A Study of the Safety, Immunopharmacodynamics and Anti-tumor Activity of Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Adenocarcinoma
Phase: PHASE1
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: Margaret Tempero

Proprietary and Confidential
The information in this document is considered privileged and confidential, 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 should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
A Study of the Safety, Immunopharmacodynamics and Anti-tumor Activity of 
Ibrutinib Combined with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic 
Pancreatic Adenocarcinoma 
Protocol Number:  CC #144525
Study Drug:  Ibrutinib
Version Number:  4.0
Version Date:  09/28/2016
IND Number:  Exempt 
Principal Investigator (Sponsor-Investigator)
Margaret Tempero, MD  
University of California San Francisco
  
Co-Investigators
Andrew Ko, MD 
Alan Venook MD
Emily Bergsland MD 
Chloe Atreya MD PhD
Eric Collisson MD PhD
R. Kate Kelley MD
Katherine Van Loon MD MPH
Pelin Cinar, MD MS
Charles Lopez, MD
Oregon Health and Science University
Sub-investigator: Gina Vaccaro, MD
Statistician
Jimmy Hwang, PhD
NCT# 02562898

Version date: 28SEP2016
Protocol CC#:144525 
Phase I/Immune Response – Ibrutinib
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Revision History
Version 4.0
09-28-16
Version 3.3
07-05-16
Version 3.2
06-08-16
Version 3.1
03-29-16
Version 3.0
01-07-16
Version 2.2
11-06-15
Version 2.1
09-02-15
Version 2.0 
07-02-15  
Version 1.3
12-17-14  
Version 1.2 
11-12-14  

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Protocol Signature Page
Protocol No.: 144525
Version Date: 28SEP2016
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with applicable CHR requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare of 
study participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with CHR policies, 
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date
Participating Site(s)
       [Name]
       [Institution name]
       [Address]
Telephone:       
E-mail:       
       [Name]
       [Institution name]
       [Address]
Telephone:       
E-mail:       
Principal Investigator
Site
Printed Name
Signature
Date

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Abstract
Title
A Study of the Safety, Immunopharmacodynamics and Anti-tumor Activity 
of Ibrutinib Combined with Gemcitabine and Nab-Paclitaxel in Patients 
with Metastatic Pancreatic Adenocarcinoma
Patient 
population
Patients with previously untreated metastatic pancreatic adenocarcinoma
Rationale for 
Study
Gemcitabine and nab-paclitaxel is a standard regimen (NCCN, Category 1) for 
patients with metastatic pancreatic ductal adenocarcinoma (PDAC). However, 
further improvement in treatment is needed. Increasingly, the nature of the 
immune infiltrate in PDAC appears to be tumor promoting. In preclinical 
studies, ibrutinib treatment, presumably by reprogramming B cells, results in 
increased CD8+ T cells to assist in tumor control. Preclinical studies of 
ibrutinib plus gemcitabine show superior antitumor effects compared to 
gemcitabine alone in both orthotopic murine pancreatic cancer cell line grafts 
and in genetically engineered mouse models. Thus, we propose a clinical trial 
of ibrutinib plus the standard gemcitabine based regimen of gemcitabine and 
nab-paclitaxel, evaluating safety, then efficacy and including correlative 
studies.
Primary 
Objectives
Phase Ib:

To determine the maximum tolerated dose of ibrutinib in combination with 
albumin bound paclitaxel and gemcitabine in patients with metastatic 
pancreatic adenocarcinoma.
Immune Response Study: 

To monitor the changes in the patients’ immune profiles during treatment 
with ibrutinib, alone and in combination with gemcitabine and nab-
paclitaxel, in the pancreatic tumor micro-environment (TME) and in the 
peripheral blood.

To confirm the pharmacodynamics of ibrutinib at dosing level 560 mg/day

To explore the relationships between the pharmacodynamics of ibrutinib in 
combination with nab-paclitaxel and gemcitabine and response prediction 
biomarkers in patients with metastatic pancreatic adenocarcinoma. 
Secondary 
Objectives
Phase Ib: 

To evaluate the safety of treatment with ibrutinib in combination with nab-
paclitaxel and gemcitabine in patients with metastatic pancreatic 
adenocarcinoma.

To evaluate the potential drug-drug interaction of ibrutinib in combination 
with nab-Paclitaxel and gemcitabine in patients with metastatic pancreatic 

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adenocarcinoma.

To clinically assess the anti-tumor effects of treatment with ibrutinib in 
combination with nab-Paclitaxel and gemcitabine. 
Immune Response Study: 

To verify and confirm the safety of ibrutinib in combination with nab-
paclitaxel and gemcitabine in patients with metastatic pancreatic 
adenocarcinoma.

To estimate the CA19-9 clinical response rate of patients with metastatic 
pancreatic adenocarcinoma treated with ibrutinib in combination with nab-
Paclitaxel and gemcitabine.

To estimate the Progression-Free Survival and Time-to-Progression and 
Overall survival of patients with metastatic pancreatic adenocarcinoma 
treated with ibrutinib in combination with nab-Paclitaxel and gemcitabine.
Study Design
This is a phase open-label study, designed to assess the safety and 
immunopharmicodynamics of ibrutinib in combination with the standard doses 
of gemcitabine and nab-paclitaxel for treating advanced pancreatic 
adenocarcinoma.  
Phase Ib:  Patients will be enrolled in the 3+3 dose escalation cohort to 
assess the safety and tolerability of the combination therapy of ibrutinib, 
gemcitabine and nab-paclitaxel*.  Dosing escalation will commence at the 560 
mg/day dose, and if no DLT is identified in the first 3 patients, the next dosing 
cohort will receive ibrutinib at 840 mg/day.  If a DLT is identified at 560 mg/day 
or at 840 mg/day, dose de-escalation will begin with dosing cohorts receiving 
560 mg/day, 420 mg/day, and 280 mg/day as necessary.  Grade 4 
hematologic adverse events are expected based on prior experience with 
gemcitabine and nab-paclitaxel, and support with colony stimulating factor will 
be allowed.   If no DLT is identified at 840 mg/day, then 840 mg/day will be 
considered the Maximum Tolerated Dose.  
Immune Response Study:  Patients will begin treatment with a one-week 
run-in of 560 mg/day of ibrutinib only.  Each patient will undergo two EUS-
guided biopsies, at least 5 days before and at least 5 days after the one-week 
run-in of ibrutinib. Combination therapy with gemcitabine and nab-paclitaxel 
will begin no later than 3 days after the second biopsy, and treatment with 
ibrutinib will resume 5-7 days after biopsy.  The tissue samples acquired 
through biopsy will be used to assess the pharmacodynamic relationship 
between treatment with ibrutinib alone and changes in the tumor 
microenvironment. Serial blood samples will be taken to monitor changes in 
circulating cytokines, to define the B and T cell receptor repertoires and the 
characteristics of circulating myeloid cells. 
Patients enrolled and treated in thephase Ib dose escalation and the Immune 
Response cohorts will continue to receive combination therapy until 

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documented disease progression, unless discontinuing therapy for the 
following reasons:

Irreversible or intolerable toxicity or clinically significant abnormal 
laboratory values thought to be related to drug toxicity 

Patient withdraws consent

Treatment-related toxicities that require a delay in scheduled dosing for 
≥21 days*

Documented symptomatic deterioration defined as global or severe 
deterioration of health status such that it requires discontinuation of trial 
treatment without evidence of disease progression at that time.

Inability of the patient to comply with trial requirements or lost to follow-
up

Conditions requiring a therapeutic intervention not permitted by the 
protocol

Intercurrent illness (this will be at the investigator’s discretion)
*In the event that a drug must be held for intolerability (ie neuropathy for nab-
paclitaxel or rash for gemcitabine) for more than 21 days, patients may 
continue on study receiving the other drugs, including ibrutinib.
Number of 
patients
 29-50
Duration of 
Therapy
10  months
Duration of 
Follow up
1 year
Duration of 
study
5 yrs
Study Drugs
Ibrutinib, in combination with gemcitabine and nab-paclitaxel  Ibrutinib 
(IMBRUVICA®) will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.
Inclusion 
Criteria
1.
Histologically or cytologically confirmed pancreatic adenocarcinoma
2.
Stage IV disease (measurable disease NOT required) 
3.
Intact primary tumor (for Immune Response Cohort only)
4.
ECOG performance score of 0-1

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5.
At least 18 years of age
6.
Female patients who are not of child-bearing potential, and fertile female 
patients of child-bearing potential, who agree to use adequate 
contraceptive measures, who are not breastfeeding, and who have a 
negative serum or urine pregnancy test within 72 hours prior to start of 
randomization.
7.
Fertile male patients willing to use adequate contraceptive measures.
8.
Adequate bone marrow function: 
•
Absolute neutrophil count (ANC) ≥ 1500/uL 
•
Platelet count ≥ 100,000/uL 
•
Hemoglobin ≥ 9.0 g/dL 
9.
Adequate hepatic function:

Total bilirubin ≤ 1.5 X ULN (unless bilirubin rise due to Gilbert’s     
syndrome

AST ≤ 3.0 X ULN (≤5.0X ULN if liver metastases are present).

ALT ≤ 3.0 X ULN (≤5.0X ULN if liver metastases are present).
10. Adequate renal function (defined as serum creatinine ≤ 1.5 X ULN)
11. Ability to understand the nature of this study protocol, comply with study 
and/or follow-up procedures, and give written informed consent
12. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures.
13. The calculated QTcF average of the triplicate screening ECGs must be 
<470 msec.
Exclusion 
Criteria
1.
Any prior systemic or investigational therapy for metastatic pancreatic 
cancer.  Systemic therapy administered alone or in combination with 
radiation in the adjuvant or neoadjuvant setting is permissible as long as 
it was completed > 6 months prior to the time of study registration. 
2.
History of other diseases, metabolic dysfunction, physical examination 
findings, or clinical laboratory findings giving reasonable suspicion of a 
disease or condition that, in the opinion of the investigator, renders the 
subject at high risk from treatment complications or might affect the 
interpretation of the results of the study. 
3.
History of previous malignancy (except in-situ cancer or basal or 
squamous cell skin cancer) within past 3 years.
4.
Life expectancy of <3 months.

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5.
Inability to undergo two sequential EUS-directed core biopsies of the 
primary tumor (for Immune Response Cohort only).
6.
Presence of known central nervous system or brain metastases.
7.
Known human immunodeficiency virus (HIV) infection.
8.
History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment.
9.
Known bleeding disorders (e.g., von Willebrand’s disease or 
hemophilia).
10. Patients receiving warfarin or other Vitamin K antagonists.  However, if 
therapeutic anticoagulation is necessary, LMWH is the anticoagulant of 
choice.
11. 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.
12. Current peripheral sensory neuropathy > Grade 1
13. Major surgery within 4 weeks of the start of study treatment (defined as 
those surgeries that require general anesthesia.  Insertion of a vascular 
access device is NOT considered major surgery. 
14. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
15. Unable to swallow capsules or has 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.

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AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
AST
aspartate aminotransferase
AUC
area under the curve
BUN
blood urea nitrogen
CA19-9
cancer antigen 19-9
CBC
complete blood cell (count)
Cmax
maximum drug concentration
CMP
comprehensive metabolic profile
CR
complete response
CRF
case report form
CT
computerized tomography
CTCs
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
D5W
dextrose 5% in water
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICH
International Conference on Harmonization
IND
investigational new drug application
IRB
Institutional Review Board
IV
Intravenous
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NE
non-evaluable
OS
overall survival
PD
progressive disease
PR
partial response
PTT
partial thromboplastin time
RECIST
Response Evaluation Criteria in Solid Tumors
SD
stable disease
List of Abbreviations 

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SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
ULN
upper limit of normal

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Table of Contents
Abstract
3
Table of Contents ........................................................................................................................10
1
Introduction......................................................................................................................15
1.1
Background Current Treatment of Advanced Pancreatic Adenocarcinoma
.................................................................................................................15
1.2
Immunotherapy for Pancreatic Adenocarcinoma.....................................15
1.3
Rationale for Targeting Regulatory B Cells in Treating Pancreatic Cancer
.................................................................................................................16
1.4
Rationale for Targeting Bruton’s Tyrosine Kinase with Ibrutinib to Alter 
TME of PDA.............................................................................................17
1.5
Rationale of Combining Ibrutinib with Gemcitabine and nab-Paclitaxel ..18
1.6
Ibrutinib ....................................................................................................19
1.7
Summary of Non-Clinical Data.................................................................20
1.7.1
Pharmacology ......................................................................................20
1.7.2
Carcinogenesis, Mutagenesis, Impairment of Fertility..........................20
1.8
Summary of Clinical Data ........................................................................21
1.8.1
Pharmacokinetics and Product Metabolism .........................................21
1.8.2
Summary of Clinical Studies Evaluating the Safety and Efficacy of 
Ibrutinib............................................................................................................21
1.8.3
Treatment Discontinuations..................................................................22
1.8.4
Bleeding-related events........................................................................23
1.8.5
Cardiac.................................................................................................23
1.8.6
Rash.....................................................................................................23
1.8.7
Non-Melanoma Skin Cancer ................................................................23
1.8.8
Infections..............................................................................................23
1.8.9
Cytopenias ...........................................................................................23
1.8.10 Diarrhea...............................................................................................23
1.8.11 Lung Disease (ILD) .............................................................................24
1.8.12 Ongoing Combination Clinical Studies in Solid Tumors* ....................24
2
Objectives of the Study....................................................................................................25
2.1
Phase Ib...................................................................................................25
2.2
Immune Response Cohort.......................................................................25
2.3
Exploratory Objectives, Other Assessments............................................26
3
Study Design ...................................................................................................................26
3.1
Eligibility Criteria ......................................................................................26
3.1.1
Inclusion Criteria...................................................................................27
3.1.2
Exclusion Criteria .................................................................................28
3.1.3
Duration of and Discontinuation from Protocol Therapy ......................28
3.1.4
Pregnancy ............................................................................................29

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Table of Contents
4
Trial Registration .............................................................................................................30
5
Treatment Plan ................................................................................................................30
5.1
Study Schema..........................................................................................31
5.2
Dosage and administration of Ibrutinib ....................................................33
5.2.1
Phase Ib Dose escalation.....................................................................33
5.2.2
Dose Limiting Toxicity ..........................................................................33
5.2.3
Combination Therapy for Phase Ib and Immune Response cohorts ...34
5.2.4
One week run-in with Ibrutinib-only for the Immune Responses Study 
Cohort34
5.3
Study Treatment phase............................................................................34
5.4
Restaging During the Combination Therapy Treatment Phase ...............35
5.5
Assessments for Exploratory Endpoints ..................................................35
5.6
General Concomitant Medication and Supportive Care Guidelines ........35
6
Dose Modifications and Dosing Delays ...........................................................................36
6.1
Dose Modifications of Ibrutinib for the Immune Response cohort ...........36
6.2
Dose Modifications for Dose Escalation and Immune Response Cohorts 
during Combination Therapy....................................................................37
6.3
Dose Modifications Tables.......................................................................38
6.3.1
Dose Modifications and Schedule for Hematologic Toxicities..............38
6.3.2
Dose Modifications and Schedule for Non-Hematologic Toxicities......40
7
Study Procedures and Observations...............................................................................44
7.1
Overview..................................................................................................44
7.2
Pre-treatment Assessments.....................................................................44
7.3
Study Treatment Assessments................................................................45
7.3.1
Immune Response Cohort:  One Week Ibrutinib-only Period ..............45
7.4
Combination Therapy Treatment Period..................................................45
7.4.1
Day 1 of all Cycles................................................................................45
7.4.2
Day 8 of all Cycles................................................................................46
7.4.3
Cycles 1 and 2, Day 15 ........................................................................46
7.4.4
Day 22 of all Cycles..............................................................................46
7.4.5
Cycle 3 and beyond Day 15 .................................................................46
7.5
Every 2 Cycles (8 weeks) ........................................................................46
7.6
End-of-Treatment.....................................................................................46
7.7
Follow-up .................................................................................................47
7.7.1
Progression-Free Survival Follow-up ...................................................47
7.7.2
Survival Follow-up................................................................................47
7.8
Comprehensive Metabolic Profile Assessment........................................47
8
Drug Formulation, Availability, Administration and Toxicity Information..........................48
8.1
Description, Supply and Storage of ibrutinib............................................48
8.1.1
Supply, Packaging and Storage...........................................................48

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Table of Contents
8.1.2
Dose and Administration ......................................................................48
8.1.3
Accountability .......................................................................................48
8.1.4
Precautions and Risks..........................................................................49
8.2
Gemcitabine.............................................................................................50
8.2.1
Drug Storage and Stability ...................................................................51
8.2.2
Drug Administration..............................................................................51
8.2.3
Side Effects ..........................................................................................51
8.3
Nab-paclitaxel (Abraxane) .......................................................................51
8.3.1
Drug Storage and Stability ...................................................................51
8.3.2
Drug Administration..............................................................................52
8.3.3
Side Effects ..........................................................................................52
9
Response Evaluations And Measurements.....................................................................52
10
Statistical Considerations ................................................................................................52
10.1
Study Design............................................................................................52
10.2
Study Endpoints.......................................................................................52
10.3
Pharmacodynamic (PD) Analysis ............................................................53
10.4
Exploratory Endpoints..............................................................................53
10.5
Randomization.........................................................................................53
10.6
Stratification .............................................................................................53
10.7
Missing Data and Replacement Policy ....................................................53
10.8
Interim Analyses and Stopping Rules......................................................53
10.9
Analyses Plans ........................................................................................53
10.10
Primary Analysis (or Analysis of Primary Endpoints)...............................53
10.11
Secondary Analysis (or Analysis of Secondary Endpoints) .....................54
10.12
Analyses of Exploratory Endpoints ..........................................................54
10.13
Evaluation of Safety.................................................................................56
11
Safety Reporting And Analyses.......................................................................................56
11.1
Adverse Events........................................................................................56
11.2
Serious Adverse Events...........................................................................58
11.3
Usage of Concurrent/Concomitant Medications ......................................64
11.3.1 Medications to be Used With Caution .................................................64
11.4
Dietary Restrictions..................................................................................64
12
Reporting and Documentation of Results........................................................................65
12.1
Evaluation of Efficacy (or Activity)............................................................65
12.1.1 Antitumor Effect – Solid Tumors .........................................................65
12.2
Evaluation of Safety.................................................................................66
12.3
Follow-up of Adverse Events ...................................................................66
12.4
Adverse Events Monitoring......................................................................66
12.5
Expedited Reporting ................................................................................66
13
Study Management .........................................................................................................67

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Table of Contents
13.1
Pre-study Documentation ........................................................................67
13.2
Institutional Review Board Approval ........................................................68
13.3
Informed Consent ....................................................................................68
13.4
Changes in the Protocol...........................................................................68
13.5
Handling and Documentation of Clinical Supplies ...................................68
13.6
Case Report Forms (CRFs).....................................................................68
13.7
Oversight and Monitoring Plan.................................................................69
13.8
Multicenter communication ......................................................................69
13.9
Record Keeping and Record Retention ...................................................69
13.10
Coordinating Center Documentation of Distribution ................................70
13.11
Regulatory Documentation ......................................................................70
14
Protection of Human Subjects .........................................................................................71
14.1
Protection from Unnecessary Harm.........................................................71
14.2
Protection of Privacy................................................................................71
References
79
Appendices
81
Appendix 1
Performance Status Criteria...............................................................................81
Appendix 2   New York Heart Association (NYHA) Classification of Cardiac Disease................82
Appendix 3
Guidelines for Women of Child-Bearing Potential..............................................83
Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ..........................84
Appendix 5
Data and Safety Monitoring Plan for a Multicenter Institutional Study (Phase 1 
Dose Escalation Institutional Study)............................................................................................89
Appendix 6
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational New Drug 
(IND)
92
Appendix 7
Data and Safety Monitoring Plan for Multicenter Institutional Study (Phase 2 or 3 
Institutional Study).......................................................................................................................94
Appendix 8
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND)...........................................................................................................................96
Appendix 9    Required Regulatory Documents for Sub-sites Participating in a UCSF Investigator 
Initiated Multicenter Trial (Checklist) ...........................................................................................98
Appendix 10
Inhibitors and Inducers of CYP3A ......................................................................99
List of Figures

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Table of Contents
Figure 1. Leukocytes in Human PDAC........................................................................................16
Figure 2.  B cells and FcRγ regulate PDAC ................................................................................17
Figure 3. Btk as a therapeutic target in PDAC ............................................................................18
List of Tables
Table 1.  Acquisition of Specimens and Analytical Procedures for Immunologic Studies...........26
Table 2.  Dose Escalation Schedule* ..........................................................................................33
Table 3.  Dose, Route and Schedule for Combination Therapy..................................................34
Table 4.  Ibrutinib Dose Modifications for the 1 week Ibrutinib-only Run In ................................37
Table 5.  Dose Reductions for Gemcitabine, Nab-paclitaxel, and Ibrutinib.................................37
Table 6. Day 1 Hematologic Dose Modifications for both Nab-Paclitaxel and Gemcitabine.......39
Table 7.  Day 8 and 15 Hematologic Dose Modifications for Nab-Paclitaxel andGemcitabine...39
Table 8. Day 1 Non-Hematologic Dose Modifications.................................................................41
Table 9.  Non-Hematologic Dose Modifications within a Cycle (Days 8 and 15) ........................41
Table 10. Dose Modifications for Hepatic Toxicities: Gemcitabine and nab-Paclitaxel...............43
Table 11. Schedule of Events and Procedures: Phase Ib Dose escalation and Safety Expansion
....................................................................................................................................................72
Table 12. Schedule of Events and Procedures: Immune Response Study.................................75

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1
Introduction
1.1
Background Current Treatment of Advanced Pancreatic Adenocarcinoma
Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related 
mortality in the United States, with an estimated 39,950 deaths attributable to PDAC in 2014 
(http://seer.cancer.gov/statfacts/html/pancreas.html). Over 90% of patients have inoperable 
disease at presentation, at which point systemic therapy becomes the primary form of 
treatment.
Treating PDAC has been challenging and few approved drugs are available. Recently, however, 
some breakthroughs have occurred, raising hope that this aggressive disease can be better 
controlled. FOLFIRINOX, a combination of 5FU, oxaliplatin, and irinotecan, has been found to 
be substantially superior to treatment of gemcitabine alone in patients with metastatic disease 
and good performance status [1].  Similarly, gemcitabine and nab-paclitaxel, a regimen with less 
non-hematologic toxicity, demonstrated improved overall survival and progression-free survival 
compared to gemcitabine alone [2].  Both of these combinations or modifications of these 
combinations are now front line options for patients with good performance status. Furthermore, 
these improvements in survival, however incremental, now afford patients with pancreatic 
cancer time to participate in and possibly benefit from clinical trials of novel therapeutics. 
1.2
Immunotherapy for Pancreatic Adenocarcinoma
Immunotherapy—recruiting a patient’s immune system to recognize and destroy malignant cells 
and control their spread—has been an ideal pursued by clinical researchers for decades.  
However, there have been very few clinical successes in the treatment of solid tumors with 
immunotherapeutic agents such as tumor-specific (TSA) and tumor-associated antigen (TAA) 
vaccines, cytokines, interleukins and other immune-modulators.  One explanation for the lack of 
success for patients with pancreatic cancer may be that global depression of the immune state 
is a characteristic of the disease—this is supported by reports of depressed or anergic immune 
responses to both common and tumor antigens in PDAC patients [3, 4].  And yet there have 
also been reports of pre-existing or natural functional tumor-reactive T cells in the peripheral 
blood and bone marrow of PDAC patients [5-7].  Furthermore, responses to tumor antigens, 
i.e.anti-TAA antibodies or TAA-reactive T-cells, have been detected in the peripheral blood of 
PDAC patients treated with tumor-derived vaccines, and in some cases these responses appear 
to correlate with better outcomes [8-10].  However, significant improvements in patient survival 
have yet to be confirmed in randomized well-controlled clinical trials.
It is now widely appreciated that the stromal environment of pancreatic tumors and other solid 
tumors is highly immune-suppressive relative to normal tissue.   There is a greater density of the 
immune suppressive FOXP3+ regulatory T cells (Tregs) in the human pancreatic  tumor infiltrate 
compared to normal pancreatic tissue [11-13].  While T cells comprise the majority of the tumor 
infiltrate, surprisingly, the most prevalent are CD8+ T cells of the antigen-experienced effector 
phenotype, capable of producing IFN-γ once removed from the influence of the regulatory 
factors of the tumor stroma [14].  The presence of FOXP3+Tregs as well as Th17 and myeloid-
derived suppressor cells in the PDAC stroma [14] suggests that there are several immune 
suppressive mechanisms and checkpoints protecting pancreatic tumor cells from destruction.  
Checkpoint-directed therapies such as ipilimumab (CTLA-4) and nivolumab (PD-1) have been 
evaluated clinically and have shown activity in other solid tumors, but none have demonstrated 
efficacy in PDAC cohorts as single-agents [15, 16].  Making headway in the treatment of PDAC 

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will most likely require combination therapies with check-point inhibitors, vaccines and other 
agents designed to alter the immune program of the tumor-associated stroma [8, 17-19].
1.3
Rationale for Targeting Regulatory B Cells in Treating Pancreatic Cancer
Preliminary preclinical data indicate that B cells may play an important pro-tumor role in PDAC.  
It was previously reported that B cells promote squamous cell carcinogenesis (SCC) via Fcγ 
receptor-dependent activation of tumor-infiltrating myeloid cells, mediated by immunoglobulin 
(Ig)-containing immune complexes deposited in (pre)malignant tissue [20, 21].  More recently, 
the same model was used to evaluate this neoplastic cell-extrinsic pathway as an anti-cancer 
target using B-cell depleting αCD20 monoclonal antibodies. In prevention and intervention 
mouse models, neoplastic progression stopped at an early hyperplastic stage subsequent to B 
cell depletion [22].  
The presence of B cell infiltration in human PDAC has been confirmed ex vivo (Coussens, et 
al.manuscript in preparation) (Figure 1): tumor tissue analyzed by Affymetrix U133 Plus 2 
microarrays and by immunohistochemical methods exhibited the molecular and histopathologic 
characteristics of B cell or plasma cell infiltration, i.e. increased expression of CD20 or Ig mRNA 
in tumor lysates, as well as a significantly increased presence of CD20-positive B cells in tumor 
relative to normal pancreas in tissue sections. Furthermore, the density of B cell infiltration 
significantly correlated with decreased overall survival.  
Figure 1. Leukocytes in Human PDAC
To investigate the B-cell specific contribution to PDAC tumor growth in vivo, B cell- and/or FcγR-
deficient mice were assessed for their ability to support growth of syngeneic orthotopic PDAC 

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(Figure 2).  Growth of PDAC tumors in mice homozygous for FcγR deficiency was significantly 
attentuated compared to the the tumors in their wild-type and heterozygous littermates. 
Moreover, αCD20 mAb-mediated B cell depletion slowed growth of preexisting PDACs.  
Macrophages isolated from PDAC tumors of αCD20 mAb -treated mice displayed 
characteristics indicative of functional type 1 re-education, concomitant with an increased 
presence of CD8+ T cells (data not shown). These data indicate that B cells, and the 
downstream myeloid-based pathways they regulate, represent tractable targets for anti-cancer 
therapy, and suggest that the immune TME in susceptible solid tumors can be effectively re-
educated to promote productive anti-tumor immune responses. 
Figure 2.  B cells and FcRγ regulate PDAC
1.4
Rationale for Targeting Bruton’s Tyrosine Kinase with Ibrutinib to Alter TME of 
PDA
Normal and malignant B cells are dependent on functional Bruton’s tyrosine kinase (Btk) for 
activation, maturation and survival.  Coussins et al evaluated the presence of active Btk (pBtk) 
in immune cells infiltrating orthotopic murine PDAC tumors by flow cytometry, and 
immunohistochemically in human PDAC tissue sections (Figure 3A and B).  Results from these 
studies indicate that pBtk is present in B cells and myeloid cells of murine and human PDAC. 
Based on these results, mice harboring syngeneic orthotopic PDAC at late-stage were treated  
with an FDA-approved BTK inhibitor (BTKi) (PCI-32765, ibrutinib) as monotherapy and in 
combination with gemcitabine, which resulted in significant reductions in tumor burden at end 
stage (Fig. 3C). Moreover, treatment of KPC transgenic mice predisposed to de novo pancreatic 
carcinogenesis with ibrutinib plus gemcitabine lead to significantly improved OS as compared to 
gemcitabine alone (Fig. 3D). By using a CD8+ T cell-depleting mAb, it was revealed that 
improved outcomes of mice treated with ibrutinib/gemcitabine are dependent on CD8+ T cells 
(Fig. 3E).

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Figure 3. Btk as a therapeutic target in PDAC
Inhibition of Btk has additional immune effects which have the potential to translate into anti-
tumor activity. Btk plays a critical role in inducible degranulation of Mast Cells [23], a process 
which has been shown to promote stromal changes that contribute to neoplastic transformation 
and tumor neoangiogenesis [24].  Systemic treatment with ibrutinib blocks mast cell 
degranulation in vivo, triggering collapse of tumor vasculature as well as tumor regression in 
insulinoma-bearing mice [24].  In another preclinical model (Massó-Vallés, et al, submitted 
manuscript), pancreatic ductal adenocarcinoma (PDAC)-bearing mice treated with Ibrutinib 
survived longer and presented with reduced tumor stroma, suggesting that targeting Mast Cells 
in patients with pancreatic cancer may positively alter the stromal architecture that protects and 
supports the growth of tumor tissue.    
Ibrutinib also targets structural homologues of Btk, and has been shown to irreversibly bind and 
inhibit interleukin 2-inducible T cell kinase (ITK)[25].  Activated ITK is implicated in maintaining 
dysregulated Th2-biased immunosuppression of T cell-mediated anti-tumor responses. 
Inhibition with ibrutinib selectively reversed Th2 bias to favor activation of Th1 t cells, further 
augmenting the immunotherapeutic effect.
1.5
Rationale of Combining Ibrutinib with Gemcitabine and nab-Paclitaxel
Gemicitabine plus nab-paclitaxel is currently one of the two standard 1st line treatments for 
PDAC, and is regarded as a less toxic and more tolerable regimen than the combination 

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chemotherapy FOLFIRINOX. Clinically, gemcitabine may be the chemotherapeutic of choice for 
combination with immunotherapeutics: Treating PDAC patients with single agent gemcitabine 
does not appear to significantly alter the absolute number of functional CD8 and CD4 T cells, B 
cells or dendritic precursors in the peripheral blood, although a decrease in the number of 
memory T-cells and an increase in naïve T-cell activation was observed [26] and;  treatment 
with gemcitabine-based therapies was reported to significantly decrease both the percentage 
and number of Tregs in the peripheral blood while having no effect on the number and function 
of other immune cells[27] [28].  Adding nab-paclitaxel to gemcitabine significantly extends 
survival, providing PDAC patients much needed time to mount effective anti-tumor responses, 
and pre-clinical studies suggest that nab-paclitaxel may accelerate depletion of the PDAC tumor 
stroma which supports tumor growth and immune tolerance [29]. The ability of Btk inhibitors to 
reprogram B cells and to block activation of signaling pathways downstream of Btk in both B 
cells and myeloid cells suggests that combining ibrutinib with gemcitabine and nab-paclitaxel to 
treat patients with PDAC may promote an anti-tumor immune response in the clinical setting.
1.6
Ibrutinib
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling 
pathways and thus prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases.  
Ibrutinib (IMBRUVICA®) is approved by the US Food and Drug Administration (FDA) for the 
treatment of : 1) mantle cell lymphoma (MCL) in patients who have received at least one prior 
therapy, 2) chronic lymphocytic leukemia (CLL) , and 3) Waldenström’s Macroglobulinemia..  
Ibrutinib is currently under investigation in various indications.  
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to antigen.  
Antigen binding induces receptor aggregation and the clustering and activation of multiple 
tyrosine kinases, which in turn activate further downstream signaling pathways [30]. 
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from mutations 
and translocations acquired during normal B-cell development [31].  Several lines of evidence 
suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies.  
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease X-
linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by reduced BCR signaling and failure to generate mature B-cells.  The BTK 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells [32].  
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from the 
plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain maximal 
pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg. In Study PCYC-
04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 560 

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mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration.
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to the 
latest version of the ibrutinib Investigator's Brochure.
1.7
Summary of Non-Clinical Data
For the most comprehensive nonclinical information regarding ibrutinib, refer to the current 
version of the Investigator's Brochure
1.7.1
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)  
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to 
the current Investigator’s Brochure. For additional information, see FDA’s Guidance Definitions 
for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories and CTEP’s Guidelines for Correlative Studies in Clinical Trials.  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.  
1.7.2
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with ibrutinib.

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Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs.
1.8
Summary of Clinical Data
For the most comprehensive clinical information regarding ibrutinib, refer to the current version 
of the Investigator's Brochure.
1.8.1
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. Taking into account the approximate doubling in mean systemic exposure 
when dosed with food and the favorable safety profile, ibrutinib can be dosed with or without 
food. Ibrutinib is extensively metabolized primarily by cytochrome P450 (CYP) 3A4. The on-
target effects of metabolite PCI-45227 are not considered clinically relevant. Steady-state 
exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure. Less than 1% of 
ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with creatinine clearance 
(CrCl) >30 mL/min. Patients with severe renal impairment or patients on dialysis have not been 
studied. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-
fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe 
(Child-Pugh class C) hepatic impairment compared to subjects with normal liver function.  A 
higher proportion of Grade 3 or higher adverse reactions were reported in patients with B-cell 
malignancies (CLL, MCL and WM) with mild hepatic impairment based on NCI organ 
dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction compared to patients 
with normal hepatic function.  
1.8.2
Summary of Clinical Studies Evaluating the Safety and Efficacy of Ibrutinib
A brief summary of safety data from monotherapy and combination therapy studies is provided 
in below. For more comprehensive safety information please refer to the current version of the 
IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC). 
1.8.2.1 Monotherapy Studies
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below. 

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Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071):
Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Febrile neutropenia
Cough
Anemia
Pyrexia
Anemia
Hypertension  
Pyrexia
Atrial fibrillation
Neutropenia 
For more detailed information refer to the current version of the IB.
1.8.2.2 Combination Therapy Studies
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below. Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone). 
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423):
Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Neutropenia
Neutropenia
Febrile neutropenia
Diarrhea
Thrombocytopenia
Pneumonia
Nausea
Febrile neutropenia
Atrial fibrillation
Thrombocytopenia
Pneumonia
Pyrexia
Fatigue
Hypertension 
For more detailed information refer to the current version of the IB.
1.8.3
Treatment Discontinuations
As of 6 April 2013, 71/636 subjects discontinued treatment due to an adverse event, across the 
monotherapy and combination therapy ibrutinib studies (excluding Study PCYC-1103-CA); 62 
subjects receiving monotherapy population and 9 subjects receiving combination therapy.  The 

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most frequently reported adverse events that led to treatment discontinuations were pneumonia 
(13 subjects), respiratory failure (4 subjects), and cardiac arrest and Richter’s Syndrome (3 
subjects each).  
1.8.4
Bleeding-related events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. 
1.8.5
Cardiac
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 with a history of cardiac arrhythmias should be monitored closely.
1.8.6 Rash
Mild to moderate rashes have been observed with ibrutinib alone or in combination with other 
drugs. A single case of Stevens-Johnson Syndrome (SJS) was reported in a male subject with 
CLL treated with ibrutinib 420 mg/day. The subject was also receiving multiple concomitant 
medications known to be associated with SJS. Subjects should be monitored closely for signs 
and symptoms suggestive of SJS.
1.8.7 Non-Melanoma Skin Cancer
Non‑melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
for the appearance of non‑melanoma skin cancer.
1.8.8
Infections
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE v4.02). The most commonly reported 
infections include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has 
not been established, cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib.
1.8.9 Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) 
were reported in subjects treated with ibrutinib. 
1.8.10 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.

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1.8.11 Lung Disease (ILD)
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD. Should symptoms develop follow the 
protocol dose modification guidelines.
1.8.12 Ongoing Combination Clinical Studies in Solid Tumors*
Three sponsored clinical trials of ibrutinib in are reported in the 2016 Ibrutinib Investigator’s 
Brochure (version 10, 29 August 2016*).  Included in the listing below is a phase 2/3, 
randomized, placebo-controlled, study of ibrutinib or placebo in combination with nab-paclitaxel 
and gemcitabine in 1st line treatment of metastatic pancreatic adenocarcinoma. The safety run-
in of 6 subjects at the 560 mg/day dose was completed without DLTs.  As of August 2016, at 
least 100 subjects have been randomized to receive either ibrutinib or placebo with nab-
paclitaxel and gemcitabine.  
Study 
Number
Description
Number of 
Subjects 
Planned/Exposeda
Study Drug(s); Dose Regimen; 
Duration of Treatment
Enrollment/Study 
Statusb
Solid Tumors
1135
Phase 1b/2, open-
label study of the 
safety and efficacy 
ibrutinib + 
MEDI4736 in 
subjects with solid 
tumors.
Phase 1b: 6-36/6
Phase 2: 130/111
ibrutinib capsules (oral)
Cohort 1: 560 mg or 420 mg daily 
in combination with MEDI4736 at 
10 or 3 mg/kg IV q2 weeks in 28-
day cycles until DLT or disease 
progression
Enrolling/Ongoing
1137
Phase 2/3, double-
blind, randomized, 
placebo-controlled, 
study of 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
326/106
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.
Enrolling/Ongoing

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Study 
Number
Description
Number of 
Subjects 
Planned/Exposeda
Study Drug(s); Dose Regimen; 
Duration of Treatment
Enrollment/Study 
Statusb
1128
A Phase 1b/2 Study 
of Ibrutinib 
Combination 
Therapy in 
Selected Advanced 
Gastrointestinal 
and Genitourinary 
Tumors
189/3
Phase 2 - recommended Phase 2 
Dose established in Phase 1b for 
ibrutinib (840 mg, 700 mg, or 560 
mg) PO daily, in combination with 
specified anticancer agent, will be 
given in 21-day cycles until 
disease progression or 
unacceptable toxicity.
Anticancer agents:
RCC - everolimus:10 mg PO qd
Urethelial - paclitaxel:80 mg/m2 IV 
qweek
Gastric - docetaxel:75 mg/m2 IV 
q3weeks
CRC - cetuximab:400 mg/m2 IV, 
then 250 mg/m2 qweek
Enrolling/Ongoing
2
Objectives of the Study
2.1
Phase Ib
Primary Objective:

To determine the maximum tolerated dose of ibrutinib in combination with albumin 
bound paclitaxel and gemcitabine in patients with metastatic pancreatic adenocarcinoma 
Secondary Objectives:

To evaluate the safety of treatment with ibrutinib in combination with nab-Paclitaxel and 
gemcitabine in patients with metastatic pancreatic adenocarcinoma.

To evaluate the potential drug-drug interaction of ibrutinib in combination with nab-
paclitaxel and gemcitabine in patients with metastatic pancreatic adenocarcinoma.

To clinically assess the anti-tumor effects of treatment with ibrutinib in combination with 
nab-Paclitaxel and gemcitabine. 
2.2
Immune Response Cohort
Primary Objectives:

To monitor the changes in the patients' immune profiles during treatment with ibrutinib, 
alone and in combination with gemcitabine and nab-paclitaxel, in the pancreatic tumor 
micro-environment (TME) and in the peripheral blood.

To confirm the pharmacodynamics of ibrutinib at dosing level 560 mg/day

To explore the relationships between the pharmcodynamics of ibrutinib in combination 
with nab-paclitaxel and gemcitabine and response prediction biomarkers in patients with 
metastatic pancreatic adenocarcinoma.

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Secondary Objectives:

To verify and confirm the safety of ibrutinib in combination with nab-Paclitaxel and 
gemcitabine in patients with metastatic pancreatic adenocarcinoma.

To estimate the CA19-9 clinical response rate of patients with metastatic pancreatic 
adenocarcinoma treated with ibrutinib in combination with nab-Paclitaxel and 
gemcitabine.

To estimate the Progression-Free Survival (PFS),Time-to-Progression (TTP), and 
Overall Survival (OS) of patients with metastatic pancreatic adenocarcinoma.treated with 
ibrutinib in combination with nab-paclitaxel and gemcitabine.
2.3
Exploratory Objectives, Other Assessments
Immunologic studies will explore immune responses in the peripheral blood and the PDAC 
tumor micro-environment (TME).  
Table 1.  Acquisition of Specimens and Analytical Procedures for Immunologic Studies
Timepoint
Specimen
Analyses
At Baseline and 
after 1 wk run-in 
Ibrutinib-only for 
Immune 
Response cohort 
only.
EUS guided biopsy tissue
Qualitative immunohistological assessment of 
immune cell subsets, i.e, T effectors, Tregs, NK 
cells, myeloid subsets, B cells; Expression of 
immune checkpoint targets such as PD-1 and 
PD-L1, and CD40+ cells; distribution of Btk and 
p-Btk.
Baseline, 
monthly for the 
first 3 cycles, 
then every 3 
months 
EDTA Plasma
Blood based biomarkers quantified by Luminex 
technology for changes in 30 cytokines over 
time; Assessment of cell-free DNA
Baseline, 
monthly for the 
first 3 cycles, 
then every 3 
months
PBMC 
Flow cytometry-based immune phenotyping 
and quantification; Functional T-Cell responses  
to mitogens and candidate tumor antigens 
(tetramer analysis);  Deep sequencing to detect 
specific T cell and B-cell receptor clones; 
Quantitative evaluation of gene and/or protein 
expression patterns of peripheral blood myeloid 
cells.
3
Study Design
3.1
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 

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about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
3.1.1
Inclusion Criteria
1.
Histologically or cytologically confirmed pancreatic adenocarcinoma
2.
Stage IV disease (measurable disease NOT required)
3.
Intact primary tumor (for Immune Response Cohort only)
4.
ECOG performance score of 0-1
5.
At least 18 years of age
6.
Female patients who are not of child-bearing potential, and fertile female patients 
of child-bearing potential who agree to use adequate contraceptive measures, 
who are not breastfeeding, and who have a negative serum or urine pregnancy 
test within 72 hours prior to start of randomization.
7.
Fertile male patients willing to use adequate contraceptive measures.
8.
Adequate bone marrow function: 
•
Absolute neutrophil count (ANC) ≥ 1500/uL
•
platelet count ≥ 100,000/uL 
•
hemoglobin ≥ 9.0 g/dL 
9.
Adequate hepatic function:

Total bilirubin ≤ 1.5 X ULN  (unless bilirubin rise due to Gilbert’s syndrome)

AST ≤ 3.0 X ULN (≤5.0X ULN if liver metastases are present.)

ALT ≤ 3.0 X ULN (≤5.0X ULN if liver metastases are present.)
10.
Adequate renal function (defined as serum creatinine ≤ 1.5 X ULN)
11.
Ability to understand the nature of this study protocol, comply with study and/or 
follow-up procedures, and give written informed consent
12.
Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures.
13.
The calculated QTcF average of the triplicate ECGs must be <470 msec.

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3.1.2
Exclusion Criteria
1.
Any prior systemic or investigational therapy for metastatic pancreatic cancer.  
Systemic therapy administered alone or in combination with radiation in the 
adjuvant or neoadjuvant setting is permissible as long as it was completed > 6 
months prior to the time of study registration.
2.
History of other diseases, metabolic dysfunction, physical examination findings, 
or clinical laboratory findings giving reasonable suspicion of a disease or 
condition that, in the opinion of the investigator, renders the subject at high risk 
from treatment complications or might affect the interpretation of the results of 
the study. 
3.
History of previous malignancy (except in-situ cancer or basal or squamous cell 
skin cancer) within past 3 years.
4.
Life expectancy of <3 months.
5.
Inability to undergo two sequential EUS-directed core biopsies of the primary 
tumor (for Immune Response Cohort only).
6.
Presence of known central nervous system or brain metastases.
7.
Known human immunodeficiency virus (HIV) infection.
8.
History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
9.
Known bleeding disorders (e.g., van Willebrand’s disease or hemophilia).
10.
Patients receiving warfarin or other Vitamin K antagonists.  However, if 
therapeutic anticoagulation is necessary, LMWH is the anticoagulant of choice.
11.
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.
12.
Current peripheral sensory neuropathy > Grade 1
13.
Major surgery within 4 weeks of the start of study treatment (defined as those 
surgeries that require general anesthesia.  Insertion of a vascular access device 
is NOT considered major surgery. 
14.
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
15.
Unable to swallow capsules or has 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.
3.1.3
Duration of and Discontinuation from Protocol Therapy
Patients will be treated until disease progression, or will be discontinued from protocol treatment 
for any of the following reasons:
•
Documented disease progression

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•
Irreversible or intolerable toxicity or clinically significant abnormal laboratory values 
thought to be related to drug toxicity (per section 6.2)
•
Patient requests to withdraw from the trial or discontinue treatment
•
Treatment-related toxicities that require a delay in scheduled dosing for ≥21 days*
•
Documented symptomatic deterioration defined as global or severe deterioration of 
health status such that it requires discontinuation of trial treatment without evidence of 
disease progression at that time.
•
Inability of the patient to comply with trial requirements or lost to follow-up
•
Conditions requiring a therapeutic intervention not permitted by the protocol
•
Intercurrent illness (this will be at the investigator’s discretion)
*In the event that a drug must be held for intolerability (ie neuropathy for nab-paclitaxel or rash 
for gemcitabine) for more than 21 days, patients may continue on study receiving the other 
drugs, including ibrutinib.
After discontinuation from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of study drug.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the investigator, these values are 
not likely to improve because of the underlying disease.  In this case, the investigators must 
record his or her reasoning for this decision in the patients’ medical records and as a comment 
on the Case Report Form (CRF).
All patients who have Grade 3 or 4 laboratory abnormalities (Common Terminology Criteria for 
Adverse Events [CTCAE] v 4.03) at the time of discontinuation must be followed until the 
laboratory values have returned to Grade 1 or 2, unless it is, in the opinion of the investigator, 
not likely that these values are to improve.  In this case, the investigator must record his or her 
reasoning for making this decision in the patients’ medical records and as a comment on the 
CRF.
3.1.4
Pregnancy
During the course of the study, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix 3)  must contact the treating 
investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period).  
If an investigator suspects that a patient may be pregnant prior to administration of study 
drug(s), the study drug(s) must be withheld until the result of the pregnancy test is confirmed.  If 
a pregnancy is confirmed, the patient must not receive any study drug(s), and must be 
discontinued from the study.  
If an investigator suspects that a patient may be pregnant after the patient has been receiving 
study drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy 
test is confirmed.  If a pregnancy is confirmed, the study drug(s) must be immediately and 
permanently stopped, the patient must be discontinued from the study, and the investigator 
must notify.  If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a 

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paper report form) should be completed.  For more details regarding handling and reporting of 
pregnancies that occur during treatment, see Section 11.4.  
4
Trial Registration
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks and 
discomforts.  Human protection committee approval of this protocol and consent form is 
required.  
5
Treatment Plan
This is a phase Ib/Immune Response study of ibrutinib in combination with nab-paclitaxel and 
gemcitabine in the management of patients with metastatic pancreatic adenocarcinoma. 
The objective of the phase Ib is to confirm the safety and toxicity of the combination of 
gemcitabine, nab-paclitaxel and ibrutinib in the management of patients with metastatic 
pancreatic adenocarcinoma.  In the first part of phase Ib, 15-30 patients will be enrolled in 3+3 
dose escalation cohorts to evaluate the safety of up to four doses of ibrutinib (280 mg, 420 mg, 
560 mg, and 840 mg QD), doses previously shown to be safe in healthy subjects and safe and 
effective in the management of patients with CLL and MCL. The first dosing cohort of 3 patients 
will receive 560 mg QD of ibrutinib in combination with gemcitabine and nab-paclitaxel.  Dose 
escalation will proceed to 840 mg QD unless a dose limiting toxicity is identified, in which case 3 
additional patients will receive 560 mg QD.  If 2 or more of 6 patients experience a DLT at 560 
mg QD, dosing will de-escalate to 420, and to 280 mg QD if necessary.  The dose level at which 
fewer than 2 of 6 patients experience a DLT will be designated as the Maximum Tolerated Dose 
(MTD). 
All patients in phase Ib will start treatment with daily dosing of ibrutinib concurrently with 
standard doses of gemcitabine and nab-paclitaxel. A cycle is defined as 28 days.  Ibrutinib (560 
mg/day, 840 mg/day, or 420 and 280 mg/day if de-escalation is necessary) will be started on 
day 1.  Gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) will be given day 1, 8 and 
15 of each cycle. Since grade 4 hematologic adverse events are expected based on prior 
experience with gemcitabine and nab-paclitaxel, and support with colony stimulating factor will 
be allowed.  
Once the safety of the combination therapy is verified at the MTD, 20 patients will be enrolled in 
into the Immune Response Study. The objectives of the Immune Response Study are to assess 
the immunologic responses to and pharmacodynamics effects of pretreatment with ibrutinib 
alone.  To address these objectives, the 20 patients  will be enrolled, and will undergo two EUS-
guided biopsies, one before and one after one week of treatment with ibrutinib-only, after which 
the patients begin the combination treatment regimen.  Patients in the Immune Response study 
will be treated with 560 mg/day, unless 420 mg/day or 280 mg/day ibrutinib is determined to be 
the MTD in phase Ib. 
In both study phases and treatment cohorts, treatment effect will be monitored every 28 days by 
clinical exam and CA 19-9. CT scans will be performed every other 28 day cycle and tumor 
measurements will be assessed using standard RECIST criteria.  Patients will continue on 
treatment until clinical or radiographic evidence of disease progression or until tolerance to 
treatment has been exceeded. 

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5.1
Study Schema
 

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5.1  Study Schema (cont’d)
 

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5.2
Dosage and administration of Ibrutinib
Treatment will be administered on an outpatient basis.
Table 2.  Dose Escalation Schedule*
Dose Level
Dose of Study Drug
Minimum Number of 
Patients
1
560 mg/d
3
2
840 mg/d
6
*Daily dosing in combination with nab-Paclitaxel at 125mg/m2 and Gemcitabine at 1000mg/m2 IV 
on day 1, 8, and 15.  If a dose is not taken at the scheduled time, it can be taken as soon as 
possible on the same day. 
5.2.1
Phase Ib Dose escalation
No more than two dose levels of ibrutinib will be evaluated in dose escalation.  If a DLT is 
identified at the 840 mg/d level, then 3 more patients will receive ibrutinib at the 560 mg/d dose 
to confirm that dosage as the maximum tolerated dose.  
Patients within a given dose cohort may be enrolled concurrently given the well-established 
safety profile of ibrutinib and non-overlapping toxicities with chemotherapy. Although the safety 
profile of gemcitabine/nab-paclitaxel plus ibrutinib (560 mg daily) has been established on a 
separate, currently enrolling, company-sponsored phase II/III trial of this combination in 
pancreatic cancer, the patients in the 840 mg/day dose cohort cannot be enrolled until the 
DSMC has completed the monitoring of the 560 mg/day cohort dose level patients and there is 
DSMC Chair approval for dose escalation to the next dose level (840 mg/day).
If DLT is identified at the 560 mg/d dose level (2 or more DLTs out of 6 patients dosed), a 
dosing de-escalation will begin at the 420 mg/d dose.  The lowest acceptable dose level is 280 
mg/d. 
5.2.2
Dose Limiting Toxicity
(DLT) will be defined as any unexpected grade 3 non-hematologic toxicity not reversible to 
grade 2 or less within 96 hours, or any grade 4 toxicity. Grade 4 hematological toxicities will not 
be considered dose limiting in this trial since a significant fraction of patients who are treated 
with gemcitabine and nab-paclitaxel are expected to experience these toxicities.  Likewise, 
grade 3 peripheral neuropathy, a common and expected toxicity of treatment with nab-
paclitaxel, will not be considered a DLT.  DLT will be based on the first course of treatment.
Toxicity will be graded according to the NCI CTCAE version 4.03. To be evaluable for toxicity, a 
patient must receive at least one dose of any component of study therapy (ibrutinib, 
gemcitabine, or nab-paclitaxel). All patients enrolled are to be fully followed for DLT, and any 
patients who are not evaluable for toxicity will be replaced. 

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The maximum tolerated dose of ibrutinib will be that dose at which fewer than one-third of 
patients experience a dose limiting toxicity.  If multiple toxicities are seen, the presence of dose 
limiting toxicity should be based on the most severe toxicity experienced.
5.2.3
Combination Therapy for Phase Ib and Immune Response cohorts
All patients in the Phase Ib safety and dose expansion and in Immune Response Study will 
received ibrutinib with nab-paclitaxel and gemcitabine in cycles of approximately 28 days in 
length. Nab-paclitaxel and gemcitabine are administered intravenously on days 1, 8 and 15 of 
each cycle.
Table 3.  Dose, Route and Schedule for Combination Therapy
Study Drug
Dose
Route
Schedule
Cycle 
Length
Ibrutinib
560, 840, 
420, or 280  
mg
Oral
Continuous 
daily dosing
Nab-
Paclitaxel
125 mg/m2
Intravenous
Days 1, 8, 
and 15 
Gemcitabine
1000 
mg/m2
Intravenous
Days 1, 8, 
and 15 
4 weeks 
(28 days)
5.2.4
One week run-in with Ibrutinib-only for the Immune Responses Study Cohort
Ibrutinib will be taken orally once per day during a 7 day run-in.  Due to increased risk of 
bleeding when taking ibrutinib, Day 1 of the run-in will begin no earlier than 5 days after the 
pretreatment biopsy.  Likewise, the post-run-in biopsy should be performed no earlier than 5 
days after the last dose of the 7 day run-in treatment period.  First infusions of gemcitabine and 
nab-paclitaxel may commence within 1-5 days after the post-run-in biopsy, but ibrutinib must be 
held until 5-7 days post-biopsy.
5.3
Study Treatment phase
Each treatment cycle generally is 28 days in length.  Treatment may be administered +/-2 days 
of the scheduled date without constituting a protocol violation.  Following the 1 week run-in with 
ibrutinib in the Immune Response cohort, the combination therapy treatment cycles will begin no 
earlier than 5 days after the 2nd biopsy, in 28-day cycles.  
Treatment may be administered +/-2 days of the scheduled date without constituting a protocol 
violation.  Ibrutinib is taken once daily; Nab-paclitaxel and gemcitabine are administered on Day 
1, 8, and 15 of each cycle.  Patients will continue 28 day treatment cycles until disease 
progression or until other reasons for discontinuation from treatment.
Ibrutinib: 560, 840, 420, or 280 or  mg, orally once per day:

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All doses of ibrutinib will be supplied by Pharmacyclics and dispensed by the Investigational 
Pharmacist or designee, and self-administered on an outpatient basis.  Each dose should be 
taken with approximately 8 ounces of water at the same time each day. 
Nab-Paclitaxel:  125mg/m2 IV Day 1, 8, and 15:  
Infuse over approximately 30-40 minutes or according to institutional standards.
Gemcitabine:  1000mg/m2 IV Day 1, 8, and 15:
Infuse over approximately 30 minutes or according to institutional standards within following the 
completion of the nab-paclitaxel.
5.4
Restaging During the Combination Therapy Treatment Phase
Restaging by CT scans per RECIST version 1.1 (see Appendix 4) will occur every 2 cycles.
5.5
Assessments for Exploratory Endpoints
Immunologic studies will explore immune responses in the peripheral blood and the PDAC 
tumor micro-environment (TME).  The biopsy specimen, blood and serum samples will be 
collected at baseline and various key times during the course of treatment will be evaluated.  
Peripheral blood lymphocytes at each pre- and post each vaccination time-points will be 
collected and analyzed at USCF, OHSU, and UCSD.  
Biopsy analyses will include: qualitative assessment of immune cell subsets such as T effectors, 
Tregs, NK cells, myeloid subsets, B cells and expression of immune checkpoint targets such as 
PD-1 and PD-L1, and CD40+ cells.  
Blood-based biomarkers, and serum will be analyzed by Luminex technology for changes in 30 
cytokines over time.  Quantitative and avidity evaluation of tumor infiltrating and peripheral blood 
mesothelin, Kras, and patient-specific mutation antigen-specific T cells will be analyzed.  
PBMC will undergo flow cytometry-based immune phenotyping and quantification.  T cells will 
be isolated for functional responses to mitogens as well as antigen specific functional responses 
to candidate pancreatic cancer antigens such as mesothelin or Kras using available peptide 
libraries and pMHC tetramers in response to treatment.  
DNA isolated from PBMCs and tissue will be analyzed by deep sequencing to detect and track 
specific T cell and B cell receptor clones.  Gene and/or protein expression of circulating myeloid 
cells will be quantitatively evaluated.  All biopsies in the safety and efficacy portion of the study 
will be assessed by IHC.  Findings will be correlated with clinical endpoints.  
5.6
General Concomitant Medication and Supportive Care Guidelines
All concomitant medications taken during the study will be documented in the CRF with the 
indication, dose information, and dates of administration.

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•
Patients should receive full supportive care during the study, including transfusion of 
blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrheals, 
analgesics, erythropoietin, or bisphosphonates, when appropriate. 
•
Alternatives should be sought for strong and moderate CYP3A inhibitors.
•
Primary prophylaxis with granulocyte colony stimulating factors (G-CSF) is not allowed 
but G-CSF may be used during the course of treatment per ASCO guidelines and the 
dose modification guidelines in Table 6 below if severe cytopenias develop.
Antiplatelet Agents and Anticoagulants

Low molecular weight (LMW) heparin may be used as an anticoagulant for 
thromboembolic events during the study.  NOTE:  receiving coumadin is an exclusion 
criterion and is not permitted on study.
Coumadin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided.  Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. For subjects requiring the 
initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), consider the risks and 
benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is clinically indicated, 
treatment with ibrutinib should be held and not be restarted until the subject is clinically stable 
and has no signs of bleeding. Subjects should be observed closely for signs and symptoms of 
bleeding. No dose reduction is required when study drug is restarted..
•
No other investigational therapy should be given to patients.  No anticancer agents other 
than the study medications administered as part of this study protocol should be given to 
patients.  If such agents are required for a patient, then the patient must first be 
withdrawn from the study.
6
Dose Modifications and Dosing Delays
6.1
Dose Modifications of Ibrutinib for the Immune Response cohort
The following dose modifications of ibrutinib apply to the subjects who are enrolled in the 
Immune Response cohort only, during the 1 week run-in of ibrutinib only. The dose of study 
drug 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 5.6 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, despite optimal anti-emetic 
and/or anti-diarrheal therapy. 

Any other Grade 4 or unmanageable Grade 3 toxicity. 

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Table 4. Ibrutinib Dose Modifications
Occurrence 
Action to be Taken 
First 
Withhold study drug until recovery 
to Grade ≤1 or baseline; may 
restart at original dose level 
Second 
Withhold study drug until recovery 
to Grade ≤1 or baseline; may 
restart at 1 dose level lower (ie, 
280 mg/day for 420 mg/day dose; 
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, 
140 mg/day for 420 mg/day dose; 
280 mg/day for 560 mg /day dose ) 
Fourth 
Discontinue study drug 
6.2
Dose Modifications for Dose Escalation and Immune Response Cohorts during 
Combination Therapy
Treatment cycles are fixed at 28 days in length.  If neither of the chemotherapies (gemcitabine 
or nab-paclitaxel) can be administered on Day 1 of a new cycle (due to toxicity or any other 
reason), that new cycle will not be considered to start until the day that one or both of the 
chemotherapies is administered to the patient. If the start of a new cycle is postponed due to 
toxicities, the day 1 procedures for that cycle do not need to be repeated at the time of resuming 
treatment, except for any relevant blood tests that caused that cycle to be postponed in the first 
place. 
Missed doses of any/all components of treatment on Days 8, 15 and 22 of a cycle will not be 
made up; i.e., cycle length will not be extended beyond 28 days. Example: On day 15 of a cycle, 
if gemcitabine and nab-paclitaxel are held due to hematologic toxicity, ibrutinib may be given as 
deemed appropriate.  On Day 22, even if counts have recovered, treatment per protocol on that 
day would consist only of Day 22 ibrutinib; the gemcitabine/nab-paclitaxel would not be ‘made 
up’ on that day.  Treatment with all study components would resume on Day 1 of the next cycle.
Brief treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation but should be recorded in CRF.  
Table 5.  Dose Reductions for Gemcitabine, Nab-paclitaxel, and Ibrutinib
Gemcitabine
Nab-paclitaxel
Ibrutinib
Starting dose level
1,000 mg/m2
125 mg/m2
840 mg*
Dose level -1
800 mg/m2
100 mg/m2
560 mg**
Dose level -2
600 mg/m2
75 mg/m2
420 mg

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Dose level -3
600 mg/m2
75 mg/m2
280 mg
*Highest dose level for Phase Ib dose escalation cohort only.
**Highest dose level for Immune Response cohort
6.3
Dose Modifications Tables
The following dose modification rules will be used with respect to potential toxicity.  Toxicity will 
be assessed according to the NCI Common Terminology Criteria for Adverse Events Version 
4.03 (CTCAE v4.03).
Patients experiencing treatment-related toxicities that require a delay in scheduled dosing for 
>21 days will be discontinued from further study participation. In the event that a drug must be 
held for intolerability (ie neuropathy for nab-paclitaxel or rash for gemcitabine) for more than 21 
days, patients may continue on study receiving the other drugs, including ibrutinib.  Once a dose 
reduction is required at any point, no dose re-escalation will be permitted for the duration of 
study treatment.  For hematologic toxicities, dose adjustments will be made as per Table 5 
below.  
When a dose reduction of ibrutinib is indicated, the treating physician will write an order to 
“decrease ibrutinib by one dose reduction”.  The drug should be labeled “first dose reduction” or 
“second dose reduction”. 
6.3.1
Dose Modifications and Schedule for Hematologic Toxicities
Dose level modifications for nab-paclitaxel and gemcitabine and ibrutinib where appropriate are 
found in Table 4 and 5.  
Grade 3 and 4 anemia will be treated per ASCO and Institutional Guidelines.
Both ibrutinib and the combination of nab-paclitaxel and gemcitabine are potentially myelotoxic, 
and because of this overlapping toxicity, it may be difficult for the investigator to determine 
whether hematological toxicity is due to ibrutinib, or the nab-paclitaxel-gemcitabine combination. 
Because of the uncertainty in determining causality, the investigator should assume that any 
hematological toxicity which occurs is due to both ibrutinib and nab-paclitaxel + gemcitabine and 
should follow the recommendations directly below for ibrutinib, and in tables 6 and 7 for nab-
paclitaxel and gemcitabine.
Ibrutinib

Grade 4 ANC (<500/µL) for more than 7 days. See Section 5.6 for instructions regarding 
the use of growth factor support. 

Grade ≥3 thrombocytopenia (<50,000/µL)
Hematologic dose modifications for ibrutinib should follow the schedule and dose levels 
recommended in tables 4 and 5.
Nab-Paclitaxel and Gemcitabine
The tables below reflect rules for modifying/holding chemotherapy identical to those used in the 
registrational phase III trial of gemcitabine/nab-paclitaxel (MPACT) in metastatic pancreatic 

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cancer. Of note, the treating physician has the prerogative to take the more conservative 
approach (e.g., hold treatment on day 8 or 15 in the face of borderline blood counts) if felt 
appropriate for safety reasons. 
Table 6. Day 1 Hematologic Dose Modifications for both Nab-Paclitaxel and Gemcitabine
Treatment Day Counts and Toxicity
ANC
Platelets
Timing
>1.5 x 109/L
And
>100 x 109/L
Treat on time, 
continue at 100% of 
present dose
<1.5 x 109/L
Or
<100 x 109/L
Delay by 1 week 
intervals until 
recovery.
Table 7.  Day 8 and 15 Hematologic Dose Modifications for Nab-Paclitaxel and 
Gemcitabine
Day 8 Blood Counts
Day 8 
Dose Modification
Day 15 
Blood Counts
Day 15
Dose Modification
ANC > 1000 and Platelets 
> 75,000
Maintain dose level
ANC 500-1000 or  Platelets 
50,000 -74,999
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
maintain same dose level
ANC > 1000 and 
Platelets > 75,000
Maintain dose level
ANC < 500a or Platelets 
<50,000
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
decrease by 1 dose level
ANC 500-1000 or
 Platelets 50,000 -74,999
Hold+ consider G-CSFa
ANC > 1000 and Platelets 
≥ 75,000
Maintain dose level
(treat on time)

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Day 8 Blood Counts
Day 8 
Dose Modification
Day 15 
Blood Counts
Day 15
Dose Modification
ANC 500-1000 or Platelets 
50,000 -74,999
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
decrease by 1 dose level
ANC < 500a or Platelets 
<50,000
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
decrease by 1 dose level
ANC > 1000 and Platelets 
≥ 75,000
Decrease by 1 dose level
(treat on time)
ANC ≤1000 or Platelets 
50,000 -74,999
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
decrease by 1 dose level
ANC < 500 or 
Platelets <50,000
Hold+ consider G-CSFa
ANC < 500a or Platelets 
<50,000
Hold+ consider G-CSFa
Upon count recovery, 
when safe to resume, 
decrease by 1 dose level
Abbreviations: G-CSF = Granulocyte colony stimulating factor.
a G-CSF is optional if descent only affects platelets.  The use of G-CSF should be according to 
Investigator preference and institutional standards.  Prophylactic antibiotics are recommended 
in the setting of ANC <1.0 x 109/L.
b If patients do not experience resolution of neutropenia >21 days, despite uninterrupted G-CSF 
treatment, study treatment will be discontinued.
c Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment 
held.  A full sepsis diagnostic work-up should be performed while continuing broad spectrum 
antibiotics.  If cultures are positive, the antibiotic may or may not be changed, depending on the 
sensitivity profile of the isolated organism.  Patients with persistent fever after 3 weeks, despite 
uninterrupted antibiotic treatment, will discontinue study treatment.  Febrile neutropenic patients 
can also receive G-CSF, in addition to antibiotic treatment, to hasten the resolution of their 
febrile neutropenia (following current institutional guidelines).  In all cases, ANC must have 
returned to >1500 and platelet count >100,000before resuming chemotherapy treatment.
6.3.2
Dose Modifications and Schedule for Non-Hematologic Toxicities
Dose level modifications for non-hematologic toxicities for nab-paclitaxel, gemcitibine and 
ibrutinib where appropriate are found in Tables 7 and 8.

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The start of a new treatment cycle with gemcitabine and/or nab-paclitaxel should not begin until 
any treatment-related non-hematologic toxicity has resolved to < Grade 1 or baseline.  In 
general all study drugs will be held.  However, if the investigator determines that the non-
hematologic toxicity was due to one study drug and not the others, treatment with the remaining 
study drugs may continue as clinically appropriate.
Based upon maximum non-hematologic toxicities experienced during the previous cycle, dose 
adjustments for subsequent cycles are to be made according to the following criteria (unless 
specified per unique toxicities as noted below):
Table 8. Day 1 Non-Hematologic Dose Modifications
CTC Grade
Gemcitabine
Nab-paclitaxel 
Ibrutinib
0-2 
Same as Day 1 previous cycle (except for Grade 2
cutaneous toxicity where doses of gemcitabine and 
nab-paclitaxel should both be reduced to next lower 
dose level)
3a, b, c 
Hold
Once the AE has been resolved to <Grade 1 or 
baseline, reduce by one dose level at the next 
administration
4c 
Off protocol therapy
a The decision as to which drug (any or all three) should be modified will depend upon the type 
of non-hematologic toxicity seen and which course is medically most sound in the judgment of 
the physician/investigator e.g., if the toxicity only affects neuropathy, then only nab-paclitaxel 
should be reduced.
b A pulmonary embolism that is Grade 3 and will be exempt from this requirement at the 
investigator’s discretion. 
c Patients who manifest a Grade 3 electrolyte value(s) i.e., hypokalemia, do not require a dose 
reduction once the electrolyte issue is resolved.  Patients do not have to be removed from 
protocol for a Grade 4 electrolyte value i.e., Grade 4 elevated glucose in a patient with diabetes 
mellitus.
Dose modifications may also be made for non-hematologic toxicity occurring WITHIN a cycle, 
as specified below:
Table 9.  Non-Hematologic Dose Modifications within a Cycle (Days 8 and 15)
CTC Grade
Dose modification of gemcitabine and/or 
nab-paclitaxel
Dose modification of Ibrutinib
0-2a 
Maintain at same dose level
3b, c, d 
Hold

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Once the AE has been resolved to <Grade 1 or baseline, reduce by one dose 
level at the next administration
4d
Off protocol therapy
a. Except for cutaneous toxicity where the dose of Gemcitabine and Nab-paclitaxel should be 
decreased one level.
b. This decision as to which drug (either or both) should be modified will depend upon the type 
of non-hematologic toxicity seen and which course is medically most sound in the judgment of 
the physician/investigator.  Once doses are reduced, they should not be re-escalated.
c. A pulmonary embolism that is Grade 3 will be exempt from this requirement at the 
investigator’s discretion.  
d. Patients who manifest a Grade 3 electrolyte value(s) i.e., hypokalemia, do not require a dose 
reduction once the electrolyte issue is resolved.  Patients do not have to be removed from 
protocol for a Grade 4 electrolyte value i.e., Grade 4 elevated glucose in a patient with diabetes 
mellitus.
6.3.2.1 Atrial Fibrillation
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 6.0).  If the 
dose of ibrutinib is reduced, at the investigator’s discretion, the dose of ibrutinib may be re-
escalated after 2 cycles of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction. The PI should be consulted before dose reescalation.
6.3.2.2 Peripheral neuropathy
Nab-paclitaxel should be held in patients who experience ≥ Grade 3 peripheral sensory 
neuropathy and may be resumed at the next lower dose level of nab-paclitaxel in subsequent 
cycles after the peripheral neuropathy improves to ≤ Grade 1.  If the toxicity does not resolve 
within 21 days, the patient will be removed from further treatment with nab-paclitaxel and may 
continue treatment with gemcitabine and ibrutinib at the discretion of the care provider, based 
on the clinical status of the patient.  Patients discontinued from study will be followed for 
progression-free survival.
6.3.2.3 Hypersensitivity Reactions
Hypersensitivity reactions are graded as follows:
•
Grade 1: Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
•
Grade 2: Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids indicated for 
≤24 hours). 
•
Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae.  Note: any infusion that is interrupted 
and not resumed within the visit will be considered a Grade 3 reaction.

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•
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Hypersensitivity reactions are not expected with either gemcitabine or nab-paclitaxel or ibrutinib, 
and, if they do occur, are generally minor.  However, in rare instances, more severe reactions 
may occur.  A patient who experiences a Grade 3 infusion reaction may either be taken off 
study protocol at the discretion of the treating physician or be rechallenged at one dose level 
lower.  A patient who experiences a Grade 4 infusion reaction should be taken off study 
protocol.
6.3.2.4 Hepatic toxicity
Ibrutinib is metabolized in the liver. For subjects who develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for ibrutinib 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.)
Table 10. Dose Modifications for Hepatic Toxicities: Gemcitabine and nab-Paclitaxel
AST and/or ALT
Total bilirubin
Gemcitabine
Nab-paclitaxel
Grade 0-2 (up to 
5x ULN)
AND/OR
Grade 0-1 (up to 
1.5x ULN)
Maintain at same dose level
Grade 0-2 (up to 
5x ULN)
AND/OR
Grade 2 (>1.5-3.0 x 
ULN)
Hold treatment; resume all drugs once 
total bilirubin resolves to Grade ≤1
1st episode: resume at same dose level
Recurrent episodes: resume at one dose 
level lower
Grade 3 (>5-20x 
ULN)
AND/OR
Grade 3 (>3-10x 
ULN)
Hold treatment; resume both drugs at 
one dose level lower once total bilirubin 
resolves to Grade ≤1 and AST/ALT to 
Grade ≤2.
Grade 4 (>20x 
ULN)
OR
Grade 4 (>10x ULN)
Remove from study treatment
Note: If elevated liver function tests (LFTs) are related to biliary obstruction and are corrected 
after appropriate intervention (e.g. stenting), no dose reductions are required.
6.3.2.5 Cutaneous Toxicity
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the 
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despite dose reduction, treatment should be discontinued.  Patients who develop Grade 4 
cutaneous toxicity should have treatment discontinued.
6.3.2.6 Pulmonary Embolism
A patient with a grade 3 pulmonary embolism can remain in therapy despite need for 
anticoagulation.  Low molecular weight (LMW) heparin may be used as an anticoagulant for 
thromboembolic events during the study.  NOTE:  Coumadin treatment is not allowed during the 
study.
6.3.2.7 Nausea/Vomiting/Diarrhea
For nausea, vomiting, and diarrhea that are attributed to one or more of the study drugs, 
maximal medical management should be employed prior to dose reductions.  If the toxicities 
persist at Grade 3 or greater despite optimal medical management, then appropriate dose holds 
and reductions should be performed.
7
Study Procedures and Observations
7.1
Overview
All patients should visit the trial center on the days specified within this protocol.  The baseline 
medical history, physical examination, ECOG PS, complete blood counts (CBC) with 3-part 
differential and platelets, comprehensive metabolic profile (CMP), coagulation tests and CA19-9 
should be done ≤ 14 days prior to initiation of treatment.  Informed consent and scans must be 
performed within 28 days prior to randomization.  Treatment or visit delays for public holidays or 
weather conditions do not constitute a protocol violation.
7.2
Pre-treatment Assessments
•
Informed consent form prior to any other study related procedures 
•
Medical history and demographics* 
•
Physical examination including measurements of height (first visit), weight, and vital 
signs (resting heart rate, blood pressure, oral temperature)*
•
ECOG PS (see Appendix 1)*
•
12-lead ECG
•
Concomitant medication and vitamin supplement review
•
CBC including 3-part differential and platelets*  
•
CMP (see Section 7.8)*
•
CA19-9 blood sample*
•
PT/INR and PTT
•
Serum or urine pregnancy test for women of child-bearing potential (must be performed 
within 72 hours prior to randomization)

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•
Archived tumor tissue if available (either FFPE tissue block or 15 or more unstained 
slides see Section 5.4.1)
•
Tumor Evaluation
•
CT Scan of chest, abdomen and pelvis with contrast
•
MRI may be used if any contraindications to CT
•
All sites of disease must be documented at baseline and followed during the trial per 
RECIST 1.1
*Must be done within <14 days prior to initiation of study treatment.
7.3
Study Treatment Assessments
7.3.1
Immune Response Cohort:  One Week Ibrutinib-only Period 
If any of the assessments were performed during the screening period within 14 days preceding 
the day of Loading Dose 1, they do not have to be repeated.
•
Physical examination (Loading Dose 1 only) including measurements of height (first 
visit), weight, and vital signs (resting heart rate, blood pressure, oral temperature) 
•
ECOG PS (See Appendix 1) (Loading Dose 1 only)
•
Concomitant medication review (Loading Dose 1 only)
•
AE assessment
•
CBC including 3-part differential and platelets (Loading Dose 1 only) 
•
CMP (See Section 7.8) (Loading Dose 1 only)
•
CA19-9 blood sample (only for patients with elevated levels ≥ 2 x ULN at baseline) 
(Loading Dose 1 only)
•
70 mL blood for correlates 

EUS Guided Biopsies*
*EUS Guided biopsies should be performed at least 5 days before day 1 and at least 5 days 
after day 7 of the ibrutinib-only run-in.
7.4
Combination Therapy Treatment Period
7.4.1
Day 1 of all Cycles 
•
Physical examination including measurement of weight and vital signs  
•
ECOG PS (see Appendix 1)  
•
AE assessment  
•
Concomitant medication review   
•
CBC, including 3-part differential and platelets  

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•
CMP
•
PT/INR and PTT (see tables 11 and 12 for phase 1b and immune response cohorts)
•
CA19-9 blood sample (only for patients with elevated levels ≥ 2 x ULN at baseline)
•
70 mL blood for correlates analyses
7.4.2
Day 8 of all Cycles
•
AE assessment
•
CBC, including 3-part differential and platelets  
•
CMP 
7.4.3
Cycles 1 and 2, Day 15
•
Physical examination including measurement of weight and vital signs (Cycle 1 only)
•
ECOG PS (see Appendix 1)  
•
AE assessment 
•
Concomitant medication review  
•
CBC, including 3-part differential and platelets 
•
CMP (See Section 7.8)  
7.4.4
Day 22 of all Cycles
•
AE assessment
7.4.5
Cycle 3 and beyond Day 15
•
AE assessment 
•
Concomitant medication review  
•
CBC, including 3-part differential and platelets 
•
CMP (See Section 7.8)  
7.5
 Every 2 Cycles (8 weeks)
Patients will be evaluated for response to treatment at the end of every 2 cycles (e.g. end of 
Cycles 2, 4, 6, etc.), during the last week of the cycle (Day 22-28).  The evaluations should be 
completed at the end of every 2 cycles regardless of any treatment delays.  The following 
assessments will be performed:
•
CT scan of chest, abdomen/pelvis.  (MRI acceptable alternative for patients in whom CT 
scan cannot be performed).
•
Patients without measurable disease at baseline will still be evaluated every 2 cycles 
(e.g. end of Cycles 2, 4, 6, etc.) for progressive disease per RECIST 1.1 criteria.
7.6
End-of-Treatment
Patients will return to the study center within 30 days after discontinuation of study treatment for 
an End of Treatment Visit.  In the event that the patient is too ill or frail to return to clinic for this 

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End of Treatment visit, the End of Treatment assessment can be performed on the same day 
the patient is removed from study therapy.
•
Physical examination including measurement of weight and vital signs  
•
ECOG PS (see Appendix 1)  
•
AE assessment 
•
Concomitant medication review  
•
CBC, including 3-part differential and platelets 
•
CMP
•
PT/INR and PTT 
•
CA19-9 blood sample (only for patients with elevated levels ≥ 2 x ULN at baseline)
•
CT Scan of chest, abdomen/pelvis if abnormal at baseline or clinically indicated if not 
performed within last 30 days.  MRI is an acceptable alternative for patients in whom CT 
scan cannot be performed).
7.7
Follow-up
7.7.1
Progression-Free Survival Follow-up
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed approximately every 8 weeks in the same modality from the date of last dose of 
ibrutinib, gemcitabine and nab-paclitaxel until disease progression or for up to 2 years 
whichever comes first.  Assessments at these visits will be performed as described in Tables 11 
and 12.  Any subsequent cancer therapy will be documented.
7.7.2
Survival Follow-up
Following documented disease progression, patients will be followed every 2 months for 2 years 
for subsequent anticancer therapy, secondary malignancies, and survival status.  Information on 
the start date, type and duration of any subsequent anticancer therapy will be collected.  This 
follow-up may be accomplished through routine clinic follow up visits, documented telephone 
contact with the patient or through contact with the primary practitioner or caregiver.
7.8
Comprehensive Metabolic Profile Assessment
The comprehensive metabolic profile (CMP) panel can sometimes vary by institution.  The 
following laboratory tests should be performed for each patient for assessment of CMP:  
•
glucose
•
blood urea nitrogen (BUN)
•
creatinine
•
sodium
•
potassium
•
chloride
•
calcium
•
carbon dioxide (CO2)
•
alkaline phosphatase
•
AST (SGOT)

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•
ALT (SGPT)
•
total bilirubin
•
total protein
•
albumin
8
Drug Formulation, Availability, Administration and Toxicity Information
8.1
Description, Supply and Storage of ibrutinib
Ibrutinib (IMBRUVICA®) will be supplied to the investigational pharmacy by Pharmacyclics, Inc.
8.1.1
Supply, Packaging and Storage
Ibrutinib (IMBRUVICA®) capsules are provided as a hard gelatin capsule containing 140 mg of 
ibrutinib.  All formulation excipients are compendial and are commonly used in oral formulations.  
Refer to the ibrutinib Investigator's Brochure for a list of excipients. 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drug will be dispensed in child-resistant packaging.  
Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling.
Study drug labels will contain information to meet the applicable regulatory requirements.
8.1.2
Dose and Administration
Ibrutinib (92ct, 140-mg capsules for 280, 420, 840 mgs and 120ct, 140-mg capsules for 
560mgs) is administered orally once daily. The capsules are to be taken around the same time 
each day with 8 ounces (approximately 240 mL) of water.  The capsules should be swallowed 
intact and patients should not attempt to open capsules or dissolve them in water. The use of 
strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the 
duration of the study (Appendix 8).
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 patient should not take extra 
capsules to make up the missed dose.
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically 
on an outpatient basis.  Ibrutinib will be dispensed to patients in bottles at each visit.  Unused 
ibrutinib dispensed during previous visits must be returned to the site and drug accountability 
records (Section 8.1.3) updated at each visit.  Returned capsules must not be redispensed to 
anyone.
8.1.3
Accountability
The pharmacist(s) must confirm the quantity of ibrutinib received with each shipment.  The 
Investigator or designee will maintain records to confirm that the product was stored at 15-30°C, 
product delivery to the trial site, product inventory at the site, the dose given to each patient, and 
the destruction of unused vials.  .

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8.1.4
Precautions and Risks
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. 
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received 
up to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 
mg. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and 
ALT) after a dose of 1680 mg. Subjects who ingested more than the recommended dosage 
should be closely monitored and given appropriate." supportive treatment.There is no specific 
antidote for ibrutinib.  In the event of an overdose, subjects should be closely monitored and 
given appropriate supportive treatment.
Refer to Section 11 for further information regarding AE reporting.
Risks and Side effects
The risks and side effects that have been seen in patients who have been treated with ibrutinib 
alone that have been felt to be possibly, probably, or definitely related to ibrutinib are defined 
below. 
Very likely (At least 20% of patients): 
Diarrhea 
Fatigue 
Nausea 
Infection
Arthralgia and Myalgia
Less likely (At least 10% of patients): 

Cough

Stomatitis

Sinusitis

Anemia

Pyrexia

Neutropenia

Dizziness

Thrombocytopenia

Constipation

Peripheral edema

Upper respiratory tract infection

Vomiting

Urinary tract infection

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
Dyspnea

Skin infection

Petechiae

Pneumonia

Headache

Muscle spasms

Epistaxis

Decreased appetite

Hypertension
Rarely (but may be serious) (At least 1% of patients): 

Dyspepsia

Blurry vision

Atrial fibrillation

Acute renal failure

Lymphocytosis and/or Leukocytosis

Sepsis

Febrile neutropenia

Subdural hematoma

Abdominal pain

Hyperuricemia

Dehydration

Asthenia

Dyspepsia

Dry mouth

Skin redness

Pleural effusion

Respiratory failure 
Rare serious side effects (less than 1% of patients):
Hypersensitivity
Cerebrovascular accident with hemorrhage
Hemorrhagic colitis
Pancytopenia
Splenomegaly
Systemic inflammatory response syndrome
8.2
Gemcitabine
Gemcitabine (2’-Deoxy-2’, 2’-difluorocytidine monohydrochloride, Gemzar) exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S phase) and also blocking the 
progression of cells through the G1/S phase boundary.  Gemcitabine is metabolized 
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(dFdCTP) nucleosides.  The cytotoxic effect of gemcitabine is attributed to a combination of two 
actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA 
synthesis.  First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is 
responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for 
DNA synthesis.  Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in 
the concentrations of deoxynucleotides, including dCTP.  Second, 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.  After this addition, 
there is inhibition of further DNA synthesis.  DNA polymerase epsilon is unable to remove the 
gemcitabine nucleotide and repair the growing DNA strands (masked chain termination).  In 
CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, one of 
the characteristics of programmed cell death.
8.2.1
Drug Storage and Stability
Gemcitabine is commercially available in 200 mg and 1 gm vials and will be obtained from 
commercial supply.  Gemcitabine should be prepared as per institutional standards.
8.2.2
Drug Administration
Gemcitabine should be prepared as per institutional standards.
8.2.3
Side Effects
Most common side effects include myelosuppresion, rash, nausea/vomiting, fever, fatigue, flu-
like symptoms, fluid retention, diarrhea, and transaminitis.  Rare but serious side effects include 
pulmonary syndromes, bronchospasm, and hemolytic-uremic syndrome.  For more information 
please see the prescribing information.
8.3
Nab-paclitaxel (Abraxane)
Abraxane (nab-paclitaxel, nanoparticle albumin-bound paclitaxel), when released as the active 
drug (paclitaxel), blocks cell replication in the G2 mitotic phase by promoting microtubule 
assembly, stabilizing existing microtubules, and inhibiting disassembly of microtubles.  Binding 
of abraxane by an albumin specific receptor (gp60) leads to activation of caveolin-1, a protein 
which mediates internalization of the compound into the endothelial cell and transport to the 
tumor interstitium.  Secreted Protein And Rich in Cysteine (SPARC), a tumor-secreted protein, 
binds albumin, releasing the active drug at the tumor cell membrane, thereby increasing its 
concentration at the target site of action.
8.3.1
Drug Storage and Stability
Abraxane (nab-paclitaxel, nanoparticle albumin-bound paclitaxel), when released as the active 
drug (paclitaxel), blocks cell replication in the G2 mitotic phase by promoting microtubule 
assembly, stabilizing existing microtubules, and inhibiting disassembly of microtubles.  Binding 
of abraxane by an albumin specific receptor (gp60) leads to activation of caveolin-1, a protein 
which mediates internalization of the compound into the endothelial cell and transport to the 
tumor interstitium.  Secreted Protein And Rich in Cysteine (SPARC), a tumor-secreted protein, 
binds albumin, releasing the active drug at the tumor cell membrane, thereby increasing its 
concentration at the target site of action.

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8.3.2
Drug Administration
Abraxane should be prepared as per institutional standards.
8.3.3
Side Effects
Most common side effects include myelosuppresion, nausea/vomiting, diarrhea, mucositis, 
sensory neuropathy, myalgia/arthralgia, infections, hypotension, abnormal ECG changes, 
cough, dyspnea, edema, bilirubin/liver enzyme elevations, allergic reactions, alopecia, asthenia.  
Rare but serious side effects include hypersensitivity reactions and cardiovascular events.  For 
more information please see the prescribing information.
9
Response Evaluations And Measurements
All patients with measurable disease will be evaluated for response using the RECIST version 
1.1 (Appendix 4) (Eisenhauer et al. 2009).
10 Statistical Considerations
10.1
Study Design
This is a phase Ib/Immune Response study of ibrutinib in combination with nab-paclitaxel and 
gemcitabine in the management of patients with metastatic pancreatic adenocarcinoma.  Phase 
Ib is a standard dose-confirmation schema with 3 to 6 patients per cohort (3+3 dose 
escalation/de-escalation design). There are two planned dose cohorts, with two additional 
cohorts at de-escalated doses if necessary. The objective of the part Ib is to confirm the safety 
and toxicity of the combination of gemcitabine and nab-paclitaxel with the doses and schedule 
of ibrutinib previously shown to be safe and effective in the management of patients with CLL 
and Mantle Cell Lymphoma,and to determine the Maximum Tolerated Dose (MTD),. See section 
5.0 and section 5.1 for more details. At least six patients total will have received the MTD to 
verify and confirm the safety and toxicity of ibrutinib in combination with nab-paclitaxel and 
gemcitabine in patients with metastatic pancreatic adenocarcinoma. These 6 patients will also 
be followed for overall survival and included in efficacy and clinical benefit analysis of the study.
The 20 patients enrolled and treated in the Immune Response study cohort will be evaluated for 
safety and followed for survival.
10.2
Study Endpoints
Phase Ib, Dose Escalation
Primary endpoints:

Safety and tolerability of ibrutinib in combination with gemcitabine and nab-paclitaxel
Immune Response Study
Primary endpoint:

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•
Changes in the immune profile of peri-tumoral environment and peripheral blood during 
and after treatment with ibrutinib, alone and in combination with gemcitabine and nab-
paclitaxel.
Secondary endpoints:
•
Median time-to-progression (TTP)
•
Median progression-free survival (PFS)
•
Median overall survival (OS)
10.3
Pharmacodynamic (PD) Analysis

Btk occupancy ratio (PBMC)
10.4
Exploratory Endpoints

Changes in T cell and B cell frequency

Changes in T cell and B cell clonality 

Changes in T cell and B cell function

Changes in circulating myeloid cell gene and protein expression profiles 
10.5
Randomization
Not Applicable
10.6
Stratification
Not applicable
10.7
Missing Data and Replacement Policy
Data for all patients will be summarized and analyzed to the extent the available data allow.  
Missing data will not be imputed or replaced.
10.8
Interim Analyses and Stopping Rules
Not applicable for phase Ib study design. Stopping rules are already included as part of 
standard 3+3 design.
10.9
Analyses Plans
Descriptive statistics will be used to summarize baseline subject characteristics, treatment 
administration, efficacy, and safety outcomes.  Summaries of discrete data will include number 
of subjects and incidence as a frequency and as a percentage.  Summaries of continuous data 
will include mean, standard deviation, median, minimum, maximum, and sample size.
10.10 Primary Analysis (or Analysis of Primary Endpoints)
Phase Ib: Safety will be assessed through summaries of DLTs and other adverse events.  
Tolerability will be described using summaries of dose reductions, dose delays, discontinuations 
for toxicity, and overall dose exposure. The safety of the MTD will be established after review by 

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the Study Team (comprised of Principal Investigator, Investigational Pharmacist, Study 
Statistician, and Site Committee quorum) taking into account the the severity and causal 
relationship for all DLTs and other AEs, and tolerability.  Review of PD parameters at each dose 
level may also be used to inform determination of MTD. Eligible patients who receive at least 
one dose of the study drug are evaluable for safety from the date and time of their first dose of 
the study drug until 30 days after last dose of study drug.
10.11 Secondary Analysis (or Analysis of Secondary Endpoints)
Kaplan-Meier methods will be used to summarize median TTP, PFS, and OS with 95% 
confidence intervals.  The proportion of patients with TTP and PFS equal to or exceeding 6 
months will also be calculated and reported along with 95% confidence intervals.
CA19-9 Response Rate
The CA19-9 Response Rate is defined as the percentage of CA 19-9 evaluable treated patients 
(baseline CA19-9 > 75 units) who have confirmed CA19-9 reduction of 75% from baseline 
value. Patients who have missing CA19-9 measurements will be treated as non-responders, 
i.e., they will be included in the denominator when calculating the percentage. The CA19-9 
Response Rate, along with exact one-sided 95% confidence intervals, will be reported for the 
study.
Time to Progression (TTP)
TTP is defined as the duration from date of first dose of protocol therapy to date of removal from 
study for radiographic (per RECIST 1.1) and/or clinical progression including death attributed to 
progression. Eligible patients are evaluable for TTP who are response-evaluable and who are 
removed from study for radiographic or clinical progression.  For patients removed from study 
for other reasons (such as for toxicity, withdrawal of consent, death without documented 
progression, or other reasons without clinical or radiographic evidence of tumor progression), 
TTP will be censored at the date of study discontinuation. 
Progression-Free Survival (PFS)
PFS is defined as the duration of time from date of first dose of protocol therapy to time of 
documented radiographic and/or clinical disease progression or death from any cause. Eligible 
patients are evaluable for PFS who are response-evaluable and who are removed from study 
for radiographic or clinical progression and/or who experience death from any cause during 
study follow up.  Patients who have not progressed or died are censored at the date last known 
to be progression-free.  
Overall Survival (OS)
Median OS for all enrolled patients will be calculated from date of first dose of protocol therapy 
until date of death, using chart review and/or follow up phone calls to determine date of death in 
patients after removal from study.  The survival of patients still alive after 2 years of follow up 
post study discontinuation will be censored.  Alive patients are censored at the date last known 
alive
10.12 Analyses of Exploratory Endpoints
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quantitatively evaluate abundance, complexity, phenotype and functional status of myeloid cells 
(TH1, TH2, TH17) using blood leukocytes from patients. Multiplex ELISA and RT-PCT will be used 
to assess a broad spectrum of TH cell responses in peripheral blood leukocytes. These 
parameters will be compared to expression levels of biomarkers and cytokines in frozen and/or 
FFPE-embedded tumor tissue from pre- and post-treatment PDA patients vs. archived PDA and 
normal pancreas tissues. Globin mRNA will be extracted using anti-globin magnetic beads prior 
to multiplex PCR analysis.
T cell frequency, clonality and function
Polychromatic flow cytometry:  Abundance, complexity, phenotype and functional status of T 
cells in peripheral blood leukocytes and tumor cell suspensions will be analyzed by FACS 
quantitation of Ag-specific CD8+ T cells in using peptide epitope-MHC class I tetramers. 
Tetramer+ and (-) CD8+ T cells will be stained for accepted markers reporting functional status 
of Ag-specific CD8+ T cells, the proliferation Ki-67, and the cellular activation markers. 
T cell frequency and function: In addition to FACS, the EPIMAX platform will be used, allowing 
assessment of a broad spectrum of T cell responses both by epitope mapping and by cytokine 
profiling[33, 34] (e.g., TNFα, IFNγ, IL2, IL4, IL10, IL17) using 9-10mer (CD8+ T cells) or 20mer 
libraries (CD4+ T cells). Morisita’s distances will be calculated for serial blood and tumor 
samples
TCR deep sequencing of tissue and blood: T cell responses, their clonality, and expansion or 
contraction over time will be monitored globally by deep sequencing of TCRβ chains to identify 
and track unique T cell clones in tissue and blood. 
Changes in Circulating and Intra-tumoral B-Cell Receptors
B cell frequency and phenotype: B cell abundance, complexity, phenotype and functional status 
of B cells will be quantitatively evaluated by FACS analysis of blood leukocytes and tumor cell 
suspensions before and after therapy with ibrutinib-only.  
BCR sequencing: Immuno-receptor loci rearrangements from genomic DNA samples reflecting 
pre- vs. post-treatment PB and tumor will be sequenced using V and J segment consensus 
primers. Sequences will be analyzed using standardized algorithms for clonotype determination. 
Clonotype identification and enumeration: The frequency of each clonotype in a sample will be 
determined by calculating the number of sequencing reads for each clonotype divided by the 
total number of passed sequencing reads in the sample, with algorithmic methods utilized for 
clonotype determination as described previously. Low quality reads, those that do not map to a 
J and a V segment and do not demonstrate high-quality sequence data in the clone-defining 
region, will be excluded. Sequence data will be analyzed to determine clonotype sequences 
including mapping to germline V and J consensus sequences. 
Determination of repertoire diversity and repertoire change: Diversity of individual sample 
repertoires will be assessed by calculating the number of unique clonotypes comprising the top 
25th % of cumulative reads after sorting by clone abundance. Repertoire change between 
sequential experiments will be measured using Morisita’s distance, which is not significantly 

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influenced by sample size1, 2, and reported as a continuous variable from 0-1 with1 indicating 
maximal dissimilarity.
Statistical Analysis
Analyses for diversity, repertoire change and identification of differentially abundant clonotypes 
will be performed as described above. In the Immune Response Study, 20 patients will be 
enrolled and their B and T cell repertoires measured at time points, including pre-, post-, start of, 
during, and end of treatment. Changes in B and T cell repertoire parameters over time will be 
modeled using mixed effects models to account for an intra-subject correlation. A binary and 
ordinal logistic regression analyses will be performed to evaluate effect of pre-treatment B and T 
cell repertoire parameters on tumor response (PD, SD, PR, CR), while Cox regression analysis 
will be performed to evaluate their impacts on disease free survival. Due to the limited sample 
size, multivariate analyses will be primarily exploratory, and include an examination of the joint 
effects of several B and T cell repertoires parameters on the clinical outcome. 
10.13 Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI CTCAE v4.03.
11 Safety Reporting And Analyses
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.
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB.
11.1
Adverse Events 
The Principal Investigator is responsible for recognizing and reporting AEs.  It is the Principal 
Investigator’s responsibility to report relevant SAEs to the applicable local and national 
regulatory bodies.
Definitions of Adverse Events
An AE is any untoward medical occurrence in a patient 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.

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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 patient and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance.
•
Any AEs experienced by the patient through the completion of final study procedures.
•
AEs not previously observed in the patient 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.
Recording and Reporting of Adverse Events
All AEs of any subject during the course of the study will be recorded in the CRF, and the 
investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration).  
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study 
treatment), and outcome, should be provided, along with the investigator’s assessment of 
causality (i.e., the relationship to the study treatment[s]).  For an AE to be a suspected 
treatment-related event there should be at least a reasonable possibility of a causal relationship 

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between the protocol treatment and the AE.  Adverse events will be graded according to the 
NCI CTCAE 4.03.   
If the AE is serious, it should be reported immediately to IRB of record.  Other untoward events 
occurring in the framework of a clinical study are also to be recorded as AEs (i.e., AEs that 
occur prior to assignment of study treatment that are related to a study-mandated intervention, 
including invasive procedures such as biopsies, medication washout, or no treatment run-in).
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, 
and collected on the relevant CRF.
Test findings will be reported as an AE if the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment; and/ or test findings require additional testing, treatment, 
or surgical intervention; a test result or finding is associated with accompanying symptoms; or a 
test result is considered to be an AE by the investigator.
All AEs regardless of seriousness or relationship to study treatment, spanning from the start of 
study treatment, until 30 calendar days after discontinuation or completion of study treatment as 
defined by the clinical study for that subject, are to be recorded in the CRF.  
Handling of Adverse Events
All AEs resulting in discontinuation from the trial should be followed until resolution or 
stabilization.  Patients must be followed for AEs for 30 calendar days after discontinuation or 
completion of clinical trial-specific treatment (e.g., chemotherapy, radiation, oral medications, 
targeted therapy, and surgery).  All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the investigator, the AE or laboratory 
abnormality/ies are not likely to improve because of the underlying disease.  In this case, the 
investigators must record his or her reasoning for this decision in the subject’s medical record 
and as a comment on the CRF.  After 30 days of completion of study-specific treatment or 
discontinuation, only AEs, SAEs, or deaths assessed by the investigator as treatment related 
are to be reported.
11.2
Serious Adverse Events 
Definitions of Serious Adverse Events 
The definitions of SAEs are given below.  The Principal Investigator is responsible for ensuring 
that all staff involved in the trial is familiar with the content of this section.
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 that:

Results in death

Is a life-threatening adverse event. Life-threatening is defined as an AE in which the 
patient 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 IND Sponsor believes that an AE meets the definition of life-threatening, it will be 
considered life threatening.

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
Requires at least a 24-hour inpatient hospitalization or prolongation of existing 
hospitalization 

Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 

Results in 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 patient or patient 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.
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported):
•
Emergency Department or Emergency Room
•
Outpatient or same-day surgery units
•
Observation or short-stay unit
•
Rehabilitation facility
•
Hospice or skilled nursing facility
•
Nursing homes, custodial care or respite care facility
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the trial) does not require reporting as an SAE to the local IRB. Deaths 
that are attributed by the Investigator solely to the progression of disease do not require 
reporting as an SAE to the the local IRB.
Serious Adverse Event Reporting by Investigators
It is important to distinguish between “serious” and “severe” adverse events, as the terms are 
not synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need 
not necessarily be considered serious.  For example, nausea which persists for several hours 
may be considered severe nausea, but may not be considered an SAE.  On the other hand, a 
stroke which results in only a limited degree of disability may be considered only a mild stroke, 
but would be considered an SAE.  Severity and seriousness should be independently assessed 
when recording AEs on the CRF and SAEs on the SAE Report Form.
Adverse events classified by the treating investigator as serious require expeditious handling 
and reporting to the sponsor in order to comply with regulatory requirements.  Serious adverse 
events may occur at any time from the start of study treatment through the 30-day follow-up 
period after the last study treatment.  The sponsor must be notified of all SAEs, regardless of 

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causality, within one business day of the first knowledge of the event by the treating physician or 
research personnel.  
To report an SAE, the SAE Report Form should be completed with the necessary information.  
All SAEs occurring from the start of study treatment, until 30 calendar days of last study 
treatment must be reported to the chair, Dr. Margaret Tempero as SAEs on the SAE Report 
Form and followed until resolution (with autopsy report if applicable).
Deaths and other SAEs occurring >30 calendar days after last study treatment that are deemed 
‘possibly’ or ‘probably’ related to study drug must be reported as SAEs on the SAE Report Form 
within 1 day of first knowledge of the event by the treating physician or research personnel (with 
an autopsy report if available).
Deaths occurring >30 calendar days after last study treatment and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the 
appropriate CRF.
To report an SAE, the SAE Report Form should be completed with the necessary information.
The SAE report Form should be sent to the study coordination site via e-mail using the following 
contact information (during both business and non-business hours):  
  
  
  
Emailof the SAE report Form should be confirmed by the site personnel submitting the report.
Reporting to Regulatory Agencies:
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 
312.32.
It is the responsibility of the Investigator and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical Practices 
(GCP), the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy.
Severity Criteria (Grade 1-5)
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE 
v4.03) will be used for grading the severity (intensity) of nonhematologic AEs.  Refer to 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html for the grading of hematologic AEs.  The CTCAE 
v4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE.  Should a patient experience any AE not listed in the CTCAE v4.03, the 
following grading system should be used to assess severity:

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•
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the patient’s daily activities
•
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, 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 patient’s usual daily activity, and require systemic drug therapy or other 
treatment
•
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be 
in imminent danger of death
•
Grade 5 (Death related to AE) – experiences which result in patient death
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.
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.
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators

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Assessment of Adverse Events
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded.  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.
Adverse Event Reporting Period
All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is 
obtained until 30 days following the last 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 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"). 
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. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported as 
a serious adverse event. 
Pregnancy
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days 
old will be requested.
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 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.  

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Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported. Any occurrence of pregnancy 
must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. 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 and this must be reported to Pharmacyclics 
Drug Safety, or designee, per SAE reporting timelines. Any congenital anomaly/birth defect 
noted in the infant must be reported as a serious adverse event.
Non-melanoma Skin Cancer and Other Malignancies
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin) 
have been reported with more frequency and may be related to the use of ibrutinib.  Other 
cancers have been been reported such as solid tumors and hematologic malignancies, and will 
be reported for the duration of study treatment and during any protocol-specified follow-up 
periods including post-progression follow-up for overall survival.
Adverse Events of Special Interest (AESI)
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to the local IRB 
per the SAE reporting timelines.  
Major Hemorrhage
Major hemorrhage is defined as any of the following:
•
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. Any 
treatment-emergent serious adverse events of bleeding of any grade
•
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or 
higher AE per CTCAE v4.02.
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to above.
Expediting Reporting Requirements for Serious Adverse Events
All serious adverse events and AESIs (initial and follow-up information) will be reported on FDA 
Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB Reporting 
Form and sent sent via email (AEintakePM@pcyc.com) or fax ((408) 215-3500), to 
Pharmacyclics Drug Safety, or designee, within 24 hrs of the event. Pharmacyclics may request 
follow-up and other additional information from the Sponsor Investigator. 
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:

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•
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)
11.3
Usage of Concurrent/Concomitant Medications
11.3.1 Medications to be Used With Caution
CYP3A- Inhibitors/Inducers
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. 

If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, 
reduce ibrutinib dose to 140 mg or withhold treatment for the duration of inhibitor use. 
Subjects should be monitored for signs of ibrutinib toxicity. 

If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 
ibrutinib to 140 mg (for 840 mg/day dose, reduce to 280 mg) for the duration of the 
inhibitor use. Avoid grapefruit and Seville oranges during 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 strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction."A comprehensive list 
of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ This website is continually revised and 
should be checked frequently for updates.
11.4
Dietary Restrictions

Ibrutinib should be taken with water.

Seville oranges or grapefruit juice should be avoided

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12 Reporting and Documentation of Results
12.1
Evaluation of Efficacy (or Activity)
12.1.1 Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria (or International Workshop on Chronic 
Lymphocytic Leukemia [IWCLL]).
12.1.1.1 Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
Evaluable for objective response
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.)
12.1.1.2 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will 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.
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI.    Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
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Non-measurable disease (Tumor Markers)
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniquesare all non-
measurable. (e.g. PSA, CA-125, CA19-9, CEA)
12.2
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events, see Section 6.3.
12.3
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
12.4
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it 
meets the FDA reporting criteria..
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s).
In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis, discussed at DSMC meetings which take place every six (6) weeks, and prior 
to dose escalation.  At the time of dose escalation, a written report will be submitted to the 
DSMC Chair (or qualified alternate) describing the cohorts, dose levels, adverse events, safety 
reports, and any Dose Limiting Toxicities observed, in accordance with the protocol.  The report 
will be reviewed by the DSMC Chair (or qualified alternate).  Approval for the dose escalation by 
the DSMC Chair (or qualified alternate) must be obtained prior to implementation.  For a 
detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 1 Dose 
Escalation Institutional Study at the Helen Diller Comprehensive Cancer Center please refer 
Appendix 2 Data and Safety Monitoring Plan for Phase 1 Dose Escalation.
12.5
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 

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or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to UCSF Committee on Human Research (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
Suspected adverse reaction (as defined in 11.1)
Unexpected (as defined in 11.2)
Serious (as defined in 11.2)
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
13 Study Management
13.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 

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requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
13.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.  
13.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
13.4
Changes in the Protocol
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.  
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol 
must be sent to Pharmacyclics for review and approval prior to submission to the IRB.  Written 
verification of IRB approval will be obtained before any amendment is implemented. If it 
becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites.
13.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
13.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 

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possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs  after that time can 
only be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager.
13.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 5 Data and Safety Monitoring Plan for Phase 1 Dose Escalation Institutional Study, for 
additional information.
13.8
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed 
to discuss risk assessment.  The following issues will be discussed as appropriate: 

Enrollment information

Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information)

Protocol violations

Other issues affecting the conduct of the study.
13.9
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  

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The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.
13.10 Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
13.11 Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization 

Participating Site IRB approved consent form 

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
Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 

Curriculum vitae and medical license for each investigator and consenting 
professional 

Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.
14
Protection of Human Subjects
14.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR mechanism and the process of informed consent. The 
CHR reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The CHR also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
14.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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Table 11. Schedule of Events and Procedures: Phase Ib Dose escalation 
Period/Procedure
Screeninga
Treatment Cycles 1-2c 
(Cycle is 28 days)
Treatment Cycles 3 
and beyondc 
(Cycle is 28 days)
End of Study 
Treatmentd
Follow-up
Study Day/Visit Day
-14 to 0
D1
D8
D15
D22
D1
D8
D15
D22
Prior 
to PDk
After 
PDl
Tests and Observations
Informed consent
X
Medical history and Demographic
X
Physical exam, weight
X
Xf
X
X
X
X
Vital signse
X
Xe
Xe
Xe
Xe
Xe
Xe
X
X
Heighte
X
ECOG PS
X
Xf
X
X
X
X
Concomitant medications
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
Archival Tissue Collection (if 
available) i
X
12-lead ECG
Xm
Xn
Subsequent Cancer Treatment
X
X
Survival Status
X
Treatment/Drug Administration
Ibrutinibb 
X
X
X
X
X
X
X
X
Gemcitabine
X
X
X
X
X
X
Nab-Paclitaxel
X
X
X
X
X
X
Laboratory procedures
CBC w/ 3 part Diff 
X
Xf
X
X
X
X
X
X
CMPg
X
Xf
X
X
X
X
X
X
Urine or serum Pregnancy test
X

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Period/Procedure
Screeninga
Treatment Cycles 1-2c 
(Cycle is 28 days)
Treatment Cycles 3 
and beyondc 
(Cycle is 28 days)
End of Study 
Treatmentd
Follow-up
Study Day/Visit Day
-14 to 0
D1
D8
D15
D22
D1
D8
D15
D22
Prior 
to PDk
After 
PDl
Hepatitis (HBV, HCV)
Xo
Coagulation (INR Pt/PTT)
X
Xf
X
CA19-9
X
Xf,f2
X f2
X f2
Blood collection for correlative 
studies, BTK occupancy assays
Xh
X
Imaging procedures
Imaging (CT or MRI) every 8 wksj
X
X
X
X
a.
Pre-treatment assessments will be completed within 14 days of start of therapy.  The Informed Consent and scans can be 
completed within 28 days of start of therapy. The pregnancy test (for women of child-bearing potential) should be completed 
within 72 hours prior start of therapy.
b.
Daily dosing with ibrutinib should begin day 1 of cycle 1, and should continue through-out the 28 day cycles until patient is off 
study treatment. 
c.
Treatment with gemcitabine and nab-paclitaxel is to be administered on days 1, 8, 15 of each 28 day cycle.  Ibrutinib will be 
taken orally, each day of the 28 day treatment cycle.  While every effort should be made to adhere to this schedule, +/- 2 days 
from any scheduled treatment is acceptable due to holidays, travel issues, or other logistics.
d.
End of study visit should be completed within 30 days of the last dose.  In the event that the patient is too ill or frail to return to 
clinic for this EOT visit, this will not constitute a protocol violation.
e.
Vital signs including BP, pulse and temperature should be documented with each PE.  Vital signs should also be documented 
with any signs or symptoms during or immediately after an infusion.  Perform complete physical examination at screening.  A 
limited PE will be repeated on Day 15 of Cycle 1 only.  A limited PE related to signs, symptoms and concurrent illnesses is 
appropriate during Study Treatment.  Height only required during Pre-treatment.
f.
These procedures to not need to be repeated if they were performed within the preceding 14 days (eg during the pre-
treatment period).
f.2. Only for patients with elevated levels ≥ 2 x ULN at baseline.

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g.
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT), 
ALT (SGPT), total bilirubin, total protein, and albumin.
h.
EDTA blood collection for baseline cytokine, B an T cell receptor profiling, and myeloid cell characterization and BTK 
occupancy assays should be drawn before beginning combination therapy on day 1 cycle 1, and day 1 of  the  subsequent 
cycles before infusion of gemcitabine and nab-paclitaxel .  The correlative blood samples will be processed at UCSF before 
shipping to other sites for analyses.
i.
Archived tumor tissue will be collected for this study.  Tissue may be collected at Pre-treatment or at any time during the 
study.
j.
Tumor assessment occurs at the end of every 2 cycles, during the last week of the cycle.  The evaluations should be 
completed at the end of every 2 cycles regardless of any treatment delays.  This typically will consist of CT scans of the 
chest/abdomen/pelvis.  MRI represents an acceptable alternative for patients with increased risk of contrast related 
nephropathy or other contraindications.  Baseline and subsequent imaging must be by the same type of procedure (e.g. CT 
vs. MRI scan).
k.
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 8 weeks from 
the date of last dose of trial drug until disease progression or for up to 2 years whichever comes first.  Any subsequent cancer 
therapy will be documented.
l.
Patients with documented disease progression will be followed every 2 months for survival status (e.g., date and cause of 
death) for up to 2 years or death whichever comes first.  Information on the start date, type and duration of any subsequent 
anticancer therapy will be collected.  Patients may be contacted during outpatient visits, by documented telephone contact 
with the patient or through contact with the primary practitioner or caregiver
m. 12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTcF average of the 3 ECGs must be <470 msec for 
eligibility.  Abnormalities noted at Screening should be included in the medical history.
n.
ECGs should be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea.
o.
Screening tests for Hepatitis Virus to include HBsAg, Hepatitis B core antibody (HBcAb), total, and HCV Antibody.  If either of 
the HBV tests are positive, order HBV DNA quantification by PCR. If HBV DNA positive, determine if anti-viral therapy if DNA 
is necessary.

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Table 12. Schedule of Events and Procedures: Immune Response Study
Period/Procedure
Screeninga
Ibrutinib
Run-in 
Periodb
Treatment Cycles 1-
2c 
(Cycle is 28 days)
Treatment Cycles 3 
and beyondc 
(Cycle is 28 days)
End of 
Study 
Treatmentd
Follow-up
Study Day/Visit Day
-14 to 0
Wk1D1
D1b
D8
D15
D22
D1
D8
D15
D22
Prior 
to 
PDk
After 
PDl
Tests and Observations
Informed consent
X
Medical history and Demographic
X
Physical exam, weight
X
Xf
X
X
X
X
X
Vital signse
X
X
Xe
Xe
Xe
Xe
Xe
Xe
X
X
Heighte
X
ECOG PS
X
Xf
X
X
X
X
X
Concomitant medications
X
Xf
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Archival Tissue Collection (if 
available) i
X
12-lead ECG
Xm
Xf
Xn
Subsequent Cancer Treatment
X
X
Survival Status
X
EUS-guided biopsy
Xb
Treatment/Drug Administration
Ibrutinibb
X
X
X
X
X
X
X
X
X
Gemcitabine
X
X
X
X
X
X

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Period/Procedure
Screeninga
Ibrutinib
Run-in 
Periodb
Treatment Cycles 1-
2c 
(Cycle is 28 days)
Treatment Cycles 3 
and beyondc 
(Cycle is 28 days)
End of 
Study 
Treatmentd
Follow-up
Study Day/Visit Day
-14 to 0
Wk1D1
D1b
D8
D15
D22
D1
D8
D15
D22
Prior 
to 
PDk
After 
PDl
Nab-Paclitaxel
X
X
X
X
X
X
Laboratory procedures
CBC w/ 3 part Diff 
X
Xf
X
X
X
X
X
X
X
CMPg
X
Xf
X
X
X
X
X
X
X
Urine or serum Pregnancy test
X
Hepatitis (HBV, HCV)
X
Coagulation (INR, Pt, PTT)
X
Xf
X
X
CA19-9
X
Xf,f2
X f2
X f2
Blood collection for correlative 
studies,BTK occupancy assays
Xh
Xh
Xh
Imaging procedures
Imaging (CT or MRI) every 8 wksj
X
X
X
X
a.
Pre-treatment assessments will be completed within 14 days of start of therapy.  The Informed Consent and scans can be 
completed within 28 days of start of therapy. The pregnancy test (for women of child-bearing potential) should be completed 
within 72 hours prior start of therapy.
b.
Day 1 of the 7 day ibrutinib-only run-in period should begin at least 5 days after the pretreatment EUS guided biopsy.  Dosing 
with ibrutinib should be stopped for at least 5 day before performing the post-ibrutinib EUS-guided biopsy.  Day 1 Cycle 1 of 
the combination treatment with gemcitabine and nab-paclitaxel may occur at 1-3 days after the post-ibrutinib run-in biopsy, 
and daily oral dosing with ibrutinib may commence 5-7 days post-biopsy. 
c.
Treatment with gemcitabine and nab-paclitaxel is to be administered on days 1, 8, 15 of each 28 day cycle.  Ibrutinib will be 
taken orally, each day of the 28 day treatment cycle.  While every effort should be made to adhere to this schedule, +/- 2 days 
from any scheduled treatment is acceptable due to holidays, travel issues, or other logistics.
d.
End of study visit should be completed within 30 days of the last dose.  In the event that the patient is too ill or frail to return to 
clinic for this EOT visit, this will not constitute a protocol violation.

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e.
Vital signs including BP, pulse and temperature should be documented with each PE.  Vital signs should also be documented 
with any signs or symptoms during or immediately after an infusion.  Perform complete physical examination at screening.  A 
limited PE will be repeated on Day 15 of Cycle 1 only.  A limited PE related to signs, symptoms and concurrent illnesses is 
appropriate during Study Treatment.  Height only required during Pre-treatment.
f.
These procedures to not need to be repeated if they were performed within the preceding 14 days (eg during the pre-
treatment period).
f.2. Only for patients with elevated levels ≥ 2 x ULN at baseline.
g.
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT), 
ALT (SGPT), total bilirubin, total protein, and albumin.
h.
EDTA Blood collection for baseline cytokine, B and T cell receptor profiling, and myeloid cell characterization and BTK 
occupancy assays should be drawn before and after the 7 day ibrutinib run-in, before the EUS-guided biopsies are 
performed.  Blood collection for the correlative analyses will also occur on day 1 of cycle 2 and subsequent cycles of 
combination therapy before infusion of gemcitabine and nab-paclitaxel begins.  The correlative blood samples will be 
processed at UCSF before shipping to other sites for analyses.
i.
Archived tumor tissue will be collected for this study.  Tissue may be collected at Pre-treatment or at any time during  the 
study.
j.
Tumor assessment occurs at the end of every 2 cycles, during the last week of the cycle.  The evaluations should be 
completed at the end of every 2 cycles regardless of any treatment delays.  This typically will consist of CT scans of the 
chest/abdomen/pelvis.  MRI represents an acceptable alternative for patients with increased risk of contrast related 
nephropathy or other contraindications.  Baseline and subsequent imaging must be by the same type of procedure (e.g. CT 
vs. MRI scan).
k.
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 8 weeks from 
the date of last dose of trial drug until disease progression or for up to 2 years whichever comes first.  Any subsequent cancer 
therapy will be documented.
l.
Patients with documented disease progression will be followed every 2 months for survival status (e.g., date and cause of 
death) for up to 2 years or death whichever comes first.  Information on the start date, type and duration of any subsequent 
anticancer therapy will be collected.  Patients may be contacted during outpatient visits, by documented telephone contact 
with the patient or through contact with the primary practitioner or caregiver.
m. 12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTcF average of the 3 ECGs must be <470 msec for 
eligibility.  Abnormalities noted at Screening should be included in the medical history.
n.
ECGs should be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea.

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o.
Screening tests for Hepatitis Virus to include HBsAg, Hepatitis B core antibody (HBcAb), total, and HCV Antibody.  If either of 
the HBV tests are positive, order HBV DNA quantification by PCR. If HBV DNA positive, determine if anti-viral therapy is 
necessary.

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References
1.
Conroy, T., et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. 
N Engl J Med, 2011. 364(19): p. 1817-25.
2.
Von Hoff, D.D., et al., Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med, 2013. 369(18): p. 1691-703.
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Poch, B., et al., Systemic immune dysfunction in pancreatic cancer patients. 
Langenbecks Arch Surg, 2007. 392(3): p. 353-8.
4.
Jaffee, E.M., et al., Novel allogeneic granulocyte-macrophage colony-stimulating 
factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and 
immune activation. J Clin Oncol, 2001. 19(1): p. 145-56.
5.
Schmitz-Winnenthal, F.H., et al., Specific immune recognition of pancreatic carcinoma 
by patient-derived CD4 and CD8 T cells and its improvement by interferon-gamma. Int 
J Oncol, 2006. 28(6): p. 1419-28.
6.
Schmitz-Winnenthal, F.H., et al., High frequencies of functional tumor-reactive T cells 
in bone marrow and blood of pancreatic cancer patients. Cancer Res, 2005. 65(21): p. 
10079-87.
7.
Kubuschok, B., et al., Naturally occurring T-cell response against mutated p21 ras 
oncoprotein in pancreatic cancer. Clin Cancer Res, 2006. 12(4): p. 1365-72.
8.
Laheru, D., et al., Allogeneic granulocyte macrophage colony-stimulating factor-
secreting tumor immunotherapy alone or in sequence with cyclophosphamide for 
metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. 
Clin Cancer Res, 2008. 14(5): p. 1455-63.
9.
Lutz, E.R., et al., Immunotherapy converts nonimmunogenic pancreatic tumors into 
immunogenic foci of immune regulation. Cancer Immunol Res, 2014. 2(7): p. 616-31.
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Tseng, J.F., et al., Patients undergoing treatment for pancreatic adenocarcinoma can 
mount an effective immune response to vaccinations. Pancreatology, 2005. 5(1): p. 
67-74.
11.
Hinz, S., et al., Foxp3 expression in pancreatic carcinoma cells as a novel mechanism 
of immune evasion in cancer. Cancer Res, 2007. 67(17): p. 8344-50.
12.
Ino, Y., et al., Immune cell infiltration as an indicator of the immune microenvironment 
of pancreatic cancer. Br J Cancer, 2013. 108(4): p. 914-23.
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Hiraoka, N., et al., Prevalence of FOXP3+ regulatory T cells increases during the 
progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin 
Cancer Res, 2006. 12(18): p. 5423-34.
14.
Shibuya, K.C., et al., Pancreatic ductal adenocarcinoma contains an effector and 
regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment. 
PLoS One, 2014. 9(5): p. e96565.
15.
Royal, R.E., et al., Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally 
advanced or metastatic pancreatic adenocarcinoma. J Immunother, 2010. 33(8): p. 
828-33.
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Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX-
1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75.
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Beatty, G.L., et al., A phase I study of an agonist CD40 monoclonal antibody (CP-
870,893) in combination with gemcitabine in patients with advanced pancreatic ductal 
adenocarcinoma. Clin Cancer Res, 2013. 19(22): p. 6286-95.

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18.
Le, D.T., et al., A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated 
Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase i 
studies of safety and immune induction. Clin Cancer Res, 2012. 18(3): p. 858-68.
19.
Le, D.T., et al., Evaluation of ipilimumab in combination with allogeneic pancreatic 
tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J 
Immunother, 2013. 36(7): p. 382-9.
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Andreu, P., et al., FcRgamma activation regulates inflammation-associated squamous 
carcinogenesis. Cancer Cell, 2010. 17(2): p. 121-34.
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Schioppa, T., et al., B regulatory cells and the tumor-promoting actions of TNF-alpha 
during squamous carcinogenesis. Proc Natl Acad Sci U S A, 2011. 108(26): p. 10662-
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Affara, N.I., et al., B cells regulate macrophage phenotype and response to 
chemotherapy in squamous carcinomas. Cancer Cell, 2014. 25(6): p. 809-21.
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Hata, D., et al., Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent 
mast cell degranulation and cytokine production. J Exp Med, 1998. 187(8): p. 1235-47.
24.
Soucek, L., et al., Modeling pharmacological inhibition of mast cell degranulation as a 
therapy for insulinoma. Neoplasia, 2011. 13(11): p. 1093-100.
25.
Dubovsky, J.A., et al., Ibrutinib is an irreversible molecular inhibitor of ITK driving a 
Th1-selective pressure in T lymphocytes. Blood, 2013. 122(15): p. 2539-49.
26.
Plate, J.M., et al., Effect of gemcitabine on immune cells in subjects with 
adenocarcinoma of the pancreas. Cancer Immunol Immunother, 2005. 54(9): p. 915-
25.
27.
Vizio, B., et al., Potential plasticity of T regulatory cells in pancreatic carcinoma in 
relation to disease progression and outcome. Exp Ther Med, 2012. 4(1): p. 70-78.
28.
Homma, Y., et al., Changes in the immune cell population and cell proliferation in 
peripheral blood after gemcitabine-based chemotherapy for pancreatic cancer. Clin 
Transl Oncol, 2014. 16(3): p. 330-5.
29.
Von Hoff, D.D., et al., Gemcitabine plus nab-paclitaxel is an active regimen in patients 
with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol, 2011. 29(34): p. 
4548-54.
30.
Bishop, G.A., et al., Antigen-specific B-lymphocyte activation. Crit Rev Immunol, 2003. 
23(3): p. 149-97.
31.
Shaffer, A.L., A. Rosenwald, and L.M. Staudt, Lymphoid malignancies: the dark side 
of B-cell differentiation. Nat Rev Immunol, 2002. 2(12): p. 920-32.
32.
Satterthwaite, A.B. and O.N. Witte, The role of Bruton's tyrosine kinase in B-cell 
development and function: a genetic perspective. Immunol Rev, 2000. 175: p. 120-7.
33.
Palucka, A.K., et al., Dendritic cells loaded with killed allogeneic melanoma cells can 
induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J 
Immunother, 2006. 29(5): p. 545-57.
34.
Vence, L., et al., Circulating tumor antigen-specific regulatory T cells in patients with 
metastatic melanoma. Proc Natl Acad Sci U S A, 2007. 104(52): p. 20884-9.

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Appendices
Appendix 1
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
2
In bed < 50% of the time
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities
Up and about more than 50% of 
waking hours
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2   New York Heart Association (NYHA) Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease.
Class
Functional Capacity
Objective 
Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective 
evidence of 
cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence 
of minimal 
cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence 
of moderately severe 
cardiovascular 
disease.
IV
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased.
Objective evidence 
of severe 
cardiovascular 
disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & 
Co; 1994:253-256.

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Appendix 3
Guidelines for Women of Child-Bearing Potential
Women of Child-Bearing Potential are Defined as Follows:

Any female who has experienced menarche and does not meet the criteria for 
“Women Not of Childbearing Potential”.
 
Women Not of Childbearing Potential are Defined as Follows:

Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy)

Women who are >45 years of age, not using hormone replacement therapy 
and who have experienced total cessation of menses for at least 1 year OR 
who have a follicle stimulating hormone (FSH) value >40 mIU/mL and an 
estradiol value <40pg/mL (140 pmol/L)

Women who are >45 years of age, using hormone replacement therapy and 
who have experienced total cessation of menses for at least 1 year OR who 
have had documented evidence of menopause based on FSH >40 mIU/mL 
and estradiol <40 pg/mL prior to initiation of hormone replacement therapy
  
Acceptable Contraception Methods:
Male patients with female partners of child-bearing potential and women patients of 
childbearing potential are required to use two forms of acceptable contraception, including 
one barrier method, during their participation in the trial and for 6 months (women) or 
6 months (men) following discontinuation of study treatment.  Male patients must also refrain 
from donating sperm for 6 months following discontinuation of study treatment.
The following are acceptable forms of barrier contraception: 

Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository
The following are acceptable forms of secondary contraception, when used with a barrier 
method and spermicide: 

True abstinence.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception

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Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
Patients with Measureable Disease
Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used, as it does not provide 
additional meaning or accuracy.
Baseline Eligibility
Measurable Disease:
Tumor lesions:  Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is 
to be recorded) with a minimum size of:
10 mm by CT scan (CT scan slice thickness no greater than 5 
mm).
10 mm caliper measurement by clinical exam (lesions that 
cannot be accurately measured with calipers should be 
recorded as non-measurable).
20 mm by chest X-ray.
Skin lesions:  Documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.
Malignant lymph nodes:  To be considered pathologically 
enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan.  At baseline and in 
follow-up, only the short axis will be measured and followed. 
Non-Measurable Disease:
All other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with >10- to <15-mm 
short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, 
abdominal masses, and abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging 
requirements. 

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Target Lesions:
Selected 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 
baseline.  
Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), should be representative 
of all involved organs, and in addition should be those that 
lend themselves to reproducible repeated measurements.  
Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or 
a short axis of >15 mm by CT scan.
A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then as noted above, only the 
short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective 
tumor response.
Non-Target Lesions:
All other lesions should be identified as non-target lesions at 
baseline.  Measurements of these lesions are not required, 
but the presence or absence of each should be noted 
throughout follow-up.
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment, as per study screening requirements.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the anti-tumor effect of a treatment.
Clinical Lesions:
Clinical lesions will only be considered measurable when they 
are superficial (e.g., 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.
Chest X-ray:
Lesions on chest X-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated 
lung.  However, CT is preferable.

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Conventional CT and MRI:
CT is the best currently available and reproducible method to 
measure target lesions selected for response assessment.  
This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm 
or less.  MRI of the chest should only be performed in 
extenuating circumstances.  Even if IV contract cannot be 
administered (for example, in the situation of allergy to 
contract), a non-contrast CT of the chest is still preferred over 
MRI.
Ultrasound:
Ultrasound should not be used to measure tumor lesions.  
Ultrasound may be useful to confirm the complete 
disappearance of superficial lesions usually assessed by 
clinical examination.
Endoscopy and 
Laparoscopy:
Use of endoscopy and laparoscopy should not be used to 
measure tumor lesions. Such techniques can be useful in 
confirming complete pathological response when biopsies are 
obtained.
Tumor Markers:
Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper limit of normal, they 
must normalize for a subject to be considered in complete 
clinical response when all lesions have disappeared.
Cytology and Histology:
Cytology and histology can be used to differentiate between 
PR and CR in rare cases (e.g., after treatment to differentiate 
between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors).

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Response Criteria
Evaluation of Target Lesions
Complete Response: 
Complete disappearance of all target lesions.  Any 
pathological lymph node (target or non-target) must have a 
reduction in short axis to < 10 mm).  
Partial Response: 
A decrease from baseline of ≥30% of the diameter(s) of all 
target lesions.
Stable Disease:  
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
(nadir) sum of the diameters of target lesions while on study.
Progressive Disease:  
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest (nadir) sum while on 
study (this includes the baseline sum if that is the smallest on 
study), or the appearance of one or more new lesions.  
Requires not only 20% increase, but absolute increase of a 
minimum of 5 mm over sum.
Evaluation of Non-Target Lesions
Complete Response:
Disappearance of all non-target lesions.  All lymph nodes 
must be non-pathological in size (<10 mm short axis).
Stable Disease:   
Persistence of one or more non-target lesions.
Progressive Disease: 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  When the subject 
also has measurable disease, to achieve “unequivocal 
progression” on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in the target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.

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Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the subject’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.  
Target Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
NO
CR
CR
SD
NO
PR
CR
NE
NO
PR
PR
SD OR NE
NO
PR
SD
SD OR NE
NO
SD
PD
ANY
YES OR NO
PD
ANY
PD
YES OR NO
PD
ANY
ANY
YES
PD
NE
SD
NO
NE
Abbreviations: CR=complete response; NE=not evaluable; PD = progressive disease; 
PR=partial response; SD=stable disease.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status. 
When nodal disease is included in the sum of target lesions, and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression, should it be based on increase in size of the nodes.  As noted earlier, this means 
that patients with CR may not have a total sum of “zero” on the CRF.

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Appendix 5
Data and Safety Monitoring Plan for a Multicenter Institutional Study (Phase 
1 Dose Escalation Institutional Study)
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:
• Review of subject data in each cohort
• Review of suspected adverse reactions considered “serious”
• Approval of dose escalation by DSMC Chair (or qualified alternate)
• Monthly monitoring (depending on study accrual)
• Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
All institutional Phase 1 therapeutic studies are designated with a high risk assessment. The 
data is monitored monthly as subjects are enrolled and includes all visits monitored up through 
the Dose Limiting Toxicity (DLT) period. At the time of dose escalation, a written report will be 
submitted to the DSMC Chair outlining the cohort dose, all adverse events and suspected 
adverse reactions considered “serious”, and any Dose Limiting Toxicity as described in the 
protocol. The report will be reviewed by the DSMC Chair or qualified alternate and written 
authorization to proceed or a request for more information will be issued within 2 business days 
of the request. The report is then reviewed at the subsequent DSMC meeting. In the event that 
the committee does not concur with the DSMC Chair’s decision, further study accrual is held 
while further investigation takes place.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at weekly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. For 
each dose level, the discussion will include the number of patients, significant toxicities in 
accordance with the protocol, doses adjustments, and observed responses.
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment. The following issues will be discussed as appropriate:

Enrollment information

Cohort updates (i.e. DLTs)

Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information)

Protocol violations

Other issues affecting the conduct of the study

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Dose Level Considerations
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls. 
The dose level for ongoing enrollment will be confirmed for each subject scheduled to be 
enrolled at a site. Dose level assignments for any subject scheduled to begin treatment must be 
confirmed by the UCSF Coordinating Center via fax or e-mail.
If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must be 
notified immediately by the UCSF Coordinating Center. The Study Chair has 1 business day 
(after first becoming aware of the event at either the UCSF Coordinating Center or the 
participating site) in which to report the information to all participating sites. If the DLT occurs at 
a participating site, the local investigator must report it to the UCSF Coordinating Center within 1 
business day, after which the UCSF Coordinating Center will notify the other participating sites.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites. The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e. 
copies of source documents) from the participating sites will be faxed over to the UCSF 
Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the 
participating site’s compliance with the protocol, patient safety, and to verify data entry.
All clinically significant adverse events (AEs), whether or not unexpected, and whether or not 
considered to be associated with the use of study drug, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.
All clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis 
at the UCSF Coordinating Center’s Site Committee. All clinically significant adverse events must 
be reported to the UCSF Coordinating Center by the participating sites within 10 business days 
of becoming aware of the event. The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s).
In addition, all suspected adverse reactions considered “serious” are entered into OnCore® and 
will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at the DSMC meetings, which take place every six (6) weeks.
All suspected adverse reactions considered “serious” should be reported to the UCSF 
Coordinating Center within 1 business day of becoming aware of the event or during the next 
scheduled conference call, whichever is sooner.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail.
Increase in Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified. The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in 
the Investigator Brochure or package insert.

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If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified
Data and Safety Monitoring Committee Contacts:
DSMC Chair: 
DSMC Monitors 
Phone: 
Email:
Address: 
 
UCSF Helen Diller Family 
Comprehensive Cancer Center
San Francisco, CA 94143
*  DSMP approved by NCI 09/February2012

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Appendix 6
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Investigator-Initiated Oncology Clinical Trials with an Investigator held Investigational 
New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:

CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals

Current and prior approved protocol versions with signed protocol signature page(s)

Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF)

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event Reporting

Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial) or Investigator Brochure

Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)

Patient handouts

Screening/enrollment log

Data and Safety Monitoring Committee (DSMC) monitoring reports

DSMC dose escalation approvals with study status summary forms

OnCore® Case Report Form (CRF) completion manual

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Documents Filed in Regulatory Binder:

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)

Site Initiation Visit (SIV) minutes and correspondence with participating site(s).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center

Serious Adverse Event (SAE) reports to CHR and sponsor.

MedWatch reporting to FDA and sponsor

Delegation of Authority Form

Drug Destruction Standard Operating Procedure (SOP)

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges

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Appendix 7 Data and Safety Monitoring Plan for Multicenter Institutional Study
(Phase 2 or 3 Institutional Study)
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 

Review of subject data

Review of suspected adverse reactions considered “serious”

Monthly monitoring (depending on study accrual)

Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three).
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes.
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate:

Enrollment information 

Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information)

Protocol violations

Other issues affecting the conduct of the study
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 

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to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site’s compliance with the protocol, patient safety, and to verify data entry.
Adverse Event Review and Monitoring
Adverse Event Monitoring
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites.
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail.
Increase in Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in 
the Investigator Brochure or package insert.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC 
must receive a formal letter within 10 business days and the CHR must be notified.
Data and Safety Monitoring Committee Contacts:
DSMC Chair: 
DSMC Monitors 
Phone: 
Email:
Address: 
 
UCSF Helen Diller Family 
Comprehensive Cancer Center
San Francisco, CA 94143
*  DSMP approved by NCI 09/February2012

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Appendix 8
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND)
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial.
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   HDFCCC Essential Regulatory Documents
Documents Filed in iMedRIS:

CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals

Current and prior approved protocol versions with signed protocol signature page(s)

Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF)

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event Reporting

Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial) or Investigator Brochure

Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC)

Patient handouts

Screening/enrollment log

Data and Safety Monitoring Committee (DSMC) monitoring reports

OnCore® Case Report Form (CRF) completion manual

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Documents Filed in Regulatory Binder:

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.)

Site Initiation Visit (SIV) minutes and correspondence with participating site(s).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center

Serious Adverse Event (SAE) reports to CHR and sponsor.

MedWatch reporting to FDA and sponsor

Delegation of Authority Form

Drug Destruction Standard Operating Procedure (SOP)

For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
2.  Additional Essential Documents for Multicenter Trials for the Coordinating 
Center (filed in Regulatory Binder or OnCore)

Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for 
the Participating Site(s)

For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational 
New Drug Application

Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). 

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s)

Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting 
fax documentation for Participating Site(s)

Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s)

Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s)

For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, 
lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating 
Site(s)

Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan 
(if an outside CRO is used for the study)

Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the 
Participating Site(s)
27 April 2012

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Appendix 9    Required Regulatory Documents for Sub-sites Participating in a UCSF 
Investigator Initiated Multicenter Trial (Checklist)
Directions: 
1)  Fax the documents listed below to the UCSF Coordinating center 
 or 
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found
1572
  PI and Sub investigators:
CV and Medical license 
Financial disclosure form
NIH or CITI human subject protection training certification
  Laboratories  
CLIA and CAP
CV of Lab Director and Lab Licenses
Laboratory reference ranges
Local Institutional Review Board 
  IRB Approval letter
  Reviewed/Approved documents

Protocol version date:  
___________

Informed consent version date:  ___________

Investigator Brochure version date:  ___________

HIPAA 
  Current IRB Roster
Other 
  Delegation of Authority Log 

Include NIH or CITI human subject protection training certificates or GCP training 
certification
  Pharmacy

Drug destruction SOP and Policy
  Protocol signature page 
  Executed sub contract
27.apr.2012

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Appendix 10 Inhibitors and Inducers of CYP3A
Strong 
inhibitors
Moderate inhibitors
Weak 
inhibitors
All Other Inhibitors
Indinavir
Aprepitant
Cimetidine
Chloramphenicol 
Nelfinavir
Amprenavir
fluvoxamine
Delaviridine
Ritonavir
Atzanavir 
Diethyl-Dithiocarbamate
Clarithromycin
Ciprofloxacin
Gestodene 
Itraconazole
Crizotinib
Mifepristone
Ketoconazole
Darunavir
Norfloxacin
Nefazodone
Diltiazem 
Norfluoxetine
Saquinavir
dronedarone
Suboxone
Erythromycin
Telithromycin
Fluconazole
cobicistat
Grapefruit Juice
boceprevir
Seville Orange Juice
mibefradil
Verapamil
telaprevir
Voriconazole
Troeandomycin
imatinib
posaconazole
Inducers
Carbamazepine
Oxcarbarzepine
Rifabutin
Efavirenz
Phenobarbital
Rifampin
Nevirapine
Phenytoin
St. John’s 
Wort
Barbiturates
Pioglitazone
Troglitazone
Glucocorticoids
Modafinil
Oxcarbarzepine
Phenobarbital
Phenytoin
Pioglitazone