Clinical trial NCT02436668
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: Pharmacyclics LLC.
Start date: 2015-05-01; Completion date: 2019-04-25
Enrollment: 430 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3 study to evaluate the efficacy of ibrutinib in combination with nab-paclitaxel and gemcitabine for the first line treatment of patients with metastatic pancreatic adenocarcinoma.

Detailed description:

Arms: arm 1: Ibrutinib daily in combination with:

Nab-paclitaxel and gemcitabine arm 2: Placebo daily in combination with:

Nab-paclitaxel and gemcitabine
Interventions: intervention 1: Ibrutinib intervention 2: Gemcitabine intervention 3: Nab-paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_001.pdf: 
IMBRUVICA® (ibrutinib) 
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PROTOCOL 
 
TITLE: 
A randomized, multicenter, double-blind, placebo-controlled, 
Phase 3 study of the Bruton’s Tyrosine Kinase inhibitor ibrutinib 
in combination with nab-paclitaxel and gemcitabine versus 
placebo in combination with nab-paclitaxel and gemcitabine, in 
the first line treatment of patients with metastatic pancreatic 
adenocarcinoma 
PROTOCOL NUMBER: 
PCYC-1137-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
124,674 
EudraCT NUMBER: 
2014-002069-31 
SPONSOR MEDICAL 
MONITOR: 
George Cole, MD 
Pharmacyclics LLC 
Phone: +1 (408) 990-7340 
Fax: 
+1 (408) 215-3684 
Email: gecole@pcyc.com 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
17 March 2015 
Amendment 1: 
15 June 2015 
Amendment 2: 
25 August 2015 
Amendment 2.1: 
18 September 2015 (UK and France only) 
Amendment 3: 
16 September 2016 
Amendment 4: 
16 December 2016 
Amendment 4.1: 
11 May 2017 (South Korea only) 
Amendment 5 
19 July 2017 
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. 


DocuSign Envelope ID: D39BE429-F4DA-4D7D-ACEE-BCB46E9B8D5F
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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................8 
LIST OF IN-TEXT TABLES .......................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................17 
1. 
BACKGROUND ........................................................................................................19 
1.1. 
Pancreatic Adenocarcinoma .........................................................................................19 
1.2. 
Current Treatment Options for Advanced Pancreatic Adenocarcinoma .....................21 
1.2.1. 
Regional Therapy .........................................................................................................21 
1.2.2. 
Chemoradiotherapy ......................................................................................................22 
1.2.3. 
Systemic Chemotherapy ..............................................................................................22 
1.3. 
Potential Role of Ibrutinib in the Treatment of Pancreatic Adenocarcinoma ..............26 
1.4. 
Ibrutinib........................................................................................................................28 
1.4.1. 
Summary of Nonclinical Data .....................................................................................29 
1.4.1.1. 
Pharmacology ..............................................................................................................29 
1.4.1.2. 
Toxicology ...................................................................................................................29 
1.4.1.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility ................................................29 
1.4.2. 
Summary of Clinical Data ...........................................................................................30 
1.4.2.1. 
Pharmacokinetics and Product Metabolism .................................................................30 
1.4.3. 
Summary of Clinical Safety .........................................................................................30 
1.4.3.1. 
Monotherapy Studies ...................................................................................................31 
1.4.3.2. 
Combination Studies ....................................................................................................31 
1.4.4. 
Risks .............................................................................................................................32 
1.4.4.1. 
Bleeding-related Events ...............................................................................................32 
1.4.4.2. 
Atrial Fibrillation .........................................................................................................32 
1.4.4.3. 
Cytopenias....................................................................................................................33 
1.4.4.4. 
Diarrhea ........................................................................................................................33 
1.4.4.5. 
Infections......................................................................................................................33 
1.4.4.6. 
Interstitial Lung Disease (ILD) ....................................................................................33 
1.4.4.7. 
Rash..............................................................................................................................33 
1.4.4.8. 
Tumor Lysis Syndrome................................................................................................33 
1.4.4.9. 
Hypertension ................................................................................................................34 
1.4.4.10. Lymphocytosis .............................................................................................................34 
1.4.4.11. Non-melanoma Skin Cancer ........................................................................................34 
1.4.5. 
Summary of Clinical Data in Pancreatic Adenocarcinoma .........................................34 
1.5. 
Nab-paclitaxel ..............................................................................................................34 
1.5.1. 
Summary of Clinical Data ...........................................................................................35 
1.5.2. 
Summary of Clinical Safety .........................................................................................35 
1.5.3. 
Summary of Clinical Data in Pancreatic Adenocarcinoma .........................................37 
1.6. 
Gemcitabine .................................................................................................................38 
1.6.1. 
Summary of Nonclinical Data .....................................................................................38 
1.6.2. 
Summary of Clinical Data ...........................................................................................39 


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1.6.3. 
Summary of Clinical Safety .........................................................................................39 
1.6.4. 
Summary of Clinical Data in Pancreatic Adenocarcinoma .........................................41 
1.6.4.1. 
Summary of Clinical Data: Gemcitabine Monotherapy ..............................................41 
1.7. 
Study Rationale ............................................................................................................42 
2. 
STUDY OBJECTIVE ................................................................................................43 
2.1. 
Primary Objective ........................................................................................................43 
2.2. 
Secondary Objective(s) ................................................................................................43 
2.3. 
Exploratory Objectives ................................................................................................43 
3. 
STUDY DESIGN ........................................................................................................43 
3.1. 
Overview of Study Design ...........................................................................................43 
3.2. 
Study Schema...............................................................................................................45 
3.3. 
Study Design Rationale ................................................................................................46 
3.3.1. 
Study Population and Treatment ..................................................................................46 
3.3.2. 
Dose Selection .............................................................................................................47 
3.3.2.1. 
Ibrutinib........................................................................................................................47 
3.3.2.2. 
Nab-paclitaxel and Gemcitabine ..................................................................................48 
4. 
SUBJECT SELECTION ...........................................................................................48 
4.1. 
Inclusion Criteria .........................................................................................................48 
4.2. 
Exclusion Criteria ........................................................................................................49 
5. 
TREATMENT OF SUBJECTS ................................................................................51 
5.1. 
Treatment Allocation and Blinding .............................................................................51 
5.1.1. 
Safety Run-in Phase .....................................................................................................51 
5.1.2. 
Randomized Double-blind Phase .................................................................................51 
5.1.2.1. 
Blinding........................................................................................................................52 
5.2. 
Study Treatment ...........................................................................................................52 
5.3. 
Study Medication .........................................................................................................52 
5.3.1. 
Ibrutinib........................................................................................................................52 
5.3.1.1. 
Formulation/Packaging/Storage ...................................................................................52 
5.3.1.2. 
Dose and Administration .............................................................................................53 
5.3.1.3. 
Overdose ......................................................................................................................53 
5.3.1.4. 
Dose Modification for Adverse Reactions ...................................................................54 
5.3.1.5. 
Dose Modification for Chronic Hepatic Impaired Subjects ........................................55 
5.3.2. 
Nab-paclitaxel and Gemcitabine ..................................................................................55 
5.3.2.1. 
Formulation/Packaging/Storage ...................................................................................55 
5.3.2.2. 
Dose and Administration .............................................................................................56 
5.3.2.3. 
Overdose ......................................................................................................................56 
5.3.2.4. 
Dose Modification for Adverse Reactions ...................................................................57 
5.4. 
Criteria for Continuation of Remaining Study Treatment(s), if One or More 
Study Treatments are Discontinued .............................................................................58 
5.5. 
Criteria for Permanent Discontinuation of Study Treatment .......................................58 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES ...........................................59 
6.1. 
Permitted Concomitant Medications............................................................................59 
6.2. 
Medications to be Used with Caution ..........................................................................59 
6.2.1. 
CYP3A Inhibitors/Inducers .........................................................................................59 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib .................60 


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6.2.3. 
QT Prolonging Agents .................................................................................................60 
6.2.4. 
Antiplatelet Agents and Anticoagulants ......................................................................60 
6.3. 
Prohibited Concomitant Medications ..........................................................................61 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ..........................61 
6.4.1. 
Minor Surgical Procedures ..........................................................................................61 
6.4.2. 
Major Surgical Procedures ...........................................................................................61 
6.4.3. 
Emergency Procedures.................................................................................................61 
7. 
STUDY EVALUATIONS ..........................................................................................61 
7.1. 
Description of Procedures ............................................................................................61 
7.1.1. 
Assessments .................................................................................................................61 
7.1.1.1. 
ICF ...............................................................................................................................61 
7.1.1.2. 
Confirm Eligibility .......................................................................................................62 
7.1.1.3. 
Medical History and Demographics ............................................................................62 
7.1.1.4. 
Prior and Concomitant Medications ............................................................................62 
7.1.1.5. 
Adverse Events ............................................................................................................62 
7.1.1.6. 
Study Drug Compliance Review .................................................................................63 
7.1.1.7. 
Physical Examination...................................................................................................63 
7.1.1.8. 
Eye-related Symptom Assessment ...............................................................................63 
7.1.1.9. 
Weight ..........................................................................................................................63 
7.1.1.10. Eastern Cooperative Oncology Group (ECOG) Performance Status ..........................63 
7.1.1.11. Karnofsky Performance Score (KPS) ..........................................................................64 
7.1.1.12. Memorial Pain Assessment Card (MPAC) ..................................................................64 
7.1.1.13. Patient-reported Outcomes (PRO) (EORTC QLQ-C30, version 3.0) .........................64 
7.1.1.14. Vital Signs ....................................................................................................................64 
7.1.2. 
Laboratory ....................................................................................................................64 
7.1.2.1. 
Hematology ..................................................................................................................65 
7.1.2.2. 
Comprehensive Chemistry Panel .................................................................................65 
7.1.2.3. 
Coagulation Studies .....................................................................................................65 
7.1.2.4. 
Hepatitis Serologies .....................................................................................................65 
7.1.2.5. 
Urinalysis .....................................................................................................................65 
7.1.2.6. 
Pregnancy Test .............................................................................................................65 
7.1.3. 
Diagnostics/Procedures ................................................................................................66 
7.1.3.1. 
ECG..............................................................................................................................66 
7.1.3.2. 
CT/MRI ........................................................................................................................66 
7.1.4. 
Pharmacokinetics .........................................................................................................67 
7.1.5. 
Biomarkers ...................................................................................................................69 
7.1.5.1. 
Carbohydrate Antigen 19-9 (CA 19-9) ........................................................................69 
7.1.5.2. 
Immunophenotyping ....................................................................................................69 
7.1.5.3. 
Molecular Markers .......................................................................................................69 
7.2. 
Efficacy Evaluations ....................................................................................................70 
7.2.1. 
Definitions....................................................................................................................70 
7.2.1.1. 
Measurable Disease .....................................................................................................70 
7.2.1.2. 
Non-measurable Disease ..............................................................................................71 
7.2.1.3. 
Target Lesions ..............................................................................................................71 
7.2.1.4. 
Non-target Lesions .......................................................................................................71 
7.2.1.5. 
New Lesions.................................................................................................................71 


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7.2.2. 
Guidelines for Evaluation of Measurable Disease .......................................................72 
7.2.3. 
Response Criteria .........................................................................................................73 
7.2.3.1. 
Evaluation of Target Lesions .......................................................................................73 
7.2.3.2. 
Evaluation of Non-target Lesions ................................................................................73 
7.2.3.3. 
Evaluation of Best Overall Response ..........................................................................73 
7.2.3.4. 
Missing Assessments or Inevaluable Lesions ..............................................................75 
7.3. 
Sample Collection and Handling .................................................................................75 
8. 
STUDY PROCEDURES ...........................................................................................76 
8.1. 
Screening Phase (Within 28 Days of Randomization) ................................................76 
8.1.1. 
Screening/Consenting Visit .........................................................................................76 
8.2. 
Treatment Phase ...........................................................................................................77 
8.2.1. 
Treatment Visits ...........................................................................................................77 
8.2.1.1. 
Cycle 1 Day 1 (C1D1) .................................................................................................77 
8.2.1.2. 
Cycle 1 Day 8 (and Subsequent Cycles) ......................................................................78 
8.2.1.3. 
Cycle 1 Day 15 (and Subsequent Cycles) ....................................................................79 
8.2.1.4. 
Cycle 1 Day 22 (and Subsequent Cycles) ....................................................................79 
8.2.1.5. 
Cycle 2 Day 1 (and Subsequent Cycles) ......................................................................80 
8.2.2. 
Efficacy Evaluations ....................................................................................................81 
8.2.3. 
End-of-Treatment (EOT) Visit ....................................................................................81 
8.3. 
Follow-up Phase...........................................................................................................82 
8.3.1. 
Efficacy Follow-up ......................................................................................................82 
8.3.2. 
Long-term Follow-up ...................................................................................................82 
9. 
SUBJECT COMPLETION AND WITHDRAWAL...............................................83 
9.1. 
Completion ...................................................................................................................83 
9.2. 
Withdrawal from Study Treatment ..............................................................................83 
9.3. 
Withdrawal from Study................................................................................................84 
10. 
STATISTICAL METHODS AND ANALYSIS ......................................................85 
10.1. 
Subject Information .....................................................................................................85 
10.1.1. 
Intention-to-treat Population (ITT) ..............................................................................85 
10.1.2. 
Safety Population (SP) .................................................................................................85 
10.1.3. 
Additional Analysis Populations ..................................................................................85 
10.1.4. 
Replacement of Subjects ..............................................................................................85 
10.2. 
Endpoints .....................................................................................................................85 
10.2.1. 
Primary Endpoints .......................................................................................................85 
10.2.2. 
Secondary Endpoints ...................................................................................................85 
10.2.3. 
Other Secondary Endpoints .........................................................................................86 
10.2.4. 
Selected Exploratory Endpoints ...................................................................................86 
10.3. 
Sample Size Determination ..........................................................................................86 
10.4. 
Efficacy Analysis .........................................................................................................87 
10.4.1. 
Primary Endpoints and Methods ..................................................................................87 
10.4.2. 
Secondary Endpoints and Methods ..............................................................................87 
10.4.2.1. Clinical Benefit Response ............................................................................................88 
10.4.2.2. Overall Response Rate .................................................................................................88 
10.4.2.3. Carbohydrate Antigen 19-9 (CA19-9) Response .........................................................88 
10.4.2.4. Patient-reported outcomes (PRO) as measured by EORTC QLQ-C30 .......................88 
10.4.2.5. Rate of venous thromboembolic events (VTE) ...........................................................88 


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10.4.3. 
Exploratory Endpoints and Methods ...........................................................................89 
10.5. 
Safety Analysis ............................................................................................................89 
10.5.1. 
Adverse Events ............................................................................................................89 
10.5.2. 
Clinical Laboratory Tests .............................................................................................89 
10.6. 
Pharmacokinetic Analyses ...........................................................................................90 
10.6.1. 
Ibrutinib........................................................................................................................90 
10.6.2. 
Gemcitabine .................................................................................................................90 
10.6.3. 
Nab-paclitaxel ..............................................................................................................91 
10.7. 
DMC Review ...............................................................................................................91 
10.8. 
Data Monitoring Committee (DMC) ...........................................................................91 
10.9. 
Independent Review .....................................................................................................92 
11. 
ADVERSE EVENT REPORTING ..........................................................................92 
11.1. 
Definitions....................................................................................................................93 
11.1.1. 
Adverse Events ............................................................................................................93 
11.1.2. 
Serious Adverse Events ...............................................................................................94 
11.1.3. 
Severity Criteria (Grade 1-5) .......................................................................................94 
11.1.4. 
Causality (Attribution) .................................................................................................95 
11.2. 
Unexpected Adverse Events ........................................................................................95 
11.3. 
Special Reporting Situations ........................................................................................95 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators .................................................................................................................96 
11.4.1. 
Assessment of Adverse Events ....................................................................................96 
11.4.2. 
Adverse Event Reporting Period .................................................................................96 
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events ...............................97 
11.4.4. 
Pregnancy .....................................................................................................................98 
11.4.5. 
Other Malignancies ......................................................................................................98 
11.4.6. 
Eye-Related Adverse Events ........................................................................................98 
11.4.7. 
Adverse Events of Special Interest (AESI) ..................................................................98 
11.4.7.1. Major Hemorrhage .......................................................................................................99 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...........99 
12.1. 
Regulatory and Ethical Compliance ............................................................................99 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval ..........................................................99 
12.3. 
Informed Consent.......................................................................................................100 
12.4. 
Quality Control and Quality Assurance .....................................................................100 
12.5. 
Protected Subject Health Information Authorization ................................................100 
12.6. 
Study Files and Record Retention..............................................................................101 
12.7. 
Case Report Forms and Record Maintenance ............................................................102 
12.8. 
Investigational Study Drug Accountability ...............................................................102 
12.9. 
Study Monitoring/Audit Requirements ......................................................................103 
12.10. 
Investigator Responsibilities ......................................................................................103 
12.11. 
Sponsor Responsibilities ............................................................................................104 
12.12. 
Financial Disclosure ...................................................................................................104 
12.13. 
Liability and Clinical Trial Insurance ........................................................................104 
12.14. 
Protocol Amendments ................................................................................................105 
12.15. 
Publication of Study Results ......................................................................................105 


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12.16. 
Study Discontinuation ................................................................................................105 
13. 
REFERENCES .........................................................................................................106 
14. 
APPENDICES ..........................................................................................................116 
 
LIST OF APPENDICES 
Appendix A. Schedule of Assessments .....................................................................................117 
Appendix B. Pharmacokinetics Sample Collection Based on Clock Time for Cycle 2 Day 1 .120 
Appendix C. Biomarker Sampling Schedule ............................................................................121 
Appendix D. Karnofsky Performance Status ............................................................................122 
Appendix E. ECOG Performance Status Scores .......................................................................123 
Appendix F. Memorial Pain Assessment Card (MPAC) ..........................................................124 
Appendix G. Inhibitors and Inducers of CYP3A ......................................................................125 
Appendix H. EORTC QLQ-C30 ...............................................................................................126 
Appendix I. 
Child-Pugh Score for Subjects with Chronic Liver Impairment .........................128 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Summary of Phase 3 Trial Results of FOLFIRINOX, Gemcitabine Plus Nab-
paclitaxel and Gemcitabine Plus Erlotinib in Pancreatic Adenocarcinoma ...........24 
Table 2. 
Efficacy Results from Randomized Study in Patients with Pancreatic 
Adenocarcinoma ....................................................................................................38 
Table 3. 
Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic 
Adenocarcinoma ....................................................................................................42 
Table 4. 
Ibrutinib/Placebo Dose Modifications ...................................................................55 
Table 5. 
Nab-paclitaxel and Gemcitabine Dose Modifications for Hematological 
Toxicity ..................................................................................................................57 
Table 6. 
Nab-paclitaxel and Gemcitabine Dose Modifications for Non-Hematological 
Toxicity ..................................................................................................................58 
Table 7. 
Dose Reduction for Nab-paclitaxel and Gemcitabine ...........................................58 
Table 8. 
Pharmacokinetics Sampling Schedule for Cycle 2 Day 1 Only ............................68 
Table 9. 
Time Point Response: Subjects with Target (+/– Non-target) Disease .................75 
 
 


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SYNOPSIS 
Study Title: 
A randomized, multicenter, double-blind, placebo-controlled, Phase 3 
study of the Bruton’s Tyrosine Kinase inhibitor ibrutinib in combination 
with nab-paclitaxel and gemcitabine versus placebo in combination with 
nab-paclitaxel and gemcitabine, in the first line treatment of patients 
with metastatic pancreatic adenocarcinoma 
Protocol Number: 
PCYC-1137-CA 
Study Phase: 
3 
Study Duration: 
Estimated to be 38 months 
Number of Subjects 
Approximately 426 (6 subjects in the Safety Run-in Phase and 
420 subjects in the Double-blind Randomized Phase) 
Investigational Product 
and Reference Therapy: 
Ibrutinib (IMBRUVICA®) will be supplied as 140 mg hard gelatin 
capsules for oral (PO) administration at a dose of 560 mg daily, in 
combination with nab-paclitaxel and gemcitabine 
Placebo will be supplied as matched hard gelatin capsules for oral (PO) 
administration, in combination with nab-paclitaxel and gemcitabine 
Gemcitabine: is available as 200 mg or 1000 mg lyophilized powder 
single use vials for reconstitution and intravenous (IV) administration 
Nab-paclitaxel: is available as 100 mg lyophilized powder single use 
vials for reconstitution and intravenous (IV) administration 
Objectives: 
Primary Objective: 
To evaluate the efficacy of ibrutinib in combination with nab-paclitaxel 
and gemcitabine versus placebo in combination with nab-paclitaxel and 
gemcitabine, based on investigator assessment of progression-free 
survival (PFS) and overall survival (OS), for the first line treatment of 
patients with metastatic pancreatic adenocarcinoma 
Secondary Objectives:  
• 
Clinical benefit response (CBR) rate 
• 
Overall response rate (ORR): complete response (CR) + partial 
response (PR), per investigator assessment 
• 
Carbohydrate antigen 19-9 (CA19-9) response 
• 
Patient-reported outcomes (PRO) by EORTC QLQ-C30 
• 
Rate of venous thromboembolic events (VTE) 
• 
To evaluate the safety and tolerability of ibrutinib in combination 
with nab-paclitaxel and gemcitabine versus placebo in 
combination with nab-paclitaxel and gemcitabine  
Study Design: 
The study will consist of two phases: 
Safety Run-in Phase: 
Six subjects will initially be recruited to receive open-label ibrutinib in 
combination with nab-paclitaxel and gemcitabine. The independent 
Data Monitoring Committee (DMC) will review data on the safety of 
ibrutinib combined with nab-paclitaxel and gemcitabine, after the first 
6 subjects have completed at least 28 days of follow-up after the 


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initiation of combination therapy as detailed in Section 10.8.  
Following DMC review and confirmation, the study may proceed to the 
Double-blind Randomized Phase. 
Double-blind Randomized Phase: 
The Double-blind Randomized Phase will compare ibrutinib in 
combination with nab-paclitaxel and gemcitabine versus placebo in 
combination with nab-paclitaxel and gemcitabine 
Approximately 420 subjects will be randomized between Arm A 
(ibrutinib in combination with nab-paclitaxel and gemcitabine) and 
Arm B (placebo in combination with nab-paclitaxel and gemcitabine). 
Randomization will be stratified according to:  
• 
Karnofsky performance status (KPS) 70-80 vs KPS 90-100 
• 
Liver metastasis (present or absent) 
• 
Age ≤65 years vs age >65 years 
Subjects will be treated until unacceptable toxicity or disease 
progression, whichever occurs first. If nab-paclitaxel and/or 
gemcitabine or ibrutinib/placebo are discontinued prior to disease 
progression, the remaining agents will be continued until unacceptable 
toxicity or disease progression. 
Population: 
Subjects with previously untreated metastatic pancreatic 
adenocarcinoma who, in the opinion of the investigator, are candidates 
for nab-paclitaxel and gemcitabine combination chemotherapy. 
Centers: 
Multicenter 
Inclusion Criteria: 
Disease-related 
1. Histologically or cytologically confirmed diagnosis of pancreatic 
adenocarcinoma. 
2. Stage IV disease diagnosed within 6 weeks of randomization. 
3. Disease which is evaluable according to RECIST 1.1, with at least 
one measurable metastatic lesion (not in a previously irradiated 
area). 
4. Disease status for which, in the opinion of the investigator, 
nab-paclitaxel and gemcitabine is considered an appropriate 
treatment choice. 
5. No previous radiotherapy, surgery, cytotoxic chemotherapy or 
investigational therapy for the treatment of metastatic pancreatic 
adenocarcinoma.  
6. No prior neo-adjuvant, peri-operative or adjuvant 
chemotherapy for primary disease of pancreatic adenocarcinoma. 
Prior treatment with 5-Fluorouracil (5-FU), gemcitabine or 
capecitabine administered as a radiation sensitizer (at non-cytotoxic 
doses) in the adjuvant setting is allowed, provided at least 6 months 
have elapsed since completion of the last dose. 
7. No clinically significant third-space fluid accumulation (eg, ascites 
or pleural effusion). 


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8. Male and female subjects of reproductive potential who agree to use 
highly effective methods of birth control (eg, implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], 
complete abstinence1, or sterilized partner) and a barrier method 
(eg, condoms, cervical ring, sponge, etc) during the period of 
therapy and for 6 months for males and females after the last dose of 
study medication.  
9. Ability to provide written informed consent and to understand and 
comply with the requirements of the study. 
Laboratory 
10. Adequate hematologic function independent of transfusion and 
growth factor support for at least 7 days prior to randomization:  
• 
Absolute neutrophil count (ANC) ≥1.5 x 109/L  
• 
Platelet count ≥100 x 109/L  
• 
Hemoglobin ≥9 g/dL 
11. Adequate hepatic and renal function defined as: 
• 
Serum aspartate transaminase (AST) and/or alanine 
transaminase (ALT) ≤5.0 x upper limit of normal (ULN) if liver 
metastases, or ≤3 x ULN without liver metastases 
• 
Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or 
bone metastases present 
• 
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin, such as hemolysis) 
• 
Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault) 
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN 
Demographic 
13. Men and women ≥18 years of age 
14. Karnofsky performance status (KPS) ≥70.  
15. ECOG 0-1 
Exclusion Criteria: 
Disease Related 
1. Prior radiotherapy to any measurable lesion at any time. 
2. Radiotherapy in the adjuvant setting, or earlier, within the last 
6 months. 
3. Previous cytotoxic chemotherapy for primary disease of pancreatic 
adenocarcinoma. 
4. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic 
carcinoma 
                                                 
 
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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Concurrent Conditions 
5. Known brain or leptomeningeal disease (CT or MRI scan of the 
brain required only in case of clinical suspicion of central nervous 
system [CNS] involvement). 
6. Prior exposure to Bruton's tyrosine kinase (BTK) inhibitor. 
7. A documented ≥10% decrease in KPS between Screening visit and 
within 72 hours prior to randomization. 
8. History of other malignancies, except:  
• 
Malignancy treated with curative intent and with no known 
active disease present for ≥3 years before the first dose of study 
drug and felt to be at low risk for recurrence by investigator. 
• 
Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease. 
• 
Adequately treated carcinoma in situ without current evidence 
of disease.  
9. Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia).  
10. 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. 
11. Live vaccination within 4 weeks prior to randomization.  
12. Any uncontrolled active systemic infection including any infection 
requiring systemic IV treatment which was completed ≤7 days 
before randomization. 
13. Major surgery within 4 weeks of first dose of study drug. 
14. 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. 
15. History of stroke or intracranial hemorrhage within 6 months prior 
to enrollment. 
16. 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, unstable 
angina, or acute coronary syndrome within 6 months prior to 
randomization. 
17. History of interstitial lung disease, idiopathic pulmonary fibrosis, or 
pulmonary hypersensitivity pneumonitis.  
18. Unable to swallow capsules or malabsorption syndrome, disease 
significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel, symptomatic inflammatory bowel disease 
or ulcerative colitis, or partial or complete bowel obstruction. 
19. Concomitant use of warfarin or other Vitamin K antagonists. 


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20. Known hypersensitivity to any study drug (nab-paclitaxel, 
gemcitabine or ibrutinib). 
21. Requires treatment with a strong cytochrome P450 (CYP) 3A 
inhibitor. 
22. Currently active, clinically significant hepatic impairment (Class B 
or C according to the Child-Pugh classification [Appendix I]). 
23. Lactating or pregnant. 
24. Unwilling or unable to participate in all required study evaluations 
and procedures. 
25. 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). 
26. Decline in serum albumin ≥20% from Screening to study 
randomization (both labs at Screening and prior to randomization 
may be confirmed locally). 
Study Treatment: 
1:1 Randomization between Arm A & Arm B 
Study medication should commence within 3 days of randomization. 
Arm A 
Ibrutinib (PO) 560 mg daily (4 capsules) until PD or unacceptable 
toxicity in combination with: 
Nab-paclitaxel (IV) 125 mg/m2 and gemcitabine (IV) 1000 mg/m2 
given on Days 1, 8, and 15 of each 28-day cycle, until evidence of 
progressive disease (PD) or is no longer tolerated by the subject. 
Arm B 
Placebo (PO) 4 matched capsules until PD or unacceptable toxicity in 
combination with: 
Nab-paclitaxel (IV) 125 mg/m2 and gemcitabine (IV) 1000 mg/m2 
given on Days 1, 8, and 15 of each 28-day cycle, until evidence of PD 
or is no longer tolerated by the subject. 
Dose Modifications 
Dose modifications for toxicity will be made separately for each agent 
as detailed in Section 5.3.1.4 for ibrutinib/placebo and Section 5.3.2.4 
for nab-paclitaxel and gemcitabine. 
Concomitant Therapy: 
Avoid co-administration with strong CYP3A or moderate CYP3A 
inhibitors and consider alternative agents with less CYP3A inhibition.  
Any non-study protocol related chemotherapy, anticancer 
immunotherapy, experimental therapy, or radiotherapy are prohibited 
while the subject is receiving study medication. Corticosteroids (at 
dosages equivalent to prednisone >20 mg/day) for >14 days should be 
avoided.  


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Safety Plan: 
The safety of this study will be monitored by an independent data 
monitoring committee (DMC) as outlined in the DMC charter and in 
accordance with the Sponsor’s Pharmacovigilance procedures. The 
DMC will consist of at least two clinicians including one medical expert 
in the management of pancreatic adenocarcinoma and at least one 
statistician.  
Safety Run-in Phase: 
The DMC will review data on the safety of ibrutinib in combination 
with nab-paclitaxel and gemcitabine, after the first six subjects have 
completed at least 28 days of follow-up after the initiation of 
combination therapy.  
Further enrollment will be suspended until the safety data have been 
reviewed. 
Depending on the outcome of their review, the DMC may recommend 
that: 
1. The study continue to the Double-blind Randomized Phase.  
2. Prior to commencing the Double-blind Randomized Phase, an 
additional safety review is performed after a total of up to 12 
subjects have been treated with ibrutinib (560 mg) in combination 
with nab-paclitaxel and gemcitabine.  
3. Prior to commencing the Double-blind Randomized Phase, the dose 
level of ibrutinib should be reduced to 420 mg and an additional 
6 subjects should be studied at this dose level, in combination with 
nab-paclitaxel and gemcitabine.  
Double-blind Randomized Phase: 
The DMC will review unblinded safety data on subjects randomized to 
each arm at periodic intervals during the study, as detailed in the DMC 
charter. The Sponsor will be reviewing blinded safety data on an 
ongoing basis and if a potential safety signal arises, additional ad hoc 
meetings may be convened, if requested by the DMC or the Sponsor. 
Statistical Methods: 
All efficacy analyses will be performed using the Intent-To-Treat 
(ITT) Population (consisting of all subjects randomized).  
Efficacy data from subjects in the open label safety run-in phase will be 
presented separately from the double-blind  randomized phase. 
Primary Endpoints: 
The primary endpoints of this study are PFS by investigator assessment, 
according to RECIST 1.1 criteria, and OS. Both PFS and OS will be 
analyzed comparing the 2 treatment arms using the log-rank test 
stratified by the stratification factors.  
Secondary Endpoints: 
• Clinical benefit response (CBR) rate will be compared using a 
chi-square test.  
• Overall response rate (ORR) will be compared using a chi-square 
test. 
• Carbohydrate antigen 19-9 (CA19-9) response will be compared 
using a chi-square test. 


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• Patient-reported outcomes (PRO) by EORTC QLQ-C30 will be 
summarized with descriptive statistics by treatment arm. 
Longitudinal analysis with repeated measures may be used as 
appropriate.  
• Rate of venous thromboembolic events (VTE) 
Multiplicity adjustment will be considered for the analysis of primary 
and secondary endpoints to control the overall Type I error. Details will 
be specified in the statistical analysis plan.   
Safety Analysis: 
Safety Run-in Phase: 
Safety data from subjects in the open label run-in phase will be 
presented separately from the randomized Safety Population. 
Double-blind Randomized Phase: 
Safety data will be generated from the Safety Population (consisting of 
all subjects randomized and receiving at least one dose of any study 
drug). 
DMC Review 
A DMC review of safety data including all death events will be 
performed approximately every 6 months after the first subject is 
randomized.  
Sample Size 
Determination 
The sample size calculation is based on a 2-sided family-wise Type I 
error rate (FWER) of 0.05 for two primary endpoints, PFS and OS. The 
FWER is controlled at 0.05 with 0.007 allocated to the PFS analysis and 
0.043 allocated to the OS analysis. 
As of 24 April 2017, a total of 424 subjects have been randomized with 
a 1:1 allocation to the two treatment arms. The calculations are based on 
the following assumptions using EAST software version 6.3.1 and the 
actual enrollment rates.  
For PFS:  
• 
Median PFS is 5.5 months for the control arm (nab-paclitaxel and 
gemcitabine) (Von Hoff 2013).  
• 
Target hazard ratio is 0.66 which corresponds to a 51% 
improvement in median PFS (eg, from 5.5 months to 8.33 
months) for the ibrutinib + nab-paclitaxel + gemcitabine arm 
compared to the placebo + nab-paclitaxel + gemcitabine arm 
• 
2-sided α = 0.007  
A total of 350 PFS events will provide approximately 88% power. 
For OS: 
• 
Median OS is 8.5 months for the control arm (nab-paclitaxel and 
gemcitabine) (Von Hoff 2013). 
• 
Target hazard ratio is 0.735 which corresponds to approximately 
36% improvement in median OS (eg, from 8.5 months to 
11.6 months) for the ibrutinib + nab-paclitaxel + gemcitabine arm 
compared to the placebo + nab-paclitaxel + gemcitabine arm 
• 
2-sided α = 0.043 


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• 
A group sequential design with one interim analysis is planned 
when at least 250 deaths occur (approximately 71% of the deaths 
occur). Lan-DeMets alpha spending function with O’Brien-
Fleming boundary for efficacy is used.  
• 
A total of 353 OS events will provide approximately 80% power 
for the study.  


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ABBREVIATIONS 
AE  
adverse event  
AESI 
Adverse Events of Special Interest (AESI) 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
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  
CYP 
cytochrome P 
BTK  
Bruton’s tyrosine kinase  
CA 19-9 
Carbohydrate antigen 19-9 
CBR 
clinical benefit response 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia  
CNS  
central nervous system  
Cmax 
maximum observed plasma concentration 
CR  
complete response  
CRF 
case report form (paper or electronic as appropriate for this study) 
CT 
Computerized Tomography 
CTCAE 
NCI Common Terminology Criteria for Adverse Events  
CYP  
cytochrome P450 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group performance status 
ECG 
Electrocardiogram 
eDC 
electronic data capture 
EFS 
Event free survival  
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End-of-Treatment  
FWER 
family-wise Type I error rate 
5-FU 
5-Fluorouracil 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV  
hepatitis C virus 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HUS 
Hemolytic Uremic Syndrome 
IC50  
concentration that inhibits a process by 50% 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normal ratio 
IB 
Investigator’s Brochure 
ILD 
interstitial lung disease 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible kinase  


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ITT 
Intent-to-treat 
IV 
intravenous 
IWRS 
interactive web response system 
KPS 
Karnofsky Performance Status 
LC-MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPAC 
Memorial Pain Assessment Card 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NSCLC 
non small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
oral 
PR  
partial response  
PRO 
patient-reported outcome(s) 
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time  
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
QLQ-C30 
EORTC core quality of life questionnaire  
QTc  
QT interval corrected for heart rate  
SCARs 
severe cutaneous adverse reactions 
SAE  
serious adverse event 
SD 
stable disease 
SJS 
Steven-Johnson syndrome 
SLL 
small lymphocytic lymphoma  
SP 
Safety Population 
t1/2 
half-life 
Tmax 
time to maximum plasma concentration  
TDP 
Time to diminished pain 
TGI 
tumor growth inhibition 
TLS 
tumor lysis syndrome 
VTE 
venous thromboembolic events 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
 
 
 


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1. 
BACKGROUND 
1.1. 
Pancreatic Adenocarcinoma  
Pancreatic adenocarcinoma remains one of the most intractable of all malignancies. The 
diagnosis is almost universally associated with exceptionally poor outcomes, resulting in an 
extremely short survival and substantial concomitant burden of both disease and treatment 
related morbidity. The bleakness of the prognosis is exemplified by the profound depression 
characterizing the condition (Boyd 2012) with suicide rates in those with pancreatic cancer 
eleven times greater than within the general population (Turarga 2011). 
Worldwide, approximately 300,000 new cases of pancreatic cancer are recorded annually, with 
over 90% being ductal adenocarcinomas. In the United States despite accounting for less than 
5% of malignancies in total, the disease remains the fourth leading cancer-related cause of death 
in both men and women (World Cancer Research Fund International 2013, Siegel 2014). 
The American Cancer Society estimates that approximately 45,000 patients were diagnosed 
with pancreatic cancer in 2013, with over 37,000 of them surviving less than a year 
(American Cancer Society 2013).  
It is therefore a devastating disease and within the entire spectrum of neoplastic conditions, 
pancreatic adenocarcinoma is a malignancy characterized by the most intractable biology and 
refractory clinical course, resulting in a rapid natural history of disease progression and death.  
In the US, the average lifetime risk for developing pancreatic cancer is 1%−2% and unlike most 
other malignancies, the incidence has been slowly increasing over the last decade 
(Malvezzi 2014).  
Identified risk factors are wide ranging and include chronic pancreatitis, smoking, diabetes 
mellitus, significant family history of the disease and certain genetic disorders such as cystic 
fibrosis, hereditary pancreatitis, Peutz-Jeghers syndrome, and Lynch syndrome (Zavoral 2011, 
Alsamarrai 2014, Larsson 2005, Li 2009). An excess incidence of pancreatic adenocarcinoma 
also appears to occur in patients with BRCA-1 and BRCA-2 mutations (Easton 1999, 
Al-Sukhni 2008). The median age at detection is 71 and the disease is extremely rare in those 
aged less than 40 (Raimondi 2009).  
The two major precursors of pancreatic adenocarcinoma are pancreatic intraepithelial neoplasia 
and intraductal papillary mucinous neoplasms. These antecedent conditions are associated with a 
stepwise pattern of histological deterioration, combined with progressively worsening genetic 
mutational alterations (Canto 2012, Hustinx 2005), ultimately resulting in overt carcinoma 
typically possessing considerable intratumoral genomic heterogeneity and multiple distinct 
subclones (Iacobuzio-Donahue 2009). 


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Characteristic features of the disease include a high rate of activating mutations in KRAS 
(>90%), progression from distinct types of precursor lesions, a propensity for both local invasion 
and distant metastasis, an extensive stromal reaction (desmoplasia) resulting in a hypovascular 
and hypoxic microenvironment, reprogramming of cellular metabolism, and evasion of tumor 
immunity (Ryan 2014, Feig 2012, Vonderheide 2013, Ogura 2013). These disease characteristics 
collectively combine to present major challenges to the development of effective therapeutic 
strategies.  
Despite the recent evolution of more sophisticated imaging modalities aimed at earlier detection, 
including high-resolution computed tomography (CT) scanning and endoscopic ultrasound 
(Langer 2009, Poley 2009), the overall 5-year survival for patients with pancreatic cancer is less 
than 5%. This poor prognosis is predominantly influenced by the majority of patients being 
diagnosed late in the disease process. Unlike many other gastrointestinal malignancies, 
pancreatic cancer tends to remain asymptomatic and undiagnosed until significant locoregional 
or distant disease is present (Furukawa 2001, Hruban 2014, Enewold 2015) with four out of five 
initially presenting with unresectable tumor burden. One-third of this advanced patient 
population will have inoperable locally-advanced disease, while the remaining two-thirds will 
have evidence of stage IV metastases at diagnosis (Brunner 2010). 
Approximately 85% of patients with distant disease will present with liver metastases, a finding 
known to be associated with poor outcomes (Papadoniou 2008, Hawes 2000, Park 2008). In 
contrast, a small proportion of patients have disseminated disease limited to isolated pulmonary 
metastases and in this sub group, a more favorable prognosis with prolonged survival has been 
reported (Katz 2009, Arnaoutakis 2011). 
Complete resection with histologically negative margins is the only intervention offering the 
possibility of long-term survival for the 20% or so of cases presenting without overt advanced 
inoperable disease at diagnosis. While early detection is rare, those with tumors limited to the 
pancreas without nodal involvement and who undergo successful resection can experience a 
median survival of over 30 months with 1-, 3-, and 5-year survivals of 80%, 49%, and 41%, 
respectively (Cameron 2006). In contrast however, many patients are unfortunately discovered to 
have extensive lymph node involvement and/or microscopically positive operative margins at the 
time of surgery (Konstantinidis 2013), findings which are incompatible with a favorable longer 
term course. 
Due to the technical challenges of surgery, only 15% of patients actually undergoing operative 
intervention achieve a sufficiently prolonged remission to be consistent with a curative outcome 
(Lowy 2008). Despite these favorable results in a few, the majority of patients receiving surgery 
will ultimately develop locoregional recurrence and/or distant metastases. In view of the limited 
overall disease control obtained with surgery alone, both chemoradiation and chemotherapy have 
therefore been utilized as adjuncts to resection, in an attempt to minimize subsequent 
locoregional and distant recurrence (Kalser 1985, Oettle 2007, Neoptolemos 2004). 


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Despite a lack of consensus over the most appropriate adjuvant intervention, clinically 
significant improvements with adjuvant therapy are clearly obtainable in some situations, 
especially in carefully selected patient sub-groups (such as those with R1 resections, or positive 
lymph nodes) with reported hazard ratios for death, compared to no adjuvant treatment, in the 
range 0.5-0.7 (Corsini 2008, Butturini 2008, Oettle 2007, Oettle 2013).  
However, any overall advantage conferred by adjuvant treatment is unfortunately constrained by 
the small proportion of the total patient population for whom it is a realistic therapeutic option. 
Additionally, the benefits that such adjuvant treatment strategies bring is modest compared to 
similar adjuvant interventions in many other solid tumor settings (Liao 2013, Raigani 2014). 
Delayed detection and hence the limited utility of surgical and adjuvant strategies is one of the 
two major drivers underlying the aggressive natural history of pancreatic adenocarcinoma. The 
second is the lack of effective chemotherapeutic strategies, most markedly in the advanced 
setting. Current chemotherapy regimens are only marginally effective in extending survival, a 
finding which has not changed in over three decades (Loc 2014, Oberstein 2013, Falconi 2003), 
underscoring the ongoing unmet medical need for novel and innovative new approaches for 
advanced disease in this most challenging of malignancies. 
1.2. 
Current Treatment Options for Advanced Pancreatic Adenocarcinoma 
1.2.1. 
Regional Therapy 
A number of evolving radiotherapy techniques are being deployed in the first line management 
of locally advanced, unresectable disease, such as intensity modulated radiotherapy (IMRT) 
(Yovino 2011), stereotactic body radiotherapy (SBRT) (Chang 2009) and intraoperative 
radiation therapy (IORT) (when used in patients found to have unresectable disease at the time of 
surgery) (Jingu 2012, Ashman 2013). 
While these modalities can achieve enhanced dose delivery to the tumor site, with reduced 
collateral irradiation of non-malignant tissue, and correspondingly improved local control, there 
is to date little evidence that this translates into an improvement in survival, possibly due to a 
confounding increase in the frequency of metastatic disease, at least in some reported series 
(Gunderson 1987, Mohuiddin 1995). 
The uncertainty around the clinical benefit of these approaches, as well as methodological 
complexities in defining optimal total and fractional radiotherapy doses, severely constrain the 
widespread application of such treatment strategies in the management of locally advanced 
unresectable disease. In general, suitable patients would only have access to such techniques 
through participation in clinical trials at specialized centres (NCCN Guidelines 2016). 


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1.2.2. 
Chemoradiotherapy 
Chemoradiation (involving sensitizers such as 5-Fluorouracil (5-FU) [Moertel 1981, 
Crane 2002], gemcitabine [Murphy 2007, Girard 2010] or capecitabine [Mukherjee 2013]) has 
established a role in the initial management of certain patient subsets with unresectable locally 
advanced disease, in particular those who do not develop metastatic dissemination during 
preceding chemotherapy. However, as with many treatment strategies in advanced pancreatic 
cancer, the utility of this approach remains controversial (Kim 2007, Cavalcante 2014).  
The choice of initial management of patients with unresectable locally advanced disease is 
further complicated by the lack of consensus over the optimal sequencing of employing 
chemoradiation at the outset versus initial chemotherapy followed by subsequent chemoradiation 
(Jones 2014, Huguet 2014). The former approach is probably most suited to selected patients 
with poorly controlled pain and/or locally invasive disease resulting in bleeding 
(Blackstock 2003) while the latter appears to confer greatest benefit in those with a good 
performance status, no detectable metastatic burden and little probability of disease reverting to a 
resectable status (Huguet 2007, Krishnan 2007).  
Overall, the balance of available evidence seems to suggest that chemoradiation is superior to 
radiation alone but there is no convincing advantage established to date for chemoradiation 
versus chemotherapy alone (Chen 2013, Hammel 2013, Azria 2014), typically with similar 
median overall survival (OS) figures of less than 12 months for either regimen. Given the 
marginal benefits of treatment, it is clear that careful selection of appropriate patient populations 
for any give modality is essential for maximizing the modest results that can be expected. 
1.2.3. 
Systemic Chemotherapy 
Patients with advanced pancreatic disease most frequently receive chemotherapy in the first line 
setting, with the aim of prolonging survival and providing palliative relief of symptoms such as 
pain, weight loss, biliary obstruction and declining performance status (NCCN Guidelines 2016, 
Seufferlein 2012). 
Gemcitabine monotherapy was the original standard of care for patients with metastatic 
pancreatic cancer for several years. Although it only showed a marginal survival benefit over 
treatment with bolus 5-FU (5.6 versus 4.4 months), there was a significantly higher proportion of 
patients who achieved clinical benefit with gemcitabine compared to 5-FU (23.8% versus 4.8%) 
(Aapro 1998, Burris 1997).  
The limited efficacy of gemcitabine monotherapy appears to be improved by administering the 
drug at a fixed dose rate (FDR), rather than the standard 30 minute infusion conventionally 
utilized, resulting in a 25% improvement in median survival (6.2 months versus 4.9 months) 
(Poplin 2009). This differential activity is probably due to greater intracellular concentrations of 
the phosphorylated active form of gemcitabine achievable with FDR (eg,10 mg/m2/min) delivery 
techniques (Grunewald 1991). 


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Numerous combination strategies with a range of chemotherapy agents, including cisplatin, 
oxaliplatin, capecitabine, 5-FU, epirubicin, paclitaxel and docetaxel (Poplin 2009, Reni 2005) 
have been studied in combination with gemcitabine in an attempt to improve treatment 
outcomes. However, despite the variety of combination approaches examined, little benefit has 
been seen over gemcitabine monotherapy in the advanced disease setting, with a significant 
increase in toxicity in all cases (Ciliberto 2013, Sun 2012). Furthermore, where any benefit has 
been seen with gemcitabine-combination therapy, it has been restricted to the small proportion of 
patients with a good performance status (Heinemann 2008, Herrmann 2007, Heinemann 2006, 
Whitehead 1997). Combination regimens which are currently endorsed by the National 
Comprehensive Cancer Network (NCCN) Pancreatic Adenocarcinoma Guidelines 
(NCCN Guidelines: Pancreatic Adenocarcinoma 2016) for this prognostically more favorable 
group include gemcitabine plus capecitabine (Li 2014) and the combination of gemcitabine, 
docetaxel and capecitabine (the GTX regimen) (Fine 2008, De Jesus-Acosta 2012).  
Gemcitabine and cisplatin combinations are also recommended for selected patients who may 
harbor BRCA mutations, based on empirical findings of superior efficacy of this approach in 
patients with a family history of pancreatic cancer (Lowery 2011). 
Despite generally highly variable results reported for taxanes when used as monotherapy 
(Androulakis 1999a, Rougier 2000, Gebbia 1996), or when given with gemcitabine (Jacobs 1999, 
Androulakis 1999b) recently the combination of gemcitabine plus nab-paclitaxel (albumin bound 
paclitaxel particles) has shown an increased median survival of 1.8 months, with improved OS at 
1 and 2 years, when compared to gemcitabine alone. Furthermore, compared to the significant 
toxicity of the FOLFIRINOX regimen discussed below, adverse effects were acceptable, mainly 
consisting of cytopenias and peripheral neuropathy (Von Hoff 2013). 
In addition to chemotherapeutic regimens, gemcitabine has also been examined in combination 
with more targeted approaches, including a number of kinase inhibitors. The range of agents 
studied encompasses bevacizumab (Kindler 2011), cetuximab (Philip 2010), saridegib 
(Richards 2012), axitinib (Kindler 2011), sorafenib (Goncalves 2012), aflibercept 
(Rougier 2013), tipifarnib (Van Cutsem 2004), marimastat (Philip 2008), pemetrexed 
(Oettle 2005) and erlotinib (Moore 2007), amongst others. Despite the mechanistic variety of 
targeted agents, erlotinib was the only combination to show a statistically significant survival 
advantage over gemcitabine monotherapy, although this was by only two weeks. However, the 
minimal survival benefit seen with this combination has been tempered by both a significant side 
effect profile and the high cost of treatment, leading to limited uptake of this combination in 
clinical practice. 
Additionally, a number of non-gemcitabine based regimens have also been examined in 
advanced pancreatic cancer, including capecitabine plus continuous infusional 5-FU 
(Boeck 2010, Cartwright 2002) and the combination of a fluoropyrimidine (5-FU/leucovorin or 
capecitabine) with oxaliplatin (Pelzer 2011, Xiong 2008). 


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Of particular note, the multidrug combination of leucovorin, fluorouracil, irinotecan, and 
oxaliplatin (FOLFIRINOX) was recently reported to provide an increased median survival of 
4.3 months when compared to gemcitabine monotherapy. However, given its significant side 
effect profile, it is effectively available only to a select group of patients with advanced 
pancreatic cancer who are able to tolerate such an intensive intervention (Conroy 2011).  
Overall, current NCCN and ESMO guidelines detail a wide range of treatment options for 
patients with advanced pancreatic cancer, with the exception of those with a poor performance 
status, where gemcitabine monotherapy is essentially the only recommendation. The broad 
variety of possible treatment choices is however an indication of the dissatisfaction with each 
individually. Choosing an appropriate treatment regimen therefore remains complicated and 
uncertain and in the absence of randomized comparative trials, there is no consensus on first-line 
therapy for these patients. Treatment choices are therefore guided empirically and pragmatically 
without evidence based, well-defined and validated treatment algorithms. 
Currently the three most widely used chemotherapy combinations for patients with a good 
performance status (ie, ECOG PS of 0 or 1, adequate pain control, a patent biliary stent and 
adequate nutritional intake), are FOLFIRINOX, gemcitabine plus nab-paclitaxel and gemcitabine 
plus erlotinib (Seufferlein 2012, NCCN Guidelines: Pancreatic Adenocarcinoma 2016). Out of 
over thirty phase 3 studies in pancreatic adenocarcinoma over the last decade, these are the only 
ones to have reported a statistically significant improvement in survival, when compared to 
gemcitabine alone. 
Results of Phase 3 trials for these three regimens are summarized in Table 1 below: 
Table 1. 
Summary of Phase 3 Trial Results of FOLFIRINOX, Gemcitabine Plus Nab-
paclitaxel and Gemcitabine Plus Erlotinib in Pancreatic Adenocarcinoma 
REGIMEN 
FOLFIRINOX vs G 
NAB-PAC + G vs G 
ERL + G vs G 
GROUP 
F 
G 
p value 
Nab+G 
G 
p value 
ERL 
G 
p value 
PFS (ms) 
6.4 
3.3 
<0.001 
5.5 
3.7 
<0.0001 
3.75 
3.55 
0.004 
OS (ms) 
11.1 
6.8 
<0.001 
8.5 
6.7 
<0.0001 
6.24 
5.91 
0.038 
12.5* 
13.7** 
 
 
 
 
 
 
 
 
ORR (%) 
31.6 
9.4 
<0.001 
23 
7 
<0.0001 
8.6 
8 
n/a 
Abbreviations: F = FOLFIRINOX, G=gemcitabine; ERL=erlotinib; Nab-PAC= nab-paclitaxel; ORR=overall 
response rate; OS=overall survival; PFS=progression-free survival  
* OS in metastatic disease from single centre MSKCC study of FOLFIROX 
** OS in locally advanced disease from single centre MSKCC study of FOLFIROX (Lowery 2012) 
Although comparison across trials is limited by methodological variations, greatest efficacy was 
seen with the FOLFIRINOX regimen although at the cost of a substantially higher burden of 
Grade 3/4 toxicity (45.7% neutropenia, 12.7% diarrhea, 9.1% thrombocytopenia, 9% sensory 
neuropathy). However, although clearly more toxic, it is notable that significantly fewer patients 


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had an impaired quality of life at six months in the FOLFIRINOX group compared to the 
gemcitabine one (31% versus 66%, p <0.001). Furthermore, a subsequent more detailed analysis 
of patient outcomes showed that patients in the FOLFIRINOX group actually maintained or even 
improved quality of life compared to those treated with gemcitabine (Gourgou-Bourgade 2013). 
Erlotinib and gemcitabine reported minimal improvement in efficacy (although greater activity 
was seen in patients developing a skin rash early on in treatment, this being a recognized 
surrogate of EGFR inhibition) (Moore 2007, Van Cutsem 2009). Furthermore the marginal 
efficacy advantage was abrogated by the finding that whilst toxicities were fairly comparable 
between the two groups, three times as many patients required a dose reduction in the erlotinib 
and gemcitabine arm, compared to gemcitabine alone (16% versus 5%). 
The Phase 3 trial of nab-paclitaxel and gemcitabine (Von Hoff 2013) reported efficacy 
improvements over gemcitabine alone.  
A total of 861 patients were randomly assigned to either nab-paclitaxel and gemcitabine (n=431) 
or gemcitabine alone (n=430). Median OS was 8.5 months with nab-paclitaxel and gemcitabine 
versus 6.7 months with gemcitabine alone (hazard ratio 0.72; 95% CI 0.62 to 0.83; P<0.001). 
The survival rate was 35% versus 22% at 1 year, and 9% versus 4% at 2 years, respectively. 
Median progression-free survival was 5.5 months for nab-paclitaxel and gemcitabine versus 
3.7 months for gemcitabine alone (hazard ratio, 0.69; 95% CI, 0.58 to 0.82; P<0.001) with a 
similar benefit (hazard ratio) for both median PFS and median OS. The rate of progression-free 
survival was 44% versus 25% at 6 months and 16% versus 9% at 1 year, respectively.  
Overall, treatment effects for both OS and PFS consistently favored the nab-paclitaxel and 
gemcitabine group across most protocol prespecified subgroups. Patients with more advanced 
disease (poorer performance status, presence of liver metastasis, more than three sites of 
metastatic disease, metastatic pancreatic cancer at initial diagnosis, or a CA19-9 level that was 
≥59 times the upper limit of the normal) had the highest reduction in the risk of death and 
greatest prolongation of PFS with nab-paclitaxel and gemcitabine compared to gemcitabine 
alone. 
The overall response rate (ORR) was 23% versus 7% in the two groups (P<0.001) while the rate 
of disease control (confirmed response or stable disease for ≥16 weeks) was 48% versus 33% 
respectively (P<0.001).  
In addition, 61% of patients in the nab-paclitaxel and gemcitabine group, versus 44% of those in 
the gemcitabine alone group, had a serum carbohydrate antigen CA19-9 decrease from baseline 
of at least 20% (P<0.001) and 31% versus 14% had a decrease of at least 90% (P<0.001). 
Patients in both treatment groups who achieved a decrease of at least 90% in the CA19-9 level 
had a median survival of 13.5 months, as compared with 8.2 months among those with a 
decrease of less than 90% (hazard ratio, 0.53; 95% CI, 0.43 to 0.67; P<0.001). 


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The most common adverse events (AEs) of grade 3 or higher severity were neutropenia (38% in 
the nab-paclitaxel and gemcitabine group versus 27% in the gemcitabine alone group), fatigue 
(17% versus 7%), and neuropathy (17% versus 1%). Febrile neutropenia occurred in 3% versus 
1% of the patients in the two groups respectively. In the nab-paclitaxel and gemcitabine group, 
neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. 
Although first line therapy with regimens such as nab-paclitaxel plus gemcitabine and 
FOLFIRINOX provide improved outcomes versus gemcitabine monotherapy, the limited extent 
of any gains and the toxicity afforded by these regimens has led to the exploration of 
maintenance strategies in those patients with stable disease or better following initial 
chemotherapy. The recently reported Phase 2 PACT-12 trial of sunitinib maintenance therapy in 
patients who had not progressed after 6 cycle of chemotherapy (Reni 2013) demonstrated a 
6-fold increase in PFS at 6 months, when compared to an observation only arm (3.6% vs 22.2%) 
and a 3-fold increase in two year OS (7.1% vs 22.9%). 
The promising nature of these results suggests that the use of targeted agents after initial 
chemotherapy is a potentially useful new treatment construct which should be explored further in 
future trials of new therapeutic approaches to advanced pancreatic adenocarcinoma. 
In view of the limited clinical activity and variable burden of toxicity with all currently available 
first line regimens and the potential promise of the combination of chemotherapy and targeted 
agent strategies, there is therefore a clear need for new treatment options with a more favorable 
efficacy-toxicity profile and improved quality of life for patients with advanced pancreatic 
adenocarcinoma, such as that presented by the addition of ibrutinib to the combination of 
nab-paclitaxel and gemcitabine.  
1.3. 
Potential Role of Ibrutinib in the Treatment of Pancreatic Adenocarcinoma 
With respect to the anti-tumor activity of ibrutinib, there are three potential mechanisms that may 
be operative in pancreatic adenocarcinoma: 1) changes in the tumor microenvironment, eg, 
inhibition of mast cell function, 2) changes in immune profiles, eg, alteration of Th1/Th2 
polarity, and 3) direct inhibition of Epidermal Growth Factor Receptor (EGFR) kinase activity. 
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 
KRAS 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). New data have just been published showing that treating 
p53ER/ER;LSLKRasG12D;pdx1-Cre mice with both ibrutinib and standard of care gemcitabine, 
ameliorated the toxicity and significantly extended survival when compared to gemcitabine 
alone. Additionally, in subcutaneous xenografts (PDX) of a patient derived tumor in the 


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NOD/SCID mouse model a significant survival advantage was seen in single agent ibrutinib 
treated mice compared to control mice (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). 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-Valles 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. 
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 KRASG12D 
(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 monotherapy, general tumor size was reduced (Soucek 2012) while the 
combination of ibrutinib and gemcitabine significantly improved survival compared to 
gemcitabine alone (P=0.02) (Masso-Valles 2013). 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 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). 
Ibrutinib is also 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 directly potentiate anti-tumor activity 
through an increased tumor influx of cytotoxic CD8+ T cells, as well as augmenting the effects of 
concomitantly administered cytotoxic chemotherapy. 


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Ibrutinib has been shown to inhibit EGFR (Honigberg 2010) and to inhibit growth of non small 
cell lung cancer (NSCLC) cells carrying EGFR gene mutations both in vitro and in vivo 
(Gao 2014), suggesting ibrutinib can function as an EGFR inhibitor.  
Human EGFR is over-expressed in many pancreatic tumors (Fjällskog 2003, Tobita 2003) and is 
associated with poor prognosis and disease progression (Xiong 2004, Ueda 2004). Treatment 
with erlotinib, an EGFR inhibitor, has shown benefit in patients with pancreatic adenocarcinoma 
in a clinical trial, although the efficacy was limited to a small subpopulation (<10%) 
(Moore 2007). Mechanistically, mutations in KRAS, known to occur in about 90% of patients 
with pancreatic cancer, has been associated with up-regulation of EGFR in pancreatic tumors 
presumably leading to enhancement of KRAS-mediated oncogenic signal(s) (Siveke 2012). 
TGFα, one of the EGFR ligands, is also known to be over-expressed in ductal epithelial cells of 
pancreatic tumors from patients (Barton 1991). In experimental models of pancreatic cancer in 
mice, pharmacological (Bruns 2000, Ng 2002, Ardito 2012) or genetic (Ardito 2012) inactivation 
of EGFR decreased the growth and metastasis of human pancreatic tumor xenografts and 
improved the anticancer effects of gemcitabine. Collectively, these results suggest that 
expression of EGFR and its activity are critical for pathogenesis of pancreatic adenocarcinoma in 
human.  
The fact that pancreatic cancer has a poor prognosis is in part related to its relative resistance to 
chemotherapy. New approaches are therefore needed to treat this aggressive disease. The effect 
of ibrutinib on mast cells and other cells in the tumor microenvironment and its potential to 
augment the antitumor activity of conventional chemotherapy combinations, such as nab-
paclitaxel plus gemcitabine, the chemotherapy combination examined in the current study, 
provide a potential alternative approach to existing therapies for this disease. 
1.4. 
Ibrutinib  
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research and Development LLC for the treatment of B-cell malignancies.  
Ibrutinib has been approved in many regions including the United States (US) and European 
Union (EU), for indications including treatment of patients with mantle cell lymphoma (MCL) 
who have received at least 1 prior therapy, patients with chronic lymphocytic leukemia 
(CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with a deletion of the short arm 
of chromosome 17 (del17p), patients with Waldenström’s Macroglobulinemia (WM), and 
patients with Marginal Zone Lymphoma (MZL) who require systemic therapy and have received 
at least one prior anti-CD20-based therapy.  
For the most up to date and comprehensive nonclinical and clinical information regarding 
ibrutinib background, safety, efficacy, in vitro and in vivo preclinical activity and toxicology of 
ibrutinib, always refer to the latest version of the ibrutinib Investigator's Brochure (IB) and/or the 
applicable regional labeling information. 


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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 B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011).  
Ibrutinib has also been reported to be an irreversible inhibitor of ITK (IC50=2-10 nM) in 
enzymatic assays and exhibiting 50% ITK occupancy in Jurkat whole cell lysates at 100 nM 
(Duvousky 2013). 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB. 
1.4.1.2. 
Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system or respiratory system in rats at any dose tested. Further, no treatment-related 
corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs.  
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).  
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic. In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in patients administered the dose of 560 mg daily, respectively.  
1.4.1.3. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib.  
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 


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Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
1.4.2. 
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 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased with substantial intersubject variability. The mean half-life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours. Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
overnight fasting with median time to Tmax delayed from 2 to 4 hours. Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with 
approximately 15 times lower inhibitory potency compared to ibrutinib. The metabolite-to-parent 
AUC ratio ranged from 0.7 to 3.4. Steady-state exposure of ibrutinib and PCI-45227 was less 
than 2-fold of first dose exposure. 
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces. Subjects with mild and moderate renal 
insufficiency (creatinine clearance >30 mL/min) were eligible to enroll in Study PCYC-1102-CA 
in which pharmacokinetic (PK) assessments were included. No dose adjustment is needed for 
mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There is no 
data in patients with severe renal impairment or patients on dialysis. In a hepatic impairment 
study, data showed an increase in ibrutinib exposure. 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 greater 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. 
1.4.3. 
Summary of Clinical Safety 
For more comprehensive safety information please refer to the current version of the 
ibrutinib IB. 


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1.4.3.1. 
Monotherapy Studies 
Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy in 13 studies 
that have completed primary analysis or final analysis included in the CSR as of the 
31 May 2016 cutoff date for the current ibrutinib IB update in B-cell malignancies are 
summarized below.  
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318): 
Most frequently reported TEAEs 
≥15% a 
Most frequently reported Grade 
3 or 4 TEAEs ≥3% b 
Most frequently reported 
Serious TEAEs ≥2% c 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia 
Hypertension   
 
Anemia 
Diarrhea    
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract infection 
 
 
Thrombocytopenia 
 
 
Oedema peripheral 
 
 
a Source is Table 6 of ibrutinib IB (v10); b Source is Table 8 of ibrutinib IB (v10); c Source is Table 9 of 
ibrutinib IB (v10). 
1.4.3.2. 
Combination Studies 
Pooled safety data from a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in subjects with B-cell malignancies are briefly 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).  


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The most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=423): 
Most frequently reported TEAEs 
≥20% a 
Most frequently reported Grade 
3 or 4 TEAEs ≥3% b 
Most frequently reported 
Serious TEAEs ≥2% c 
Neutropenia 
Neutropenia 
Pneumonia 
Diarrhea 
Thrombocytopenia 
Febrile neutropenia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anaemia 
Anaemia 
 
Pyrexia  
Fatigue  
 
 
Hypertension  
 
 
Diarrhea  
 
a Source is Table 10 of ibrutinib IB (v10); b Source is Table 12 of ibrutinib IB (v10); c Source is Table 13 of 
ibrutinib IB (v10). 
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, 
subdural 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 6.2.4 for guidance 
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, hypertension, acute infections, and a previous 
history of atrial fibrillation. Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea should be evaluated clinically, and if indicated, have 
an ECG performed. For atrial fibrillation which persists, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines (see Section 5.3.1.4). 


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1.4.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 
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 are rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.3.1.4). 
1.4.4.5. 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these infections have been associated with hospitalization 
and death. Consider prophylaxis according to standard of care in subjects who are at increased 
risk for opportunistic infections (Section 6.1). Although causality has not been established, cases 
of progressive multifocal leukoencephalopathy (PML) and hepatitis B reactivation have occurred 
in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, 
chills, weakness, confusion, vomiting, and jaundice) and appropriate therapy should be instituted 
as indicated. 
1.4.4.6. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.3.1.4). 
1.4.4.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Isolated cases of severe cutaneous adverse reactions (SCARs) 
including Stevens-Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib. 
Subjects should be closely monitored for signs and symptoms suggestive of SCAR including 
SJS. Subjects receiving ibrutinib should be observed closely for rashes and treated 
symptomatically, including interruption of the suspected agent as appropriate. In addition, 
hypersensitivity-related events including erythema, urticaria, and angioedema have been 
reported. 
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 tumor lysis 


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syndrome are those with comorbidities and risk factors such as high tumor burden prior to 
treatment, increased uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and 
pre-existing kidney abnormalities. 
1.4.4.9. 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
1.4.4.10. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5,000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with CLL/SLL treated with ibrutinib. This effect has also 
been observed in some subjects with MCL treated with ibrutinib. This observed lymphocytosis 
(increase in the number of circulating lymphocytes eg, >400,000/µL) is a pharmacodynamic 
effect and should not be considered progressive disease in the absence of other clinical findings. 
In both disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy 
and typically resolves within a median of 8 weeks in subjects with MCL and 14 weeks in 
subjects with CLL/SLL. This pharmacodynamic effect was less prominent or not observed in 
other indications.  
1.4.4.11. 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.4.5. 
Summary of Clinical Data in Pancreatic Adenocarcinoma 
To date, there is no clinical experience with ibrutinib, either as monotherapy or in combination, 
in patients with pancreatic adenocarcinoma.  
1.5. 
Nab-paclitaxel  
Nab-paclitaxel (ABRAXANE®) is an albumin-bound form of paclitaxel with a mean particle size 
of approximately 130 nanometers. Paclitaxel exists in the particles in a noncrystalline, 
amorphous state. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-
hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-
phenylisoserine. 
Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin 
dimers and stabilizes microtubules by preventing depolymerization. This stability results in the 
inhibition of the normal dynamic reorganization of the microtubule network that is essential for 


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vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” 
of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. 
1.5.1. 
Summary of Clinical Data 
Nab-paclitaxel (ABRAXANE®) is indicated for use in the following conditions: 
• Metastatic breast cancer, after failure of combination chemotherapy for metastatic disease 
or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included 
an anthracycline unless clinically contraindicated.  
• Locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line 
treatment in combination with carboplatin, in patients who are not candidates for curative 
surgery or radiation therapy 
• Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with 
gemcitabine.  
For more information on clinical data for nab-paclitaxel, please refer to the ABRAXANE® 
product labeling. 
1.5.2. 
Summary of Clinical Safety   
Hematologic Effects 
Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity 
of nab-paclitaxel. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with 
metastatic breast cancer, 47% of patients with non-small cell lung cancer (NSCLC), and 38% of 
patients with pancreatic cancer. 
Nervous System 
Sensory neuropathy is dose- and schedule-dependent. The occurrence of Grade 1 or 2 sensory 
neuropathy does not generally require dose modification. If Grade ≥3 sensory neuropathy 
develops, nab-paclitaxel treatment should be withheld until resolution Grade ≤1 for pancreatic 
cancer followed by a dose reduction for all subsequent courses.  
Sepsis 
Sepsis occurred in 5% of patients with or without neutropenia who received nab-paclitaxel in 
combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors 
for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) treatment should be 
initiated with broad spectrum antibiotics. For febrile neutropenia, nab-paclitaxel and gemcitabine 
should be interrupted until fever resolves and ANC ≥1500/µL and then resumed at a reduced 
dose.  


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Pneumonitis 
Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving 
nab-paclitaxel in combination with gemcitabine. Patients should be monitored for signs and 
symptoms of pneumonitis and there should be an interruption of nab-paclitaxel and gemcitabine 
during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon 
making a diagnosis of pneumonitis, treatment should be permanently discontinued. 
Hypersensitivity 
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have 
been reported. Patients who experience a severe hypersensitivity reaction to nab-paclitaxel 
should not be re-challenged with the drug. 
Hepatic Impairment 
Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, 
administration of nab-paclitaxel in patients with hepatic impairment should be performed with 
caution. Nab-paclitaxel is not recommended in patients with pancreatic carcinoma who have 
moderate or severe hepatic failure. 
Albumin (Human) 
Nab-paclitaxel contains albumin (human), a derivative of human blood. Based on effective donor 
screening and product manufacturing processes, it carries a remote risk for transmission of viral 
diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also 
considered extremely remote. No cases of transmission of viral diseases or CJD have ever been 
identified for albumin. 
Use in Pregnancy 
Nab-paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of 
paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum 
recommended human dose, based on body surface area, caused embryofetal toxicities, including 
intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. 
There are no adequate and well-controlled studies in pregnant women receiving nab-paclitaxel. If 
the drug is used during pregnancy, or if a patient becomes pregnant while receiving the drug, the 
patient should be apprised of the potential hazard to the fetus. 
Women of childbearing potential should be advised to avoid becoming pregnant while receiving 
nab-paclitaxel. 


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Use in Men 
Men should be advised not to father a child while receiving nab-paclitaxel. 
For more information on clinical safety data for nab-paclitaxel, please refer to the 
ABRAXANE® product labeling. 
1.5.3. 
Summary of Clinical Data in Pancreatic Adenocarcinoma 
A multicenter, multinational, randomized, open-label study was conducted in 861 patients 
comparing nab-paclitaxel and gemcitabine versus gemcitabine monotherapy as first-line 
treatment of metastatic adenocarcinoma of the pancreas.  
Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, 
transaminase levels ≤2.5 times the upper limit of normal (ULN) or ≤5 times the ULN for patients 
with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic 
disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung 
disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14-day 
Screening period prior to study randomization were ineligible. A total of 861 patients were 
randomized (1:1) to the nab-paclitaxel and gemcitabine arm (n=431) or to the gemcitabine arm 
(n=430).  
Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, 
or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus 
no). Patients randomized to nab-paclitaxel and/gemcitabine received nab-paclitaxel 125 mg/m2 
as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2 as an 
intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients 
randomized to gemcitabine received 1000 mg/m2 as an intravenous infusion over 30-40 minutes 
weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m2 on Days 1, 
8 and 15 of each subsequent 28-day cycle.  
Patients in both arms received treatment until disease progression or unacceptable toxicity. The 
major efficacy outcome measure was OS. Additional outcome measures were progression-free 
survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded 
radiological review using Response Evaluation Criteria In Solid Tumors (RECIST) criteria 
(version 1.0).  
In the intent-to-treat (all randomized) population, the median age was 63 years (range 27−88 
years) with 42% ≥65 years of age; 58% were men; 93% were White and KPS was 90-100 in 
60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of 
patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of 
pancreas (43%), body (31%), or tail (25%). 


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Results of this study are summarized in Table 2 below: 
Table 2. 
Efficacy Results from Randomized Study in Patients with Pancreatic 
Adenocarcinoma 
 
Nab-paclitaxel and 
gemcitabine 
(N=431) 
Gemcitabine 
(N=430) 
Overall Survival 
 
 
Number of deaths, n (%) 
333 (77) 
359 (83) 
Median Overall Survival (Months) 
8.5 
6.7 
95% CI 
7.9,9.5 
6.0,7.2 
HR (95% CI) 
0.72 (0.06,0.83) 
p-value 
<0.0001 
Progression-free Survival 
 
 
Death or progression, n (%) 
277 (64) 
265 (62) 
Median Progression-free survival 
5.5 
3.7 
95% CI 
4.5, 5.9 
3.6, 4.0 
HR (95% CI) 
0.69 (0.58, 0.82) 
p-value 
<0.0001 
Overall Response Rate 
 
 
Confirmed complete or partial overall response, n (%) 
99 (23) 
31 (7) 
95% CI 
19.1. 27.2 
5.0, 10.1 
p-value 
<0.0001 
Abbreviations: CI = confidence interval; HR = hazard ratio; 
Reference: ABRAXANE® prescribing information 
1.6. 
Gemcitabine 
Gemcitabine (GEMZAR®) is a nucleoside metabolic inhibitor that exhibits antitumor activity. 
Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer). 
1.6.1. 
Summary of Nonclinical Data 
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through 
the G1/S-phase boundary.  
Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate 
(dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme 
responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA 
synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP.  
Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the 
intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation 
of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is 
incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, 
which eventually results in the initiation of apoptotic cell death. 


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1.6.2. 
Summary of Clinical Data 
Gemcitabine is indicated: 
• In combination with carboplatin, for the treatment of advanced ovarian cancer that has 
relapsed at least 6 months after completion of platinum based therapy  
• In combination with paclitaxel, for first-line treatment of metastatic breast cancer after 
failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines 
were clinically contraindicated 
• In combination with cisplatin for the treatment of non-small cell lung cancer  
• As a single agent for the treatment of pancreatic cancer 
For more information on clinical data for gemcitabine, please refer to the most current local 
gemcitabine product labeling. 
1.6.3. 
Summary of Clinical Safety 
Schedule-dependent Toxicity 
In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the 
infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased 
incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and 
asthenia. The half-life of gemcitabine is influenced by the length of the infusion. 
Myelosuppression 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with 
gemcitabine as a single agent and the risks are increased when gemcitabine is combined with 
other cytotoxic drugs.  
In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, 
and 5%, respectively of patients receiving single-agent. The frequencies of Grade 3-4 
neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, 
respectively, in patients receiving gemcitabine in combination with another drug. 
Pulmonary Toxicity and Respiratory Failure 
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, 
and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these 
pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy.  
The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. 
Gemcitabine should be discontinued in patients who develop unexplained dyspnea, with or 
without bronchospasm, or have any evidence of pulmonary toxicity. 


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Hemolytic Uremic Syndrome (HUS) 
Hemolytic Uremic Syndrome (HUS), including fatalities from renal failure or the requirement 
for dialysis can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 
6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Renal function 
should be assessed prior to initiation of gemcitabine and periodically during treatment. 
The diagnosis of HUS should be considered in patients who develop anemia with evidence of 
microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe 
thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). 
Gemcitabine should be permanently discontinued in patients with HUS or severe renal 
impairment. Renal failure may not be reversible even with discontinuation of therapy.  
Hepatic Toxicity 
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. 
Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing 
medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the 
underlying hepatic insufficiency.  
Hepatic function should be assessed prior to initiation of gemcitabine and periodically during 
treatment. Gemcitabine should be discontinued in patients who develop severe liver injury. 
Embryofetal Toxicity 
Gemcitabine can cause fetal harm when administered to a pregnant woman, based on its 
mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and 
rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking 
gemcitabine, the patient should be apprised of the potential hazard to a fetus.  
Exacerbation of Radiation Therapy Toxicity 
Gemcitabine is not indicated for use in combination with radiation therapy.  
Concurrent (given together or ≤7 days apart)  
Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which 
gemcitabine was administered at a dose of 1000 mg/m2 to patients with non-small cell lung 
cancer for up to 6 consecutive weeks concurrently with thoracic radiation. 


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Non-concurrent (given >7 days apart)  
Excessive toxicity has not been observed when gemcitabine is administered more than 7 days 
before or after radiation. Radiation recall has been reported in patients who receive gemcitabine 
after prior radiation. 
Capillary Leak Syndrome 
Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving 
gemcitabine as a single agent or in combination with other chemotherapeutic agents. 
Gemcitabine should be discontinued if CLS develops during therapy. 
For more information on clinical safety data for gemcitabine, please refer to the local 
gemcitabine product labeling.  
1.6.4. 
Summary of Clinical Data in Pancreatic Adenocarcinoma 
1.6.4.1. 
Summary of Clinical Data: Gemcitabine Monotherapy 
The safety and efficacy of gemcitabine was evaluated in two studies, a randomized, single-blind, 
two-arm (gemcitabine versus 5-fluorouracil), active-controlled trial conducted in patients with 
locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in 
a single arm, open-label, multicenter trial conducted in patients with locally advanced or 
metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen.  
The primary efficacy outcome measure in both trials was clinical benefit response (CBR). 
In the randomized study, patients treated with gemcitabine had statistically significant increases 
in clinical benefit response, survival, and time to disease progression compared to those 
randomized to receive 5-FU. No confirmed objective tumor responses were observed in either 
treatment arm.  
Efficacy outcome results are summarized in the Table 3 below. 


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Table 3. 
Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic 
Adenocarcinoma 
Efficacy Outcomes 
Gemcitabine 
(n =63) 
5-FU 
(n=63) 
Clinical Benefit Response 
22.2% 
4.8% 
p-value 
0.004 
Overall Survival 
 
Median (months) 
5.7 
4.2 
(95% CI) 
4.7, 6.9 
3.1, 5.1 
p-value  
0.0009 
Time to Disease Progression 
 
Median (months) 
2.1 
0.9 
(95% CI) 
1.9, 3.4 
0.9, 1.1 
p-value 
0.0013 
Reference: GEMZAR® prescribing information 
1.7. 
Study Rationale 
Advanced pancreatic adenocarcinoma is one of the most aggressive malignancies and even with 
the most intensive chemotherapeutic strategies median survival is less than one year, often with a 
significantly impaired quality of life. Treatment options remain limited and the combination of 
nab-paclitaxel and gemcitabine represents one of the most widely used therapeutic strategies in 
patients with a better performance status. However, outcomes with this regimen are limited to a 
median survival of less than nine months and a progression-free interval of only five and a half 
months. 
There is therefore an overwhelming and urgent need for more effective and innovative 
approaches with acceptable toxicity, such as the proposed three agent combination of ibrutinib, 
nab-paclitaxel and gemcitabine which will be examined in the current trial. The nab-paclitaxel 
and gemcitabine regimen is considered the most appropriate combination with which to evaluate 
ibrutinib, as the pattern of significant efficacy and manageable toxicity facilitate its first line use 
in the widest range of patients with advanced pancreatic disease (Hoy 2014, Cecco 2014, 
Al-Batran 2014). 
Addition of ibrutinib to a nab-paclitaxel and gemcitabine chemotherapy backbone is supported 
by the biologic rationale that ibrutinib exerts direct anti-tumor, collagen-induced platelet 
aggregation inhibition (Ninomoto 2017) and antivascular effects via mast cell stabilization 
(Masso-Valles 2015) and also modifies the tumor microenvironment and associated immune 
profile through alteration of Th1/Th2 polarity, with a concomitant cytotoxic T cell influx. The 
immuno-mediated anti-tumor effects of ibrutinib appear to be mechanistically distinctive to and 
separate from the cytotoxic activity of nab-paclitaxel and gemcitabine. The direct anti-tumor, 
collagen-induced platelet aggregation inhibition (Ninomoto 2017), and antivascular properties of 


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ibrutinib should further augment the existing efficacy of the nab-paclitaxel and gemcitabine 
combination.  
2. 
STUDY OBJECTIVE   
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of ibrutinib in combination with 
nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and 
gemcitabine, based on investigator assessment of progression-free survival (PFS) and overall 
survival (OS), for the first line treatment of patients with metastatic pancreatic adenocarcinoma.  
2.2. 
Secondary Objective(s) 
• Clinical benefit response (CBR) rate 
• Overall response rate (ORR): complete response (CR) + partial response (PR), per 
investigator assessment 
• Carbohydrate antigen 19-9 (CA19-9) response 
• Patient-reported outcome (PRO) by EORTC QLQ-C30 
• Rate of venous thromboembolic events (VTE) 
• To evaluate the safety and tolerability of ibrutinib in combination with nab-paclitaxel and 
gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine  
2.3. 
Exploratory Objectives 
To compare the treatment arms in terms of the following: 
• Time to diminished pain: time to 50% reduction in pain score as assessed on MPAC pain 
assessment tool  
• Disease control rate (DCR): the proportion of subjects who achieve a best response of 
complete response (CR), partial response (PR) or stable disease (SD) (≥8 weeks) per 
investigator assessment, in accordance with RECIST 1.1 criteria.  
• Exploratory tumor and circulating biomarkers  
• Pharmacokinetic (PK) parameters of ibrutinib, gemcitabine and paclitaxel when dosed in 
combination  
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This is a randomized, multicenter, double blind placebo-controlled, Phase 3 study comparing 
ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with 


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nab-paclitaxel and gemcitabine, in the first line treatment of subjects with metastatic pancreatic 
adenocarcinoma. The primary endpoints are PFS as determined by investigator assessment 
according to RECIST 1.1 and OS. The secondary endpoints will evaluate clinical benefit rate, 
overall response, carbohydrate CA19-9 response, patient-reported outcomes, and VTE rate.  
A Data Monitoring Committee (DMC) review of safety data including death events will be 
performed approximately every 6 months after the first subject is randomized.  
The study will consist of two phases. 
Safety Run-in Phase: 
Six subjects will initially be recruited to receive open-label ibrutinib in combination with 
nab-paclitaxel and gemcitabine. The independent Data Monitoring Committee (DMC) will 
review data on the safety of ibrutinib combined with nab-paclitaxel and gemcitabine, after the 
first 6 subjects have completed at least 28 days of follow-up after the initiation of combination 
therapy as detailed in Section 10.8.  
Depending on the outcome of their review, the DMC may recommend that: 
a) the study continue to the Double-blind Randomized Phase. 
b) prior to commencing the Double-blind Randomized Phase, an additional safety review is 
performed after a total of up to 12 subjects have been treated with ibrutinib (560 mg) in 
combination with nab-paclitaxel and gemcitabine. 
c) prior to commencing the Double-blind Randomized Phase, the dose level of ibrutinib 
should be reduced to 420 mg and an additional 6 subjects should be studied at this dose 
level, in combination with nab-paclitaxel and gemcitabine prior to a subsequent review 
by the DMC. 
Double-blind Randomized Phase 
The second phase of the study will be a randomized, double-blind comparison of ibrutinib in 
combination with nab-paclitaxel and gemcitabine versus placebo in combination with 
nab-paclitaxel and gemcitabine. 
Approximately 420 subjects will be randomized between Arm A (ibrutinib in combination with 
nab-paclitaxel and gemcitabine) and Arm B (placebo in combination with nab-paclitaxel and 
gemcitabine). 
Randomization will be stratified according to:  
• KPS 70-80 vs KPS 90-100 
• Liver metastasis (present or absent) 
• Age ≤65 years vs age >65 years  
Subjects will be treated until unacceptable toxicity or disease progression, whichever occurs first. 
If nab-paclitaxel and/or gemcitabine or ibrutinib/placebo are discontinued prior to disease 
progression, the remaining agents will be continued until unacceptable toxicity or disease 
progression. 


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3.2. 
Study Schema 
Randomization
Arm A: Ibrutinib  in combination with nab-paclitaxel plus gemcitabine
Vs.
Arm B: Placebo in combination with nab-paclitaxel plus gemcitabine
Screening Phase
(within 28 days of randomization)
Treatment Phase to continue until
Follow-up Phase
(until death or consent withdrawal)
Survival, subsequent anticancer therapy, PRO,  clinical benefit ( including KPS analgesic consumption, MPAC, and weight)
Double-Blind Randomized Phase
Maintenance treatment 
with ibrutinib/placebo is 
no longer tolerated by 
subject
Maintenance treatment 
with ibrutinib/placebo in 
treatment phase
Treatment with nab-paclitaxel 
and gemcitabine is no longer 
tolerated by the subject
Progressive Disease (PD) 
confirmed by CT/MRI per 
RECIST 1.1
Continue Efficacy Evaluations 
untill Progresive Disease 
confirmed by CT/MRI per 
RECIST 1.1
Perform End Of Treatment 
Visit
 (30 days
 after last dose of 
1) ibrutinib/placebo  
or 2) last dose of nab-
paclitaxel/gemcitabine) 
(whichever 
occurs LAST)
Perform End Of Treatment 
Visit
 (30 days
 after last dose of 1) ibrutinib/
placebo  or 2) last dose of 
nab-paclitaxel/gemcitabine)
Perform End Of 
Treatment Visit
 (30 days
 after last dose of 
ibrutinib/placebo)  
Progressive Disease confirmed by 
CT/MRI per RECIST 1.1
Treatment with ibrutinib/
placebo is no longer 
tolerated by the subject
  Continue treatment with 
nab-paclitaxel and 
gemcitabine in treatment 
phase
Treatment with nab-paclitaxel 
and gemcitabine is no longer 
tolerated by subject
Perform End Of Treatment Visit
 (30 days
 after last dose of nab-paclitaxel/
gemcitabine) 
 
Note: Shaded box represents Treatment Phase. See Schedule of Assessment (Appendix A) for details of procedures. 


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3.3. 
Study Design Rationale 
This is a double-blind, randomized, placebo-controlled trial, comparing ibrutinib in combination 
with the established regimen of nab-paclitaxel and gemcitabine to placebo in combination with 
nab-paclitaxel and gemcitabine in subjects with advanced pancreatic adenocarcinoma, with 
primary endpoints of PFS as determined by investigator assessment according to RECIST 1.1 
and OS. 
While there is no agreed standard of care in the management of advanced pancreatic 
adenocarcinoma, nab-paclitaxel and gemcitabine is a very widely used regimen in patients with a 
good performance status and hence is considered to be a suitable comparator control regimen for 
this trial. 
Progression-free survival (PFS) is considered an appropriate primary endpoint in a patient 
population which has an exceptionally limited life expectancy and for whom a prolonged period 
of disease control, with a corresponding stabilization of quality of life, is probably the most 
important outcome of therapeutic intervention, given the very modest improvements in OS 
afforded by existing treatment options. Subsequently this study is designed to detect a clinically 
meaningful difference in PFS (Ellis 2014) target hazard ratio (0.6 to 0.75) with OS as an 
additional primary endpoint.  
As this is a novel combination, an initial open-label Safety Run-in Phase of 6 subjects is 
considered an appropriate means of establishing the safety and tolerability of ibrutinib in 
combination with nab-paclitaxel and gemcitabine. Safety data from this initial cohort will be 
reviewed by an independent DMC, prior to enrollment continuing. Furthermore, the DMC will 
have the authority to request that safety and tolerability are examined in additional subjects, at 
the same or a lower dose of ibrutinib, before proceeding to the Double-blind Randomized Phase 
of the study. 
The double-blind, placebo-controlled study design is considered the optimal means for 
comparatively assessing the efficacy, safety and tolerability of the two treatment arms. 
3.3.1. 
Study Population and Treatment 
Subjects with previously untreated metastatic pancreatic adenocarcinoma who, in the opinion of 
the investigator, are candidates for nab-paclitaxel and gemcitabine combination chemotherapy. 
Subjects will be randomized to treatment with either continuous daily ibrutinib or placebo, in 
combination with nab-paclitaxel and gemcitabine given on Days 1, 8, and 15 of continual 28-day 
cycles, until disease progression, or unacceptable toxicity, whichever occurs first. If clinically 
appropriate, the investigator may start dosing with the oral study drug (ibrutinib/placebo) up to 
48 hours before beginning chemotherapy.  


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Subjects will be treated until unacceptable toxicity or disease progression, whichever occurs first. 
If nab-paclitaxel and/or gemcitabine or ibrutinib/placebo are discontinued prior to disease 
progression, the remaining agents will be continued until unacceptable toxicity or disease 
progression. 
3.3.2. 
Dose Selection 
3.3.2.1. 
Ibrutinib 
Ibrutinib has been FDA-approved for MCL at a dose of 560 mg and for CLL and WM 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 pharmacodynamic effect in the vast majority of patients. The sustained 
pharmacodynamic 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 may 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). 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).  


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Due to the extensive clinical experience with the 560 mg dose in terms of safety and efficacy, 
and due to variability in the sensitivity of solid tumors studied to date, a dose of 560 mg/day has 
been chosen for this study involving pancreatic ductal adenocarcinoma. 
3.3.2.2. 
Nab-paclitaxel and Gemcitabine 
The schedule of nab-paclitaxel (IV) 125 mg/m2 and gemcitabine (IV) 1000 mg/m2 given on 
Days 1, 8 and 15 of each 28-day cycle is the schedule of administration in the approved US 
Prescribing Information for nab-paclitaxel when given in combination with gemcitabine for the 
treatment of pancreatic adenocarcinoma (ABRAXANE® Prescribing Information) and hence is 
considered appropriate for the current study. 
4. 
 SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria. 
Disease-related 
1. Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma.  
2. Stage IV disease diagnosed within 6 weeks of randomization. 
3. Disease which is evaluable according to RECIST 1.1, with at least one measurable 
metastatic lesion (not in a previously irradiated area). 
4. Disease status for which, in the opinion of the investigator, nab-paclitaxel and 
gemcitabine is considered an appropriate treatment choice. 
5. No previous radiotherapy, surgery, cytotoxic chemotherapy or investigational therapy for 
the treatment of metastatic pancreatic adenocarcinoma.  
6. No prior neo-adjuvant, peri-operative or adjuvant chemotherapy for primary disease 
of pancreatic adenocarcinoma. Prior treatment with 5-FU, gemcitabine or capecitabine 
administered as a radiation sensitizer (at non-cytotoxic doses) in the adjuvant setting is 
allowed, provided at least 6 months have elapsed since completion of the last dose. 
7. No clinically significant third-space fluid accumulation (eg, ascites or pleural effusion). 
8. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence 2, or sterilized partner) and a barrier 
                                                 
 
2 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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method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 
6 months for males and females after the last dose of study medication. 
9. Ability to provide written informed consent and to understand and comply with the 
requirements of the study. 
Laboratory 
10. Adequate hematologic function independent of transfusion and growth factor support for 
at least 7 days prior to randomization:  
• Absolute neutrophil count (ANC) ≥1.5 x 109/L 
• Platelet count ≥100 x 109/L 
• Hemoglobin ≥9 g/dL 
11. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper 
limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases 
• Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin, such as hemolysis) 
• Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault) 
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN 
Demographic 
13. Men and women ≥18 years of age. 
14. Karnofsky performance status (KPS) ≥70. Two observers will be required to assess KPS 
at Screening. If discrepant, the one with the lowest assessment will be accepted. 
15. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Disease-related 
1. Prior radiotherapy to any measurable lesion at any time. 
2. Radiotherapy in the adjuvant setting, or earlier, within the last 6 months. 
3. Previous cytotoxic chemotherapy for primary disease of pancreatic adenocarcinoma. 
4. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 


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Concurrent Conditions 
5. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in 
case of clinical suspicion of central nervous system involvement). 
6. Prior exposure to BTK inhibitor. 
7. A documented ≥10% decrease in KPS between Screening visit and within 72 hours prior 
to randomization. 
8. History of other malignancies, except:  
• Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study drug and felt to be at low risk for recurrence by 
investigator. 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
• Adequately treated carcinoma in situ without current evidence of disease.  
9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). 
10. 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. 
11. Live vaccination within 4 weeks prior to randomization. 
12. Any uncontrolled active systemic infection including any infection requiring systemic IV 
treatment which was completed ≤7 days before randomization. 
13. Major surgery within 4 weeks of first dose of study drug. 
14. 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. 
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
16. 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, unstable 
angina, or acute coronary syndrome within 6 months prior to randomization. 
17. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary 
hypersensitivity pneumonitis.  
18. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel 
obstruction. 
19. Concomitant use of warfarin or other Vitamin K antagonists. 


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20. Known hypersensitivity to any study drug (nab-paclitaxel, gemcitabine, or ibrutinib). 
21. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor. 
22. Currently active, clinically significant hepatic impairment (Class B or C according to the 
Child-Pugh classification [Appendix I]). 
23. Lactating or pregnant. 
24. Unwilling or unable to participate in all required study evaluations and procedures. 
25. 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). 
26. Decline in serum albumin ≥20% from Screening to study randomization (both labs at 
Screening and prior to randomization may be confirmed locally). 
5. 
TREATMENT OF SUBJECTS  
5.1. 
Treatment Allocation and Blinding  
5.1.1. 
Safety Run-in Phase 
Six subjects will be enrolled to receive open-label ibrutinib in combination with nab-paclitaxel 
and gemcitabine. Prior to enrollment, all subjects must receive approval from the Sponsor's 
Medical Monitor or designee. 
5.1.2. 
Randomized Double-blind Phase 
After the subject has completed all baseline (screening) procedures and met all requirements of 
the inclusion/exclusion criteria study personnel will register the subject into the Interactive Web 
Response System (IWRS); subsequently the study personnel will answer key questions to 
randomize the subject and have drug assigned. The first dose of study drug must be administered 
after randomization, which should be no more than 72 hours after the subject has been 
randomized by IWRS. 
Approximately 420 subjects will be randomized in a 1:1 ratio to each of the 2 treatment arms. 
Treatment Arm A: ibrutinib in combination with nab-paclitaxel and gemcitabine  
Treatment Arm B: placebo in combination with nab-paclitaxel and gemcitabine  
Randomization will be stratified according to: 
• 
KPS 70-80 vs KPS 90-100 
• 
Liver metastasis (present or absent) 
• 
Age ≤65 years vs age >65 years  


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5.1.2.1. 
Blinding  
This is a double-blind study; therefore, subjects, investigators, and the Sponsor’s study team 
members will remain blinded to treatment assignment. The investigator will not be provided with 
randomization codes. The codes will be maintained within the IWRS, which has the functionality 
to allow the investigator to break the blind for an individual subject if necessary to appropriately 
manage or treat the subject. Data that may potentially unblind the treatment assignment (ie, study 
drug plasma concentrations) will be handled with special care to ensure that the integrity of the 
blind is maintained and the potential for bias is minimized. 
It is recommended that the investigator contact the Sponsor or its designee to discuss the 
particular situation before breaking the blind whenever possible. Telephone contact with the 
Sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the Sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented within the IWRS in the appropriate section of the eCRF and 
in the source document. The confirmation received from the IWRS indicating the code break 
must be retained with the subject's source documents in a secure manner. A subject whose 
treatment assignment has been unblinded may continue the study treatment if the subject is 
expected to continue receiving clinical benefit. The subject should continue to return for 
scheduled study visits. The single-blind (ie, subject remains blinded to treatment assignment) 
should be maintained provided the subject’s safety is not compromised.   
5.2. 
Study Treatment 
Ibrutinib (560 mg) or matching placebo will be given orally once daily continuously starting on 
Cycle 1 Day 1 until disease progression is documented or unacceptable toxicity.  
Nab-paclitaxel (IV) 125 mg/m2 and gemcitabine (IV) 1000 mg/m2 will be given on Days 1, 8, 
and 15 of each 28-day cycle until disease progression or unacceptable toxicity. 
5.3. 
Study Medication 
5.3.1. 
Ibrutinib  
5.3.1.1. 
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 (or placebo) capsules will be packaged in opaque high-density polyethylene plastic 
bottles with labels bearing the appropriate label text as required by governing regulatory 
agencies. All study drug will be dispensed in child-resistant packaging.  


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Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.3.1.2. 
Dose and Administration  
The first dose of study treatment including ibrutinib should be given no more than 72 hours after 
randomization. Ibrutinib 560 mg (4 x 140-mg capsules) (or placebo) will be administered orally 
once daily beginning on Day 1 of Cycle 1 of the Treatment Phase.  
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. 
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. 
Dosing on days which coincide with administration of nab-paclitaxel and gemcitabine will be 
given in the clinic. On all other days, dosing will be on a domiciliary basis.  
On Day 1 of Cycle 1 only, all subjects will be observed for 2 hours after completion of nab-
paclitaxel and gemcitabine administration, to ensure that there are no acute clinical effects of co-
administering ibrutinib/placebo in combination with nab-paclitaxel and gemcitabine.  
On Day1 of Cycle 2 only, subjects will be on site for 6 hours after initiation of nab-paclitaxel 
and gemcitabine administration, to allow collection of blood samples for PK analysis (see 
Appendix B). 
Ibrutinib/placebo will be dispensed to subjects in bottles at the beginning of each cycle. Unused 
ibrutinib/placebo must be returned to the site (Section 12.8) at each visit. All returned 
ibrutinib/placebo will be reconciled and documented at the end of each cycle. Returned 
ibrutinib/placebo capsules must not be redispensed to anyone. 
5.3.1.3. 
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 Serious Adverse Event 
criterion must be reported as a Serious Adverse Event 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 


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(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 11.4 for further information regarding AE reporting. 
5.3.1.4. 
Dose Modification for Adverse Reactions  
The dose of ibrutinib/placebo should be modified according to the dose modification guidelines 
in Table 4 if any of the following toxicities occur: 
• Grade 4 ANC (<500/µL) for more than 7 days. See Section 6.1 for instructions regarding 
the use of growth factor support.  
• Grade 3 thrombocytopenia (<50,000/µL) in the presence of clinically significant bleeding 
events. 
• Grade 4 thrombocytopenia (<25,000/µL). 
• Grade 3 or 4 nausea, vomiting, or diarrhea if persistent (>3 days), despite optimal 
anti-emetic and/or anti-diarrheal therapy.  
• Any other Grade 4 or unmanageable Grade 3 toxicity. 
Persistent atrial fibrillation of any grade continuing despite adequate treatment, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 6.2.4). 
In the event that the investigator manages dose modifications differently than what is outlined in 
Section 5.3.1.4 please consult the medical monitor. 
If the dose of ibrutinib/placebo is reduced, at the investigator’s discretion, the dose of 
ibrutinib/placebo 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. The medical monitor should be consulted 
before dose re-escalation. Dose changes must be recorded in the Dose Administration eCRF.  


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Table 4. 
Ibrutinib/Placebo 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 560 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 560 mg /day dose ) 
Fourth 
Discontinue study drug 
5.3.1.5. 
Dose Modification for Chronic Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver. For subjects with existing chronic mild hepatic impairment 
(Child-Pugh class A) the starting dose has to be adjusted to a level of 280 mg daily (two 
capsules). For subjects with a history of chronic liver impairment who develop liver impairment 
while on study (Child-Pugh class A), the recommended dose reduction for ibrutinib/placebo is to 
a level of 280 mg daily (two capsules). For subjects who develop moderate liver impairment 
(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, and could be 
re-treated according to resolved hepatic conditions (ie, 140 mg or 280 mg for moderate or mild 
impairment, respectively). In the case of South Korea, dose modification for subjects with 
chronic hepatic impairment should follow the approved regional label in South Korea for 
Imbruvica®. Monitor subjects for signs of toxicity and follow dose modification guidance as 
needed (refer to Appendix I). 
5.3.2. 
Nab-paclitaxel and Gemcitabine  
5.3.2.1. 
Formulation/Packaging/Storage 
5.3.2.1.1. 
Nab-paclitaxel (ABRAXANE®) 
Nab-paclitaxel is available as lyophilized powder containing 100 mg of paclitaxel in single-use 
vial for reconstitution. 
Vials should be stored in original cartons at 20ºC to 25ºC (68ºF to 77ºF) and retained in the 
original package to protect from bright light. 
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
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5.3.2.1.2. 
Gemcitabine 
Gemcitabine for injection, USP, is available in sterile single-use vials individually packaged in a 
carton containing: either 200 mg or 1000 mg white to off-white, lyophilized powder in a sterile 
single-use vial. 
Unopened vials of gemcitabine are stable until the expiration date indicated on the package when 
stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions 
between 15° and 30°C (59° and 86°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. 
5.3.2.2. 
Dose and Administration 
Nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 will be administered on Days 1, 8, and 
15 of each 28-day cycle, each as a 30-40 minute intravenous infusion, with gemcitabine 
administration initiating immediately (or as soon as practically possible) after the nab-paclitaxel 
infusion has ended. On nab-paclitaxel and gemcitabine administration days, ibrutinib/placebo 
will be given immediately prior to initiation of the nab-paclitaxel infusion. 
Nab-paclitaxel and gemcitabine will be administered in the chemotherapy suite, in accordance 
with local institutional policies and procedures. Pre-medication will be given in accordance with 
the ABRAXANE® package insert and local institutional policies and procedures. 
On Day 1 of Cycle 1 only, subjects will be observed for 2 hours after completion of 
nab-paclitaxel and gemcitabine administration, to ensure that there are no acute clinical effects of 
co-administering ibrutinib/placebo in combination with nab-paclitaxel and gemcitabine. 
On Day1 of Cycle 2 only, subjects will be on site for 6 hours after initiation of nab-paclitaxel 
and gemcitabine administration, to allow collection of blood samples for PK analysis 
(see Appendix B). 
5.3.2.3. 
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 Serious Adverse Event criterion 
must be reported as a Serious Adverse Event 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. 


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5.3.2.3.1. 
Nab-paclitaxel Overdose 
There are no specific antidotes for nab-paclitaxel. The primary anticipated complications of 
overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 
5.3.2.3.2. 
Gemcitabine Overdose 
There are no specific antidotes for gemcitabine. Myelosuppression, paresthesias, and severe rash 
were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by 
intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study 
(gemcitabine prescribing information). 
5.3.2.4. 
Dose Modification for Adverse Reactions 
Recommended dose reductions and/or delays for nab-paclitaxel and gemcitabine for 
hematological toxicity at the start of, or within, a cycle are summarized in Table 5 below. 
Table 5. 
Nab-paclitaxel and Gemcitabine Dose Modifications for Hematological 
Toxicity 
Cycle  
Day 
ANC  
(cells/mm3) 
 
Platelet Count  
(cells/mm3) 
Nab-paclitaxel + Gemcitabine 
Day 1 
<1500 
OR 
<100,000 
Delay doses until recovery 
Day 8 
500 to <1000 
OR 
50,000 to <75,000 
Reduce one dose level 
 
<500 
OR 
<50,000 
Withhold doses 
Day 15: If Day 8 doses were reduced or given without modification 
 
500 to <1000 
OR 
50,000 to <75,000 
Reduce one dose level from Day 8 
 
<500 
OR 
<50,000 
Withhold doses 
Day 15: If Day 8 doses were withheld 
 
≥1000 
OR 
≥75,000 
Reduce one dose level from Day 1 
 
500 to <1000 
OR 
50,000 to <75,000 
Reduce two dose levels from Day 1 
 
<500 
OR 
<50,000 
Withhold doses 
 
Recommended dose reductions and/or delays for nab-paclitaxel and gemcitabine for 
non-hematological toxicity are summarized in Table 6 below. 


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Table 6. 
Nab-paclitaxel and Gemcitabine Dose Modifications for Non-Hematological 
Toxicity 
Adverse Drug Reaction 
Nab-paclitaxel 
Gemcitabine 
Febrile Neutropenia 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥1500/µL; resume at next 
lower dose level 
Peripheral Neuropathy 
Grade 3 or 4 
Withhold until improves to Grade 
≤1; resume at next lower dose 
level 
No dose reduction 
Cutaneous Toxicity 
Grade 2 or 3 
 
Reduce to next lower dose level; discontinue of toxicity persists 
Gastrointestinal Toxicity: 
Grade 3 mucositis or diarrhea 
 
Withhold until improves to Grade ≤1; resume at next lower dose 
level 
 
Dose reductions for nab-paclitaxel and gemcitabine referred to in Table 5 and Table 6 are 
summarized below in Table 7. 
Table 7. 
Dose Reduction for Nab-paclitaxel and Gemcitabine  
Dose Level 
Nab-paclitaxel (mg/m2) 
Gemcitabine (mg/m2) 
Full dose 
125 
1000 
1st dose reduction 
100 
800 
2nd dose reduction 
75 
600 
If any additional dose reduction 
required 
Discontinue 
Discontinue 
5.4. 
Criteria for Continuation of Remaining Study Treatment(s), if One or More Study 
Treatments are Discontinued 
Subjects will be treated until disease progression in the absence of unacceptable toxicity 
(see separate dose management guidelines for toxicity for each agent). If nab-paclitaxel and/or 
gemcitabine or ibrutinib/placebo are discontinued prior to disease progression, the remaining 
agents will be continued until unacceptable toxicity or disease progression. 
5.5. 
Criteria for Permanent Discontinuation of Study Treatment 
Investigators are encouraged to keep a subject who in the judgment of the investigator, is 
experiencing benefit on study treatment unless significant toxicity puts the subject at risk or 
routine noncompliance puts the study outcomes at risk. In addition, 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 by radiologic assessment (eg, CT/MRI) 
according to RECIST 1.1 criteria. If treatment is discontinued due to disease progression that is 
not confirmed by radiologic assessment the medical monitor should be notified within 24 hours. 


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For a complete list of criteria for permanent discontinuation of study treatment, refer to 
Section 9.2. 
An End-of-Treatment Visit (Section 8.2.3) is required for all subjects once all study drugs have 
been discontinued except for those subjects who have withdrawn full consent. 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded from the time of ICF signing until 30 days after the last 
dose of study drugs. 
6.1. 
Permitted Concomitant Medications  
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  
Use of antimicrobial prophylaxis in accordance with standard practice (eg, ASCO 
guidelines [Flowers 2013]) is permitted and should be considered in patients who are at 
increased risk for opportunistic infections. 
Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) is permitted per institutional policy and in accordance with the ASCO 
guidelines (Smith 2006). Transfusions may be given in accordance with institutional policy.  
Corticosteroids at dosages equivalent to prednisone >20 mg/day administered consecutively 
for >14 days are to be avoided. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4.  Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure and therefore strong 
CYP3A inhibitors should be avoided. 
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, cobicistat, and posaconazole) must 
be used, reduce ibrutinib/placebo dose to 140 mg for the duration of the inhibitor use or 
withhold ibrutinib treatment temporarily (for 7 days or less). Subjects should be monitored 
for signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, fluconazole, voriconazole, erythromycin, amprenavir, 
aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, 
verapamil, amiodarone, and dronedarone) is indicated, reduce ibrutinib dose to 140 mg for 
the duration of the inhibitor use. Avoid grapefruit or Seville oranges during 


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ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A  
(see Section 5.3.1.2). 
• 
No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of systemic strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix G. For further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
This website is continually revised and should be checked frequently for updates. 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib  
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL). Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There are no clinical data available. Therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib/placebo.  
6.2.3. 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered.  
6.2.4. 
Antiplatelet Agents and Anticoagulants  
Warfarin or vitamin K antagonists should not be administered concomitantly with 
ibrutinib/placebo. Supplements such as fish oil and vitamin E preparations should be avoided. 
Use ibrutinib/placebo with caution in subjects requiring other anticoagulants or medications that 
inhibit platelet function. Subjects with congenital bleeding diathesis have not been studied. For 
guidance on ibrutinib/placebo 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/placebo treatment. If therapeutic 
anticoagulation is clinically indicated, treatment with ibrutinib/placebo 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 
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6.3. 
Prohibited Concomitant Medications 
Chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are prohibited 
while the subject is receiving study medication. Live vaccinations are prohibited while the 
subject is receiving gemcitabine and for 6 weeks after last dose of gemcitabine. 
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 risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib/placebo in the perioperative period for subjects 
who require surgical intervention or an invasive procedure while receiving ibrutinib/placebo.  
6.4.1. 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib/placebo 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.  
6.4.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib/placebo 
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.  
6.4.3. 
Emergency Procedures 
For emergency procedures, ibrutinib/placebo should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
7. 
STUDY EVALUATIONS   
7.1. 
Description of Procedures 
Where appropriate, all procedures/assessments must be performed prior to dosing with any study 
drug at all clinic visits. 
7.1.1. 
Assessments  
7.1.1.1. 
ICF 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 


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confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. All 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 as additional information is provided.  
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 at Screening (Section 4). Blood 
samples for serum chemistry, hematology, coagulation, and hepatitis serologies will be evaluated 
by a central laboratory to confirm eligibility with the exception of albumin where eligibility can 
be determined based on local labs. If central laboratory evaluation is not available (eg, specimen 
clotted, hemolysis, or otherwise not resulted), the Medical Monitor may review and approve 
submitted local labs to support eligibility on a case by case basis provided another sample is 
redrawn and submitted to the central laboratory prior to treatment. 
7.1.1.3. 
Medical History and Demographics 
The subject’s complete clinically relevant history will be collected and recorded through review 
of medical records and by interview. 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 initial 
diagnosis and 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 medications continuous from the signing of ICF or 14 days prior the first dose of study drug 
(whichever is greater) through 30 days after the last dose of study drug will be documented. 
After a subject discontinues study treatment, receipt of all subsequent anticancer therapies and 
analgesics consumption will be collected until death, subject withdrawal of full consent, lost to 
follow-up, or study termination by Sponsor, whichever comes first. 
7.1.1.5. 
Adverse Events 
The accepted regulatory definition for an adverse event is provided in Section 11.1. All medical 
occurrences that meet the adverse event definition must be recorded from the time the ICF is 
signed until 30 days after the last dose of study drug. Laboratory abnormalities designated 
clinically significant by the investigator will also be recorded as adverse events. Additional 
important requirements for adverse event and serious adverse event reporting are explained in 
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In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies are to be reported as adverse events during all 
protocol-specified follow-up periods including post-progression follow-up for OS. 
7.1.1.6. 
Study Drug Compliance Review 
Study drug compliance should be assessed on Day 1 of each cycle while continuing to administer 
ibrutinib/placebo. The patient diary should be reviewed along with ibrutinib/placebo counts to 
ensure that all missed doses or dose changes have been documented. 
7.1.1.7. 
Physical Examination 
The Screening and End-of-Treatment Visit physical examination will include, at a minimum, the 
general appearance of the subject, height (Screening only), and examination of the general 
appearance, head, eyes, ears, nose and throat (HEENT), cardiovascular, dermatologic, lymphatic, 
respiratory, gastrointestinal, genitourinary, musculoskeletal, nervous, and lymphatic systems. 
Abnormalities at Screening should be reported as medical history. 
A physical examination is required on Day 1 of each cycle, and Efficacy Follow-up Visits. All 
physical exams will include a pancreatic cancer disease assessment include the following; 
assessment of palpable masses and new sites of disease, hepatospenomegaly, third space fluid 
accumulation (ascites or pleural fluid), and signs of jaundice, cachexia, muscle atrophy, or 
lethargy. If ascites and/or pleural effusion fluid is removed/assessed cytology should be sent and 
volume of fluid removed quantified and entered into the eCRF. New metastatic sites should be 
biopsied with pathology information entered to eCRF. 
7.1.1.8. 
Eye-related Symptom Assessment 
The subjects will be asked about eye-related symptoms at Screening and with all subsequent 
physical exams while on treatment (refer to Appendix A). 
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subject 
develops any eye-related symptoms of severity Grade ≥2 while on study treatment, an 
ophthalmologic evaluation/consult must be performed and the outcome must be reported on the 
ophthalmologic eCRF. 
7.1.1.9. 
Weight 
Weight will be collected per visit schedule listed in Appendix A until death, subject withdrawal, 
lost to follow-up, or study termination by the Sponsor, whichever occurs first. 
7.1.1.10. 
Eastern Cooperative Oncology Group (ECOG) Performance Status  
The Eastern Cooperative Oncology Group Performance Status scale is provided in Appendix E. 
ECOG performance status will be assessed at Screening.  


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7.1.1.11. 
Karnofsky Performance Score (KPS) 
The Karnofsky Performance Scale is provided in Appendix D. Performance score will be 
assessed at Screening, C1D1, and every 2 weeks until death, subject withdrawal, lost to follow-
up, or study termination by the Sponsor, whichever occurs first. Two observers will be required 
to assess KPS at Screening. If discrepant, the one with the lowest assessment will be accepted. 
7.1.1.12. 
Memorial Pain Assessment Card (MPAC) 
The Memorial Pain Assessment Card (MPAC) is provided in Appendix F. Pain, mood and relief 
will be assessed prior to any other procedures (including investigator and staff interaction) at 
Screening and then every 2 weeks after the first dose, until death, subject withdrawal, lost to 
follow-up, or study termination by the Sponsor, whichever occurs first. 
7.1.1.13. 
Patient-reported Outcomes (PRO) (EORTC QLQ-C30, version 3.0) 
The EORTC Quality of Life Questionnaire (QLQ-C30) is provided in Appendix H. The 
QLQ-C30 questionnaire will be completed every 2 weeks immediately following the MPAC 
beginning on C1D1. The assessment will be completed until death, subject withdrawal, lost to 
follow-up, or study termination by the Sponsor, whichever occurs first. The QLQ-C30 
questionnaire will be administered to all randomized subjects in this study. This is to be 
completed by the subject prior to any other study procedures at weeks specified in the Schedule 
of Assessments (Appendix A).  
The QLQ-C30 questionnaire is an integrated modular tool incorporating nine multi-item scales: 
5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, 
pain, and nausea and vomiting), and a global health and quality-of-life scale. Several single-item 
symptom measures are also included (such as appetite loss, constipation, diarrhoea, dyspnea, 
financial impact and sleep disturbance). 
Individual questions are answered within a 4-point scale (not at all, a little, quite a bit, very 
much) and typically patients can complete the entire questionnaire in about ten minutes with 
minimal assistance. 
7.1.1.14. 
Vital Signs 
Vital signs including blood pressure, heart rate, respiratory rate, and body temperature should be 
assessed after the subject has been resting in the sitting position for at least 3 minutes. Vital signs 
are taken during Screening, Day 1 of every cycle, and End-of-Treatment Visit. 
7.1.2. 
Laboratory 
All tests will be performed by a study specific central laboratory except serum/urine pregnancy 
and urinalysis testing which will be performed locally. Hematology for Cycle 1 and Cycle 2 


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Day 22 visits must be performed centrally. All subsequent Day 22 hematology labs from Cycle 3 
onwards will be performed at the discretion of the investigator and may be performed locally.  
7.1.2.1. 
Hematology 
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils 
and bands (if reported).  
7.1.2.2. 
Comprehensive Chemistry Panel 
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN), creatinine, creatinine clearance (Cockroft-Gault) (done at Screening only), glucose, 
calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, lactate 
dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate.  
7.1.2.3. 
Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening using a study specific central laboratory.  
7.1.2.4. 
Hepatitis Serologies 
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody will be evaluated. If hepatitis B core antibody, hepatitis B surface antigen or 
hepatitis C antibody is positive, then PCR to quantitate hepatitis B/C DNA can be performed 
locally and must be negative prior to randomization/enrollment.  
7.1.2.5. 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
7.1.2.6. 
Pregnancy Test 
A serum or urine pregnancy test will be required at Screening and on Day 1 prior to the first dose 
for women of childbearing potential (ie, post-menopausal by history - no menses for ≥1 year; OR 
history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral 
oophorectomy). If positive, pregnancy must be ruled out by ultrasound to be eligible for 
randomization. This test will also be performed at End-of-Treatment visit and may be performed 
more frequently if required by local regulatory authorities. 


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7.1.3. 
Diagnostics/Procedures 
7.1.3.1. 
ECG 
At Screening, 12-lead ECGs will be done in triplicate (≥1 minute apart). ECG abnormalities 
noted at Screening must be included in the medical history. 
Subsequent ECGs should be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea with results 
noted collected in the eCRF. 
Subjects should be in supine position and resting for at least 10 minutes before all study-related 
ECGs. 
7.1.3.2. 
CT/MRI 
Documented tumor measurement is required using CT scans, PET/CT or MRI, as appropriate, 
and is to be performed at Screening and every 8 weeks following initiation of study drug until 
documented disease progression by RECIST 1.1, death, withdrawal of consent for further follow 
up, or lost to follow up, whichever occurs first. 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 visits.  
Pretreatment tumor assessment will be performed within 28 days before the first dose of study 
drug. A CT scan (with contrast unless contraindicated) of thorax, liver, abdomen and other areas 
if clinically indicated, 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 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 specified slice thickness/scan 
parameters, and includes the use of IV contrast. The PET scan must be performed prior to 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 scan must be performed prior to CT with IV contrast. 


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Subjects who refuse CT/MRI scans and/or miss more than one scan may be removed from the 
study, at the discretion of the investigator and following discussion with the medical monitor. 
De-identified copies of all scans (including those from Screening and any unscheduled scans) 
must be provided to the Sponsor or designee (eg, central imaging vendor). At the Sponsor’s 
discretion, the Sponsor or designee may conduct an independent review of the investigator 
assessments. 
7.1.4. 
Pharmacokinetics 
Refer to the Laboratory Manual for instructions on collecting and processing these samples. PK 
samples will be taken from all subjects except for gemcitabine PK, which will be collected in 
subjects enrolled in selective regions only. Prior to Cycle 2 Day 1 (C2D1) visit, the clinical staff 
will instruct the subject not to take the ibrutinib dose before arrival at the clinic on C2D1. 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. 
Plasma concentrations of ibrutinib and metabolite PCI-45227, gemcitabine and metabolite 
2',2'-difluorodeoxyuridine (dFdU), and nab-paclitaxel will be determined using validated 
analytical methods. Other potential metabolites of ibrutinib may be explored. Refer to the 
Table 8 and Appendix B for Pharmacokinetics Sampling Schedule. 


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Table 8. 
Pharmacokinetics Sampling Schedule for Cycle 2 Day 1 Only 
Study 
Cycle & 
Day 
Time points 
Ibrutinib/ 
Placebo 
Nab- 
Paclitaxel 
Gemcitabinec 
Cycle 2 
Day 1 
Predose a 
X 
X 
X 
Drug Administration/Infusion  
(Time 0) 
Drug 
Administration 
Start Infusion 
 
Infusion (Time 0.5 hr) 
 
End of 
Infusion  
Xb 
Start of 
Infusion 
Infusion (Time 1.0 hr) 
 
 
End of 
Infusion  
Xb 
0.5 hr post end of dose/infusion 
(±5 min) 
 
X 
 
1.0 hr post end of dose/infusion  
(±15 min) 
X 
 
X 
1.5 hr post end of dose/infusion  
(±15 min) 
 
X 
 
2.0 hr post end of dose/infusion  
(±15 min) 
X 
 
 
3.0 hr post end of dose/infusion  
(±15 min) 
 
 
X 
3.5 hr post end of dose/infusion  
(±15 min) 
 
X 
 
4.0 hr post end of dose/infusion  
(±15 min) 
X 
 
 
5.0 hr post end of dose/infusion  
(±15 min) 
 
 
X 
5.5 hr post end of dose/infusion  
(±15 min) 
 
X 
 
6.0 hr post end of dose/infusion  
(±15 min) 
X 
 
 
a. 
Predose samples should be collected prior to the administration of any drug. 
b. 
End of infusion samples for both gemcitabine and nab-paclitaxel should be collected within 
5 minutes before the infusion is stopped.  
c. 
Gemcitabine PK samples will be collected only in selective regions. 
Note:  
- 
Ibrutinib/placebo should be dosed at clock time zero. Immediately following ibrutinib/placebo 
administration, nab-paclitaxel infusion should begin. Once nab-paclitaxel infusion is stopped  
(30-40 minutes after infusion start), gemcitabine infusion should be started immediately thereafter 
(infusion time is about 30-40 minutes). 
- 
Clock times are approximate and assumes a 30 minute infusion for both gemcitabine and nab-
paclitaxel 
- 
X indicates timepoint after the administration of ibrutinib/placebo that associated PK should be 
drawn and likewise time after each infusion is completed that the associated PK is drawn. 
 


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7.1.5. 
Biomarkers 
7.1.5.1. 
Carbohydrate Antigen 19-9 (CA 19-9) 
Blood samples for serum carbohydrate antigen 19-9 (CA 19-9) levels will be collected and sent 
to the central lab at Screening and prior to dosing on Day 1 of each cycle. If study drugs are 
discontinued, blood samples for CA 19-9 will be collected and sent to a central laboratory every 
4 weeks.  
7.1.5.2. 
Immunophenotyping 
Blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected and sent to the central lab prior to dosing on Day 1 of each cycle of nab-paclitaxel and 
gemcitabine for the first 3 cycles and then every 3 cycles thereafter until treatment 
discontinuation. Percentages and absolute counts of CD3+, CD4+, CD8+, CD19+ and CD16/56+ 
cells will be determined. Additional assessment of T, B, macrophages subsets may also be 
performed.  
7.1.5.3. 
Molecular Markers 
Blood and urine samples will be collected and sent to the central laboratory prior to dosing on 
Day 1 of each cycle of nab-paclitaxel and gemcitabine for the first 3 cycles and then only blood 
sample will be collected every 3 cycles thereafter until documented disease progression per 
RECIST 1.1. Buccal swabs will be collected from all subjects on Cycle 1 Day 1. Archival tumor 
tissue will be provided if available and/or fresh tumor tissue will be collected at Screening if 
consented by subject. If a fresh tumor biopsy is performed at Screening, it should be at least 
7 days prior to the first dose of study drug or at least 3 days prior to the first dose of study drug 
for a fine needle aspiration (FNA). Upon RECIST 1.1 documented disease progression, an 
optional fresh tumor biopsy may be collected from consenting subjects.  
Cytokines/chemokines, secreted protein markers and cell surface/genomic markers may be tested 
in peripheral blood and tumor tissue, respectively. In the presence of sufficient samples, tumor 
biopsies may be evaluated by qualitative immunohistological assessment of immune cell subsets, 
ie, T cells, B cells, NK cells, and macrophages. Expression of BTK and pBTK expression in 
tumor biopsies may be evaluated, and in addition staining for immune checkpoint targets such as 
PD-1 and PD-L1 may also be performed. Additional genomic analyses, TCRb and BCR 
sequencing may be performed on the tumor samples of some subjects to identify clonality of 
T and B cells in tumor tissues. Functional T-Cell responses to mitogens and candidate tumor 
antigens (tetramer analysis) may also be explored. 
All sample types may undergo additional testing 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 techniques such as gene expression profiling, targeted 
sequencing for genomic alterations, and intracellular pathway analyses. Inhibition of BTK, ITK 


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and other relevant kinases may also be explored. These efforts may identify biomarkers that 
could assist with future development of ibrutinib.  
Pharmacodynamics assays, including BTK and ITK occupancy, may be performed to correlate 
results of biomarker assessments to the clinical effects of ibrutinib in combination with 
nab-paclitaxel and gemcitabine. 
Additional testing may be performed on stored samples as new methods are developed to further 
understand the origin, progression, and resistance of cancer and its relationship to the study 
drug(s). In addition, these samples may be used for research that may lead to the development of 
medical products or processes. All leftover samples will be de-identified prior to shipping to a 
central vendor and will be destroyed no later than 10 years after study completion. 
See Appendix C for biomarker sampling schedule.  
7.2. 
Efficacy Evaluations  
All radiologic scans will be assessed for response or progression using RECIST 1.1 
guidelines (Eisenhauer 2009). Grading for best response will be categorized as complete 
response (CR), partial response (PR), stable disease (≥8 weeks) (SD), or progressive disease 
(PD). Additional information can be found at 
https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf.  
7.2.1. 
Definitions 
Response and progression will be evaluated in this study using RECIST 1.1 
guidelines (Eisenhauer 2009). Changes in only the longest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST 1.1 guidelines to assess response, 
with the exception of lymph nodes, where changes in the shortest diameter are utilized. 
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 to be recorded) with a minimum size as follows: 
• 10 mm with CT scan with a slice thickness of no greater than 5 mm. If the slice thickness 
is >5 mm, the minimum size for a measurable lesion is twice the slice thickness. 
• 10 mm caliper measurement by clinical exam. 
• If the CT slice thickness is >5 mm, the extranodal disease must be ≥ twice the slice 
thickness. 


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Lymph nodes can only be considered as target lesions if they are ≥15 mm in the short axis. 
Although lymph nodes ≥10 mm are considered pathological, they cannot be categorized as target 
lesions per RECIST 1.1 guidelines.  
7.2.1.2. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm using 
spiral 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. 
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 (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) 
for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum 
LD 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 
of each should be noted throughout follow-up. Measurements are not required and these lesions 
should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 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 complete response, progressive disease is declared. 


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However, if such a lesion behaves in this manner in a subject with stable disease or partial 
response, it is the change in sum of target disease 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 progressive disease, if confirmed by a repeat scan 
obtained at least 4 weeks after the initial scan. 
7.2.2. 
Guidelines for Evaluation of Measurable Disease 
Standard training on RECIST 1.1 guidelines and implementation of the guidelines will be 
provided to clinical trial sites. All measurements for target lesions 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 
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 
(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.  
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 


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disease is mandatory to differentiate between response or stable disease (an effusion may be a 
side effect of the treatment) and progressive disease. 
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. 
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 
appearance of one or more new lesions. 
Note: To be considered unequivocal progression on the basis of non-target lesions only, the 
overall tumor burden must have increased. 
In the event that worsening in non-target disease cannot be easily quantified for unequivocal 
progression, it is appropriate to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for radiographically measurable disease. For example, an increase in a 
malignant pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic disease from 
localized to widespread. If ‘unequivocal progression’ is seen, the subject should be considered 
to have had overall PD at that point. 
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 


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treatment started). The subject’s best response assignment will depend on meeting RECIST 1.1 
criteria (Table 9). 
Subjects who have signs and symptoms of progression outside of the scheduled assessment, 
should be evaluated by the investigator and a CT/MRI scan performed to determine if disease 
progression can be confirmed by RECIST 1.1 criteria. 
If a subject shows signs or symptoms of disease progression, the subject may continue study 
treatment with ibrutinib/placebo until disease progression is confirmed by radiologic assessment 
(eg, CT/MRI) according to RECIST 1.1 criteria. If a subject experiences clinical deterioration 
consistent with progression but does not clearly meet progression by RECIST 1.1 by CT or MRI, 
when clinically appropriate, based on investigator perceived risk benefit assessment, the subject 
may continue treatment until progression can be confirmed by a repeat scan unless considered 
medically contraindicated. 
Subjects may continue study treatment until progression is confirmed by a serial exam at least 
2 weeks later. New anticancer therapy should be withheld if clinically appropriate in the absence 
of confirmed progressive disease by CT/MRI per RECIST 1.1 criteria. 
In order to accommodate the potential for pseudoprogression, treatment with ibrutinib + 
nab-paclitaxel + gemcitabine or placebo + nab-paclitaxel + gemcitabine 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 therapy 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 
pseudoprogression (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. Therapy should be discontinued if there is confirmed PD per RECIST 1.1 
guidelines or other clinical data suggest clear evidence of progression (symptomatic 
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Table 9. 
Time Point Response: Subjects with Target (+/– Non-target) Disease 
Target Lesions 
Non Target 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. 
 
NOTE: Subjects that require discontinuation of treatment for progression without CT or MRI 
confirmation or biopsy to document at that time should be classified as having disease 
progression. Every effort should be made to document progression by CT scan or MRI even after 
discontinuation of treatment. If a subject has evidence of disease progression and is unable to 
obtain CT or MRI for radiology confirmation of disease progression, data to support disease 
progression must be entered into the eCRF. For example, laboratory assessments, physical exam 
findings including the pancreatic disease assessment, and findings from third space fluid 
accumulation or biopsies must be provided to support disease progression. 
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, 
the subject is not evaluable (NE) at that time point. 
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 A) for the timing and frequency of all sample collections. 


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Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 
8. 
STUDY PROCEDURES  
8.1. 
Screening Phase (Within 28 Days of Randomization) 
8.1.1. 
Screening/Consenting Visit 
• Informed Consent 
• Confirmation of eligibility criteria 
• Medical history  
• Adverse Events (including new malignant tumors) 
• Complete physical exam 
• Eye-related symptoms assessment (ophthalmic exam for any eye related symptoms of 
severity Grade ≥2) 
• Weight 
• Vitals signs 
• Review of prior medications (including analgesic consumption) 
• Eastern Cooperative Oncology Group Performance Status (ECOG) 
• Karnofsky performance status (KPS) 
• Memorial Pain Assessment Card (MPAC)  
• 12-lead ECG (in triplicate, ≥1 minutes apart) 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 
o Coagulation panel (PT, aPTT, INR) 
o Hepatitis serologies 
o Creatinine clearance  
o Urinalysis 
o Serum pregnancy test (for women of childbearing potential only) 
o Serum CA-19-9 
• Imaging by CT, PET/CT, MRI of thorax/liver/abdomen + other areas if clinically 
indicated, as described in Section 7.1.3.2  
• Biomarkers 


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o Confirmation of tumor tissue availability 
− Archival tissue, or 
− Fresh tumor biopsy (optional) collected at least 7 days prior to dosing, or 
− FNA at least 3 days prior to dosing (refer to Section 7.1.5.3) 
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 pre-dose C1D1 
laboratory assessments and are not required to be repeated. Refer to Sections 5.1.1 and 5.1.2 for 
details regarding enrollment and randomization process.  
Eligibility must be confirmed by the investigator prior to randomization. Eligibility Worksheet 
must be submitted for Safety Run-in Phase (within 48 hours of anticipated enrollment) and 
approved by the Sponsor or designee prior to enrollment in IWRS. 
Pre-dose 
• Eligibility confirmation 
• Memorial Pain Assessment Card (MPAC)  
• PRO (QLQ-C30) 
• Symptom directed physical exam 
• Eye-related symptom assessment (ophthalmic exam for any eye-related symptoms of 
severity Grade ≥2) 
• Weight 
• Vital signs  
• Review of concomitant medications (including analgesic consumption) 
• Review of adverse events (including any new malignant tumors) 
• Karnofsky Performance Status (KPS) 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 
o Urine pregnancy test (for women of childbearing potential only) 
o Urinalysis 
o Serum CA 19-9 


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• Biomarker sampling 
o Blood and urine sample collection for immunophenotyping and molecular markers  
o Buccal swab  
Dosing 
• Dispense ibrutinib/placebo (optional to be provided 48 hours prior to C1D1 
administration of chemo if appropriate, C1D1 labs should be obtained for baseline prior 
to administration of any study drug) 
• In-clinic administration of ibrutinib/placebo (prior to commencement of nab-paclitaxel 
infusion) 
• In-clinic administration of nab-paclitaxel and gemcitabine 
Post-dose 
• Assessment of adverse events for 2 hours post completion of nab-paclitaxel and 
gemcitabine administration 
• Subject may leave clinic at the discretion of the investigator, 2 hours post completion of 
nab-paclitaxel and gemcitabine administration 
8.2.1.2. 
Cycle 1 Day 8 (and Subsequent Cycles) 
Pre-dose 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 
o Urinalysis 
• Review of concomitant medications (including analgesic consumption) 
• Weight 
• Review of adverse events (including any new malignant tumors) 
Dosing 
• Assess need for dose modification/dose delay for ibrutinib/placebo based on laboratory 
test results and reported AEs, if any 
• Assess need for dose modification/dose delay for nab-paclitaxel and gemcitabine based 
on laboratory test results and reported AEs, if any 
• In-clinic administration of ibrutinib/placebo (immediately prior to commencement of 
nab-paclitaxel infusion) 
• In-clinic administration of nab-paclitaxel and gemcitabine 


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Post-dose 
• Subject may leave clinic after completion of nab-paclitaxel and gemcitabine 
administration 
8.2.1.3. 
Cycle 1 Day 15 (and Subsequent Cycles) 
Pre-dose 
• Memorial Pain Assessment Card (MPAC)  
• PRO (QLQ-C30) 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 
o Urinalysis 
• Review of concomitant medications (including analgesic consumption) 
• Weight 
• Review of adverse events (including any new malignant tumors) 
• Karnofsky Performance Status (KPS) 
Dosing 
• Assess need for dose modification/dose delay for ibrutinib/placebo based on laboratory 
test results and reported AEs, if any 
• Assess need for dose modification/dose delay for nab-paclitaxel and gemcitabine based 
on laboratory test results and reported AEs, if any 
• In-clinic administration of ibrutinib/placebo (immediately prior to commencement of 
nab-paclitaxel infusion) 
• In-clinic administration of nab-paclitaxel and gemcitabine 
Post-dose 
• Subject may leave clinic after completion of nab-paclitaxel and gemcitabine 
administration 
8.2.1.4. 
Cycle 1 Day 22 (and Subsequent Cycles) 
• Laboratory tests for: 
o Hematology for Cycles 1 and 2, Day 22 visits must be performed centrally. All 
subsequent Day 22 hematology labs from Cycle 3 onwards will be performed at the 
discretion of the investigator and may be performed locally.  


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8.2.1.5. 
Cycle 2 Day 1 (and Subsequent Cycles) 
Pre-dose 
• Memorial Pain Assessment Card (MPAC)  
• PRO (QLQ-C30) 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 
o Urinalysis 
o Urine pregnancy test (for women of child bearing potential) 
• Symptom directed physical exam  
• Weight 
• Vital signs  
• Review of concomitant medications (including analgesic consumption) 
• Review of ibrutinib/placebo compliance 
• Review of adverse events (including new malignant tumors) 
• Karnofsky Performance Status (KPS) 
• Serum CA 19-9 on Day 1 of each Cycle until disease progression) 
• Blood and urine sample collection for immunophenotyping and molecular markers 
(Cycles 2 and 3 and then only blood sample will be collected every THIRD cycle 
thereafter until disease progression) 
• PK sampling for ibrutinib/placebo, nab-paclitaxel, and gemcitabine* on Cycle 2 Day 1 
ONLY - must collect pre-dose samples prior to any study drug administration (including 
ibrutinib/placebo) 
*Note: gemcitabine PK sampling will be collected in selective regions only. 
• Imaging by CT, PET/CT, MRI (every 8 weeks, starting with Cycle 3. Scan to be 
performed within +/- 7 days of scheduled dosing visit) 
• RECIST 1.1 response evaluation (every 8 weeks, starting with Cycle 3) 
Dosing 
• Assess need for dose modification/dose delay for ibrutinib/placebo based on laboratory 
test results and reported AEs, if any 
• Assess need for dose modification/dose delay for nab-paclitaxel and gemcitabine based 
on laboratory test results and reported AEs, if any 
• In-clinic administration of ibrutinib/placebo (immediately prior to commencement of 
nab-paclitaxel infusion) 


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• In-clinic administration of nab-paclitaxel and gemcitabine 
• PK sampling for ibrutinib/placebo, nab-paclitaxel, gemcitabine* on Cycle 2 Day 1 
ONLY 
* Note: gemcitabine PK sampling will be collected in selective regions only. 
Post-dose 
• Dispense ibrutinib/placebo  
• Subject may leave clinic after completion of nab-paclitaxel and gemcitabine 
administration (other than Cycle 2 Day1) 
• PK sampling for ibrutinib/placebo, nab-paclitaxel, gemcitabine* up to 5.0 hr after end of 
gemcitabine infusion on Cycle 2 Day 1 ONLY 
* Note: gemcitabine PK sampling will be collected in selective regions only. 
8.2.2. 
Efficacy Evaluations 
Efficacy evaluations will be performed per the schedule outlined in Appendix A. The following 
procedures will be performed in conjunction with standard visits as follows: 
• Radiologic exam by CT, PET/CT, and/or MRI should be performed every 8 weeks and to 
confirm progressive disease  
• RECIST 1.1 Evaluation (to correspond with radiological exam) 
8.2.3. 
End-of-Treatment (EOT) Visit 
An End-of-Treatment (EOT) Visit should occur 30 days (+7 days) after all study drugs have 
been discontinued or prior to starting any new anticancer treatment.  
Subjects who withdraw consent to treatment should still have an EOT Visit, if subject consents. 
The following procedures will be performed at the EOT Visit: 
• Memorial Pain Assessment Card (MPAC)  
• PRO (QLQ-C30) 
• Complete physical exam 
• Eye-related symptoms assessment (ophthalmic exam for eye related symptoms Grade ≥2) 
• Weight 
• Vital signs   
• Karnofsky Performance Status (KPS) 
• Clinical laboratory tests for: 
o Hematology 
o Comprehensive chemistry panel 


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o Urine pregnancy test  
o Serum CA 19-9 
• Blood and urine sample collection for immunophenotyping and molecular markers 
• Review of AEs and concomitant medications (including analgesic consumption and new 
malignant tumors) 
• Optional fresh tumor biopsy in consenting subjects (if RECIST 1.1 determined disease 
progression has been documented at the time of the EOT visit). 
8.3. 
Follow-up Phase 
After completing the EOT Visit, subjects will enter the Long-term Follow-up Phase provided 
they have RECIST1.1 documented disease progression at the EOT Visit. Subjects who withdraw 
from treatment for reasons other than RECIST1.1 documented progressive disease will 
participate in the Efficacy Follow-ups. 
8.3.1. 
Efficacy Follow-up 
Subjects who discontinue treatment for reasons other than RECIST1.1 documented disease 
progression will continue to have normally scheduled clinical assessments (every 2 weeks or as 
specified below) until RECIST1.1 disease progression is documented, death, withdrawal of 
consent for further follow up, or lost to further follow up. 
• Physical exam 
• Radiological disease assessments (CT, PET/CT, or MRI) every 8 weeks 
• Serum CA 19-9 measurements every 4 weeks. 
• Clinical benefit, including: 
o KPS 
o MPAC 
o Analgesic consumption 
o PRO (QLQ-C30)  
o Weight 
• Optional fresh tumor biopsy in consenting subjects (if RECIST 1.1 determined disease 
progression has been documented) 
8.3.2. 
Long-term Follow-up 
For subjects who terminate study treatment, have documented RECIST1.1 disease progression, 
and have not withdrawn consent for Long-term Follow-up, they (or a partner/relative where 
appropriate) will be contacted approximately every 2 weeks (±7 days) by clinic visit or telephone 
to assess. 


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• Survival  
• Use of subsequent anticancer therapy  
• Clinical benefit (if visit is done in the clinic, not applicable for phone follow up), 
including: 
o KPS 
o MPAC 
o Analgesic consumption 
o PRO 
o Weight  
Subjects will be contacted until death or complete withdrawal of consent. 
9. 
SUBJECT COMPLETION AND WITHDRAWAL  
9.1. 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.  
9.2. 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• Radiologically confirmed progressive disease (PD). 
• Unacceptable drug related toxicity, or other event that prevents further administration of 
any study medication (ie, so that the subject can no longer tolerate ibrutinib/placebo and 
nab-paclitaxel and gemcitabine). 
• Death 
• Withdrawal of consent for treatment with any further study medications. If a subject 
withdraws consent for all further treatment with study medication, the site must clarify 
with the subject whether their intent is to i) withdraw from the study (as detailed in 
Section 9.3) ii) permit continuing protocol specified follow-up visits (including 
assessment for progression) or iii) permit only protocol specified follow up for survival 
status. 
The study medical monitor should be notified wihin 24 hours of a patient modifying their 
consent. 
• Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject including clinical deterioration without progression) 
• Study termination by Sponsor 
• Subject becomes pregnant 


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All subjects, regardless of reason for discontinuation of study treatment will undergo an End-of-
Treatment Visit and be followed for progression and survival.  
If a subject shows signs of disease progression on physical examination or laboratory 
assessment, the subject may continue study treatment, at the discretion of the investigator, until 
disease progression is confirmed by radiologic assessment (eg, CT/MRI) according to 
RECIST 1.1 criteria. 
In order to accommodate the potential for pseudoprogression, treatment with ibrutinib + nab-
paclitaxel + gemcitabine or placebo + nab-paclitaxel + gemcitabine 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 therapy 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 
pseudoprogression (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. Therapy should be discontinued if there is confirmed PD per RECIST 1.1 
guidelines or other clinical data suggest clear evidence of progression (symptomatic 
deterioration). 
9.3. 
Withdrawal from Study 
Withdrawal from study will occur under the following circumstances: 
• 
Withdrawal of consent for follow-up observation by the subject. If a subject withdraws from 
treatment only, then this is not considered to be a withdrawal from study. 
• 
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 
• 
Given that OS is a primary endpoint of this study and a critical endpoint to understand if 
ibrutinib improves outcomes for pancreatic cancer patients – physicians and subjects should 
be encouraged to allow for survival follow-up as deemed appropriate and agreeable to 
subjects.  


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10. STATISTICAL METHODS AND ANALYSIS  
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
10.1. 
Subject Information 
10.1.1. 
Intention-to-treat Population (ITT) 
The ITT Population is defined as all subjects who are randomized to study medication. 
The ITT population will be used as the primary population for analysis of efficacy. 
10.1.2. 
Safety Population (SP) 
The Safety Population will consist of all randomized subjects who received at least one dose of 
any study treatment. The Safety Population will be used for the analysis of safety data. 
10.1.3. 
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. 
Safety and efficacy data from subjects in the open label run-in phase will be presented 
descriptively and separately from the randomized efficacy ITT and Safety Populations. 
10.1.4. 
Replacement of Subjects 
Subjects who are randomized but subsequently withdrawn for any reason will not be replaced. 
10.2. 
Endpoints 
10.2.1. 
Primary Endpoints 
The primary endpoints are progression-free survival (PFS), as determined by investigator 
assessment, according to RECIST 1.1 criteria and overall survival (OS). 
10.2.2. 
Secondary Endpoints 
• Clinical benefit response (CBR) rate 
• Overall response rate (ORR): CR + PR, per investigator assessment 
• Carbohydrate antigen 19-9 (CA19-9) response 
• Patient-reported outcomes (PRO): global health status based on QLQ-C30 


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• Rate of venous thromboembolic events (VTE) 
10.2.3. 
Other Secondary Endpoints 
The safety and tolerability of ibrutinib/placebo in combination with nab-paclitaxel and 
gemcitabine versus the combination of placebo with nab-paclitaxel and gemcitabine 
10.2.4. 
Selected Exploratory Endpoints 
• Overall survival maintenance in a subgroup of subjects, who are progression-free and 
alive at 6 months of treatment. This subgroup is defined as no PD or death at 6 months 
who continue on ibrutinib/placebo after having discontinued nab-paclitaxel and 
gemcitabine. 
• Exploratory tumor and circulating biomarkers 
• Pharmacokinetic (PK) parameters of ibrutinib, gemcitabine and paclitaxel 
10.3. 
Sample Size Determination 
The sample size calculation is based on a 2-sided family-wise Type I error rate (FWER) of 0.05 
for two primary endpoints, PFS and OS. The FWER is controlled at 0.05 with 0.007 allocated to 
the PFS analysis and 0.043 allocated to the OS analysis. 
As of 24 April 2017, a total of 424 subjects have been randomized with a 1:1 allocation to the 
two treatment arms. The calculations are based on the following assumptions and a sample size 
of 424 subjects, using EAST software version 6.3.1 and the actual enrollment rates.  
For PFS:  
• 
Median PFS is 5.5 months for the control arm (nab-paclitaxel and gemcitabine) 
(Von Hoff 2013).  
• 
Target hazard ratio is 0.66 which corresponds to a 51% improvement in median PFS 
(eg, from 5.5 months to 8.33 months) for the ibrutinib + nab-paclitaxel + gemcitabine arm 
compared to the placebo + nab-paclitaxel + gemcitabine arm 
• 
2-sided α = 0.007  
• 
A total of 350 PFS events will provide approximately 88% power. No interim analysis is 
planned. 


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For OS: 
• 
Median OS is 8.5 months for the control arm (nab-paclitaxel and gemcitabine) 
(Von Hoff 2013). 
• 
Target hazard ratio is 0.735 which corresponds to approximately 36% improvement in 
median OS (eg, from 8.5 months to 11.6 months) for the ibrutinib + nab-paclitaxel + 
gemcitabine arm compared to the placebo + nab-paclitaxel + gemcitabine arm 
• 
2-sided α = 0.043 
• 
A group sequential design with one interim analysis is planned when at least 250 deaths 
occur (approximately 71% of death events). Lan-DeMets alpha spending function with 
O’Brien-Fleming boundary for efficacy is used. 
• 
A total of 353 OS events will provide approximately 80% power for the study. 
10.4. 
Efficacy Analysis 
10.4.1. 
Primary Endpoints and Methods 
A primary efficacy endpoint , PFS, is  defined as the time from the date of randomization until 
disease progression per RECIST 1.1 criteria assessed by investigator, or death from any cause, 
whichever occurs first.  
The additional primary endpoint, OS, is defined as the time from date of randomization until date 
of death from any cause. The primary analyses of PFS and OS will be performed in the ITT 
population using the log-rank test stratified by the stratification factors. PFS final analysis and 
OS interim analysis will be carried out at the same time after at least 350 PFS events and 
250 death events (approximately 71% of death events) are observed.  
To control the family-wise Type I error rate the fallback method as specified in the FDA Draft 
Guidance (Multiple Endpoints in Clinical Trials, 2017), will be used to test the two primary 
endpoints. A 2-sided family-wise Type I error rate (FWER) of 0.05 will be used with 0.007 
allocated to the PFS hypothesis testing and 0.043 allocated to the OS hypothesis testing. 
Lan-DeMets alpha spending function with O’Brien-Fleming boundary for efficacy will be used 
to determine the Type I error rate for the interim and final OS analyses depending on whether an 
alpha of 0.043 or 0.05 is used.  
Additional details will be provided in the SAP. 
10.4.2. 
Secondary Endpoints and Methods 
Multiplicity adjustment will be made for the analysis of the primary and secondary endpoints to 
control the overall Type I error. Following statistically significant test results for one or both 
primary endpoints, the secondary endpoints will be tested sequentially in a pre-defined order as 
outlined in the SAP.  


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10.4.2.1. 
Clinical Benefit Response 
Clinical benefit response (CBR) is defined as: 
Subject achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card [MPAC]) 
or analgesic consumption, or a 20-point or greater improvement in KPS for a period of at least 
4 consecutive weeks, without showing any sustained worsening in other parameters. 
OR 
Subject was stable on all of the aforementioned parameters, and showed a marked, sustained 
weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid 
accumulation (Burris 1997). 
A chi-square test will be used to compare the two treatment arms. 
10.4.2.2. 
Overall Response Rate 
Overall response rate (ORR) is defined as the proportion of subjects who achieve a complete 
response or partial response, based on investigator assessment according to RECIST 1.1.  
A chi-square test will be used to compare the two treatment arms. 
10.4.2.3. 
Carbohydrate Antigen 19-9 (CA19-9) Response 
CA19-9 response rate will be the proportion of subjects with a decline of 20%, 90% and other 
thresholds considered clinically meaningful, from baseline. The rate will be compared between 
the two treatment arms using the chi-square test (details will be pre-specified in the SAP).  
10.4.2.4. 
Patient-reported outcomes (PRO) as measured by EORTC QLQ-C30  
Scores and change from baseline for EORTC QLQ-C30 will be descriptively summarized by 
treatment group and visit. Longitudinal analysis with repeated measures may be used as 
appropriate.  
10.4.2.5. 
Rate of venous thromboembolic events (VTE) 
The occlusion, or partial occlusion of a vessel by a thrombus which subsequently migrates to a 
distal site in a vessel is a known complication of patients with pancreatic carcinoma. This 
includes venous thrombosis and pulmonary emboli. The VTE rate is defined as proportion of 
subjects with VTE (details will be pre-specified in the SAP). A 30% relative reduction from the 
control arm is considered clinically meaningful.  


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10.4.3. 
Exploratory Endpoints and Methods 
Exploratory endpoints will be evaluated to compare treatment effects between the two treatment 
arms. Descriptive statistics will be used to summarize these exploratory endpoints. Further 
details will be provided in the SAP. 
10.5. 
Safety Analysis 
Analysis of safety data will be conducted primarily on the safety population, which includes all 
randomized subjects who receive at least one dose of any study drug. 
Safety Run-in Phase: 
Safety data from subjects in the open label run-in phase will be presented separately from the 
randomized Safety Population. 
Double-blind Randomized Phase: 
Safety data will be generated from the Safety Population (SP) (consisting of all subjects 
randomized and receiving at least one dose of any study drug). 
The safety variables to be analyzed include adverse events, clinical laboratory test results 
(hematology and chemistry), and vital signs measurements. No formal statistical testing is 
planned. 
10.5.1. 
Adverse Events 
The verbatim terms used in the eCRF by Investigators will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events are those 
adverse events that emerge during treatment, having been absent pretreatment, or worsen relative 
to the pretreatment state. All treatment-emergent adverse events will be included in the analysis. 
For each adverse event, the percentage of subjects who experience at least 1 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 (NCI 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 adverse event, or who experience a severe or a serious 
adverse event. 
10.5.2. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry. Laboratory 
values will be converted to standard international units and will be graded using the 
NCI CTCAE v4.03 for those to which a grade can be applied. 


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10.6. 
Pharmacokinetic Analyses  
10.6.1. 
Ibrutinib 
Ibrutinib and PCI-45227 bioanalytical data will be used in noncompartmental PK analysis. 
Plasma concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the PK report. 
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point and PK parameters of ibrutinib and PCI-45227 (including, but not limited 
to: Cmax, Tmax, AUClast, and t1/2). 
Individual and mean plasma ibrutinib and PCI-45227 concentration time profiles will be plotted. 
Ibrutinib data from this study may also be combined with data from other studies performed with 
ibrutinib in subjects with hematologic malignancies as part of a population-PK analysis using 
nonlinear mixed effects models. For the population-PK analysis, covariates that could potentially 
correlate with plasma PK parameters will be evaluated. The results of the population-PK 
analyses (if performed) will be presented in a separate report. 
Ibrutinib PK data in this study will be compared to observed/reported concentration data for 
ibrutinib and/or population PK models to explore the potential for a pharmacokinetic interaction 
between ibrutinib in combination use with gemcitabine and nab-paclitaxel. Gemcitabine and 
nab-paclitaxel PK data in this study will be compared between two arms with and without 
ibrutinib to explore the potential for a pharmacokinetic interaction between gemcitabine and 
nab-paclitaxel in combination use with ibrutinib. 
For the drug combination of ibrutinib, paclitaxel, and gemcitabine, 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. 
10.6.2. 
Gemcitabine 
Individual gemcitabine and dFdU concentrations will be tabulated along with descriptive 
statistics. Individual and mean concentration-time profiles will be generated and included in the 
report. Pharmacokinetic parameters will be determined using standard non-compartmental 
methods. The following PK parameters will be determined: peak concentration (Cmax), time to 
peak concentration (Tmax) and area under the curve (AUC), as data allow. Descriptive statistics 
of non-compartmental PK parameters will be provided. 


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10.6.3. 
Nab-paclitaxel 
Individual nab-paclitaxel concentrations will be tabulated along with descriptive statistics. 
Individual and mean concentration-time profiles will be generated and included in the report. 
Pharmacokinetic parameters will be determined using standard non-compartmental methods. The 
following PK parameters will be determined: peak concentration (Cmax), time to peak 
concentration (Tmax) and area under the curve (AUC), as data allow. Descriptive statistics of 
non-compartmental PK parameters will be provided. 
10.7. 
DMC Review  
A DMC review of safety data including all death events will be performed approximately every 
6 months after the first subject is randomized.  
10.8. 
Data Monitoring Committee (DMC) 
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled/randomized in this study and to evaluate safety and 
efficacy results. Further details will be provided in the DMC Charter. 
Safety Run-in Phase: 
The DMC will review data on the safety of ibrutinib combined with nab-paclitaxel and 
gemcitabine, after the first 6 subjects have either completed at least 28 days of follow-up after 
the initiation of combination therapy or terminated therapy at an earlier time point due to 
toxicity. If a subject discontinues treatment before 28 days (eg, death due to PD), subjects may 
be replaced. Following DMC review and confirmation, the study may proceed to the 
Double-blind Randomized Phase. 
The DMC assessment will focus on deaths, treatment discontinuations, SAEs, AEs of special 
interest (see Section 11.4.7) and Grade 3/4 AEs to identify any potential added toxicity when 
ibrutinib is combined with nab-paclitaxel and gemcitabine. 
Adverse events including grade 3/4 myelotoxicity, nausea, vomiting, diarrhea and peripheral 
neuropathy are expected with the combination of nab-paclitaxel and gemcitabine and therefore 
will not be considered a safety signal unless the duration is unusually prolonged, or unexpected 
increase in frequency observed and/or unresponsive to supportive management. For example, all 
grades of venous thromboembolism are frequent and expected complications of metastatic 
pancreatic cancer regardless of therapy and will not be considered a safety signal unless 
occurring at an unexpectedly high rate. These and other appropriate factors will be considered by 
the DMC when reviewing the safety data of the subjects treated with the combination of ibrutinib 
and nab-paclitaxel plus gemcitabine during the safety run in stage of the study. 
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a) the study continues to the Double-blind Randomized Phase 
b) prior to commencing the Double-blind Randomized Phase, an additional safety review is 
performed after a total of up to 12 subjects have been treated with ibrutinib (560 mg) in 
combination with nab-paclitaxel and gemcitabine (with all subjects having either 
completed at least 28 days of follow-up after the initiation of combination therapy or 
terminated therapy at an earlier time point due to toxicity). 
c) Prior to commencing the Double-blind Randomized Phase, the dose level of ibrutinib 
should be reduced to 420 mg and an additional 6 subjects should be studied at this dose 
level, in combination with nab-paclitaxel and gemcitabine (with all subjects having either 
completed at least 28 days of follow-up after the initiation of combination therapy or 
terminated therapy at an earlier time point due to toxicity) prior to a subsequent review 
by the DMC. 
Double-blind Randomized Phase: 
The DMC will review unblinded safety data on subjects randomized to each arm at periodic 
intervals during the study, as detailed in the DMC charter. The Sponsor will assess blinded safety 
data on an ongoing basis and all deaths, treatment discontinuations, and SAEs will be reviewed 
by the Sponsor’s responsible physician to identify safety concerns. If a potential safety signal is 
identified, additional ad hoc meetings may be convened, if requested by the DMC or the 
Sponsor. 
The DMC will consist of at least one medical expert in the management of pancreatic 
adenocarcinoma and at least one statistician. The DMC responsibilities, authorities, and 
procedures will be documented in the DMC charter. 
10.9. 
Independent Review  
Investigator assessed PFS is one of the primary endpoints in this double blinded study. Scans 
(CT/PET-CT/MRI) will be collected and held for blinded independent review and assessment of 
disease progression events if necessary, the details of which will be outlined in a separate 
independent review committee charter.  
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 
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 to 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 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 situation on a sponsor study 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 timepoints 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 from the time signed and dated ICF 
is obtained until 30 days following the last dose of study drug. SAEs will be reported to the 
Sponsor Drug Safety via an SAE reporting form and will be recorded in the eCRF from the time 
of ICF signing. Non-serious AEs will be recorded in source documents from the time of ICF 
signing and will be recorded in the eCRF from the first dose of study drug. 
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. (See Section 11.1.1.) 
All 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, investigator’s evaluation of its relationship to the study drug, and the event 


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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 study drug, 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. 
(See Section 5.1.2.1 for unblinding details.) 
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 the local regulations.  
The investigator (or sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 


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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 initial dose to 6 months after the last dose of study drug. A male subject must 
immediately inform the Investigator if his partner becomes pregnant from the time of initial dose 
to 6 months 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 female subject or female partners of male subjects 
from the time of initial dose to 6 months 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 primary 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 OS. If observed, 
relevant data will be entered in the corresponding eCRF. 
11.4.6. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF. 
11.4.7. 
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 


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on the Serious Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug 
Safety, or designee, within 24 hours of awareness.  
11.4.7.1. 
Major Hemorrhage 
Major hemorrhage is defined as any one of the following: 
1. Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*  
2. Any treatment-emergent serious adverse events of bleeding of any grade 
3. 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 11.4.7 above. 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS  
12.1. 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.  
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation. Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF.  


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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 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements. This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with 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. 


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During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. 
Study Files and Record Retention 
The investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study. For those subjects subsequently excluded 
from enrollment, the reason(s) for exclusion is to be recorded. 
The investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 
transmitted to Pharmacyclics and notification of SAEs and related reports, source 
documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
All essential documentation will be retained by the investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time. Should an investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics. Pharmacyclics will 
inform the investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the investigator wishes 
to move study records to another location or assign responsibility for record retention to another 
party. If the investigator cannot guarantee the archiving requirements set forth herein at his or her 
study site for all such documents, special arrangements must be made between the investigator 
and Pharmacyclics to store such documents in sealed containers away from the study site so that 
they can be returned sealed to the investigator for audit purposes. 


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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 exists 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 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 
at the study site. 
12.8. 
Investigational Study Drug Accountability 
Study medication used must be kept in a locked limited access room. Study drug must not be 
used outside the context of the protocol. Under no circumstances should the investigator or other 
site personnel supply study medication 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 all study drugs must be maintained and 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-1137-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib/placebo and nab-paclitaxel plus gemcitabine dispensed for that 
subject 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject 


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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. During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study. However, because of the experimental nature of this treatment, the investigator 
agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics, its designated agents and 
authorized employees of the appropriate Regulatory Authority to inspect the facilities used in 
this study and, for purposes of verification, allow direct access to the hospital or clinic records of 
all subjects enrolled into this study. A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. 
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation. 
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
12.10. 
Investigator Responsibilities 
A complete list of investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the 
investigator before commencement of the study. In summary, the investigator will conduct the 
study according to the current protocol; will read and understand the IB; will obtain 


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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 regulation 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. 
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. 


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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. 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects and 
those with substantial input to study design 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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14. 
APPENDICES 


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Appendix A. Schedule of Assessments 
 
Screening 
Phase 
Treatment Phase c 
Follow-up Phase  
(refer to protocol Sections 7 & 8) 
 
Cycle 1 
Cycle 2 through 
Treatment Discontinuation 
Efficacy 
Evaluations 
End-of-
Treatment 
Efficacy Follow-up 
(until PD) 
Long Term  
Follow-up 
 
D1  
Baseline 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
Every 
8 weeks 
30 days after 
treatment d/c 
Every 2 weeks  
or as specified 
Every  
2 weeks 
Visit Window 
-28 days 
-2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
+7d 
±3d 
±7d 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Confirmation of eligibility criteria 
X 
X 
  
  
  
  
  
  
  
 
  
  
  
Randomization 
X 
Medical history and demographics 
X 
Physical exam (including disease related 
symptoms) 
X 
Xa 
Xa 
X 
Xa 
Eye-related symptom assessment 
X 
X 
X 
X 
Vital Signsd 
X 
X 
  
  
  
X 
  
  
  
 
X 
  
  
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Concomitant medications q 
X 
X 
X 
X 
X 
X 
X 
X 
 Xr 
Xr 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Status (KPS) 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
Xt 
MPAC Pain Assessment Cardb 
X 
X 
X 
  
X 
  
X 
  
  
X 
X 
Xt 
PRO (QLQ-C30)b 
X 
  
X 
  
X 
  
X 
  
X 
X 
Xt 
Adverse eventse 
X 
Xk 
X 
X 
X 
X 
X 
X 
  
  
12-lead ECGi 
X 
If clinically indicated (eg, subjects with palpitations, lightheadedness)  
  
Laboratory: 
   
Hematology 
X 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
  
  
Serum chemistry 
X 
X 
X  
X 
  
X 
 X 
X 
  
X 
  
  
Coagulation panel 
X 
  
  
  
  
  
  
  
  
 
 
  
  
Hepatitis serologiesf 
X 
  
  
  
  
  
  
  
  
  
  
  
Creatinine clearance (Cockcroft-Gault) 
X 
  
  
  
  
  
  
  
  
 
  
  
  
Urinalysis g 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Pregnancy Testh 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
Carbohydrate antigen (CA) 19-9  
X 
X 
 
 
 
X 
 
 
 
 
X 
Xp 
 
Disease Assessment: 
   
CT, PET/CT, MRI scan 
X 
  
  
  
  
  
  
  
  
X 
  
Xm 
  
RECIST 1.1 Overall efficacy assessment 
  
  
  
  
  
  
  
  
  
X 
Xm 
  


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Screening 
Phase 
Treatment Phase c 
Follow-up Phase  
(refer to protocol Sections 7 & 8) 
 
Cycle 1 
Cycle 2 through 
Treatment Discontinuation 
Efficacy 
Evaluations 
End-of-
Treatment 
Efficacy Follow-up 
(until PD) 
Long Term  
Follow-up 
 
D1  
Baseline 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
Every 
8 weeks 
30 days after 
treatment d/c 
Every 2 weeks  
or as specified 
Every  
2 weeks 
Visit Window 
-28 days 
-2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
+7d 
±3d 
±7d 
Pharmacokinetics/Biomarkers 
  
Pharmacokinetics (PK)  
(See Appendix B) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Immunophenotyping o 
Xr 
X 
X 
Molecular markers - blood & urineo 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Buccal Swab 
X 
Tumor biopsy (archival/fresh) j 
X 
X 
Study Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
Dispense ibrutinib/placebo 
  
X 
  
  
  
X 
  
  
  
 
  
  
  
In-clinic administration of ibrutinib / 
placebo 
  
Xs 
X 
X 
X 
X 
X 
  
  
  
In-clinic administration of nab-paclitaxel 
+ gemcitabine 
  
Xs 
X 
X 
  
X 
X 
X 
  
 
  
  
  
Study drug compliance reviewn 
  
X 
  
  
  
Survival and subsequent anticancer 
therapy 
  
  
  
  
  
  
  
  
  
  
  
X 
CT = computed tomography, D or d = day(s), d/c = discontinuation; ECG = electrocardiogram, FU = follow-up, ibr = ibrutinib, ICF = informed consent form, MRI = magnetic resonance 
imaging, PD = progressive disease, PK = pharmacokinetics, RECIST = response evaluation criteria in solid tumors 
Footnotes: 
a. A symptom-directed physical examination is required on Day 1 of each  cycle and Efficacy Follow Up visits. These physical exams will include pancreatic 
cancer disease related symptoms assessment and ascities/pleural effusion assessment (if applicable). 
b. To be completed prior to any other procedures or physician interactions. MPAC to be performed first.  
c. All assessments are to be performed prior to dosing unless otherwise specified. 
d. Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
e. AEs are reported from the time the subject signs the Informed Consent Form until 30 days following last dose of study drug. All new malignant tumors are to 
be reported as adverse events through Long Term Follow-up for OS. 
f. Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR to 
quantitate hepatitis B/C DNA must be performed and must be negative prior to randomization/enrollment.  
g. Tests will be performed locally.  
h. Serum or urine pregnancy test will be required at Screening and on Day 1 prior to first dose for women of childbearing potential. The test will be performed 
locally. 
i. At Screening, 12-lead ECGs will be done in triplicate (≥1 minute apart). Abnormalities noted at Screening should be included in the medical history.  


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j. Archival tumor biopsy tissue may be provided if available and/or fresh tumor tissue will be collected at Screening if consented by subject. If a fresh tumor 
biopsy is performed at Screening, it should be at least 7 days prior to the first dose of study drug or at least 3 days prior to the first dose of study drug for a fine 
needle aspiration (FNA). Upon RECIST 1.1 documented disease progression, an optional fresh tumor biopsy may be collected from consenting subjects. 
k. Cycle 1 Day 1 ONLY: Assessment of adverse events for 2 hours post completion of nab-paclitaxel and gemcitabine administration. At the discretion of the 
investigator, subject may leave clinic 2 hours post completion of nab-paclitaxel and gemcitabine administration. 
l. Subjects who are withdrawn for reasons other than RECIST1.1 documented disease progression will continue to have normally scheduled clinical and 
radiological disease assessments (CT, CT/PET or MRI) until disease progression is documented, death, withdrawal of consent for further follow up, or lost to 
follow up, whichever occurs first. 
m. To be performed every 8 weeks until disease progression is documented, death, withdrawal of consent for further follow up, or lost to follow up, whichever 
occurs first.  Optional fresh tumor biopsy in consenting subjects (if RECIST 1.1 documented disease progression). 
n. Cycle 1 and Cycle 2 Day 22 hematology assessments must be performed centrally. Subsequent assessments may be performed locally and at the discretion of 
the investigator. 
o. Blood and urine samples for biomarkers will be collected prior to dosing on Day 1 for the first 3 cycles and then only blood sample will be collected every 
3 cycles thereafter until RECIST 1.1 documented disease progression. 
p. CA 19-9 will be collected every 4 weeks during efficacy follow up. 
q. Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose of study drug. 
r. Analgesic consumption only. 
s. Must be administered on Cycle 1 Day 1. 
t. Not required if Follow-up visit was done via the telephone.


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Appendix B. Pharmacokinetics Sample Collection Based on Clock Time for Cycle 2 Day 1 
 
 
Note: Gemcitabine PK samples will be collected only in selective regions. 


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Appendix C. Biomarker Sampling Schedule 
 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and Every 3 Cycles until 
Treatment Discontinuation 
 
Day 1 
Day 1 
Day 1 
Immunophenotyping 
 
Xa 
Xa 
Xa 
Molecular markers 
 
Xa 
Xa 
Xa 
Buccal swab 
 
Xa 
 
 
Tumor biopsyb 
Xb 
 
 
Xb 
End-of-Treatment Visit Only 
a. Collected predose. Urine sample is required only on Cycles 1 to 3 visits and End of Treatment Visit. 
b. Archival tumor biopsy tissue may be collected where available and optional fresh tumor biopsies will be collected 
on consenting subjects at Screening and on documented progression. 
 
 


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Appendix D. Karnofsky Performance Status 
 
% 
Karnofsky Performance Status 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Care for self. Unable to carry on normal activity or do active work. 
60 
Requires occasional assistance but is able to care for most of his or her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled; hospitalization is indicated though death not imminent. 
20 
Hospitalization necessary; very sick; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
 
 


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Appendix E. ECOG Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Statusa 
0 
Fully active, able to carry on all pre-disease 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. 
a. 
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 F. Memorial Pain Assessment Card (MPAC)  
 
 
 
Reference: 
 
1. Fishman B, Pasternak S, Wallenstein SL, Houde RW, Holland JC, Foley KM. The Memorial Pain 
Assessment Card. A valid instrument for the evaluation of cancer pain. Cancer. 1987;60:1151-8. 
 
 
 
 


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Appendix G. 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 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole a 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole a 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
a. 
Classification based on internal data. . 
 


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Appendix H. EORTC QLQ-C30 
 
 


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Appendix I. Child-Pugh Score for Subjects with Chronic 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, Pietroni MC, Williams R. “Transection of the oesophagus for 
bleeding oesophageal varices”. The British journal of surgery, 1973;60:646-9. 
 

SAP_000.pdf: 
 
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Statistical Analysis Plan 
 
 
A randomized, multicenter, double-blind, placebo-controlled, Phase 3 study of 
the Bruton’s Tyrosine Kinase inhibitor ibrutinib in combination with nab-
paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel 
and gemcitabine, in the first line treatment of patients with metastatic 
pancreatic adenocarcinoma (Amendment 5) 
 
 
PCYC-1137-CA 
 
 
January 15, 2018 
Version 1.0 
 
 
 
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 
 
1 
INTRODUCTION ............................................................................................. 7 
1.1 
Study Design ..................................................................................................................7 
1.2 
Endpoints .......................................................................................................................8 
1.2.1 
Primary Endpoints ............................................................................................8 
1.2.2 
Secondary Endpoints ........................................................................................8 
1.2.3 
Safety Assessments ...........................................................................................8 
1.2.4 
Exploratory Endpoints ......................................................................................8 
1.3 
Statistical Hypotheses ....................................................................................................9 
1.4 
Sample Size Determination............................................................................................9 
1.5 
Planned Analysis ..........................................................................................................10 
1.5.1 
Final Analysis PFS and OS Interim Analysis .................................................10 
1.5.2 
Final Analysis OS ...........................................................................................10 
1.6 
Testing Procedure and Level of Significance ..............................................................10 
1.7 
Blinding and Randomization Methods ........................................................................11 
1.7.1 
Blinding Method .............................................................................................11 
1.7.2 
Randomization Method ..................................................................................11 
2 
GENERAL ANALYSIS CONSIDERATION ............................................... 11 
2.1 
Analysis Sets ................................................................................................................12 
2.2 
Definition of Subgroups ...............................................................................................12 
3 
SUBJECT INFORMATION ........................................................................... 14 
3.1 
Subject Disposition ......................................................................................................14 
3.2 
Demographics and Baseline Characteristics ................................................................14 
3.3 
Concomitant Medications ............................................................................................14 
3.4 
Extent of Exposure to Study Treatment .......................................................................14 
3.5 
Subsequent Anti-Cancer Treatment .............................................................................15 
4 
ANALYSIS FOR ENDPOINTS ..................................................................... 16 
5 
SAFETY ASSESSMENTS .............................................................................. 20 
6 
CHANGES IN PROTOCOL PLANNED ANALYSIS ................................ 21 
7 
REFERENCES ................................................................................................. 22 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Counts 
ANC 
Absolute Neutrophil Counts 
ATC 
Anatomical Therapeutic Chemical 
BSA 
Body Surface Area 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaires Core 30 
EU 
European Union 
FDA 
Food and Drug Administration 
Hgb 
Hemoglobin  
DMC 
Data Monitoring Committee 
ITT 
Intent-To- Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NE 
NLR 
Not Evaluable 
Neutrophil/Lymphocyte Ratio 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCYC 
Pharmacyclics 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QoL 
Quality of life 
SAP 
Statistical Analysis Plan 


 
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SD 
Stable Disease 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Events 
VTE 
Venous Thromboembolic Events 
UNK 
Unknown 
WHO 
World Health Organization 


 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol Amendment 5 and is to define key 
elements including variable definitions, and statistical methods for analysis of data in evaluation 
of efficacy and safety of the study PCYC-1137-CA. Analyses of biomarker and 
pharmacokinetics (PK) data will be addressed in separate documents. Throughout this SAP, 
“study treatment” and “study drug” are used interchangeably, both referred to as 
ibrutinib/placebo, nab-paclitaxel, and/or gemcitabine 
Analysis methods specified in this document take precedence over those described in protocol 
should there be any difference. This SAP will be finalized before unblinding.  
1.1 
Study Design 
This is a randomized, multicenter, double-blind placebo-controlled, Phase 3 study comparing 
ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with 
nab-paclitaxel and gemcitabine in the first-line treatment of subjects with metastatic pancreatic 
adenocarcinoma.  
Safety Run-in Phase: 
Six subjects will initially be recruited to receive open-label ibrutinib in combination with nab-
paclitaxel and gemcitabine. The independent Data Monitoring Committee (DMC) will review 
data on the safety of ibrutinib combined with nab-paclitaxel and gemcitabine after the first 
6 subjects have completed at least 28 days of follow-up after the initiation of combination 
therapy. Following DMC review and confirmation, the study may proceed to the Double-blind 
Randomized Phase. 
Double-blind Randomized Phase: 
The second phase of the study will be a randomized, double-blind comparison of ibrutinib in 
combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-
paclitaxel and gemcitabine. 
Approximately 420 subjects will be randomized between Arm A (ibrutinib in combination with 
nab-paclitaxel and gemcitabine) and Arm B (placebo in combination with nab-paclitaxel and 
gemcitabine). All subjects in Arm A and Arm B are to receive nab-paclitaxel (intravenous [IV]) 
125 mg/m2 and gemcitabine (IV) 1000 mg/m2 given on Days 1, 8, and 15 of each 28-day cycle 
until disease progression or unacceptable toxicity. Unless otherwise indicated, all subjects in 
Arm A and Arm B per randomization are to receive oral ibrutinib 560 mg or matching placebo 
given orally once daily continuously starting on Cycle 1 Day 1 until disease progression or 
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prior to disease progression, the remaining agents will be continued until unacceptable toxicity or 
disease progression. 
1.2 
Endpoints 
1.2.1 
Primary Endpoints 
The primary endpoints are progression-free survival (PFS), as assessed by the investigator-based 
on RECIST 1.1 and overall survival (OS). 
1.2.2 
Secondary Endpoints 
• 
Overall response rate (ORR):  complete response (CR) + partial response (PR) per 
investigator assessment 
• 
Carbohydrate antigen (CA) 19-9 (CA19-9) response: proportion of subjects with a decline of 
≥ 60% from baseline 
• 
Patient-reported outcome (PRO) by EORTC QLQ-C30: time until definitive deterioration 
(TUDD1) for global health status/quality-of-life (QoL) scale. 
• 
Rate of venous thromboembolic events (VTE)  
• 
Clinical benefit response (CBR) rate  
1.2.3 
Safety Assessments 
• 
Safety and tolerability of the study treatment (ibrutinib/placebo, nab-paclitaxel, and/or 
gemcitabine)  
1.2.4 
Exploratory Endpoints 
Exploratory endpoints to be included in the CSR are,  
• 
CA19-9 response rate for a ≥ 20% reduction and a ≥ 90% reduction 
• 
Disease control rate (DCR) 
• 
Time to diminished pain (TDP) 
• 
OS for the survival maintenance subgroup, and  
• 
EORTC QLQ-C30 Global Health Status/QoL scale: time until definitive deterioration 
(TUDD2) (see Table 3 for endpoint definition).  
In addition, baseline serum cytokine and C-reactive protein (CRP) biomarkers compared to PFS 
and OS will be explored.  


 
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1.3 
Statistical Hypotheses 
The statistical hypotheses for each of the primary endpoints (PFS or OS) can be written as 
follows: 
H0:  SI(t) = SC(t), for all t > 0, where SI(t), and SC(t) are survival functions for the experimental 
and control arms, respectively at all time points t:  
vs. 
H1: SI(t) ≠ SC(t), for some t > 0  
These hypotheses will be tested for the primary endpoints using a 2-sided stratified log-rank test 
at an α level specified in Section 1.6. The source of the stratification factors will be based on 
Interactive Web Response System (IWRS) data.  
1.4 
 Sample Size Determination 
The sample size calculation is based on a 2-sided family-wise Type I error rate (aka. family-wise 
error rate, FWER) of 0.05 for 2 primary endpoints, PFS and OS. The FWER is controlled 
at 0.05, with 0.007 allocated to the PFS endpoint and 0.043 allocated to the OS endpoint. 
In this protocol amendment, a total of 424 subjects have been randomized with a 1:1 allocation 
to the 2 treatment arms. The calculations are based on the following assumptions using EAST 
software Version 6.3.1 and the actual enrollment rates. 
For PFS: 
• 
Median PFS is 5.5 months for the control arm (nab-paclitaxel and gemcitabine) (Von Hoff 
2013).  
• 
Target hazard ratio is 0.66 which corresponds to a 51% improvement in median PFS (eg, 
from 5.5 months to 8.33 months) for the ibrutinib + nab-paclitaxel + gemcitabine arm 
compared to the placebo + nab-paclitaxel + gemcitabine arm 
• 
2-sided α = 0.007  
• 
A total of 350 PFS events will provide approximately 88% power. 
For OS:  
• 
Median OS is 8.5 months for the control arm (nab-paclitaxel and gemcitabine) (Von Hoff 
2013). 
• 
Target hazard ratio is 0.735 which corresponds to approximately 36% improvement in 
median OS (e.g., from 8.5 months to 11.6 months) for the ibrutinib + nab-
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• 
2-sided α = 0.043 
• 
A group sequential design with 1 interim analysis is planned when at least 250 deaths occur 
(approximately 71% of the deaths occur). The Lan-DeMets alpha spending function with 
O’Brien-Fleming boundary for efficacy will be used. 
• 
A total of 353 OS events will provide approximately 80% power for the study. 
1.5 
Planned Analysis 
1.5.1 
Final Analysis PFS and OS Interim Analysis 
The OS interim analysis strategy has been changed from Protocol Section 10.4.1.  Conditions for 
conducting the OS interim analysis are described below. 
At the time of the planned final PFS analysis (i.e., at least 350 PFS events as specified in the 
protocol), if the total number of OS events is ≥ 333 (i.e., ≥ 94% of the OS information fraction) 
the PFS final analysis will be delayed until approximately 350 OS events have been reached. On 
the other hand, if the total number of the OS events is < 333 at the time of the final PFS analysis, 
the PFS final analysis will take place, and the OS interim analysis will only be conducted when 
the PFS endpoint is statistically significant. A Heybittle-Peto boundary with a 2-sided 
significance level of 0.0001 will be used for the OS interim analysis. Otherwise, a final OS 
analysis will be performed at approximately 350 events if the PFS endpoint is not statistically 
significant.  
Secondary endpoints will be tested following a prespecified hierarchical order. If both PFS and 
OS endpoints are statistically significant, the secondary endpoints will be tested using a 2-sided 
alpha of 0.05. However, if only the OS endpoint (or PFS endpoint) is statistically significant, the 
secondary endpoints will be tested using a 2-sided alpha of 0.043 (or 0.007). 
1.5.2 
Final Analysis OS 
The final analysis for the OS will be conducted after approximately 350–353 OS events are 
reached.   
1.6 
Testing Procedure and Level of Significance 
The Type I error rate will be controlled for testing the primary and secondary endpoints. A 2-
sided FWER of 0.05 will be used, with 0.007 allocated to the PFS hypothesis testing and 0.043 
allocated to the OS hypothesis testing. The alpha level for the OS interim analysis will be based 
on a Heybittle-Peto boundary with a 2-sided significance level of 0.0001. The plan for 
conducting the interim and final OS analyses is specified in Section 1.5.1 and Section 1.5.2, 
respectively.   
The secondary endpoint hypotheses will be tested sequentially with a 2-sided alpha level of 5% 
if both PFS and OS analyses show superiority. However, if only OS (or PFS) endpoint shows 


 
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superiority, the secondary endpoint hypotheses will be tested sequentially at an alpha level 
of 4.3% (or 0.7%).    
The secondary endpoints will be ranked in the following hierarchical order. Statistical testing 
will follow this sequence.   
1) 
ORR:  CR  + PR per investigator assessment 
2) 
CA19-9 response:  proportion of subjects with a decline of ≥ 60% from baseline 
3) 
PRO by EORTC QLQ-C30: TUDD1 for global health status/QoL scale. 
4) 
VTE rate 
5) 
CBR rate  
1.7 Blinding and Randomization Methods 
1.7.1 Blinding Method 
This is a double-blind study; the blinding method is described in the protocol (ie, Section 5.1 
“Treatment Allocation and Blinding”) and the DMC charter. 
1.7.2 Randomization Method 
Randomization will be implemented in this study using IWRS. The randomization of treatment 
assignment will be stratified by the following factors: 
• 
Karnofsky Performance Status (KPS) 70-80 vs. 90-100 
• 
Liver metastasis (present vs. absent) 
• 
Age ≤ 65 years vs. > 65 years. 
Subjects will be randomly assigned in a 1:1 ratio to the 2 treatment arms within each 
of 8 randomization strata using permuted block stratified randomization.   
2 
GENERAL ANALYSIS CONSIDERATION 
The statistical analysis sections in this SAP are mainly for the Double-blind Randomized Phase. 
Subjects will be analyzed and summarized by treatment as randomized for all safety and efficacy 
endpoints. Safety run-in data will be summarized or listed separately from Phase 3 data and 
placed in an appendix of the clinical study report (CSR). They include tables for demographic, 
baseline characteristics and baseline disease characteristics; overview of treatment-emergent 
adverse events (TEAEs), all TEAEs by system organ class (SOC)/preferred term (PT), and 
maximum severity; and 1 efficacy listing (for best overall response, progression/death, and 
associated dates).  


 
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Unless otherwise specified, the baseline value is defined as the last non-missing valid value 
collected prior to the first administration of study treatment. For subjects who have been 
randomized but not treated, randomization date will be used as the reference date for baseline. 
Subgroup analyses are mainly to demonstrate trend and assess internal consistency of any 
treatment benefit and/or safety signal. Forest plots of hazard ratios and associated confidence 
intervals will be provided to show the trend. Statistical tests will not be performed. 
2.1 
Analysis Sets 
Intent-to-Treat Population 
The intent-to-treat (ITT) population includes all subjects randomized into the study.     
Safety Population 
The safety population (SP) includes all subjects in the ITT population who received at least 
1 dose of any study treatment (ibrutinib/placebo, nab-paclitaxel, and/or gemcitabine)  
2.2 Definition of Subgroups  
Analyses for the baseline subgroups (hereafter referred as “subgroup” or “subgroups”) will be 
performed for selected variables. The baseline subgroup variables (Table 1) and the cutoff values 
are subject to change if warranted to better represent the data.  
Post-baseline outcome subgroups (hereafter referred as “post- baseline subgroup” or “post- 
baseline subgroups” as needed) are outcome variables and are exploratory in nature. Selected 
data will be summarized by these post- baseline subgroups (Table 2).  


 
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Table 1 
Baseline Subgroups 
Subgroup 
Definition of Subgroup 
Analysis Type 
Age 
≤ 65, > 65   
B, E, S,  
Gender 
Male, Female 
B, E, S,  
Race 
White, Non-White 
B, E, S,  
Geographic region 
US, EU, Asia Pacific 
B, E, S 
Neutrophil/Lymphocyte Ratio 
(NLR) 
≤ 4, > 4 
E 
KPS 
70-80, 90-100   
E,  
Liver metastasis 
Present, absent 
E,  
Renal function (creatinine clearance) < 30, 30 - < 60, ≥ 60 mL/min 
S 
Hepatic function (NCI ODWG 
definition) 
normal, mild, moderate, severe 
(or normal vs. non-normal as 
appropriate) 
S 
Analysis type:  B=Demographics, Baseline Characteristics, Baseline Disease Characteristics; E = Efficacy (PFS 
and OS); KPS: Karnofsky Performance Status; NCI ODWG: NCI Organ Dysfunction Working Group Liver 
Function Classification (Ramanathan et al, 2008); S = Safety (Overview TEAE, TEAE by SOC/PT, Grade 3 or 
higher TEAE by SOC/PT). 
Table  2 
Post-Baseline Outcome Subgroups 
Subgroup 
Definition of Subgroup 
Analysis Type 
CYP3A inhibitor (for concomitant 
medications only) 
Strong vs. other user 
S  
 
Strong/moderate vs. other user 
S 
Survival Maintenance Subgroup 
Subjects who are progression-free 
and alive at 6 months of treatment 
and who continue 
ibrutinib/placebo after having 
discontinued the 
2 chemotherapies 
Overall survival 
Analysis type: S = Safety (Overview TEAE, TEAE by SOC/PT). 


 
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3 
SUBJECT INFORMATION  
3.1 
Subject Disposition 
The disposition tables will include the following summaries by treatment and overall. 
• 
Analysis populations (all subjects) 
• 
Enrollment by region, country and investigator (ITT population) 
• 
Summary of randomization stratification per IWRS (ITT population) 
• 
Study Treatment Disposition and Discontinuation (ITT population) 
• 
Study Status, Duration of Treatment and Study Exit (ITT population). 
The Kaplan-Meier estimates will be calculated to estimate the time on study using reversed 
censoring from the OS analysis. 
3.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized with descriptive statistics 
for the ITT population by treatment arm. 
3.3 
Concomitant Medications 
Medications will be coded to Anatomical Therapeutic Chemical (ATC) class and the preferred 
drug name (hereafter referred as “preferred name”) per World Health Organization (WHO) Drug 
dictionary.  
Concomitant medications will be summarized by ATC class and preferred term for each 
treatment arm in the safety population. The summarization includes all the concomitant 
medications taken any time while on study treatment (ie, from the date of first dose through the 
date of last dose of the study treatment). Each subject will be counted once for each preferred 
term, and each ATC class. The following concomitant medications will be summarized 
separately.  Details are in the mock-up tables. 
• 
CYP3A inhibitors and inducers – This list requires a medical and pharmacology review, 
with finalization at the time of analysis 
• 
Anticoagulants and antiplatelet agents will need medical review as above 
3.4 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized by treatment arm for the safety population. 
Descriptive statistics will be provided for the following data for each of the 3 drugs unless 
otherwise specified: treatment duration (month), total number of doses received, total number of 
cycles received (for each chemotherapy), total cumulative dose administered for each drug, dose 


 
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intensity and relative dose intensity (%), and number (%) of subjects with dose reduction due to 
adverse events (AEs). 
3.5 
Subsequent Anti-Cancer Treatment 
Subsequent anti-cancer treatment (including anti-cancer chemotherapy, anti-cancer radiation, and 
surgeries and procedures performed with therapeutic intent) will be summarized by treatment 
arm for the safety population. The ATC level will be specified in the mock-up table footnote. 


 
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ANALYSIS FOR ENDPOINTS 
Analysis of endpoints will be conducted on the ITT population unless otherwise specified. For 
subgroup, sensitivity, and exploratory analyses, only the analyses that provide meaningful 
information will be presented for the CSR. The following 3 randomization stratification factors 
will be used for the stratified analysis/test: KPS (70-80 vs. 90-100), liver metastasis (present vs. 
absent), and age (≤ 65 years vs > 65 years). All stratified tests will be based on randomization 
stratification factors as recorded in the IWRS. 
Table 3 
Definitions and Analyses for Endpoints 
Endpoint 
Definition 
Analysis Method  
Primary Endpoints 
 
 
PFS assessed by 
investigator 
Time from the date of 
randomization to the date of the 
first documented disease 
progression per RECIST 1.1 or 
death due to any cause, 
whichever occurred first, 
regardless of the use of 
subsequent anticancer therapy 
prior to documented PD or death. 
Primary Analysis: 
Stratified log-rank test is the primary 
analysis comparing treatment 
differences. Stratified Cox regression 
model with Efron’s tie handling method 
will be used to estimate HR and its 
associated 2-sided 95% CI. In addition, 
Kaplan-Meier estimates and median PFS 
with its associated 95% CI will be 
displayed. Subjects without an event will 
be censored at the last adequate tumor 
assessment date showing no evidence of 
progressive disease.  
Sensitivity Analysis: 
1) Same analysis as the primary analysis 
except subjects who received 
subsequent anticancer therapy prior 
to documented progression or death 
will be censored at the date of the last 
adequate tumor assessment showing 
no evidence of progressive disease 
prior to or on the initiation of the new 
therapy. 
2) Unstratified log-rank test, 
unstratified Cox regression model, 
confidence intervals using same 
censoring rule as for the primary 
analysis. 
Subgroup Analysis: 
Hazard ratio and its 95% CI from 


 
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Endpoint 
Definition 
Analysis Method  
unstratified Cox regression model for 
each subgroup. 
OS 
Time from the date of 
randomization to the date of 
death from any cause 
Primary Analysis: 
Stratified log-rank test is the primary 
analysis comparing treatment 
differences. Stratified Cox regression 
model with Efron’s tie handling method 
will be used to estimate HR and its 
associated 2-sided 95% CI. In addition, 
Kaplan-Meier estimates and median OS 
with its associated 95% CI will be 
displayed. Subjects who did not die will 
be censored at the last known alive date. 
Sensitivity Analysis: 
Unstratified log-rank test, unstratified 
Cox regression model and associated 
confidence intervals. 
Subgroup Analysis: 
Hazard ratio and its 95% CI from 
unstratified Cox regression model for 
each subgroup. 
Secondary Endpoints: 
 
 
ORR 
The proportion of subjects 
achieving a best overall response 
of CR or PR per investigator 
assessment per RECIST 1.1 at or 
prior to initiation of subsequent 
anticancer therapy 
CMH chi-square test controlled for 
3 stratification factors 
CA19-9 response rate 
for ≥ 60% reduction 
The proportion of subjects with 
at least a 60% decrease from 
baseline at or prior to initiation 
of subsequent anticancer therapy.  
CMH chi-square test of response rate 
controlling for 3 stratification factors;  
Descriptive statistics of change and 
percentage change from baseline will be 
summarized by time. 
EORTC QLQ-C30 
Global Health 
Status/QoL scale: time 
until definitive 
deterioration (TUDD1) 
TUDD1 was defined as the time 
interval between randomization 
and the first occurrence of a 
decrease in QLQ-C30 score 
≥ 10 points without any further 
improvement in QoL score of 
≥ 10 points or any further 
available QoL data due to 
Stratified log-rank test. Descriptive 
statistics by time, Kaplan-Meier 
estimates  


 
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Endpoint 
Definition 
Analysis Method  
dropping out after the 
deterioration (Bonnetain et al, 
2010).  
VTE 
Proportion of subjects with 
TEAE VTE of any grade defined 
by SMQ terms as “embolic and 
thrombotic events, venous“ 
Chi-square test 
CBR rate 
Proportion of subjects who meet 
the “responder” criteria below 
prior to initiation of the 
subsequent anticancer therapy. 
Response was defined as 
achievement of a ≥50% 
reduction in MPAC visual 
analog scale which measures 
pain intensity or analgesic 
consumption, or a ≥ 20-point 
improvement from baseline in 
KPS sustained for a period of 
≥ 4 consecutive weeks without 
showing any sustained 
worsening from baseline in any 
of the other parameters 
OR 
Subject was stable on all 
aforementioned parameters (pain 
and KPS), and also showed a 
marked, sustained weight gain 
(≥ 7% increase from baseline 
maintained for ≥ 4 weeks) not 
due to fluid accumulation (Burris 
et al, 1997) 
CMH chi-square test controlled for 
3 stratification factors; descriptive 
statistics for 4 categories (i.e., MPAC 
pain intensity reduction ≥ 50%, analgesic 
consumption reduction≥ 50%, KPS 
improvement ≥ 20 points, weight gain 
≥ 7%) 
Exploratory Endpoints 
 
 
CA19-9 response rate 
for ≥ 20% and ≥ 90% 
reductions 
The proportions of subjects with 
at least a 20%, 90% decrease 
from baseline at or prior to 
initiation of subsequent 
anticancer therapy 
CMH chi-square test controlling for 
3 stratification factors 
Descriptive statistics of change and 
percentage change from baseline will be 
summarized by time. 
DCR 
Proportion of subjects achieving 
best response of CR, PR, or SD 
(≥ 8 weeks) per investigator 
assessment per RECIST 1.1 at or 
CMH chi-square test controlled for 
3 stratification factors  


 
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Endpoint 
Definition 
Analysis Method  
prior to initiation of subsequent 
anticancer therapy 
TDP 
Time to the first 50% reduction 
from baseline in MPAC visual 
analog scale of pain intensity 
sustained for 4 weeks or longer 
on or prior to initiation of 
subsequent anticancer therapy. 
Kaplan-Meier estimates, median TDP 
and its 2-sided 95% CI. 
EORTC QLQ-C30 
Global Health 
Status/QoL scale: time 
until definitive 
deterioration (TUDD2) 
TUDD2 is defined as the time 
interval between randomization 
and the first occurrence of a 
decrease in QLQ-C30 score 
≥ 10 points observed at all time 
points after the first deterioration 
or the subject dropped out after 
deterioration resulting in missing 
data (Anota et al, 2015). 
Descriptive statistics by time, Kaplan-
Meier estimates and hazard ratio 
CBR: Clinical Benefit Response Rate; CMH: Cochran-Mantel-Haenszel; CI: confidence interval; CR: complete 
response; HR: estimate hazard ratio; KPS: Karnofsky Performance Status; MPAC: Memorial pain Assessment 
Card; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; 
PR: partial response; RECIST 1.1: Response Evaluation Criteria In Solid Tumors; SD: stable disease; TEAE: 
treatment-emergent adverse event; SMQ; standardized MedDRA (Medical Dictionary for Regulatory Activities) 
query; VTE: Venous thromboembolic event, DCR: disease control rate. TDP: time to diminished pain.  
All primary and secondary endpoints will be analyzed for the ITT population. 


 
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SAFETY ASSESSMENTS 
Safety data will be summarized by treatment. Table 4 summarizes the safety analyses to be 
carried out. 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 National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE), Version 4.03. Events of special interest such as hemorrhagic events, major 
hemorrhage, and other safety observations such as hypertension, interstitial lung disease (ILD), 
severe cutaneous adverse reactions (SCAR), rash, cardiac arrhythmia excluding atrial fibrillation, 
and other malignancies will be included. 
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 the date of the last dose of study treatment or the day 
before initiation of subsequent antineoplastic therapy, whichever comes first. Treatment-
emergent adverse events are those events that occur or worsen during the treatment-emergent 
period or that are related to the study treatment or events with a complete missing onset date but 
with a resolution date during the treatment phase. 
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, Version 4.03. Unless otherwise specified, only 
baseline and post-baseline values collected during the treatment-emergent period will be 
included in the safety analysis.  
Table 4 
Summary of Safety Assessments 
Assessment Type 
Definition   
Analysis Methods 
AE 
TEAEs, SAEs, Grade 3 or higher 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 
Descriptive summary 
statistics and/or listings 
Laboratory Parameters 
Worst post-baseline toxicity grade for 
CTCAE gradable hematology and 
chemistry.  Abnormalities in creatinine 
clearance, uric acid, and liver function  
Descriptive summary 
statistics and/or listings 
Vital Signs and other 
Observations Related to 
Safety 
Blood pressure, heart rate, new or worsened 
eye-related symptoms 
Descriptive summary 
statistics and/or listings 
AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events; SAE: serious adverse event; 
TEAE: treatment-emergent adverse event 


 
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CHANGES IN PROTOCOL PLANNED ANALYSIS  
Protocol Section 10.4.1 states the following: 
“PFS final analysis and OS interim analysis will be carried out at the same time after at least 
350 PFS events and 250 death events (approximately 71% of death events) are observed. To 
control the family-wise Type I error rate the fallback method as specified in the FDA Draft 
Guidance (Multiple Endpoints in Clinical Trials, 2017), will be used to test the two primary 
endpoints. A 2-sided family-wise Type I error rate (FWER) of 0.05 will be used with 0.007 
allocated to the PFS hypothesis testing and 0.043 allocated to the OS hypothesis testing. Lan-
DeMets alpha spending function with O’Brien-Fleming boundary for efficacy will be used to 
determine the Type I error rate for the interim and final OS analyses depending on whether an 
alpha of 0.043 or 0.05 is used.” 
However, the OS interim analysis strategy has been changed from Protocol Section 10.4.1. 
Conditions for conducting the OS interim analysis are outlined below: 
1) 
If at the time of the planned final PFS analysis, (i.e., at least 350 PFS events as specified in 
the protocol) the total number of OS events is ≥ 333 (ie, ≥ 94% of the OS information 
fraction), the PFS final analysis will be delayed until the final OS events of 
approximately 350 have been reached.  
2) 
If at the time of the planned final PFS analysis, the total number of the OS events is < 333, 
the PFS final analysis will take place.  
a. If the PFS endpoint at the final analysis is significant, the OS interim analysis will be 
conducted using the Heybittle-Peto boundary.  
i. 
The interim analysis boundary will be based on a fixed Heybittle-Peto boundary 
using a 2-sided significance level of 0.0001.  
b. If the PFS endpoint at the final analysis is not significant, the OS will be tested at the 
time of the final analysis when a total of ~350 OS events have occurred.  


 
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