:646-9. 
 
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SAP_000.pdf: 
 
PCYC-1135-CA 
Statistical Analysis Plan 
Page 1 of 15 
 
Version 3.0 
Proprietary and Confidential                                               01 December 2017 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
A Multi-Center Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, 
Ibrutinib, in combination with Durvalumab (MEDI4736), in Subjects with 
Relapsed or Refractory Solid Tumors 
 
 
 
PCYC-1135-CA 
Prepared by:  Shanhong Guan 
 
1 December 2017 
Version 3.0 
 
 
 
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 .......................................................................................................................7 
1.3. 
Statistical Hypotheses ....................................................................................................8 
1.4. 
Sample Size Determination............................................................................................8 
1.5. 
Planned Analyses ...........................................................................................................9 
1.5.1. Phase 1b Analyses ............................................................................................9 
1.5.2. Phase 2 Analyses ..............................................................................................9 
1.6. 
Testing Procedure and Level of Significance ................................................................9 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................10 
2.1. 
Analysis Sets ................................................................................................................10 
Enrolled Population ....................................................................................................10 
DLT Evaluable Population for Phase 1b ....................................................................10 
2.2. 
Definition of Subgroups ...............................................................................................10 
3. 
SUBJECT INFORMATION................................................................................................11 
3.1. 
Subject Disposition ......................................................................................................11 
3.2. 
Demographics and Baseline Characteristics ................................................................11 
3.3. 
Prior and Concomitant Medications ............................................................................11 
3.4. 
Extent of Exposure to Study Treatment .......................................................................11 
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies ......................11 
4. 
EFFICACY AND SAFETY ANALYSES ...........................................................................11 
4.1. 
Efficacy Analyses ........................................................................................................11 
4.2. 
Safety Analyses ............................................................................................................13 
5. 
MODIFICATION OF ANALYSIS TO THE PROTOCOL .............................................15 
6. 
REFERENCES .....................................................................................................................15 
 
 
LIST OF TABLES 
Table 1 Phase 1b Dosing Levels ......................................................................................................6 
Table 2 Summary of Efficacy Analyses ........................................................................................12 
Table 3 Summary of Safety Analyses  ...........................................................................................14 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ANC 
Absolute neutrophil counts 
ATC 
Anatomical Therapeutic Chemical 
BOR 
best overall response 
CBC 
complete blood count 
CIT 
Chemoimmunotherapy 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DOR 
Duration of response 
DLT 
Dose limiting toxicity 
EOT 
End of treatment 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
Hgb 
hemoglobin 
IPD 
important protocol deviation 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
overall response rate 
OS 
overall survival 
PCYC 
Pharmacyclics LLC 
PD 
progressive disease 
PFS 
Progression free survival 


 
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Abbreviation 
Definition 
PK 
Pharmacokinetic 
PLT 
platelets 
PR 
partial response 
RP2D 
Recommended Phase 2 dose 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
Treatment-emergent adverse events 
TNM 
Tumor node metastases staging 
TTP 
time to progression 
TTR 
time to response 
UNK 
unknown 
WBC 
white blood count 
WHO 
World Health Organization 


 
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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-1135-CA study. 
Analyses of pharmacokinetics data and biomarkers will be addressed in separate documents.  
1.1. 
Stud y Design 
This is a non-randomized, open-label, multi-center, Phase 1b/2 study to evaluate the efficacy and 
safety of ibrutinib in combination with durvalumab in subjects with relapsed or refractory solid 
tumor types (Stage III/IV per TNM staging): 
• Non-small Cell Lung cancer (NSCLC): adenocarcinoma or squamous-cell carcinoma 
• Breast cancer: HER2 positive or triple negative 
• Pancreatic cancer: adenocarcinoma 
RECIST 1.1 criteria will be used to evaluate response and document objective disease 
progression. 
Phase 1b: 
Phase 1b will follow a 6+3 dose de-escalation design to evaluate dose limiting toxicity (DLT) 
and determine the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) for 
this study. In cohort 1 (consisting 6 subjects regardless of tumor type), ibrutinib will be 
administered PO at a dose of 560 mg daily in combination with durvalumab at a dose of 10 
mg/kg IV every 2 weeks in 28-day cycles until DLT or disease progression occurs. The DLT 
observation period includes Cycle 1 and laboratory assessments on Day 1 of Cycle 2 which will 
occur before the durvalumab infusion on Day 1 of Cycle 2. 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 subjects experience a DLT, dose de-escalation will occur. If the subject 
incidence of DLTs during the first 28 days (Cycle 1=28 days and including laboratory 
assessments on Day 1 Cycle 2) of study treatment 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. A DLT is 
defined as any Grade 3 or higher non-hematologic or Grade 4 hematologic AE possibly related 
to study treatment(s) occurring during the DLT observation period. 
A similar 6+3 cohort design will be utilized in the dose de-escalation cohorts (see Table 1). 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 of the RP2D 
will be based on the safety profile of the 2 treatment regimens. If necessary, the dose de-
escalation cohort -2 will be enrolled thereafter. 


 
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Table 1: Phase 1b Dosing Levels 
28-Day Dosing Cycle  
Ibrutinib 
MEDI4736 
Cohort 1 
560 mg once daily PO 
10 mg/kg IV 
Cohort -1A* 
420 mg once daily PO 
10 mg/kg IV 
Cohort -1B* 
560 mg once daily PO 
3 mg/kg IV 
Cohort -2 
420 mg once daily PO 
3 mg/kg IV 
*: Cohorts -1A and -1B are 2 parallel cohorts and will be enrolled concurrently in the sequence of -1A followed by 
-1B. 
After the RP2D is determined, 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. All subjects 
enrolled under Phase 1b will be followed for response evaluation and overall survival. 
Phase 2: 
Subjects with one of three solid tumor types (Stage III/IV) will be enrolled per the specifications 
below. 
• 
NSCLC (adenocarcinoma and squamous-cell carcinoma at an approximate 2:1 ratio) (ie, at 
least 15 subjects with squamous-cell carcinoma will be enrolled) 
• 
Breast cancer (triple-negative and HER2-positive cancer at an approximate 2:1 ratio) (ie, 15 
subjects with triple-negative breast cancer will be enrolled) 
• 
Pancreatic Cancer Cohort: (adenocarcinoma) 
For each of the above three cohorts, the statistical framework of Simon’s optimal 2-stage design 
will be implemented to enroll subjects (an interim analysis for futility in the first stage and the 
final analysis in the second stage). The interim analysis for futility will be performed to evaluate 
the response and safety profile. Enrollment will continue while the interim analysis is performed. 
A cohort may be discontinued based on the interim efficacy and/or safety results. The decisions 
based on the results of the interim analysis are independent in the 3 individual disease cohorts. 
At the time of the interim safety assessment, Investigators that enrolled subjects and the Sponsor 
(at a minimum: a Medical Monitor, a Drug Safety representative, and a Biostatistician) will 
review safety data and make recommendations for the conduct of the study: continue the trial 
unchanged, consider modifying in part or in whole, or stop the trial due to safety concerns. 
NSCLC and breast cancer cohorts (n=43 per cohort): 
The breast and NSCLC cohorts will each enroll 43 evaluable subjects. Subjects who discontinue 
prior to the first tumor response assessment for reasons other than progressive disease will not be 
considered evaluable for response. An interim analysis for futility will be performed for each 
cohort independently after first 18 subjects in a cohort are evaluable for tumor response. If 2 or 
fewer responders are observed among the 18 evaluable subjects, the Sponsor may consider 
discontinuation of this cohort; however, assessment of biomarkers (that may aid in prospective 


 
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enrichment for responders) or tumor measurements (showing clinically relevant tumor 
reductions, ie, <30%, that fit the criteria for SD) may support continued enrollment. 
Pancreatic cancer cohort (n=44): 
This cohort will enroll 44 evaluable subjects. An interim analysis for futility will be performed 
after 17 subjects are evaluable for tumor response. If 1 or no responder is observed among the 
first 17 evaluable subjects, the Sponsor may consider discontinuation of this cohort. Same as in 
the other two cohorts, the assessment of biomarkers or tumor measurements may support 
continued enrollment.  
 
1.2. 
Endpoints 
Primary Endpoints 
Phase 1b: 
• Recommended Phase 2 Dose (RP2D) or Maximum Tolerated Dose (MTD) 
• Safety and tolerability of ibrutinib in combination with durvalumab 
Phase 2: 
• Overall Response Rate (ORR) 
 
Secondary Endpoints 
Phase 1b: 
• ORR 
• Disease control rate (DCR) at Week 20 (end of Cycle 5) 
• Duration of response (DOR) 
Phase 2:  
• DCR at Week 20 (end of Cycle 5) 
• DOR 
• Progression-free survival (PFS) 
• Overall survival (OS) 
 
Safety Assessments  


 
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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 NSCLC cohort and breast cancer cohort, a true response rate of 10% (H0) versus 25% (Ha) 
will be tested. For pancreatic cancer cohort, a true response rate of 5% (H0) versus 18% (Ha) will 
be tested.  
1.4. 
Sample Size Determination  
The study is not powered for comparison of dose cohorts or tumor type cohorts. 
Phase 1b: Dose de-escalation will follow the 6+3 design and up to four dose cohorts will be 
enrolled for the DLT to determine the RP2D for the combination therapy. Therefore, Phase 1b 
will enroll a minimum of 6 and a maximum of 36 evaluable subjects. 
Phase 2: Hypothesis for the true response rate will be tested as described below independently 
for each tumor type cohort based on the statistical framework of Simon’s optimal 2-stage design. 
With a 1-sided error rate of 0.05, each tumor type cohort would have 80% power based on the 
true response rate in the alternative hypothesis. Approximately 130 subjects (including the 
subjects treated at the RP2D in Phase 1b and with the tumor type) across the three tumor type 
cohorts will be included in the Phase 2 analyses. 
NSCLC cohort and breast cancer cohort (n=18 for interim and n=43 for final per cohort): 
For each of the two tumor type cohorts, a true response rate of 10% (H0) versus 25% (Ha) will be 
tested and the probability of early stopping is at least 73.4% if the true response rate is ≤10% 
(H0), and no greater than 13.5% if the true response rate is ≥25% (Ha). 
An interim analysis (for futility) will be performed based on the first 18 evaluable subjects for 
each cohort independently. If 2 or fewer responders are observed among the 18 evaluable 
subjects in a cohort, the enrollment may be stopped. Otherwise, the cohort will continue to enroll 
an additional 25 evaluable subjects for a total of 43 evaluable subjects for the final analysis. The 
null hypothesis will be rejected if 8 or more responders are observed among the 43 evaluable 
subjects. 


 
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Each cohort will enroll subjects according to the histology ratio described in Section 1.1. 
Pancreatic cancer cohort (n=17 for interim and n=44 for final): 
A true response rate of 5% (H0) versus 18% (Ha) will be tested and the probability of early 
stopping is at least 79.2% if the true response rate is ≤5% (H0), and no greater than 16.2% if the 
true response rate is ≥18% (Ha). 
An interim analysis (for futility) will be performed based on the first 17 evaluable subjects. If 1 
or no responder is observed among the 17 evaluable subjects, the enrollment may be stopped. 
Otherwise, this cohort will continue to enroll an additional 27 evaluable subjects for a total of 44 
evaluable subjects for the final analysis. The null hypothesis will be rejected if 5 or more 
responders are observed among the 44 evaluable subjects. 
  
1.5. 
Planned Analyses 
1.5.1. 
Phase 1b Analyses 
The primary objective of Phase 1b is to determine the RP2D or MTD and to evaluate safety and 
tolerability of ibrutinib in combination with durvalumab. The secondary objectives are to 
evaluate efficacy and PK and PD in subjects receiving the combination regimen. 
1.5.2. 
Phase 2 Analyses 
Interim Analysis for Futility: For each tumor type cohort, the interim analysis will be performed 
after the first 18 evaluable subjects (for the NSCLC and breast cancer cohorts) /17 evaluable 
subjects (for the pancreatic cancer cohort) completed at least one tumor response assessment or 
at least 3 responders (in the NSCLC and breast cancer cohorts) / 2 responders (in the pancreatic 
cancer cohort) were observed, whichever occurs first. Confirmation of response is not required 
for those responders for the interim analysis. 
Final Analysis: The final analysis for both safety and efficacy will be performed at the end of the 
study based on all subjects treated for this study. A Clinical Study Report (CSR) will be 
produced when the analysis has been performed for all three cohorts. 
 
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.  


 
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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 
Enrolled Population 
This population includes all subjects who were enrolled in Phase 1b and Phase 2 (signed the 
informed consent and met all eligibility criteria). 
Response-evaluable Population 
The Response-evaluable Population is defined as all enrolled subjects who received at least one 
dose of study treatment (ibrutinib or durvalumab) 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 and disease control rate at Week 20 (end of Cycle 5). 
Safety Population (Treated Population) 
Safety population (Treated Population) includes all subjects who received at least 1 dose of study 
treatment (ibrutinib or durvalumab). Subjects in this population will be analyzed as randomized 
for the randomized subjects. The safety population will be used to summarize the safety 
(including dosing) data.   
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 (in Section 1.4.1) during the DLT observation period. 
2.2. 
Definition of Subgroups 
Subgroup 
Definition of subgroup 
Type of Analysis  
PD-L1 Expression 
High versus Low/None 
D, E (ORR) 
Histology for NSCLC cohort 
adenocarcinoma versus squamous-
cell carcinoma 
D, E (ORR) 
Histology for Breast Cancer cohort HER2-positive versus triple-negative 
D, E (ORR) 


 
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D: Demographics and baseline disease characteristics. E: Efficacy. ORR: Overall response rate. 
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 
antiplatelets.  
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 2.  


 
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Table 2: Summary of Efficacy Analyses 
 
Endpoint 
Definition 
Analysis Methods 
Primary Endpoint 
Overall 
Response 
Rate 
(ORR) 
Proportion of subjects achieving the 
best overall responses of CR or PR 
with confirmation 
Primary (Response-evaluable population) 
• Proportion and 2-sided 95% CI based on exact 
Binomial distribution (Clopper-Pearson) 
• Waterfall plot on tumor load from target lesion 
Sensitivity (Treated population) 
Proportion and 2-sided 95% CI based on exact 
Binomial distribution (Clopper-Pearson 
Subgroup (Response-evaluable population) 
• PD-L1: High vs. Low/None (all cohorts) 
• Histology (Breast Ca: HER2 positive vs. 
Triple negative; NSCLC: Adenocarcinoma vs. 
Squamous-cell Carcinoma) 
 
Secondary Endpoints 
Disease 
Control 
Rate 
(DCR) at 
Cycle 5 
Proportion of response-evaluable 
subjects who maintain disease 
control (CR, PR or SD) at Week 20 
(Cycle 5) 
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) 
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) 
Proportion and Kaplan-Meier estimate 
Sensitivity (Response-evaluable population) 
Proportion and Kaplan-Meier estimate for 
confirmed and unconfirmed response 
Progression 
Free 
Survival 
(PFS) 
Duration of time from the first 
dose date of study treatment 
(ibrutinib or durvalumab) to the first 
documentation of disease  
Primary (Treated population) 
• All PD and death considered events regardless 
any anticancer therapy prior to PD 
• Kaplan-Meier curve 


 
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Endpoint 
Definition 
Analysis Methods 
progression or the date of death due 
to any cause, whichever occurs first 
 
Sensitivity (Treated population) 
• Subjects are censored for use of subsequent 
anticancer therapy prior to PD or death; 
subjects are censored after missing two or 
more consecutive assessment prior to PD or 
death 
•  Kaplan-Meier curve 
 
Overall 
Survival 
(OS) 
Duration of time from the first dose 
date of study treatment 
(ibrutinib or durvalumab) to the date 
of death due to any cause 
Primary (Treated population) 
• All death considered events regardless of any 
anticancer therapy prior to death 
• Kaplan-Meier curve 
4.2. 
Safety Analyses 
Safety data will be summarized by tumor type cohorts. Table 3 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. In general, the treatment-
emergent period is defined as the period from the date of the first dose of study treatment up to 
30 days after last dose of ibrutinib or 90 days after last dose of durvalumab, whichever occurs 
later, or the day before initiation of subsequent antineoplastic therapy.  
The treatment-emergent adverse events (TEAEs) are those events that occur or worsen during 
the treatment-emergent period or that are related to the study treatment. Safety data include 
subject disposition/ study status, demographics, baseline characteristics and baseline disease 
characteristics, study drug and treatment exposure, treatment discontinuation and study exit 
including primary reason, duration of treatment, TEAEs of grade 3 and above, serious TEAEs, 
TEAEs of major hemorrhage, TEAEs leading to any study treatment discontinuation, survival 
status, and death listings. 
 


 
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Table 3: 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, 
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: 
• Data from all three tumor type cohorts will be pooled together to perform a total 
analysis in the final analysis. This analysis is not specified in the protocol. 
• The terminology ‘Safety Assessments’ instead of ‘Safety Endpoints’ is used in 
Section 1.2 safety analysis part 
    
6. REFERENCES 
Simon R, “Optimal Two-Stage Designs for Phase II Clinical Trials” Controlled Clinical Trials 
10:1-10 (1989) 
Rubinstein L and Simon R, “Phase I Clinical Trial Design” Biometric Research Branch, National 
Cancer Institute, Handbook of Anticancer Drug Development (2004) 
Eisenhauer EA et al, “New Response Evaluation Criteria in Solid Tumors; Revised RECIST 
Guideline (version 1.1). European Journal of Cancer 45:228-247 (2009) 
US Food and Drug Administration, “Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics” (May 2007) 
US Food and Drug Administration, “Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Non-Small Cell Lung Cancer Drugs and Biologics” (April 2015) 
EMA, Appendix1 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man: 
Methodological Considerations for Using Progression-free Survival (PFS) or Disease-free Survival 
in Confirmatory Trials (2011) 
Fleming TR, Rothmann MD, and Lu HL, “Issues in using progression-free survival when 
evaluating oncology products” J Clin Oncol 27:2874-2880 (2009)