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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  
  
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  
  
Sub-investigator: Gina Vaccaro, MD
Statistician Jimmy Hwang, PhD
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.  
| 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.
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participating site(s)

[Name]
[Institution name] [Address] Telephone: E-mail:
[Name]  
  
  
[Institution name] [Address] Telephone: E-mail:
Principal Investigator **Site**  
 Printed Name Signature Date  
| 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 Patients with previously untreated metastatic pancreatic adenocarcinoma                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                            |
|-----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Patient  population   | Gemcitabine and nab-paclitaxel is a standard regimen (NCCN, Category 1) for                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                            |
| Rationale for         | patients with metastatic pancreatic ductal adenocarcinoma (PDAC). However,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                            |
| Study                 | 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. Phase Ib: |                                                                                                                                                                            |
| Primary  Objectives   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 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 nabpaclitaxel, 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.  Phase Ib:                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                            |
| Secondary  Objectives |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | To evaluate the safety of treatment with ibrutinib in combination with nabpaclitaxel 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. |
| Immune Response Study:   To verify and confirm the safety of ibrutinib in combination with nabpaclitaxel 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 nabPaclitaxel 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 EUSguided 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                                                                                                                              |  
| 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 followup  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 nabpaclitaxel or rash for gemcitabine) for more than 21 days, patients may  continue on study receiving the other drugs, including ibrutinib.  29-50                                |                                                                                                                                                                       |                                                                     |
|--------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|
| Number of  patients            | 10 months                                                                                                                                                             |                                                                     |
| Duration of  Therapy           | 1 year                                                                                                                                                                |                                                                     |
| Duration of  Follow up         | 5 yrs                                                                                                                                                                 |                                                                     |
| Duration of  study 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                      | 1.                                                                                                                                                                    | Histologically or cytologically confirmed pancreatic adenocarcinoma |
| Criteria                       | 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 screening ECGs must be  <470 msec. 1. Any prior systemic or investigational therapy for metastatic pancreatic |                                                                                                                                                                                                                                                                                                                                                    |
| Exclusion  Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 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., 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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list of abbreviations

| 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                                 |  
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                                                                                                                                                                       | I INTRODUCTION                                                                                                                              |
| 1.1                                                                                                                                                                     | Background Current Treatment of Advanced Pancreatic Adenocarcinoma                                                                          |
| ..............................................................................................................................15                                        |                                                                                                                                             |
| 1.2                                                                                                                                                                     | lmmunotherapy for Pancreatic Adenocarcinoma                                                                                                 |
| 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                                   |                                                                                                                                             |
| Rationale of Combining Ibrutinib with Gemcitabine and nab-Paclitaxel ..18                                                                                               |                                                                                                                                             |
| 1.5                                                                                                                                                                     |                                                                                                                                             |
| 1.6                                                                                                                                                                     | Ibrutinib .............................................................................................................................19   |
| 1.7                                                                                                                                                                     | Summary of Non-Clinical Data                                                                                                                |
| Pharmacology .................................................................................................................20                                        |                                                                                                                                             |
| 1.7.1                                                                                                                                                                   |                                                                                                                                             |
| 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                                                                           |
| lbrutinib                                                                                                                                                               |                                                                                                                                             |
| 1.8.3                                                                                                                                                                   | Treatment Discontinuations                                                                                                                  |
| 1.8.4                                                                                                                                                                   | Bleeding-related events.....................................................................................................23              |
| 1.8.5                                                                                                                                                                   | CC                                                                                                                                          |
| 1.8.6                                                                                                                                                                   | Rash                                                                                                                                        |
| 1.8.7                                                                                                                                                                   | Non-Melanoma Skin Cancer .....................................................................................23                            |
| 1.8.8                                                                                                                                                                   | Infections .                                                                                                                                |
| 1.8.9                                                                                                                                                                   | Cytopenias .                                                                                                                                |
| Diarrhea                                                                                                                                                                |                                                                                                                                             |
| 1.8.10                                                                                                                                                                  |                                                                                                                                             |
| 1.8.11                                                                                                                                                                  | Lung Disease (ILD) .....................................................................................................24                  |
| 1.8.12                                                                                                                                                                  | Ongoing Combination Clinical Studies in Solid Tumors* .....................24                                                               |
| 2                                                                                                                                                                       | Objectives of the Study                                                                                                                     |
| Phase Ib                                                                                                                                                                |                                                                                                                                             |
| 2.1                                                                                                                                                                     |                                                                                                                                             |
| 2.2                                                                                                                                                                     | lmmune Response Cohort...............................................................................................25                     |
| 2.3                                                                                                                                                                     | Exploratory Objectives, Other Assessments.....................................................26                                            |
| 3                                                                                                                                                                       | Study Design .                                                                                                                              |
| 3.1                                                                                                                                                                     | Eligibility Criteria ..............................................................................................................26       |
| Inclusion Criteria                                                                                                                                                      |                                                                                                                                             |
| 3.1.1                                                                                                                                                                   |                                                                                                                                             |
| 3.1.2                                                                                                                                                                   | Exclusion Criteria ...........................................................................................................28            |
| 3.1.3                                                                                                                                                                   | Duration of and Discontinuation from Protocol Therapy .........................28                                                           |
| 3.1.4                                                                                                                                                                   | Pregnancy ...............................................................................................................................29 |  
| 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                                                                  |  
| Table of Contents                                                                                          |                                                                                                                                                         |                |
|------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| 8.1.2                                                                                                      | Dose and Administration ...................................................................................48                                           |                |
| 8.1.3                                                                                                      | Accountability ......................................................................................................48                                 |                |
| 8.1.4                                                                                                      | Precautions and Risks                                                                                                                                   |                |
| 8.2                                                                                                        | Gemcitabine                                                                                                                                             |                |
| 8.2.1                                                                                                      | Drug Storage and Stability ........................................................................................51                                   |                |
| 8.2.2                                                                                                      | Drug Administration                                                                                                                                     |                |
| 8.2.3                                                                                                      | Side Effects .                                                                                                                                          |                |
| 8.3                                                                                                        | Nab-paclitaxel (Abraxane) ........................................................................................51                                    |                |
| 8.3.1                                                                                                      | Drug Storage and Stability ..........................................................................................51                                 |                |
| 8.3.2                                                                                                      | Drug Administration                                                                                                                                     |                |
| 8.3.3                                                                                                      | Side Effects .                                                                                                                                          |                |
| 9                                                                                                          | Response Evaluations And Measurements                                                                                                                   |                |
| Statistical Considerations .                                                                               |                                                                                                                                                         |                |
| 10                                                                                                         | 10.1                                                                                                                                                    | Study Design   |
| 10.2                                                                                                       | Study Endpoints                                                                                                                                         |                |
| 10.3                                                                                                       | Pharmacodynamic (PD) Analysis ...............................................................................53                                         |                |
| 10.4                                                                                                       | Exploratory Endpoints                                                                                                                                   |                |
| 10.5                                                                                                       | Randomization                                                                                                                                           |                |
| 10.6                                                                                                       | Stratification .                                                                                                                                        |                |
| Missing Data and Replacement Policy ....................................................................53 |                                                                                                                                                         |                |
| 10.7                                                                                                       |                                                                                                                                                         |                |
| 10.8                                                                                                       | Interim Analyses and Stopping Rules ........................................................................53                                          |                |
| 10.9                                                                                                       | Analyses Plans .                                                                                                                                        |                |
| Primary Analysis (or Analysis of Primary Endpoints)....................................53                  |                                                                                                                                                         |                |
| 10.10                                                                                                      |                                                                                                                                                         |                |
| 10.11                                                                                                      | Secondary Analysis (or Analysis of Secondary Endpoints) .......................54                                                                       |                |
| 10.12                                                                                                      | Analyses of Exploratory Endpoints ............................................................................54                                        |                |
| 10.13                                                                                                      | Evaluation of Safety .                                                                                                                                  |                |
| Safety Reporting And Analyses                                                                              |                                                                                                                                                         |                |
| 1                                                                                                          | 1.1                                                                                                                                                     | Adverse Events |
| 1.2                                                                                                        | Serious Adverse Events                                                                                                                                  |                |
| 1.3                                                                                                        | Usage of Concurrent/Concomitant Medications ...........................................64                                                               |                |
| 1.3.1 Medications to be Used With Caution .......................................................64        |                                                                                                                                                         |                |
| 1.4                                                                                                        | Dietary Restrictions ......................................................................................................64                           |                |
| 12                                                                                                         | Reporting and Documentation of Results .......................................................................................65                        |                |
| 12.1                                                                                                       | Evaluation of Efficacy (or Activity).......................................................................65                                           |                |
| Antitumor Effect - Solid Tumors .....................................................................65    |                                                                                                                                                         |                |
| 12.1.1                                                                                                     |                                                                                                                                                         |                |
| 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 |                |  
| 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 |                                                                      |
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list of figures table of

| 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   |
|--------------------------------------------------------------------------------------------------------------------------------------|
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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

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.
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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 myeloidderived 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 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].
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1.3 rationale for targeting regulatory

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.  
  
To investigate the B-cell specific contribution to PDAC tumor growth *in vivo*, B cell- and/or FcγRdeficient mice were assessed for their ability to support growth of syngeneic orthotopic PDAC
(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 reeducated to promote productive anti-tumor immune responses.
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1.4 rationale for targeting bruton's

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).  
  
Inhibition of Btk has additional immune effects which have the potential to translate into antitumor 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.
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1.5 rationale of combining ibrutinib

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 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.
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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 Xlinked 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 PCYC04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug administration. 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.
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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
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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.
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1.7.2 carcinogenesis mutagenesis impairment of

Carcinogenicity studies have not been conducted with ibrutinib. Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs.
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1.8 summary of clinical data

For the most comprehensive clinical information regarding ibrutinib, refer to the current version of the Investigator's Brochure.
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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 ontarget 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 9.8fold 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.
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1.8.2 summary of clinical studies

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).
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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.  
| Most frequently reported   | Most frequently reported   | Most frequently reported   |
|----------------------------|----------------------------|----------------------------|
| TEAEs >10%                 | Grade 3 or 4 TEAEs >2%     | Serious TEAEs >1%          |
| Diarrhea                   | Neutropenia                | Pneumonia                  |
| Fatigue                    | Pneumonia                  | Atrial fibrillation        |
| Nausea                     | Thrombocytopenia           | Febrile neutropenia        |
| Cough                      | Anemia                     | Pyrexia                    |
| Anemia                     | Hypertension               |                            |
| Pyrexia                    | Atrial fibrillation        |                            |
| Neutropenia                |                            |                            |  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving ibrutinib as monotherapy (N=1071): For more detailed information refer to the current version of the IB.
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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   | Most frequently reported   | Most frequently reported   |
|----------------------------|----------------------------|----------------------------|
| TEAEs >10%                 | Grade 3 or 4 TEAEs >2%     | 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.
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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 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).
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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.
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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.
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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.
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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.
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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.
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1.8.9 cytopenias

Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported in subjects treated with ibrutinib.
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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.
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1.8.12 ongoing combination clinical studies

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 runin 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 nabpaclitaxel and gemcitabine.  
| Study                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Description                                                                                                                                      | Number of                 |       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|-------|
| Number                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Subjects                                                                                                                                         |                           |       |
| Planned/Exposeda                                                                                                                                                                                                                                                                                                                                                                                                                                           | Study Drug(s); Dose Regimen;                                                                                                                     | Enrollment/Study          |       |
| Duration of Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                      | Statusb                                                                                                                                          |                           |       |
| Solid Tumors 1135 Phase 1b/2, openlabel study of the  safety and efficacy  ibrutinib +  MEDI4736 in  subjects with solid  tumors.                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Phase 1b: 6-36/6                                                                                                                                 | ibrutinib capsules (oral) |       |
| Phase 2: 130/111                                                                                                                                                                                                                                                                                                                                                                                                                                           | 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, doubleblind, 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                                                                                                                                |                           |       |  
| Study                 | Description                                                                                                               | Number of        |                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                   |
|-----------------------|---------------------------------------------------------------------------------------------------------------------------|------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|
| Number                | Subjects                                                                                                                  |                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                   |
| Planned/Exposeda      | Study Drug(s); Dose Regimen;                                                                                              | Enrollment/Study |                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                   |
| Duration of Treatment | 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 |
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2 objectives of the study

To determine the maximum tolerated dose of ibrutinib in combination with albumin bound paclitaxel and gemcitabine in patients with metastatic pancreatic adenocarcinoma
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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 nabpaclitaxel 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.
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2.2 immune response cohort primary

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.
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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. |
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3 study design 3.1 eligibility

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 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.
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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.
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3.1.3 duration of and discontinuation

Patients will be treated until disease progression, or will be discontinued from protocol treatment for any of the following reasons: - Documented disease progression - 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.
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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 paper report form) should be completed. For more details regarding handling and reporting of pregnancies that occur during treatment, see Section 11.4.
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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.
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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 EUSguided 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 (cont'd) immune

Pre-treatment EUS-directed core biopsy, CA 19-9 (n=20)  
  
  
lbrutinib at 560, 420 or 280 mg/day days 1-7 Post-ibrutinib  EUS-directed core biopsy,  CA19-9,  Baseline CT* scans BCR/TCR sequencing, immunophenotyping (blood)
Start Treatment  
  
  
  
End of Treatment Visit Follow-Up CA19-9, Baseline CT scans Blood draws for Correlative Studies BCR/TCR seq, immunophenotyping (blood)  
  
*Non-hematologic DLT
*560 mg/day  unless 420 or 280 mg/day  determined to be MTD
**
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5.2 dosage and administration of

Treatment will be administered on an outpatient basis.  
| Table 2. Dose Escalation Schedule* Minimum Number of                                          |                    |          |
|-----------------------------------------------------------------------------------------------|--------------------|----------|
| Dose Level                                                                                    | Dose of Study Drug | 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 |                    |          |  
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.
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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.
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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 nabpaclitaxel, 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. 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.
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5.2.3 combination therapy for phase

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.  
| Cycle       |                          |             |                    |        |
|-------------|--------------------------|-------------|--------------------|--------|
| Study Drug  | Dose                     | Route       | Schedule           | Length |
| 560, 840,   | Continuous  daily dosing |             |                    |        |
| Ibrutinib   | 420, or 280              | Oral        |                    |        |
| mg          | 4 weeks  (28 days)       |             |                    |        |
| Nab             |                          |             |                    |        |
| Paclitaxel  | 125 mg/m2                | Intravenous | Days 1, 8,  and 15 |        |
| Gemcitabine | 1000  mg/m2              | Intravenous | Days 1, 8,  and 15 |        |
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5.2.4 one week run-in with

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.
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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.
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ibrutinib 560 840 420 or

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.
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gemcitabine 1000mg/m2 iv day 1

Infuse over approximately 30 minutes or according to institutional standards within following the completion of the nab-paclitaxel.
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5.4 restaging during the combination

Restaging by CT scans per RECIST version 1.1 (see Appendix 4) will occur every 2 cycles.
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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.
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5.6 general concomitant medication and

All concomitant medications taken during the study will be documented in the CRF with the indication, dose information, and dates of administration. - 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.
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6 dose modifications and dosing

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.  
| 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                                                                                                                                                   |
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6.2 dose modifications for dose

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.  
| 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   |  
| 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
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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".
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6.3.1 dose modifications and schedule

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 nabpaclitaxel and gemcitabine.
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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.
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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 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.  
| Treatment Day Counts and Toxicity   |           |               |                                                                    |
|-------------------------------------|-----------|---------------|--------------------------------------------------------------------|
| ANC                                 | Platelets | Timing        |                                                                    |
| Treat on time,                      |           |               |                                                                    |
| >1.5 x 109 /L                       | And       | >100 x 109 /L | continue at 100% of  present dose Delay by 1 week  intervals until |
| <1.5 x 109 /L                       | Or        | <100 x 109 /L | recovery.                                                          |  
| Gemcitabine              |                                                                      |                          |                     |
|--------------------------|----------------------------------------------------------------------|--------------------------|---------------------|
| Day 8 Blood Counts       | Day 8                                                                | Day 15                   | Day 15              |
| Dose Modification        | Blood Counts                                                         | Dose Modification        |                     |
| ANC > 1000 and           | Maintain dose level                                                  | ANC > 1000 and Platelets | Maintain dose level |
| > 75,000                 |                                                                      |                          |                     |
| Platelets > 75,000       | ANC 500-1000 or Platelets                                            | Hold+ consider G-CSFa    |                     |
| 50,000 -74,999           | Upon count recovery,  when safe to resume,  maintain same dose level |                          |                     |
| ANC < 500a or Platelets  | Hold+ consider G-CSFa                                                |                          |                     |
| <50,000                  | Upon count recovery,  when safe to resume,  decrease by 1 dose level |                          |                     |
| ANC 500-1000 or          | Hold+ consider G-CSFa                                                | ANC > 1000 and Platelets | Maintain dose level |
| ≥ 75,000                 |                                                                      |                          |                     |
| Platelets 50,000 -74,999 | (treat on time)                                                      |                          |                     |  
| Day 8 Blood Counts                                            | Day 8                                                                | Day 15                   | Day 15                   |
|---------------------------------------------------------------|----------------------------------------------------------------------|--------------------------|--------------------------|
| Dose Modification                                             | Blood Counts                                                         | Dose Modification        |                          |
| ANC 500-1000 or Platelets                                     | Hold+ consider G-CSFa                                                |                          |                          |
| 50,000 -74,999                                                | Upon count recovery,  when safe to resume,  decrease by 1 dose level |                          |                          |
| ANC < 500a or Platelets                                       | Hold+ consider G-CSFa                                                |                          |                          |
| <50,000                                                       | Upon count recovery,  when safe to resume,  decrease by 1 dose level |                          |                          |
| ANC < 500 or                                                  | Hold+ consider G-CSFa                                                | ANC > 1000 and Platelets | Decrease by 1 dose level |
| ≥ 75,000                                                      |                                                                      |                          |                          |
| Platelets <50,000                                             | (treat on time)                                                      |                          |                          |
| ANC ≤1000 or Platelets                                        | Hold+ consider G-CSFa                                                |                          |                          |
| 50,000 -74,999                                                | Upon count recovery,  when safe to resume,  decrease by 1 dose level |                          |                          |
| ANC < 500a or Platelets                                       | Hold+ consider G-CSFa                                                |                          |                          |
| <50,000                                                       | Upon count recovery,  when safe to resume,  decrease by 1 dose level |                          |                          |
| Abbreviations: G-CSF = Granulocyte colony stimulating factor. |                                                                      |                          |                          |  
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.
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6.3.2 dose modifications and schedule

Dose level modifications for non-hematologic toxicities for nab-paclitaxel, gemcitibine and ibrutinib where appropriate are found in Tables 7 and 8. 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 nonhematologic 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) |                |           |
| 3 a, b, c                                                                                                    | Hold                                                                                                                                                                 |                |           |
| Once the AE has been resolved to <Grade 1 or  baseline, reduce by one dose level at the next  administration |                                                                                                                                                                      |                |           |
| 4 c                                                                                                          | Off protocol therapy                                                                                                                                                 |                |           |
| a The decision as to which drug (any or all three) should be modified will depend upon the type              |                                                                                                                                                                      |                |           |  
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:  
| CTC Grade      | Dose modification of gemcitabine and/or   | Dose modification of Ibrutinib   |
|----------------|-------------------------------------------|----------------------------------|
| nab-paclitaxel |                                           |                                  |
| 0-2a           | Maintain at same dose level               |                                  |
| b, c, d        | Hold                                      |                                  |
| 3              |                                           |                                  |  
| Once the AE has been resolved to <Grade 1 or baseline, reduce by one dose  level at the next administration   |                      |
|---------------------------------------------------------------------------------------------------------------|----------------------|
| 4 d                                                                                                           | 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.
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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 reescalated 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.
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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.
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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.  
- 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.
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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                                                                                                                                                                     | AND/OR          | Grade 0-1 (up to  1.5x ULN)                                                                                                      | Maintain at same dose level           |
| 5x ULN) Grade 0-2 (up to                                                                                                                                                             | AND/OR          | Grade 2 (>1.5-3.0 x                                                                                                              | Hold treatment; resume all drugs once |
| 5x ULN)                                                                                                                                                                              | ULN)            | total bilirubin resolves to Grade ≤1 1 st episode: resume at same dose level Recurrent episodes: resume at one dose  level lower |                                       |
| Grade 3 (>5-20x                                                                                                                                                                      | AND/OR          | Grade 3 (>3-10x                                                                                                                  | Hold treatment; resume both drugs at  |
| ULN)                                                                                                                                                                                 | ULN)            | one dose level lower once total bilirubin  resolves to Grade ≤1 and AST/ALT to  Grade ≤2.                                        |                                       |
| Grade 4 (>20x                                                                                                                                                                        | OR              | Grade 4 (>10x ULN)                                                                                                               | Remove from study treatment           |
| ULN)                                                                                                                                                                                 |                 |                                                                                                                                  |                                       |
| 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. |                 |                                                                                                                                  |                                       |
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6.3.2.5 cutaneous toxicity

Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the next lower dose level for nab-pa. If the patient continues to experience Grade 2 or 3 reactions, despite dose reduction, treatment should be discontinued. Patients who develop Grade 4 cutaneous toxicity should have treatment discontinued.
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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.
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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.
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7 study procedures and observations

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.
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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)*
- 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)
- ECOG PS (see Appendix 1)*
- 12-lead ECG
- 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.
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7.3 study treatment assessments 7.3.1

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.
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7.4 combination therapy treatment period

- 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 (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
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7.4.2 day 8 of all

- AE assessment - CBC, including 3-part differential and platelets - CMP
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7.4.3 cycles 1 and 2

- 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)
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7.4.5 cycle 3 and beyond

- AE assessment - Concomitant medication review - CBC, including 3-part differential and platelets - CMP (See Section 7.8)
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7.5 every 2 cycles (8

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.
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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 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).
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7.7 follow-up 7.7.1 progression-free survival

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.
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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.
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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)
- ALT (SGPT) - total bilirubin - total protein - albumin
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8 drug formulation availability administration

Ibrutinib (IMBRUVICA®) will be supplied to the investigational pharmacy by Pharmacyclics, Inc.
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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.
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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.
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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.
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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.
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less likely (at least 10%

Cough Stomatitis Sinusitis Anemia Pyrexia Neutropenia Dizziness Thrombocytopenia Constipation Peripheral edema Upper respiratory tract infection Vomiting Urinary tract infection
Dyspnea Skin infection Petechiae Pneumonia Headache Muscle spasms Epistaxis Decreased appetite Hypertension
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rarely (but may be serious)

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
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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 intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (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.
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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.
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8.2.3 side effects

Most common side effects include myelosuppresion, rash, nausea/vomiting, fever, fatigue, flulike 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.
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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.
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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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8.3.3 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.
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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).
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10 statistical considerations 10.1 study

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.
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10.2 study endpoints phase ib

Safety and tolerability of ibrutinib in combination with gemcitabine and nab-paclitaxel
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immune response study

Primary endpoint:  
- 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 nabpaclitaxel.
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secondary endpoints

- Median time-to-progression (TTP)
- Median progression-free survival (PFS)  
- Median overall survival (OS)
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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
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10.7 missing data and replacement

Data for all patients will be summarized and analyzed to the extent the available data allow. Missing data will not be imputed or replaced.
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10.8 interim analyses and stopping

Not applicable for phase Ib study design. Stopping rules are already included as part of standard 3+3 design.
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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.
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10.10 primary analysis (or analysis

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 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.
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10.11 secondary analysis (or analysis

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.
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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.
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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.
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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.
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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
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10.12 analyses of exploratory endpoints

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.
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t cell frequency clonality and

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.
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changes in circulating and intra-tumoral

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 influenced by sample size1, 2, and reported as a continuous variable from 0-1 with1 indicating maximal dissimilarity.
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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.
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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.
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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.
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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.