Conditions: Acute Myeloid Leukemia (AML)
Keywords: Acute Myeloid Leukemia AML Ibrutinib Cytarabine LD-AraC Azacitidine
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety and tolerability of ibrutinib alone or in combination with either cytarabine or azacitidine in the treatment of subjects with Acute Myeloid Leukemia (AML) who have failed standard treatment, or subjects without prior therapy who refuse standard chemotherapy.

Detailed description:

Arms:
arm 1: Up to 33 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis. arm 2: Up to 25-28 additional response evaluable subjects (for a total of 34 subjects) will receive ibrutinib 560 mg once daily on a continuous basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 10 days of a 28-day cycle. arm 3: Up to 34 response evaluable subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75mg/m2 IV once daily Days 1-7 of a 28-day cycle (with an option to increase to 100mg/m2 after 2 cycles).

Interventions: intervention 1: Ibrutinib intervention 2: Ibrutinib + LD-AraC intervention 3: Ibrutinib+Azacitidine
Intervention descriptions: intervention 1: Subjects will receive ibrutinib 560 mg once daily on a continuing basis. intervention 2: Subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 10 days of a 28-day cycle. intervention 3: Subjects will receive ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle (with an option to increase to 100 mg/m2 after 2 cycles).

Protocol document:
Prot_000.pdf: 
IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 1 
 
 
 
 
 
 
 
PROTOCOL 
 
 
TITLE: 
A Multicenter Open-Label Phase 2a Study of Ibrutinib 
Monotherapy or in Combination with either Cytarabine or 
Azacitidine in Subjects with Acute Myeloid Leukemia 
PROTOCOL NUMBER: 
PCYC-1131-CA 
STUDY DRUG: 
IMBRUVICA® (ibrutinib) 
IND NUMBER: 
102,688 
SPONSOR MEDICAL 
MONITOR: 
Nora Marie Cavazos, MD 
Pharmacyclics LLC 
Phone: +1 (408) 215-3489 
Fax: +1 (408) 215-3684 
Email: ncavazos@pcyc.com 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
08 August 2014 
AMENDMENT 1: 
15 January 2016 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee.  This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics LLC. 
 
 


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PROTOCOL APPROVAL PAGE 
Study Title: A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or 
in Combination with either Cytarabine or Azacitidine in Subjects with 
Acute Myeloid Leukemia 
Study Number: PCYC-1131-CA 
Protocol Date: 08 August 2014 
Amendment 1 Date: 15 January 2016 
 
I have carefully read Protocol PCYC-1131-CA entitled “A Multicenter Open-Label Phase 2a 
Study of Ibrutinib Monotherapy or in Combination with either Cytarabine or Azacitidine in 
Subjects with Acute Myeloid Leukemia”.  I agree to conduct this study as outlined herein and in 
compliance with Good Clinical Practices (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that the Sponsor, Pharmacyclics, and the Institutional Review 
Board/Research Ethics Board/Independent Ethics Committee (IRB/REB/IEC) must approve any 
changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
of Pharmacyclics.  All data pertaining to this study will be provided to Pharmacyclics.  
The policy of Pharmacyclics LLC requires that any presentation or publication of study data by 
clinical Investigators be reviewed by Pharmacyclics, before release, as specified in the protocol. 
Principal Investigator’s Signature 
Date 
Print Name 
The following Pharmacyclics LLC representative is authorized to sign the protocol and any 
amendments: 
Medical Monitor’s Signature 
Date 
Nora Marie Cavazos, MD 
Clinical Development, Pharmacyclics LLC 
 
 


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PCYC-1131-CA-Amendment 1 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................9 
LIST OF IN-TEXT TABLES .......................................................................................................9 
SYNOPSIS ....................................................................................................................................10 
ABBREVIATIONS ......................................................................................................................15 
1. 
BACKGROUND ............................................................................................................17 
1.1. 
Acute Myeloid Leukemia (AML) ...................................................................................17 
1.1.1. 
Treatment Options ...........................................................................................................17 
1.1.2. 
Role of Bruton Tyrosine Kinase (BTK) in Acute Myeloid Leukemia ............................18 
1.2. 
Investigational Product Name and Description ...............................................................19 
1.3. 
Summary of Nonclinical Data .........................................................................................19 
1.3.1. 
Pharmacology ..................................................................................................................19 
1.3.2. 
Safety Pharmacology and Toxicology .............................................................................20 
1.4. 
Summary of Clinical Data ...............................................................................................20 
1.4.1. 
Pharmacokinetics and Product Metabolism ....................................................................20 
1.5. 
Summary of Clinical Safety ............................................................................................21 
1.5.1. 
Monotherapy Studies .......................................................................................................21 
1.5.2. 
Combination Studies .......................................................................................................22 
1.5.3. 
Risks ................................................................................................................................22 
1.5.3.1. Bleeding-related Events ...................................................................................................22 
1.5.3.2. Atrial Fibrillation .............................................................................................................22 
1.5.3.3. Cytopenias .......................................................................................................................23 
1.5.3.4. Diarrhea ...........................................................................................................................23 
1.5.3.5. Infections .........................................................................................................................23 
1.5.3.6. Second primary Malignancies .........................................................................................23 
1.5.3.7. Rash .................................................................................................................................23 
1.5.3.8. Lymphocytosis and Leukostasis ......................................................................................23 
1.5.3.9. Tumor Lysis Syndrome ...................................................................................................24 
1.6. 
Summary of Clinical Data ...............................................................................................24 
1.7. 
Study Rationale ...............................................................................................................24 
2. 
STUDY OBJECTIVES .................................................................................................25 
2.1. 
Primary Objectives ..........................................................................................................25 


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2.2. 
Secondary Objectives ......................................................................................................26 
2.3. 
Exploratory Objectives ....................................................................................................26 
3. 
STUDY DESIGN ...........................................................................................................26 
3.1. 
Overview of Study Design ..............................................................................................26 
3.1.1. 
Study Schema – Cohorts 1 and 2 .....................................................................................28 
3.1.2. 
Study Schema – Cohorts 3 ..............................................................................................29 
3.2. 
Study Design Rationale ...................................................................................................30 
3.2.1. 
Study Population and Treatment .....................................................................................30 
3.2.2 
Dose Selection .................................................................................................................31 
4. 
SUBJECT SELECTION ...............................................................................................31 
4.1. 
Inclusion Criteria .............................................................................................................31 
4.2. 
Exclusion Criteria ............................................................................................................32 
5. 
TREATMENT OF SUBJECTS ....................................................................................34 
5.1. 
Treatment Allocation and Blinding .................................................................................34 
5.2. 
Definition of Dose Limiting Toxicity (DLT) ..................................................................34 
5.3. 
Study Treatment ..............................................................................................................35 
5.4. 
Study Medication .............................................................................................................36 
5.4.1. 
Ibrutinib ...........................................................................................................................36 
5.4.1.1. Formulation/Packaging/Storage ......................................................................................36 
5.4.1.2. Dose and Administration .................................................................................................36 
5.4.1.3. Overdose ..........................................................................................................................36 
5.4.1.4. Dose Modification for Adverse Reactions ......................................................................37 
5.4.1.5. Dose Modification for Hepatic Impaired Subjects ..........................................................38 
5.4.2. 
LD-AraC ..........................................................................................................................38 
5.4.2.1. Formulation/Packaging/Storage ......................................................................................38 
5.4.2.2. Dose and Administration .................................................................................................38 
5.4.2.3. Overdose ..........................................................................................................................39 
5.4.2.4. Dose Modification for Adverse Reactions ......................................................................39 
5.4.3. 
Azacitidine .......................................................................................................................39 
5.4.3.1. Formulation/Packaging/Storage ......................................................................................39 
5.4.3.2. Dose and Administration .................................................................................................39 
5.4.3.3. Overdose ..........................................................................................................................39 
5.4.3.4. Dose Modification for Adverse Reactions ......................................................................39 
5.5. 
Criteria for Permanent Discontinuation of Study Drug ...................................................39 


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6. 
CONCOMITANT MEDICATIONS/PROCEDURES ...............................................40 
6.1. 
Permitted Concomitant Medications ...............................................................................40 
6.2. 
Medications to be Used with Caution .............................................................................40 
6.2.1. 
CYP3A Inhibitors/Inducers .............................................................................................40 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib .....................41 
6.2.3. 
QT Prolonging Agents .....................................................................................................41 
6.2.4. 
Antiplatelet Agents and Anticoagulants ..........................................................................41 
6.3. 
Prohibited Concomitant Medications ..............................................................................42 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ..............................42 
6.4.1. 
Minor Surgical Procedures ..............................................................................................42 
6.4.2. 
Major Surgical Procedures ..............................................................................................42 
6.4.3. 
Emergency Procedures ....................................................................................................42 
7. 
STUDY EVALUATIONS .............................................................................................42 
7.1. 
Description of Procedures ...............................................................................................42 
7.1.1. 
Assessments .....................................................................................................................43 
7.1.1.1. ICF ...................................................................................................................................43 
7.1.1.2. Confirm Eligibility ..........................................................................................................43 
7.1.1.3. Medical History and Demographics ................................................................................43 
7.1.1.4. Prior and Concomitant Medications ................................................................................44 
7.1.1.5. Adverse Events ................................................................................................................44 
7.1.1.6. Physical Examination ......................................................................................................44 
7.1.1.7. Vital Signs .......................................................................................................................44 
7.1.1.8. ECOG ..............................................................................................................................44 
7.1.2. 
Laboratory .......................................................................................................................45 
7.1.2.1. Hematology .....................................................................................................................45 
7.1.2.2. Chemistry (Serum) ..........................................................................................................45 
7.1.2.3. Coagulation Studies .........................................................................................................45 
7.1.2.4. Hepatitis Serologies .........................................................................................................45 
7.1.2.5. Urinalysis .........................................................................................................................45 
7.1.2.6. Pregnancy Test ................................................................................................................45 
7.1.3. 
Diagnostics/Procedures ...................................................................................................46 
7.1.3.1. ECG .................................................................................................................................46 
7.1.3.2. Bone Marrow Aspirate/Biopsy ........................................................................................46 
7.1.3.3. Cytogenetics/Karyotype ..................................................................................................46 


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7.1.3.4. Cerebrospinal Fluid Collection ........................................................................................46 
7.1.3.5. Pharmacokinetics .............................................................................................................47 
7.1.3.6. T/B/NK Cell Count ..........................................................................................................48 
7.1.3.7. Predictive Biomarkers and Mechanisms of Resistance ...................................................48 
7.1.3.8. Genetic and Molecular Prognostic Markers ....................................................................49 
7.2. 
Efficacy Evaluations ........................................................................................................49 
7.3. 
Sample Collection and Handling .....................................................................................50 
8. 
STUDY PROCEDURES ...............................................................................................50 
8.1. 
Overview .........................................................................................................................50 
8.2. 
Screening Phase ...............................................................................................................50 
8.3. 
Treatment Phase ..............................................................................................................51 
8.3.1. 
Treatment Visits - Ibrutinib + LD-AraC Combination Cohort .......................................51 
8.3.1.1. Ibrutinib Run-in Day 1 Visit ............................................................................................51 
8.3.1.2. Ibrutinib Run-in Day 2 Visit ............................................................................................52 
8.3.1.3. Cycle 1 Day 1 Visit .........................................................................................................52 
8.3.1.4. Cycle 1 Day 8 Visit .........................................................................................................53 
8.3.1.5. Cycle 1 Day 15 Visit .......................................................................................................53 
8.3.1.6. Cycle 1 Day 22 Visit .......................................................................................................54 
8.3.1.7. Cycle 2 Day 1 Visit .........................................................................................................54 
8.3.1.8. Cycle 2 Day 8 Visit .........................................................................................................55 
8.3.1.9. Cycle 2 Day 15 Visit .......................................................................................................55 
8.3.1.10. Cycle 2 Day 22 Visit .......................................................................................................55 
8.3.1.11. Cycle 3 Day 1 Visit .........................................................................................................56 
8.3.1.12. Cycle 3 Day 15 Visit .......................................................................................................56 
8.3.1.13. Cycle 4 Day 1 Visit .........................................................................................................57 
8.3.1.14. Cycle 4 Day 15 Visit .......................................................................................................57 
8.3.1.15. Cycle 5 and Beyond, Day 1 Visit ....................................................................................58 
8.3.2. 
Treatment Visits - Ibrutinib Monotherapy Cohort ..........................................................58 
8.3.2.1. Cycle 1 Day 1 Visit .........................................................................................................58 
8.3.2.2. Cycle 1 Day 2 Visit .........................................................................................................59 
8.3.2.3. Cycle 1, Day 8 Visit ........................................................................................................59 
8.3.2.4. Cycle 1 Day 15 Visit .......................................................................................................60 
8.3.2.5. Cycle 1 Day 22 Visit .......................................................................................................60 
8.3.2.6. Cycle 2 Day 1 Visit .........................................................................................................61 


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8.3.2.7. Cycle 2 Day 8 Visit .........................................................................................................61 
8.3.2.8. Cycle 2 Day 15 Visit .......................................................................................................62 
8.3.2.9. Cycle 2 Day 22 Visit .......................................................................................................62 
8.3.2.10. Cycle 3 Day 1 Visit .........................................................................................................62 
8.3.2.11. Cycle 3 Day 15 Visit .......................................................................................................63 
8.3.2.12. Cycle 4 Day 1 Visit .........................................................................................................63 
8.3.2.13. Cycle 4 Day 15 Visit .......................................................................................................64 
8.3.2.14. Cycle 5 and Beyond, Day 1 Visit ....................................................................................64 
8.3.3. 
Treatment Visits - Ibrutinib + Azacitidine Combination Cohort ....................................65 
8.3.3.1. Ibrutinib Run-in Day 1 Visit ............................................................................................65 
8.3.3.2. Cycle 1 Day 1 Visit .........................................................................................................65 
8.3.3.3. Cycle 1 Day 7 Visit .........................................................................................................66 
8.3.3.4. Cycle 1 Day 15 Visit .......................................................................................................66 
8.3.3.5. Cycle 1 Day 22 Visit .......................................................................................................67 
8.3.3.6. Cycle 2 Day 1 Visit .........................................................................................................67 
8.3.3.7. Cycle 2 Day 7 Visit .........................................................................................................68 
8.3.3.8. Cycle 2 Day 15 Visit .......................................................................................................68 
8.3.3.9. Cycle 2 Day 22 Visit .......................................................................................................68 
8.3.3.10. Cycle 3 Day 1 Visit .........................................................................................................69 
8.3.3.11. Cycle 3 Day 15 Visit .......................................................................................................69 
8.3.3.12. Cycle 4 Day 1 Visit .........................................................................................................70 
8.3.3.13. Cycle 4 Day 15 Visit .......................................................................................................70 
8.3.3.14. Cycle 5 and Beyond, Day 1 Visit ....................................................................................71 
8.3.4. 
Treatment Failure (TF) Visit ...........................................................................................71 
8.3.5. 
End-of-Treatment (EOT) Visit ........................................................................................71 
8.4. 
Follow-up Phase ..............................................................................................................72 
8.4.1. 
Response Follow-up (RFU) .............................................................................................72 
8.4.2. 
Long-Term Follow-up (LTFU) .......................................................................................72 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................73 
9.1. 
Completion ......................................................................................................................73 
9.2. 
Withdrawal from Study Treatment ..................................................................................73 
9.3. 
Withdrawal from Study ...................................................................................................73 
10. 
STATISTICAL METHODS AND ANALYSIS ..........................................................74 
10.1. 
Demographics, Baseline Characteristics and Study Conduct ..........................................74 


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10.2. 
Endpoints .........................................................................................................................74 
10.2.1. Primary Efficacy Endpoint ..............................................................................................74 
10.2.2. Secondary Efficacy Endpoints ........................................................................................74 
10.3. 
Sample Size Determination .............................................................................................75 
10.4. 
Efficacy Analysis .............................................................................................................75 
10.5. 
Safety Analysis ................................................................................................................76 
10.6. 
Pharmacokinetic Analysis ...............................................................................................77 
10.7. 
Biomarker Analyses ........................................................................................................77 
11. 
ADVERSE EVENT REPORTING ..............................................................................78 
11.1. 
Definitions .......................................................................................................................78 
11.1.1. Adverse Events ................................................................................................................78 
11.1.2. Serious Adverse Events ...................................................................................................79 
11.1.3. Severity Criteria (Grade 1-5) ...........................................................................................79 
11.1.4. Causality (Attribution) .....................................................................................................80 
11.2. 
Unexpected Adverse Events ............................................................................................80 
11.3. 
Special Reporting Situations ...........................................................................................81 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ....................................................................................................................81 
11.4.1. Assessment of Adverse Events ........................................................................................81 
11.4.2. Adverse Event Reporting Period .....................................................................................81 
11.4.3. Expediting Reporting Requirements for Serious Adverse Events ..................................82 
11.4.4. Pregnancy ........................................................................................................................83 
11.4.5. Other Malignancies .........................................................................................................83 
11.4.6. Adverse Events of Special Interest (AESI) .....................................................................83 
11.4.6.1. Major Hemorrhage ..........................................................................................................84 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............84 
12.1. 
Regulatory and Ethical Compliance ................................................................................84 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ..................................................................................84 
12.3. 
Informed Consent ............................................................................................................85 
12.4. 
Quality Control and Quality Assurance ..........................................................................85 
12.5. 
Protected Subject Health Information Authorization ......................................................85 
12.6. 
Study Files and Record Retention ...................................................................................86 
12.7. 
Case Report Forms and Record Maintenance .................................................................87 
12.8. 
Investigational Study Drug Accountability .....................................................................87 


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12.9. 
Study Monitoring/Audit Requirements ...........................................................................88 
12.10. 
Investigator Responsibilities ...........................................................................................88 
12.11. 
Sponsor Responsibilities .................................................................................................89 
12.12. 
Financial Disclosure ........................................................................................................89 
12.13. 
Liability and Clinical Trial Insurance ..............................................................................89 
12.14. 
Protocol Amendments .....................................................................................................90 
12.15. 
Publication of Study Results ...........................................................................................90 
12.16. 
Study Discontinuation .....................................................................................................90 
13. 
REFERENCES ..............................................................................................................91 
14. 
APPENDICES ................................................................................................................93 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments – Ibrutinib + LD-AraC Combination Cohort ...............94 
Appendix 2: 
Schedule of Assessments – Ibrutinib Monotherapy Cohort ..................................96 
Appendix 3: 
Schedule of Assessments – Ibrutinib + Azacitidine Combination Cohort 
(Cohort 3) ...............................................................................................................98 
Appendix 4: 
ECOG Status Scores ............................................................................................100 
Appendix 5: 
Inhibitors and Inducers of CYP3A ......................................................................101 
Appendix 6: 
Response Criteria .................................................................................................102 
Appendix 7: 
Child-Pugh Score for Subjects with Liver Impairment .......................................103 
 
LIST OF IN-TEXT TABLES 
Table 1.  Ibrutinib Dose Modifications ..........................................................................................38 
Table 2.  Ibrutinib + LD-AraC Combination Cohort .....................................................................47 
Table 3.  Ibrutinib Monotherapy Cohort ........................................................................................47 
Table 4.  Ibrutinib + Azacitidine Combination Cohort ..................................................................47 
 
 
 


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SYNOPSIS 
Study Title: 
A Multicenter Open-Label Phase 2a Study of Ibrutinib Monotherapy or in 
Combination with either Cytarabine or Azacitidine in Subjects with Acute 
Myeloid Leukemia  
Protocol Number: 
PCYC-1131-CA 
Study Phase: 
2a 
Study Duration: 
Estimated to be 3.5 – 4 years 
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
Low-dose cytosine arabinoside (LD-AraC) will be administered at 20 mg 
twice daily (BID) subcutaneously (sc) for 10 days of a 28-day cycle.  
Azacitidine will be administered at 75 mg/m2 intravenously (IV) once 
daily on Days 1-7 of a 28-day cycle (with an option to increase to 
100 mg/m2 IV once daily after 2 cycles). 
Objectives: 
Primary Objectives: 
• 
To evaluate the efficacy of ibrutinib monotherapy or in combination 
with either LD-AraC or azacitidine in the treatment of Acute Myeloid 
Leukemia (AML) using the overall remission rate (defined as 
proportion of subjects achieving a CR or CRi) according to the 
LeukemiaNet guidelines (Döhner 2010) 
• 
To evaluate the safety and tolerability of ibrutinib monotherapy or in 
combination with either LD-AraC or azacitidine in subjects with 
AML 
Secondary Objectives: 
• 
To evaluate clinical efficacy by assessing relapse-free survival (RFS), 
event-free survival (EFS), and overall survival (OS)  
• 
To evaluate clinical benefit defined as complete remission (CR), 
complete remission with incomplete marrow recovery (CRi), 
morphologic leukemia-free state, or partial remission (PR) 
Exploratory Objectives: 
• 
To determine the plasma pharmacokinetics (PK) of ibrutinib 
monotherapy or in combination with either LD-AraC or azacitidine in 
an AML population 
• 
To evaluate prognostic and predictive biomarkers relative to 
treatment outcomes (ie, Btk/pBtk, secreted proteins, gene expression 
profiling, mutational analysis) 
Study Design: 
This Phase 2a open-label, non-randomized U.S. multicenter study is 
designed to evaluate the safety and efficacy of ibrutinib monotherapy or 
in combination with either cytarabine or azacitidine in the treatment of 
subjects with AML.  
A maximum of 101 response evaluable subjects will be enrolled in up to 
3 treatment cohorts: 
• 
Cohort 1 – ibrutinib monotherapy: ibrutinib 560 mg once daily on a 


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continuous basis. 
• 
Cohort 2 – ibrutinib + LD-AraC:  ibrutinib 560 mg once daily on a 
continuous basis plus low dose cytarabine. 
• 
Cohort 3 – ibrutinib + azacitidine: ibrutinib 560 mg once daily on a 
continuous basis plus IV azacitidine. 
The study will begin with a safety run-in in the ibrutinib + LD-AraC 
combination cohort only.  Six subjects will receive ibrutinib at a dose 
level of 560 mg once daily on a continuing basis starting 2 days prior to 
the first cytarabine dose.  LD-AraC will be administered at 20 mg twice 
daily (BID) subcutaneously (sc) for 10 days of a 28-day cycle. 
Assessment for dose limiting toxicities (DLTs) will continue for the first 
treatment cycle.  Refer to Section 5.2. 
If 2 of the first 6 subjects experience DLTs, 3 additional subjects will be 
assessed for DLT(s).  If 3 or more of the 9 subjects experience DLTs, 
enrollment will be halted at the 560 mg dose level.  At Sponsor’s 
discretion a dose of 420 mg ibrutinib or lower (plus LD-AraC) may be 
explored.  
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience 
DLT(s), additional subjects will be enrolled in one of two treatment 
cohorts:  
• 
Cohort 1: ibrutinib monotherapy: up to 33 response evaluable 
subjects will receive ibrutinib 560 mg once daily on a continuous 
basis. 
OR 
• 
Cohort 2: ibrutinib + LD-AraC: up to 25-28 additional response 
evaluable subjects (for a total of 34 subjects) will receive ibrutinib 
560 mg once daily on a continuous basis starting 2 days prior to first 
cytarabine dose (20 mg BID sc) for 10 days of a 28-day cycle. 
Subjects will be assigned to either treatment cohort at the discretion of the 
treating investigator.   
Efficacy parameters will be monitored closely.  In the event response 
assessments suggest futility in the ibrutinib + AraC cohort, further 
enrollment in either the ibrutinib monotherapy or the ibrutinib + AraC 
cohorts will be closed and a new cohort of ibrutinib + azacitidine will be 
started:  
• 
Cohort 3: ibrutinib + azacitidine: up to 34 response evaluable subjects 
will receive ibrutinib 560 mg once daily on a continuous basis 
starting 1 day prior to first azacitidine dose + azacitidine 75mg/m2 IV 
once daily Days 1-7  of a 28-day cycle (with an option to increase to 
100 mg/m2 after 2 cycles). 
For Cohort 3 the same safety run-in principle as Cohort 2 (6+3 design) 
will be implemented.  If less than 2 out of 6 subjects or less than 3 out of 
9 subjects experience DLT(s), additional subjects will be enrolled.  If 3 or 
more of the 9 subjects experience DLTs, enrollment will be halted at the 
560 mg dose level.  At Sponsor’s discretion a dose of 420 mg ibrutinib or 
lower (plus azacitidine) may be explored.  
Study treatment will continue in subjects who demonstrate a PR or better 


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on their Cycle 2 Day 1 bone marrow assessment according to the 
LeukemiaNet guidelines (Döhner 2010) or based on clinical benefit as 
determined by the treating physician.  Treatment may continue thereafter 
until unacceptable toxicity, treatment failure (TF), or withdrawal of 
consent.  
Subjects treated in the ibrutinib monotherapy cohort who experience a 
documented TF or relapse will be permitted to add LD-AraC to ibrutinib 
per investigator discretion.  
Population: 
Adult subjects with pathologically documented AML that have failed 
standard treatment, or subjects without prior therapy who refuse standard 
chemotherapy 
Centers: 
Approximately 10-15 US centers  
Inclusion Criteria: 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
• 
Male and female ≥18 years of age. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 
0-2 
• 
Subjects with pathologically documented AML that has failed 
standard treatment (based on NCCN guidelines), or subjects without 
prior therapy who refuse standard treatment options  
• 
Screening bone marrow aspirate/biopsy results showing >5% blasts.  
• 
WBC count <25,000 cells/mm3 (25 x 109/L). 
o The use of hydroxyurea (HU) during the screening phase is 
permitted to control the peripheral blood count until 1 day 
(~5 half lives) prior study treatment.   
• 
Platelet count >10,000 cells/mm3 (10 x 109/L).  
• 
Adequate hepatic and renal function defined as: 
o For Cohorts 1 and 2: Serum aspartate transaminase (AST) or 
alanine transaminase (ALT) ≤3.0 x upper limit of normal (ULN); 
for Cohort 3: ALT ≤2.5 or AST ≤2.5 x ULN 
o Serum creatinine ≤2 mg/dL or Estimated Creatinine Clearance 
≥30 mL/min (Cockcroft-Gault) 
o Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin) 
• 
PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless 
abnormalities are unrelated to coagulopathy or bleeding disorder).  
When treated with warfarin or other vitamin K antagonists, then INR 
≤3.0). 
 Exclusion Criteria: 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
• 
Acute promyelocytic leukemia (French-American-British Class M3 
AML) 
• 
Known active central nervous system (CNS) leukemia 
• 
Known active systemic infection (Grade ≥2) 
• 
Clinical signs of bleeding (Grade ≥2) 
• 
Prior treatment with a BTK inhibitor 
• 
For Cohort 3 subjects, prior treatment with hypomethylating agents 


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• 
Prior bone marrow transplant that requires immunosuppressant 
therapy or presents with graft vs host disease (GVHD) 
• 
Anticancer therapy including chemotherapy, immunotherapy, 
radiotherapy, hormonal or any investigational therapy within 14 days 
or 5 half-lives (whichever is shorter) prior to first dose of study drug. 
• 
Subject has received a monoclonal antibody for anticancer intent 
within 8 weeks prior to the first dose of study drug. 
• 
Vaccinated with live, attenuated vaccines within 4 weeks of first dose 
of study drug. 
• 
Recent infection requiring intravenous (IV) systemic treatment that 
was completed ≤14 days before the first dose of study drug. 
• 
Known bleeding disorders (eg, von Willebrand’s disease) or 
hemophilia. 
• 
History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment. 
• 
Known history of human immunodeficiency virus (HIV) or active 
with hepatitis C virus (HCV) or hepatitis B virus (HBV).  Subjects 
who are positive for hepatitis B core antibody or hepatitis B surface 
antigen must have a negative polymerase chain reaction (PCR) result 
before enrollment.  Those who are PCR positive will be excluded. 
• 
Major surgery within 4 weeks of first dose of study drug. 
• 
Concomitant use of warfarin or other Vitamin K antagonists. 
• 
Requires treatment or prophylaxis with a strong cytochrome P450 
(CYP) 3A inhibitor (see Appendix 5)  
• 
Currently active, clinically significant hepatic impairment 
(≥ moderate hepatic impairment according to the Child Pugh 
classification [Appendix 7]).  
• 
Unable to understand the purpose and risks of the study and to 
provide a signed and dated informed consent form (ICF) and 
authorization to use protected health information (in accordance with 
national and local subject privacy regulations) 
Study Treatment: 
Cohort 1 – ibrutinib monotherapy: ibrutinib 560 mg once daily on a 
continuous basis 
Cohort 2 – ibrutinib + AraC: ibrutinib 560 mg once daily on a continuous 
basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 
10 days of a 28-day cycle 
Cohort 3 –ibrutinib + azacitidine: ibrutinib 560 mg once daily on a 
continuous basis starting 1 day prior to first azacitidine dose + azacitidine 
75 mg/m2 IV once daily on Days 1-7  of a 28-day cycle (with an option to 
increase to 100 mg/m2 after 2 cycles). 
Concomitant Therapy: 
Refer to Section 6 for information on concomitant therapy. 
Safety Plan: 
 
A safety review will be conducted for Cohort 2 (ibrutinib + AraC) after 
the first 6-9 subjects have completed the first cycle of treatment.   
A safety review will be conducted for Cohort 3 (ibrutinib + azacitidine) 
after the first 6-9 subjects have completed the first cycle of treatment.  


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The study will be monitored in accordance to the Sponsor’s 
Pharmacovigilance procedures.  Adverse events and serious adverse 
events (SAEs) will be reviewed internally on an ongoing basis to identify 
safety concerns.  
Statistical Methods and 
Data Analysis: 
Primary Efficacy Analysis: 
Overall remission rate (ORR) is defined as the proportion of response 
evaluable subjects who achieve a complete remission (CR) or complete 
remission with incomplete marrow recovery (CRi).  The ORR along with 
its 95% exact binomial confidence interval will be presented for each 
cohort separately.  
Response evaluable subjects are defined as subjects who had at least 1 
post-baseline response assessment or any subjects who died due to an 
AML-related cause or were discontinued early due to an AML-related 
event without at least 1 post-baseline response assessment.  
Secondary Efficacy Analyses: 
Secondary efficacy variables including relapse-free survival (RFS), 
event-free survival (EFS), overall survival (OS), and clinical benefit rate 
(CBR) will be analyzed. 
The efficacy of two treatment cohorts (ibrutinib monotherapy and 
ibrutinib with LD-AraC) will be evaluated separately.  No multiplicity 
adjustment will be applied to the analysis. 
Safety Analysis: 
Analysis of safety data will be conducted on the all treated population, 
which includes enrolled subjects who receive at least 1 dose of study drug 
(ibrutinib).  All subjects are to be monitored for adverse events during the 
study.  Other safety measurements include clinical laboratory tests and 
vital signs.  Descriptive statistics for each cohort will be used to 
summarize safety data (adverse events [AEs], clinical laboratory tests and 
vital signs) for all subjects receiving the study drug.  Summary statistics 
will include incidence, means, standard deviations, and medians for 
continuous variables and proportions for categorical variables. 
Interim Analysis 
No formal interim analysis is planned.  
Sample Size Determination 
Sample size was calculated to detect a meaningful signal of activity of 
each treatment cohort while minimizing risk of continuing enrollment 
under null conditions.  The sample size was estimated for each treatment 
cohort without multiplicity adjustment. 
The study will enroll up to 33 response evaluable subjects in the 
monotherapy cohort and up to 34 response evaluable subjects in each of 
the for combination cohorts.   
The sample size of 33 subjects was calculated to test the null hypothesis 
that the ORR of ibrutinib monotherapy is ≤5% (not clinically compelling) 
versus the alternative hypothesis that ORR will be ≥20%, with a 
significance level of 5%, and 80% power.   
The sample size of 34 subjects was calculated to test the null hypothesis 
that the ORR of ibrutinib plus LD-AraC or ibrutinib plus azacitidine is 
≤15% (not clinically compelling) versus the alternative hypothesis that 
ORR will be ≥35%, with a significance level of 5%, and 80% power.   


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ABBREVIATIONS 
AEs 
adverse events 
AESI 
Adverse events of special interest 
ANC 
absolute neutrophil count  
AML 
Acute myeloid leukemia 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time  
AST 
aspartate transaminase  
AUC 
area under the curve 
BCR 
B-cell receptor 
BID 
twice daily 
BMSCs 
bone-marrow stromal cells 
BR 
bendamustine and rituximab 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen  
CBR 
clinical benefit rate 
CFR 
Code of federal regulation 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete remission 
CRF 
case report form (paper or electronic as appropriate for this study) 
CRi 
complete remission with incomplete marrow recovery 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Event 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DLTs 
dose limiting toxicities 
ECG 
Electrocardiogram 
eDC 
electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
EFS  
event-free survival  
EOT 
End-of-treatment visit 
FDA 
U.S. Food and Drug Administration 
FCR 
fludarabine, cyclophosphamide, and rituximab  
GCP 
Good Clinical Practice 
GVHD 
Graft vs. Host disease 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 


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HU 
Hydroxyurea 
IB 
Investigator's Brochure 
IC50 
concentration that inhibits a process by 50%  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normal ratio 
IRB 
Institutional Review Board 
IUDs 
intrauterine devices 
IV 
Intravenous 
LC-MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry 
LD-AraC 
low-dose cytarabine  
LDH 
lactate dehydrogenase 
LTFU 
Long-term follow up 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
overall remission rate 
OS 
overall survival  
pBTK 
Bruton's tyrosine kinase protein 
PCR 
polymerase chain reaction  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PML 
progressive multifocal encephalopathy 
PO 
for oral 
PR 
partial remission 
PT 
prothrombin time 
QTc 
corrected QT interval 
RFS 
relapse-free survival 
RFU 
response follow up 
R-CHOP 
rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone 
SAEs 
serious adverse events 
sc 
Subcutaneous 
SJS 
Stevens-Johnson Syndrome 
SLL 
small lymphocytic lymphoma 
t1/2 
half life 
Tmax 
time to maximum plasma concentration  
TF 
treatment failure 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal  
WBC 
White blood cell 
WHO 
World Health Organization 
 
 


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1. 
BACKGROUND 
1.1. 
Acute Myeloid Leukemia (AML)  
Acute myeloid leukemia (AML) is characterized by the proliferation and accumulation of 
myeloid progenitor cells in the bone marrow, which leads to hematopoietic failure (Robak 2009).  
AML is the most frequent acute leukemia in adults and its incidence increases with age.  
An estimated 18,860 people will be diagnosed with AML in 2014 in the U.S. and 10,460 will die 
of the disease (Siegel 2013).  The median age at diagnosis is 66 years, with 54% of patients 
diagnosed at 65 years or older and approximately a third diagnosed at 75 years of age or older 
(Yin 2012).  Causes of AML include chemical exposure, prior chemotherapy and radiation, as 
well as other environmental toxins.  Of all the leukemias, AML has the lowest survival rate 
particularly in elderly subgroups as a result of poorer tolerability to standard therapy and the fact 
that elderly patients more frequently present with poor prognostic features.   
In 2008 the World Health Organization (WHO) revised the diagnostic and response criteria for 
AML, which was based on cytochemical stains and morphology, to include additional recurrent 
genetic abnormalities and molecular markers that appear to have prognostic impact.  In the past 
5 years the presence of autosomal monosomies (5 and 7) was found to be associated with 
decreased overall survival in patients aged 60 years and older.  Molecular profiling is increasing 
the ability to identify mutations that carry prognostic impact, particularly in patients with normal 
karyotype.  Markers that have been incorporated into risk categorization include FMS-like 
tyrosine kinase 3 (FLT3), c-KIT, nucleophosmin (NPM1) and CEBPA gene mutations.  
Molecular genetics is a rapidly evolving field in AML, and risk stratification is modified based 
on continuous evaluation of evolving data. 
1.1.1. 
Treatment Options  
Treatment of acute leukemia consists of induction chemotherapy and post-remission therapy.  
Standard induction therapies in patients younger than 60 years are based on high dose cytarabine 
and/or anthracyclines, with remission rates of 60%–70% and cure rates of 15%–25%.  
Post remission treatments consist of 3–4 cycles of high dose cytarabine regimens.  Despite the 
use of higher doses of cytarabine or addition of other chemotherapy agents (eg, etoposide, 
fludarabine) to the standard combination, the median progression-free survival is only 
approximately 7 months and most patients with AML will still succumb to their disease 
(Kern 2006).  
Treatment of AML in first relapse is associated with relatively low response rates.  Whenever 
second complete remission (CR) is attained, the median duration of the second relapse-free 
interval is generally considerably shorter compared to the first response (Leopold 2002).  
Patients failing to respond to one or two cycles of induction treatment may be considered for 
allogeneic stem cell transplantation if an HLA-matched donor is available.  For patients who 
emerge from the induction phase in poor condition to tolerate active treatment, best supportive 
care is provided.  Because only a minority of the patients who are refractory or experience 


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relapse will derive durable benefit from re-induction therapy, relapsed or refractory AML 
remains a field of high unmet need for new therapeutic options.   
Several studies suggest that elderly patients are often not offered standard induction 
chemotherapy given that early treatment related mortality can be in the range of 30% 
(Tilly 1990).  Median survival in patients 60 years of age or older is approximately 2 years and 
the overall cure rate is <20% (Menzin 2002).  The creation of separate guidelines for patients 
older than 60 recognizes their poor outcomes associated with an increased proportion of 
unfavorable karyotypes and mutations with multidrug resistance, as well as treatment-related 
mortality that exceeds any expected response in this age group (Appelbaum 2006).  For patients 
who cannot tolerate standard induction or intermediate intensity treatment, the NCCN guidelines 
(AML, Version 1 2015) options for low-intensity treatments include subcutaneous low-dose 
cytarabine, azaditidine and decitabine.  Studies of these treatments in treatment naïve patients 
unfit for chemotherapy have demonstrated CR rates between 18% and 35%, and disease free 
survival in patients who achieved CR of approximately 8 months (Burnett 2007, Fenaux 2010, 
Cashen 2010).  There is an urgent need to identify treatment strategies for AML which are not 
only effective but can be tolerated by older, relatively unfit patients. 
The use of ibrutinib as a potent covalent BTK inhibitor for the treatment of AML has not yet 
been investigated and may represent a safe and effective addition to the therapeutic arsenal.  
Moreover, the favorable toxicity profile of ibrutinib lends itself well to combination trials with 
the standard chemotherapeutic agents and potentially other targeted agents of interest in AML. 
1.1.2. 
Role of Bruton Tyrosine Kinase (BTK) in Acute Myeloid Leukemia 
Bruton tyrosine kinase (BTK) is an essential mediator in B lymphocytes coupling activated 
immunoreceptors to downstream signaling events that affect diverse biological functions, from 
cellular proliferation, differentiation and adhesion to innate and adaptive immune responses in 
the treatments of B cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle 
cell lymphoma (MCL) (Byrd 2013, Wang 2013), and is also an attractive potential approach for 
autoimmune diseases and inflammatory disorders (Honigberg 2010, Chang 2011). 
While BTK plays an important role in BCR-mediated signaling in the B-cell lineage, it is also 
expressed in other hematopoietic cell types such as monocytes/macrophages and neutrophils and 
contributes to immune-complex mediated activation of the FcγR signaling pathway as well as in 
TLR systems in these cells. 
Studies in AML derived cell lines suggest a role for BTK as a potential therapeutic target in 
AML (Rushworth 2014).  BTK phosphorylation (at Y223 and possibly Y551) was identified in 
AML blasts and ibrutinib was able to occupy the active site of BTK in AML cells with 
equivalent efficiency as it does in CLL.  The majority of the primary AML blasts displayed 
therapeutic responses to the BTK inhibitor ibrutinib on cell growth, adhesion and colony 
formation.  In addition, ibrutinib augmented the cytotoxic effects of both cytarabine and 
daurorubicin to BTK expressing AML cells in colony forming assays. 


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AML cell lines pretreated with ibrutinib at concentrations achievable in vivo and subsequently 
exposed to SDF1 (stromal derived factor 1) demonstrated CXCR4-mediated inhibition of cell 
migration compared to untreated controls (Zaitseva 2014), a mechanism that has been previously 
reported for CLL and other B-cell malignancies.  
BTK-dependent signaling has been shown to be highly context-dependent.  In 
FLT3-ITD-positive AML, BTK mediates FLT3-ITD dependent activation.  Combined targeting 
of FLT3-ITD and BTK using various concentrations of quizartinib and ibrutinib demonstrated an 
additive anti-proliferative effect (Oellerich 2015). 
1.2. 
Investigational Product Name and Description  
Ibrutinib (IMBRUVICA ®) is a first-in-class, potent, orally administered covalently-binding 
inhibitor of Bruton’s tyrosine kinase (BTK) developed by Pharmacyclics LLC for the treatment 
of B-cell malignancies.   
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia 
(CLL) who has received at least 1 prior therapy, first-line treatment of patients with CLL with a 
deletion of the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients with 
Waldenström’s macroglobulinemia.  Ibrutinib is currently under investigation in various 
indications as a single agent and in combinations.   
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigen.  Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways 
(Bishop 2003).  
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure (IB). 
1.3. 
Summary of Nonclinical Data  
1.3.1. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the BTK (Pan 2007).  In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position.  
When added directly to human whole blood, ibrutinib inhibits signal transduction from the BCR 


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and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed 
by CD69 expression (Herman 2011).   
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell lines 
in vitro and inhibited tumor growth in vivo in xenograft models (Herman 2011).  Ibrutinib also 
inhibited adhesion and migration of MCL cells in co-culture and reduced tumor burden in lymph 
node and bone marrow in a murine model of MCL dissemination and progression (Chang 2013a, 
Chang 2013b). 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB. 
1.3.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested.  Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs.  
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, 
the greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).   
In studies in pregnant rats and rabbits, ibrutinib administration was associated with 
malformations (teratogenicity) at ibrutinib doses that result in approximately 14 and 2 times the 
exposure (AUC) in patients administered the dose of 560 mg daily, respectively.  Fetal loss and 
reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib.  In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic.  No effects on fertility or reproductive 
capacities were observed in a study in male and female rats. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current IB.  
1.4. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the IB.  
1.4.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability.  


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The mean half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours.  Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food.  Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4.  The on-target effects of metabolite PCI-45227 are not considered clinically 
relevant.  Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose 
exposure.  Less than 1% of ibrutinib is excreted renally.  Ibrutinib exposure is not altered in 
patients with creatinine clearance (CrCl) >30 mL/min.  Patients with severe renal impairment or 
patients on dialysis have not been studied.  Following single dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects 
with normal liver function.  A higher proportion of Grade 3 or higher adverse reactions were 
reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.   
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the IB. 
1.5. 
Summary of Clinical Safety 
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below.  For more comprehensive safety information please refer to the current version of the IB.  
Additional safety information may be available for approved indications in regional prescribing 
labels where the study is conducted (eg, USPI, SmPC).  
1.5.1. 
Monotherapy Studies 
Pooled safety data for total of 1071 subjects treated with ibrutinib monotherapy from 9 studies in 
B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs >10%   
Most frequently reported Grade 
3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 


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1.5.2. 
Combination Studies 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below.  Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone).  
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 
Most frequently reported 
TEAEs >10%   
Most frequently reported Grade 3 
or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
 
1.5.3. 
Risks 
1.5.3.1. 
Bleeding-related Events  
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia.  These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria.  Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.  
Subjects with congenital bleeding diathesis have not been studied.  See Section 6.2.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See 
Section 6.4 for guidance on ibrutinib management with surgeries or procedures.   
At this time there are no data available to describe or predict how ibrutinib will affect the 
circulating levels of myeloid blasts.  
1.5.3.2. 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation.  For atrial fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines (see Section 5.4.1.4). 


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1.5.3.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
1.5.3.4. 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation.  These events are rarely severe.  Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.4.1.4). 
1.5.3.5. 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE v4.03).  The most commonly reported 
infections include pneumonia, cellulitis, urinary tract infection and sepsis.  Although causality 
has not been established, cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib.  
1.5.3.6. 
Second primary Malignancies 
Second primary malignancies, most frequently skin cancers, have occurred in subjects treated 
with ibrutinib.  Second primary malignancies including non-skin carcinomas have occurred in 
patients treated with ibrutinib.  The most frequent second primary malignancy was non-
melanoma skin cancer. 
1.5.3.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to 
moderate in severity. 
1.5.3.8. 
Lymphocytosis and Leukostasis 
Leukostasis  
There were isolated cases of leukostasis reported in subjects with CLL and NHL treated with 
ibrutinib.  A high number of circulating lymphocytes (>400,000/µL) may confer increased risk.   
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, 


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has been observed in most subjects with CLL/ small lymphocytic lymphoma (SLL) treated with 
ibrutinib.  This effect has also been observed in some subjects with MCL treated with ibrutinib.  
This observed lymphocytosis is a pharmacodynamic effect and should not be considered 
progressive disease in the absence of other clinical findings.  In both disease types, 
lymphocytosis typically occurs during the first few weeks of ibrutinib therapy (median time 
1.1 weeks) and typically resolves within a median of 8.0 weeks in subjects with MCL and 
18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, >400,000/µL) has been observed 
in some subjects.  Lymphocytosis was not observed in subjects with Waldenström’s 
macroglobulinemia treated with ibrutinib.  Lymphocytosis appeared to occur in lower incidence 
and at lesser magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy. 
At this time there are no data available to describe or predict how ibrutinib will affect the 
circulating levels of myeloid blasts.  
1.5.3.9. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-
agent ibrutinib or in combination with chemotherapy.  Subjects at risk of TLS are those with 
comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric 
acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and 
pre‐existing kidney abnormalities.  
1.6. 
Summary of Clinical Data  
This is the first clinical study of ibrutinib in subjects with AML.  
1.7. 
Study Rationale  
The study will enroll adult subjects with pathologically documented AML who have failed 
standard treatment, or subjects without prior therapy who cannot tolerate or refuse standard 
chemotherapy.  Subjects will receive ibrutinib monotherapy or in combination with either low-
dose cytarabine (LD-AraC) or azacitidine.   LD-AraC and hypomethylating agents (azacitidine 
and decitabine) are recommended by the NCCN guidelines for patients who are deemed unfit for 
standard induction or intermediate-intensity therapy.  Low dose cytarabine resulted in a survival 
benefit and a CR rate of 18% vs. 1% compared to hydroxyurea in newly diagnosed AML older 
patients with favorable or normal karyotype (Burnett 2007).  Azacitidine was compared to 
conventional care (Fenaux 2010) in high risk MDS and AML showed a significant survival 
benefit in favor of azacitidine in patients with AML.  Even with the low intensity treatment 
approach overall prognosis remains poor for older patients.   


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Studies with AML patient-derived blasts and established AML cell lines suggested BTK as a 
potential therapeutic target in AML (Rushworth 2014).  Primary AML cells had increased levels 
of BTK phosphorylation at tyrosine-223 (the auto-phosphorylation site) compared to CD34+ 
immature hematopoietic cells derived from healthy volunteers, suggesting BTK activity is 
elevated in AML cells.  Ibrutinib was able to bind BTK in AML cells comparably as it does in 
CLL cells.  The majority of patient-derived AML blasts were inhibited by ibrutinib in cell 
growth assays including clonogenic colony formation in soft agar.  Furthermore, ibrutinib 
augmented the cytotoxic effects of both cytarabine and daurorubicin to BTK-expressing AML 
cells in colony formation assays.  Importantly, there was an association of ibrutinib inhibition in 
growth assays with the level of BTK phosphorylation, suggesting that BTK inhibition by 
ibrutinib has a direct impact on AML cell proliferation. 
Another key element for the efficacy of ibrutinib in human AML patients is its potential impact 
on cell adhesion to the bone marrow microenvironment where tumor cells are well protected and 
nurtured by stromal and other accessory cells.  Ibrutinib inhibited the adhesion of AML cells to 
bone-marrow stromal cells (BMSCs) in the co-culture system at the potency required to inhibit 
BTK activity (Rushworth 2014).  Interaction between AML cells and the bone marrow 
microenvironment is believed to be critical in regulating tumor survival and resistance to 
chemotherapy.  In fact, inhibition of AML blast adhesion to BMSCs has been associated with 
improved tumor cytotoxicity (Becker 2012).  
The effect of BTK inhibition on tumor microenvironment via ibrutinib has been investigated in 
various types of blood cancer, namely CLL, MCL and multiple myeloma.  For example, ibrutinib 
significantly reduced adhesion and migration of MCL cells in co-culture with BMSCs.  In human 
MCL patients, treatment with ibrutinib resulted in transient mobilization of lymphocytes or light 
chain-restricted CD19+CD5+ cell fraction into the peripheral blood with concomitant decrease 
of tumor volume.  These results suggested that ibrutinib alone promoted tumor cell egress from 
the microenvironment and sensitized them to cell death (Chang 2013a).  
In summary, ibrutinib appears to have a dual anti-AML effect through 1) potentially mobilizing 
cells from its protective microenvironment and 2) exhibiting direct anti-proliferative/cytotoxic 
activity.  These preclinical studies provided a strong rationale for investigation of ibrutinib 
against AML as a single agent or a cell-mobilizing/chemo-sensitizing agent in combination with 
other chemotherapeutics such as cytarabine or hypomethylating agents. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
• To evaluate the efficacy of ibrutinib monotherapy or in combination with either LD-AraC 
or azacitidine in the treatment of Acute Myeloid Leukemia (AML) using the overall 
remission rate (defined as proportion of subjects achieving a CR or CRi) according to the 
LeukemiaNet guidelines (Döhner 2010). 


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• To evaluate the safety and tolerability of ibrutinib monotherapy or in combination with 
either LD-AraC or azacitidine in subjects with AML 
2.2. 
Secondary Objectives  
• To evaluate clinical efficacy by assessing relapse-free survival (RFS), event-free survival 
(EFS) and overall survival (OS)  
• To evaluate clinical benefit defined as CR, CRi, morphologic leukemia-free state, and 
partial remission (PR) 
2.3. 
Exploratory Objectives  
• To determine the pharmacokinetics (PK) of ibrutinib monotherapy or in combination 
with either LD-AraC or azacitidine in an AML population  
• To evaluate prognostic and predictive biomarkers relative to treatment outcomes 
(ie, Btk/pBtk, secreted proteins, gene expression profiling, mutational analysis) 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This Phase 2a open-label, non-randomized, U.S. multicenter study is designed to evaluate the 
safety and efficacy of ibrutinib monotherapy or in combination with either cytarabine or 
azacitidne in the treatment of subjects with AML.  
A maximum of 101 response evaluable subjects will be enrolled in up to 3 treatment cohorts: 
• Cohort 1 – ibrutinib monotherapy: ibrutinib 560 mg once daily on a continuous basis. 
• Cohort 2 – ibrutinib + LD-AraC:  ibrutinib 560 mg once daily on a continuous basis plus 
low dose cytarabine. 
• Cohort 3 – ibrutinib + azacitidine: ibrutinib 560 mg once daily on a continuous basis plus 
IV azacitidine.  
The study will begin with a safety run-in in the ibrutinib + LD-AraC combination cohort only.  
Six subjects will receive ibrutinib at a dose level of 560 mg once daily on a continuing basis 
starting 2 days prior to the first cytarabine dose.  LD-AraC will be administered at 20 mg twice 
daily (BID) subcutaneously (sc) for 10 days of a 28-day cycle.  
During the initial safety run-in, the 6 subjects will be assessed for dose limiting toxicities (DLTs) 
during the first treatment cycle.  The DLT assessment period may be extended for up to 2 weeks 
beyond the end of the first cycle for pancytopenia follow up without treatment interruption. 
(Refer to Section 5.2 for details).   
If 2 of the 6 subjects experience DLT(s) (Section 5.2), 3 additional subjects will be assessed for 
DLTs.  If 3 or more of the 9 subjects experience DLTs, enrollment will be halted at the 560 mg 


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dose level.  At Sponsor’s discretion a dose of 420 mg ibrutinib or lower (plus LD-AraC) may be 
explored.  
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience DLT(s), additional 
subjects will be enrolled in one of two treatment cohorts:   
• Cohort 1 – ibrutinib monotherapy:  up to 33 response evaluable subjects will receive 
ibrutinib 560 mg once daily on a continuous basis 
OR 
• Cohort 2 – ibrutinib + LD-AraC:  up to 25-28 additional response evaluable subjects (for 
a total of 34) will receive ibrutinib 560 mg once daily (or a lower dose) on a continuous 
basis starting 2 days prior to first cytarabine dose (20 mg BID sc) for 10 days of a 28-day 
cycle 
Subjects will be assigned to either treatment cohort at the discretion of the treating investigator.   
Efficacy parameters will be monitored closely.  In the event response assessments suggest futility 
in the ibrutinib + AraC cohort, further enrollment in both the ibrutinib monotherapy and the 
ibrutinib + AraC cohorts will be closed and a new cohort (Cohort 3) of ibrutinib + azacitidine 
will be started:  
• Cohort 3 – ibrutinib + azacitidine: up to 34 response evaluable subjects will receive 
ibrutinib 560 mg once daily on a continuous basis starting 1 day prior to first azacitidine 
dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle (with an option 
to increase to 100 mg/m2 after 2 cycles). 
For Cohort 3, the same safety run-in principle (6+3 design) will be implemented.  If less than 
2 out of 6 subjects or less than 3 out of 9 subjects experience DLT(s), additional subjects will be 
enrolled.  If 3 or more of the 9 subjects experience DLTs, enrollment will be halted at the 560 
mg dose level.  At Sponsor’s discretion a dose of 420 mg ibrutinib or lower (plus azacitidine) 
may be explored.  
Study treatment will continue in subjects who demonstrate a PR or better on their Cycle 2 Day 1 
bone marrow assessment according to the LeukemiaNet guidelines (Döhner 2010), or based on 
clinical benefit as determined by the treating physician.  Treatment may continue thereafter until 
unacceptable toxicity, treatment failure (TF), or withdrawal of consent.   
Subjects treated in the ibrutinib monotherapy cohort who experience a documented TF or relapse 
will be permitted to add the protocol-specified dose and regimen of LD-AraC to ibrutinib per 
investigator discretion, and will follow the combination cohort schedule and procedures 
(Appendix 1) beginning with the Cycle 1 Day 1 visit.  Baseline parameters for response will be 
based on the most recent bone marrow and hematology results prior to the first dose of add-on 
LD-AraC.   


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3.1.1. 
Study Schema – Cohorts 1 and 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening  
(within 28 days before enrollment)  
Assess Eligibility Criteria 
Safety Run-in 
6–9 subjects will receive ibrutinib + LD-AraC combination therapy. 
Subjects will be monitored for DLTs during the first treatment cycle. 
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience 
DLT(s), enrollment will continue. 
Treatment assignment of subjects to one of the following cohorts will be at 
the discretion of the treating investigator
Ibrutinib monotherapy cohort:  
Approximately 33 subjects will receive ibrutinib 
560 mg once daily on a continuous basis 
At the discretion of the Investigator, subjects in the 
monotherapy cohort will be permitted to add LD-AraC 
to ibrutinib upon treatment failure or relapse 
Ibrutinib + LD-AraC combination cohort:  
25–28 additional subjects (for a total of 34 subjects) will 
receive ibrutinib 560 mg once daily (or a lower dose) on a 
continuous basis starting 2 days prior to first cytarabine 
dose of 20 mg BID sc for 10 days of a 28-day cycle 
Subjects who demonstrate a PR or better per Cycle 2 Day 1 
marrow assessment/clinical benefit will continue treatment  
until treatment failure (TF) or unacceptable toxicity. 
Treatment Discontinuation 
Complete End-of-Treatment (EOT) Visit  
Long-Term Follow-up 
Following TF 
Follow-up for survival status, including other 
malignancies, and subsequent anticancer therapies  
Treatment Failure 
Response Follow-up  
Prior to TF or relapse (if applicable):  
• 
Continue disease evaluations 
• 
Follow-up for subsequent anticancer therapy 


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3.1.2. 
Study Schema – Cohorts 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ibrutinib + azacitidine combination cohort: 
Additional 25-28 response evaluable subjects (up to 
34 total) will receive ibrutinib 560 mg once daily on a 
continuous basis starting 1 day prior to first azacitidine 
dose + azacitidine 75 mg/m2 IV once daily on Days 1-7 of 
a 28-day cycle (with option increase to 100 mg/m2 after 
2 cycles). 
Screening 
(within 28 days before enrollment)  
Assess Eligibility Criteria 
Safety Run-in 
6–9 subjects will receive ibrutinib + azacitidine combination therapy. 
Subjects will be monitored for DLTs during the first treatment cycle. 
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience 
DLT(s), enrollment will continue. 
Subjects who demonstrate a PR or better per Cycle 2 Day 1 marrow assessment/clinical 
benefit will continue treatment until treatment failure (TF) or unacceptable toxicity. 
Treatment Discontinuation 
Complete End-of-Treatment (EOT) Visit  
Long-Term Follow-up 
Following TF 
Follow-up for survival status, including other 
malignancies, and subsequent anticancer therapies  
Treatment Failure 
Response Follow-up  
Prior to TF or relapse (if applicable):  
• 
Continue disease evaluations 
• 
Follow-up for subsequent anticancer therapy 


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3.2. 
Study Design Rationale 
This is a Phase 2a study designed to assess the safety and efficacy of ibrutinib as monotherapy or 
in combination with either LD-AraC or azacitidine in treatment naïve or relapsed/refractory 
subjects with AML.  
Ibrutinib alone or in combination with other treatments has demonstrated a favorable safety 
profile in CLL and non-Hodgkin lymphoma.  The addition of ibrutinib to LD-AraC or to 
azacitidine in this study may improve the outcomes of thesetreatments for AML, and ibrutinib 
monotherapy may constitute an alternative for subjects with AML who cannot tolerate or refuse 
standard treatment options.  
Ibrutinib will be added to the LD-AraC or the azacitidine standard regimens recommended for 
elderly or unfit AML subjects.  Based on the enhanced cytotoxic effect of ibrutinib and 
chemotherapy in AML cell lines (Rushworth 2014), it is hypothesized that the addition of 
ibrutinib will improve treatment outcomes with limited effect on tolerability.  Ibrutinib inhibits 
blast proliferation of human AML cells and BTK was shown to be constitutively phosphorylated 
in the majority of AML cells evaluated (Rushworth 2014), providing a rationale for the clinical 
evaluation of ibrutinib in AML patients.  These data suggest that BTK inhibition may result in 
therapeutic response in AML, either directly and/or by enhancing the effects of conventional 
chemotherapy in AML. 
Initially, the safety of the ibrutinib + LD-AraC combination will be assessed in 6–9 subjects.  
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience DLT(s) during the first 
treatment cycle, enrollment will continue in the ibrutinib monotherapy and the 
ibrutinib +LD-AraC cohorts as described in Section 3.1.  Subjects who experience TF or relapse 
on ibrutinib monotherapy will have an opportunity, at the discretion of the investigator, to be 
treated with add-on LD-AraC in combination with ibrutinib. 
Efficacy parameters will be monitored closely.  In the event response assessments suggest futility 
in the ibrutinib + AraC cohort, further enrollment in both the ibrutinib monotherapy and the 
ibrutinib + AraC cohorts will be closed and a new cohort of ibrutinib + azacitidine will be started 
using the same safety run-in principle (6+3 design).   
3.2.1. 
Study Population and Treatment 
The study will enroll adult subjects with pathologically documented AML that have failed 
standard treatment, or subjects without prior therapy who refuse standard chemotherapy.  
Ibrutinib monotherapy or in combination with either LD-AraC or azacitidine will be 
investigated.  The assigned study treatment will continue in subjects who at the time of their 
Cycle 2 Day 1 bone marrow assessment, demonstrate at least a PR according to the LeukemiaNet 
guidelines (Döhner 2010), or clinical benefit as determined by the treating physician.  Treatment 


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may continue thereafter until unacceptable toxicity, treatment failure, withdrawal of consent, or 
any other reason for discontinuation of treatment as named in Section 9.2.   
At the discretion of the Investigator, subjects in the ibrutinib monotherapy cohort will be 
permitted to add LD-AraC upon designation of treatment failure or relapse.  
3.2.2 
Dose Selection 
The selected dose of ibrutinib is 560 mg (4 x 140 mg capsules) once daily.  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.  Average dose-normalized ibrutinib exposure, based on AUC, was approximately 
2 times higher in the 2.5 mg/kg dose cohort in the PCYC-04753 study.  Given the atypically high 
level of exposure to ibrutinib at the 2.5 mg/kg dose level and the inter patient variability in 
plasma levels observed in this study (coefficient of variation [CV] for Cmax = 59% to 136% and 
CV for AUC = 60% to 107%), there was concern that in a larger population some patients may 
experience low exposures and may not achieve the targeted pharmacodynamic effect.  Therefore, 
a dose greater than 2.5 mg/kg was considered necessary to achieve consistent, full BTK 
occupancy.  In Study PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 
12.5 mg/kg/day cohorts and for the 560 mg continuous dosing cohort, were all above 90% at 
either 4 or 24 hours after drug administration.  This dose has shown to be safe in Phase 1 and 
Phase 2 studies conducted in various B-cell malignancies alone and in combination with other 
agents.  
4. 
 SUBJECT SELECTION  
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria. 
Disease Related 
1. Pathologically documented AML that has failed standard treatment (based on NCCN 
guidelines), or subjects without prior therapy who refuse standard treatment options.  
2. Screening bone marrow aspirate/biopsy results showing >5% blasts. 
3. White blood cell (WBC) count <25,000 cells/mm3 (25 x 109/L).  
• The use of hydroxyurea (HU) during the screening phase is permitted to control the 
peripheral blood count until 1 day (~5 half lives) prior study treatment. 
4. Platelet count >10,000 cells/mm3 (10 x 109/L).  
5. Adequate hepatic and renal function defined as: 


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• For Cohorts 1 and 2: serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤3.0 x upper limit of normal (ULN); for Cohort 3: ALT ≤2.5 or AST ≤2.5 ULN. 
• Serum creatinine ≤2 mg/dL or Estimated Creatinine Clearance ≥30 mL/min 
(Cockcroft-Gault). 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin). 
6. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to 
coagulopathy or bleeding disorder).  When treated with warfarin or other vitamin K 
antagonists, then INR ≤3.0). 
Demographic 
7. Male and female ≥18 years of age. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 
Ethical/Other 
9. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy).  Female subjects of reproductive potential must have a 
negative serum pregnancy test upon study entry. 
10. Male and female subjects of reproductive potential agree to use highly effective methods of 
birth control (eg, condoms, implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence1, or sterilized partner) during the period of 
therapy and for 90 days after the last dose of study drug. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Disease-Related 
1. Acute promyelocytic leukemia (French-American-British Class M3 AML). 
2. Known active central nervous system (CNS) leukemia. 
3. Known active systemic infection (Grade ≥2). 
4. Active bleeding disorders or clinical signs of bleeding (Grade ≥2). 
5. Prior bone marrow transplant that requires immunosuppressant therapy or presents with graft 
vs host disease (GVHD). 
                                                 
1 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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Concurrent Conditions 
6. History of other malignancies, except:  
• Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study drug and with low risk of recurrence by treating 
physician. 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
• Adequately treated carcinoma in situ without evidence of disease.  
7. Prior treatment with a BTK inhibitor. 
8. For Cohort 3 subjects, prior treatment with hypomethylating agents (eg, azacitidine, 
decitabine) 
9. Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any 
investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose 
of study drug. 
10. Subject has received a monoclonal antibody for anticancer intent within 8 weeks prior to the 
first dose of study drug. 
11. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
12. Recent infection requiring intravenous (IV) systemic treatment that was completed ≤14 days 
before the first dose of study drug. 
13. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, 
unless otherwise defined in the inclusion/exclusion criteria with the exception of alopecia. 
14. Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. 
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
16. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV).  Subjects who are positive for hepatitis B core antibody or 
hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result 
before enrollment.  Those who are PCR positive will be excluded. 
17. Major surgery within 4 weeks of first dose of study drug. 
18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk. 
19. 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. 
20. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 


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21. Concomitant use of warfarin or other Vitamin K antagonists. 
22. Requires treatment or prophylaxis with a strong cytochrome P450 (CYP) 3A inhibitor 
(see Appendix 5). 
23. Currently active, clinically significant hepatic impairment (≥ moderate hepatic impairment 
according to the Child Pugh classification [Appendix 7]).  
24. Lactating or pregnant. 
25. Unwilling or unable to participate in all required study evaluations and procedures. 
26. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations). 
5. 
TREATMENT OF SUBJECTS 
5.1. 
Treatment Allocation and Blinding 
There will be no blinded study treatments.  This is an open-label, non-randomized study.  
The first 6–9 subjects will be allocated to the ibrutinib + LD-AraC combination cohort.  If less 
than 2 out of 6 subjects or less than 3 out of 9 of the subjects experience DLTs during the first 
treatment cycle, additional subjects will be enrolled in two treatment cohorts: ibrutinib 
monotherapy or ibrutinib + LD-AraC.  
Treatment assignment to either cohort will be at the discretion of the treating investigator until 
enrollment targets for each cohort are met.  In the event efficacy assessments suggest futility in 
the ibrutinib + LD-AraC cohort, further enrollment in both the ibrutinib monotherapy and the 
ibrutinib + LD-AraC cohorts will be closed and a new cohort of ibrutinib + azacitidine will be 
started using the same safety run-in principle (6+3 design) described above. 
5.2. 
Definition of Dose Limiting Toxicity (DLT) 
The first 6 subjects will be assessed for DLTs.  DLTs will be assessed during the first treatment 
cycle.  However, prolonged pancytopenia in the presence of a hypocellular bone marrow that 
lasts ≥6 weeks (42 days) from the start of therapy will be considered a DLT (see below).  
Hematologic: 
Due to the nature of this disease, hematologic AEs will not be considered DLTs.   
• However, prolonged pancytopenia in the presence of a hypocellular bone marrow 
(ie, cellularity 5% or less without evidence of leukemia) that lasts ≥6 weeks (42 days) 
from the start of therapy will be considered dose limiting myelosuppression.  


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Non-Hematologic: 
• Any Grade ≥3 non-hematologic event (NCI CTCAE, v4.03) that occurs during the first 
treatment cycle (C1D1 – C2D1pre-dose) and is considered-related to the study treatment 
in the opinion of the investigator with the following modifications: 
 Grade 3 nausea, vomiting or diarrhea persisting ≤7 days  
 Grade 3 fatigue persisting ≤7 days  
 Grade 3 infection is not a DLT, however an infection with life-threatening 
consequences or requiring urgent intervention (Grade 4) will be considered a DLT 
If 2 or more of the 6 subjects experience DLT(s) during the assessment period, 3 additional 
subjects will be assessed for DLTs.  If 3 or more of the 9 subjects experience DLTs, enrollment 
will be halted at the 560 mg dose level.  At Sponsor’s discretion a dose of 420 mg ibrutinib or 
lower (plus LD-AraC) may be explored.  
If less than 2 out of 6 subjects or less than 3 out of 9 subjects experience DLT(s), additional 
subjects will be enrolled.  
Replacement of subjects:   
If a subject misses ≥7 of the 30 planned ibrutinib doses and/or: for Cohort 2, ≥5 of the 
20 planned LD-AraC doses; for Cohort 3, ≥2 of the 7 planned azacitidine doses, from the first 
ibrutinib dose (Run-in Day 1) to Cycle 1 Day 28 for reasons other than toxicity (eg, non-
compliance), or if a subject ends treatment for any reason other than toxicity, (eg, withdraws 
consent, treatment failure), the subject will be replaced.  This replacement rule will apply only to 
the safety run-in subjects.   
5.3. 
Study Treatment 
Cohort 1 –ibrutinib monotherapy: ibrutinib 560 mg once daily on a continuous basis 
Cohort 2 –ibrutinib + LD-AraC: ibrutinib 560 mg once daily on a continuous basis and LD-AraC 
20 mg BID sc for 10 days of a 28-day cycle.  This cohort will receive ibrutinib alone for 2 days 
prior to the start of the LD-AraC regimen.  
Cohort 3 – ibrutinib + azacitidine: ibrutinib 560 mg once daily on a continuous basis and 
azacitidine 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle.  This cohort will receive 
ibrutinib alone for 1 day prior to starting azacitidine.  At the investigator’s discretion, the 
azacitidine dose may be increased to 100 mg/m2 after 2 cycles. 


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5.4. 
Study Medication 
5.4.1. 
Ibrutinib 
5.4.1.1. 
Formulation/Packaging/Storage  
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  
All formulation excipients are compendial and are commonly used in oral formulations.  Refer to 
the ibrutinib IB for a list of excipients.  
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drugs will be dispensed in child-resistant packaging.   
Refer to the Pharmacy Manual for additional guidance on study drug storage, preparation and 
handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.4.1.2. 
Dose and Administration 
Ibrutinib 560 mg (4 x 140 mg capsules) is administered orally once daily.  The capsules are to be 
taken around the same time each day with 8 ounces (approximately 240 mL) of water.  
The capsules should be swallowed intact and subjects should not attempt to open capsules or 
dissolve them in water.  The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville 
oranges should be avoided for the duration of the study (Appendix 5). 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day.  The subject should not take extra 
capsules to make up the missed dose. 
The first dose will be delivered in the clinic, after which subsequent dosing is typically on an 
outpatient basis, except for days on which PK samples are to be drawn in the clinic.  On the PK 
sampling days, the subject will be required to hold that day’s ibrutinib dose so that the dose can 
be administered by the study staff who will record the exact time of dose.  Ibrutinib will be 
dispensed to subjects in bottles.  Unused ibrutinib dispensed during previous visits must be 
returned to the site and drug accountability records (Section 12.8) updated at each visit.  
Returned capsules must not be redispensed to anyone. 
5.4.1.3. 
Overdose  
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose.  Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame and 
documented as clinical sequelae to an overdose.   


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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. 
Refer to Section 11.4 for further information regarding AE reporting.  
5.4.1.4. 
Dose Modification for Adverse Reactions  
Due to the nature of this disease, hematologic AEs will not be considered DLTs except in the 
case of prolonged myelosuppression, defined as marrow cellularity of <5% without evidence of 
leukemia on Day 42 or later (6 weeks) from start of therapy.  During the first 6 weeks, platelets 
should be maintained at a minimum level of 10,000/µL per institutional guidelines. 
The dose of ibrutinib should be modified according to the dose modification guidance in Table 1 
if any of the following toxicities occur: 
• Grade 4 neutropenia ANC (<500/µL) for more than 7 days (not applicable during the first 
42 days of study treatment).  Not applicable during the first 42 days of study treatment.   
• The use of neutrophil growth factors is permitted per institutional policy after the first 
treatment cycle and must be recorded in the electronic case report form (eCRF). 
• Grade 4 thrombocytopenia (platelets<25,000/µL).  Not applicable during the first 42 days 
of study treatment.   
• 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 attributed to study drug. 
• For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade consider the 
risks and benefits of ibrutinib treatment.  If clinically indicated, the use of anti-coagulants 
or anti-platelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 6.2.4).  
In the event that the investigator feels that a necessary dose modification other than the 
recommendations above is required, please consult the medical monitor to discuss for approval.   
If the dose of ibrutinib is reduced, at the investigator’s discretion, the dose of ibrutinib may be 
re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction.  Dose changes must be recorded in the Dose Administration eCRF.  


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Table 1.  Ibrutinib Dose Modifications  
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib until recovery of AEs to Grade ≤1 or baseline, may restart at original 
dose level 
Second 
Withhold ibrutinib until recovery of AEs 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 ibrutinib until recovery of AEs 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 ibrutinib 
Dose modifications must be recorded in the Dose Administration eCRF. 
 
For required dose modification for hepatic impairment refer to Section 5.4.1.5 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1.   
Study treatment should be discontinued in the event of a toxicity lasting more than 28 days, 
unless reviewed and approved by the medical monitor. 
5.4.1.5. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child- Pugh class B or C) are excluded from study 
participation.  For subjects who develop mild liver impairment while on study (Child-Pugh 
class A), the recommended dose reduction for ibrutinib/placebo is to a level of 280 mg daily 
(two capsules).  For subjects who develop moderate liver impairment while on study 
(Child-Pugh class B), the recommended dose reduction is to a level of 140 mg daily (one 
capsule). Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study 
drug until resolved to moderate impairment (Child-Pugh class B) or better.  Monitor subjects for 
signs of toxicity and follow dose modification guidance as needed (Refer to Appendix 7).  
5.4.2. 
LD-AraC  
5.4.2.1. 
Formulation/Packaging/Storage  
Cytarabine for sc injection will be supplied by the investigative site. 
5.4.2.2. 
Dose and Administration 
Low-dose cytarabine (LD-AraC) will be administered at 20 mg BID subcutaneously (sc) for 
10 days of a 28-day cycle. 


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5.4.2.3. 
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. 
5.4.2.4. 
Dose Modification for Adverse Reactions  
Toxicities should be managed per institutional practice.  Dosing with LD-AraC may resume at 
the same dose upon recovery.  Missed doses will not be replaced and treatment cycles will not be 
prolonged.  
5.4.3. 
Azacitidine 
5.4.3.1. 
Formulation/Packaging/Storage  
Azacitidine for IV infusion will be supplied by the investigative site. 
5.4.3.2. 
Dose and Administration 
Azacitidine will be administered at 75 mg/m2 IV once daily on Days 1-7 of a 28-day cycle.  
Subjects should be premedicated for nausea and vomiting.  At the investigator’s discretion, the 
azacitidine dose may be increased to 100 mg/m2 IV once daily on Days 1-7 of a 28-day cycle 
after 2 cycles. 
5.4.3.3. 
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. 
5.4.3.4. 
Dose Modification for Adverse Reactions  
Toxicities should be managed per institutional practice.  Missed doses will not be replaced.  
5.5. 
Criteria for Permanent Discontinuation of Study Drug 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk.  For a complete list of criteria for permanent discontinuation of study 
treatment, refer to Section 9.2. 
A Follow-up Visit (Section 8.4) is required for all subjects except for those subjects who have 
withdrawn full consent (see Section 9.3). 


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6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded from the time of ICF signing until 30 days after the last 
dose of study drug. 
6.1. 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  Transfusions may be given in accordance with institutional policy.   
Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) is permitted per institutional policy after the first treatment cycle and in 
accordance with the ASCO guidelines (Smith 2006) after completion of Cycle 1. 
After consultation with the medical monitor the following may be considered; localized 
hormonal or bone sparing treatment for non-B-cell malignancies, and localized radiotherapy for 
medical conditions other than the underlying B-cell malignancies.   
Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (eg, joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that do 
not exceed 100 mg per day of prednisone or equivalent are permitted. 
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent. 
The use of hydroxyurea (HU) during the screening phase is permitted to control the peripheral 
blood count until 1 day (~5 half lives) prior study treatment. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Inhibitors/Inducers  
Ibrutinib is metabolized primarily by CYP3A.  Avoid co-administration with strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
Subjects taking prophylactic antifungals that are moderate CYP3A inhibitors prior to starting 
dosing with ibrutinib may continue receiving the antifungals and will start ibrutinib at 140 mg 
daily.  
• If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, 
reduce ibrutinib dose to 140 mg or withhold treatment for the duration of inhibitor use.  
Subjects should be monitored for signs of ibrutinib toxicity.   
• If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 


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ibrutinib to 140 mg for the duration of the inhibitor use.  Avoid grapefruit and Seville 
oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see 
Section 5.4.1.2). 
• No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort).  Consider alternative agents with less CYP3A induction. 
For subjects who must start a moderate or strong CYP3A inhibitor while on treatment with 
ibrutinib, additional PK blood samples for evaluation of ibrutinib exposure will be requested 
(see Section 7.1.3.4).   
A list of common CYP3A inhibitors and inducers is provided in Appendix 5.  For further 
information, please refer to the current version of the IB and examples of inhibitors, inducers, 
and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This 
website is continually revised and should be checked frequently for updates.  
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib  
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor.  Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates.  
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose.  There is no clinical data available.  Therefore, to avoid a potential interaction in the GI 
tract, narrow therapeutic range P-gp substrates such as digoxin, should be taken at least 6 hours 
before or after ibrutinib.  
6.2.3. 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
electrocardiogram (ECG) and electrolyte monitoring should be considered.  
6.2.4. 
Antiplatelet Agents and Anticoagulants  
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil and vitamin E preparations should be avoided.  Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function.  
Subjects with congenital bleeding diathesis have not been studied.For guidance on ibrutinib and 
the use of anticoagulants during procedures/surgeries see Section 6.4. 
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. 


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6.3. 
Prohibited Concomitant Medications  
Any non-study protocol related chemotherapy, anticancer immunotherapy, experimental therapy, 
or radiotherapy are prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying malignancy are prohibited.  Refer to 
Section 6.1 for further guidance.Erythropoietic growth factors (eg, erythropoietin) and 
neutrophil growth factors (eg, filgrastim and peg-filgrastim) are prohibited during the first 
treatment cycle during the DLT assessment period. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures  
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   
6.4.1. 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should be held for at least 
3 days prior to the procedure and should not be restarted for at least 3 days after the procedure.  
For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary 
to hold ibrutinib. 
6.4.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention and should be held at least 7 days after the procedure 
and restarted at the discretion of the investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes.   
6.4.3. 
Emergency Procedures 
For emergency procedures, ibrutinib should be held as soon as possible and until the surgical site 
is reasonably healed or for at least 7 days after the urgent surgical procedure, whichever is 
longer. 
7. 
STUDY EVALUATIONS  
7.1. 
Description of Procedures 
A cycle has a duration of 28 days throughout this study.  


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All screening clinical and laboratory assessments must be performed within 28 days of Study 
Day 1 and prior to the first dose of study treatment. 
All study tests and procedures should be performed at the study center at which the subject was 
enrolled and will be receiving treatment with the exception of specified lab specimens designated 
to be shipped to a central lab or PCYC for analysis.    
7.1.1. 
Assessments  
7.1.1.1. 
ICF 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. 
Subjects must also grant permission to use protected health information per the Health Insurance 
Portability and Accountability Act (HIPAA).  In addition, subjects must sign all approved ICF 
amendments per the site IRB/REB/IEC guidelines during the course of the study.  
The subject may be enrolled in the study only after signing the ICF and being deemed eligible 
for entry based on screening procedures and history review. 
7.1.1.2. 
Confirm Eligibility 
All necessary screening procedures and evaluations, along with review of medical history, must 
be performed to document that the subject meets all of the inclusion criteria and none of the 
exclusion criteria and prior to first dose on Day 1 (Section 4).  In addition to the review of 
screening procedures and results, documentation of pathologic confirmation of disease (AML) is 
required for confirmation of eligibility prior to enrollment. 
Each subject must have an Eligibility Checklist completed by the site and review/approved by 
the Sponsor medical monitor prior to enrollment. 
7.1.1.3. 
Medical History and Demographics 
The subject’s relevant medical history through review of medical records and by interview will 
be collected and recorded.  Concurrent medical signs and symptoms during screening and prior 
to first dose of study treatment must be documented to establish baseline severities.  A disease 
history, including the date of initial diagnosis and a list of all prior anticancer treatments, dates 
administered, response, and duration of response to these treatments is required to be clearly 
documented in the subject’s medical records.  


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7.1.1.4. 
Prior and Concomitant Medications 
All medications from the signing of ICF through 30 days after the last dose of study drug will be 
documented.  After a subject discontinues study treatment, receipt of all subsequent anticancer 
therapies will be collected until one of the following events takes place: death, subject 
withdrawal of full consent, subject is deemed lost to follow-up, or the study is terminated by 
Sponsor. 
7.1.1.5. 
Adverse Events 
The accepted regulatory definition for an adverse event (AE) is provided in Section 11.1.  The 
occurrence of AE at the time the ICF is signed until first dose should be recorded under medical 
history in the eCRF form.  All medical occurrences after the first dose with study drug until 
30 days after the last dose of study drug that meet the AE definition must be recorded as AEs in 
the eCRF.  Laboratory abnormalities deemed clinically significant by the Investigator will also 
be documented as AEs. 
Additional important requirements for AE and SAE reporting are explained in Section 11.4. 
7.1.1.6. 
Physical Examination  
The Screening and End-of-Treatment physical examination will include, at a minimum, the 
general appearance of the subject, height (Screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
nervous system, and lymphatic system.  This complete physical examination will also be 
required at the Day 1 visit for each study Cycle as well as the TF and End-of-Treatment visits. 
Periodically monitor subjects clinically for atrial fibrillation. 
A limited symptom-directed physical examination is required weekly during the first 2 study 
cycles, unless a complete physical examination is required as above.   
7.1.1.7. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and will 
be assessed after the subject has been resting in the sitting position for at least 3 minutes.  
7.1.1.8. 
ECOG 
This assessment must be performed during the screening assessments as well as the day of the 
first study treatment and prior to the first dose.  Subsequent assessments will be performed as per 
the Schedule of Assessments (Appendix 1, Appendix 2, and Appendix 3).  
The ECOG performance index is provided in Appendix 4.  A score of 2 or less is required for 
enrollment. 


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7.1.2. 
Laboratory 
7.1.2.1. 
Hematology 
Hematology parameters will include a complete blood count including platelets and differential.  
Subjects with platelet counts ≤25,000/µL at baseline or during the first cycle will be required to 
have platelet assessment 3 times a week until the end of first treatment cycle.  Thereafter, follow 
the Schedule of Assessment and hematological and dosing guidelines provided in 
Section 5.4.1.4). 
7.1.2.2. 
Chemistry (Serum) 
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN)/Urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and 
bicarbonate. 
7.1.2.3. 
Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening using a local laboratory.   
7.1.2.4. 
Hepatitis Serologies 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, , and Hepatitis B 
core antibody and will be evaluated.  If Hepatitis B core antibody, Hepatitis B surface antigen, or 
Hepatitis C antibody is positive, then PCR to quantitate Hepatitis B DNA or hepatitis C RNA 
must be performed and must be negative prior to enrollment. 
7.1.2.5. 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
7.1.2.6. 
Pregnancy Test 
Serum or urine pregnancy test will be required at Screening by local laboratory only for women 
of childbearing potential.  A serum or urine pregnancy test will also be performed on Day 1 prior 
to first dose.  If positive, pregnancy must be ruled out by ultrasound to be eligible.  This test may 
be performed more frequently if required by local regulatory authorities. 


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7.1.3. 
Diagnostics/Procedures 
7.1.3.1. 
ECG 
ECGs should be performed at screening and subsequently at the investigator’s discretion, 
particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new 
onset dyspnea. 
During visits in which both ECGs and blood draws are performed, ECGs should be performed 
first. 
At Screening, 12-lead ECG will be done in triplicate (≥1 minute apart); the calculated QTcF 
average of the 3 ECGs must be <470 msec for eligibility.  
Abnormalities noted at Screening should be included in the medical history.  
7.1.3.2. 
Bone Marrow Aspirate/Biopsy   
A bone marrow aspirate/biopsy will be obtained at screening within 7 days before the first dose 
of ibrutinib, at Cycle 2 Day 1 (±3 days), Cycle 4 Day 1 (±3 days), then every 3 cycles (±5 days) 
(ie, Cycles 7, 10, and 13), and every 6 cycles (±5 days) thereafter until designation of TF or 
withdrawal of consent.   
Subjects with prolonged pancytopenia (≥42 days) and hypocellular bone marrow (ie, cellularity 
5% or less without evidence of leukemia) at the Cycle 2 Day 1 assessments must undergo an 
additional bone marrow assessment on Day 42 (±3 days) after initiation of study treatment. 
At each time point, up to an additional 10 unstained slides and up to 20 mL aspirate samples will 
be collected for biomarker evaluation.  These blood and bone marrow aspirate samples will be 
used to help identify genes and other markers that may enhance our understanding of the cancer 
and/or determine how subjects respond (positively or negatively) to ibrutinib. 
Refer to the Laboratory Manual for detailed collection and handling procedures for the additional 
aspirate samples and slides noted above. 
7.1.3.3. 
Cytogenetics/Karyotype 
Cytogenetic and karyotype assessments will be performed on the screening bone marrow sample 
and may be performed on additional bone marrow samples collected during the study. 
7.1.3.4. 
Cerebrospinal Fluid Collection 
In subjects who develop CNS progression, cerebrospinal fluid (CSF) will be obtained for PK, 
PD, and other disease related testing.  At the time of CSF sampling, one additional blood PK 
sample would be required.  


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Refer to the Laboratory Manual for detailed collection and handling procedures. 
7.1.3.5. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and PCI-45227 will be determined using a validated analytical 
method. Other potential metabolites of ibrutinib may be explored.  Refer to the Schedule of 
Assessments (Appendix 1, Appendix 2, and Appendix 3) and the Pharmacokinetic Sample 
Schedule (Table 2, Table 3, and Table 4).  
Table 2.  Ibrutinib + LD-AraC Combination Cohort  
 
Study 
Day 
Predose 
Time After Dosinga 
Period 
1h±15 min 
2 h±15 min 
4 h±30 min 
6 h±1 h 
Ibrutinib Run-in 
1 
X 
X 
X 
X 
X 
Ibrutinib Run-in 
2 
Xb 
 
 
 
 
Cycle 1 
8 
X 
X 
X 
X 
X 
a. Record actual time of sample collection. 
b. Sample collected 24 hours (±2 hours) after Day 1 dose and prior to dosing on Day 2. 
 
Table 3.  Ibrutinib Monotherapy Cohort  
Period 
Study 
Day 
Predose 
Time After Dosinga 
1h±15 min 
2 h±15 min 
4 h±30 min 
6 h±1 h 
Cycle 1 
1 
X 
X 
X 
X 
X 
 
2 
Xb 
 
 
 
 
 
8 
X 
X 
X 
X 
X 
a. Record actual time of sample collection. 
b. Sample collected 24 hours (±2 hours) after Day 1 dose and prior to dosing on Day 2. 
 
Table 4.  Ibrutinib + Azacitidine Combination Cohort  
 
Study 
Day 
Predose 
Time After Dosinga 
Period 
1h±15 min 
2 h±15 min 
4 h±30 min 
6 h±1 h 
Ibrutinib Run-in 
1 
X 
X 
X 
X 
X 
Cycle 1 
1 
Xb 
 
X 
 
 
Cycle 1 
7 
X 
X 
X 
X 
X 
a. 
Record actual time of sample collection. 
b. 
Sample collected 24 hours (±2 hours) after Run-in Day 1 dose and prior to dosing with ibrutinib and azacitidine 
on Cycle 1 Day 1. 
 


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Pharmacokinetic Sample Collection for Subjects Starting a Concomitant CYP3A Inhibitor 
While on Ibrutinib Treatment 
For subjects who must start a moderate or strong CYP3A inhibitor while on treatment with 
ibrutinib, additional PK blood samples for evaluation of ibrutinib exposure is requested at the 
following scheduled visit after concomitant CYP3A inhibitor has started and is still in use.  
PK samples will be collected at the following timepoints: 
• Pre-dose (If possible, sample should be obtained 22–24 hours post the previous day’s 
dose and before dosing on the day of the scheduled visit)  
• 1 hour ± 15 min 
• 2 hours ± 15 min 
• 4 hours ± 30 min 
• 6 hours ± 1 h 
Refer to the Laboratory Manual for instructions on collecting and processing these samples.  
On the day of the sampling visit, the clinical staff will instruct the subject to not take a dose 
before arrival at the clinic.  Study drug intake will be observed by clinic staff.  The actual time 
(versus requested time) that each sample is drawn must be recorded using a 24 hour format.  
The same clock should be used for recording the time of dosing. 
7.1.3.6. 
T/B/NK Cell Count 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected before dosing at the protocol specified timepoints.  Percentages and absolute counts of 
CD3+, CD4+, CD8+, CD19+, CD56+ and CD16/56+ cells will be determined.  Reference the 
Schedule of Assessments (Appendix 1, Appendix 2, and Appendix 3) for other sample 
timepoints for this assay. 
7.1.3.7. 
Predictive Biomarkers and Mechanisms of Resistance 
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib will be explored in this study.  
A predose blood sample will be collected as shown in the schedule of events.  Samples collected 
may be used for pharmacodynamic and biomarker assessments including BTK and other kinase 
activity and signaling, expression analysis, sequencing, flow cytometry and secreted protein 
analyses.   
A portion of pre-treatment bone marrow samples collected may be used by Sponsor for further 
biomarker analysis. 


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7.1.3.8. 
Genetic and Molecular Prognostic Markers 
Cytokines, chemokines, cell surface markers and exploratory investigations of predictive 
biomarkers and mechanism of resistance will be tested in peripheral blood and bone marrow. 
Samples will be collected from all subjects.  Bone marrow aspirate will be collected at the time 
points specified in the Schedule of Assessment (Appendix 1, Appendix 2, and Appendix 3).  
Samples may be tested to evaluate potential biomarkers related to disease response and 
investigate potential mechanism of treatment resistance.  These samples may be characterized by 
technologies such as gene expression profiling, targeted sequencing for genomic alterations and 
intracellular pathway analysis. Inhibition of BTK and other related kinases may also be explored.  
These efforts may identify biomarkers that could assist with future development of this 
compound.  Pharmacodynamics assays, ie, BTK occupancy, may be performed to correlate 
results of biomarker assessments to the physiological effects of ibrutinib. 
7.2. 
Efficacy Evaluations  
A bone marrow aspirate/biopsy will be obtained at screening within 7 days before the first dose 
of ibrutinib.  Follow up bone marrow examination for efficacy evaluation will be performed at 
Cycle 2 Day 1 (±3 days), at Cycle 4 Day 1 (±3 days), then every 3 cycles on Day 1 (±5 days) of 
Cycles 7, 10, 13, and every 6 cycles (±5 days) thereafter until designation of TF or withdraw of 
consent.  Peripheral blood and bone marrow aspirate smears will be examined morphologically 
for changes in AML blast counts using routine diagnostic procedures at the investigative site.  
Determination of response will be made by the Investigator according to the LeukemiaNet 
guidelines (Döhner 2010). 
Complete Remission (CR) 
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; 
absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); 
independence of red cell transfusions (all criteria need to be fulfilled). 
Complete Remission with Incomplete Recovery (CRi) 
All CR criteria except for residual neutropenia (<1.0 x 109/L [1000/µL]) or thrombocytopenia 
(<100 x 109/L [100000/µL]). 
Morphologic Leukemia-Free State 
Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; 
no hematologic recovery required. 


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Partial Remission (PR)  
All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and 
decrease of pretreatment bone marrow blast percentage by at least 50%. 
Treatment Failure (TF) 
Failure to achieve at least a PR; relapse from CR or CRi, or death from any cause. 
Relapse  
Bone marrow blasts >5%; or reappearance of blasts in the blood; or development of 
extramedullary disease. 
Investigator will be permitted to add the protocol-specified LD-AraC regimen for subjects 
treated in the ibrutinib monotherapy cohort who experience a documented treatment-failure (TF) 
or relapse.  These subjects will follow the combination cohort schedule and procedures 
(Appendix 1) beginning with the Cycle 1 Day 1 visit.  Baseline parameters for response will be 
based on the most recent bone marrow and hematology results prior to the first dose of add-on 
LD-AraC.  
7.3. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form.  Refer to the Schedule of Assessments 
(Appendix 1, Appendix 2, and Appendix 3) for the timing and frequency of all sample 
collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 
8. 
STUDY PROCEDURES 
8.1. 
Overview 
For each subject enrolled, this study is divided into a Screening Phase, a Treatment Phase, and a 
Follow-up Phase.  The Schedules of Assessments (Appendix 1, Appendix 2, and Appendix 3) 
summarize the frequency and timing of efficacy, PK, biomarker, and safety measurements and 
procedures that are applicable to this study.   
8.2. 
Screening Phase 
Screening procedures will be performed up to 28 days prior to the first dose of study treatment, 
unless otherwise specified.  Obtain written informed consent as indicated by subject’s signature 
on the IRB/IEC approved ICF. 


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• Informed Consent 
• Medical history and demographics 
• Complete physical exam including height and weight 
• ECOG Performance Status 
• Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature) 
• 12-lead ECG (in triplicate [≥1 minute apart]) 
• Review and recording of all current, ongoing medications and any medications taken 
within 30 days prior to start of study medication (including over-the-counter drugs, 
vitamins and herbs) 
• Bone marrow aspirate and biopsy including bone marrow smear slides (within 7 days 
before the first administration of study drug) 
• Laboratory tests for: 
 
Hematology including differential 
 
Serum chemistry 
 
Coagulation (PT/INR and PTT) 
 
Serum pregnancy test (for women of childbearing potential only) 
 
Hepatitis serologies: Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
surface antibody, and Hepatitis B core antibody 
 
Urinalysis 
• Review of eligibility criteria 
• Confirm eligibility – complete enrollment checklist and submit to Sponsor for 
review/approval prior to enrollment 
• Assignment to treatment cohort   
8.3. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects 
are enrolled.  Enrollment should occur as close to the time of the expected first dose as possible, 
ie, not more than 3 business days prior to expected first dose with study drug. 
8.3.1. 
Treatment Visits - Ibrutinib + LD-AraC Combination Cohort 
8.3.1.1. 
Ibrutinib Run-in Day 1 Visit 
Predose 
• Review of medical history and demographics 
• Review of current medications and any new medications since screening visit 
• Review of current signs/symptoms including any new untoward events since screening  
• Complete physical exam and weight  
• Vital signs 
• ECOG status 


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• Reconfirm eligibility 
• Laboratory tests for: 
 
Hematology including differential 
 
Serum chemistry 
• Laboratory blood samples for: 
 
PK analysis  
 
T/B/NK 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for run-in and Cycle 1 
• PK blood sample collection at  
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min)  
 
6 hours (±1 hour)  
• Biomarker blood sample at 4 hours (±30 min)  
8.3.1.2. 
Ibrutinib Run-in Day 2 Visit 
Predose 
• Review of concomitant medications  
• Review of adverse events 
• PK blood sample collection  
Postdose 
• Dose administration - ibrutinib 
8.3.1.3. 
Cycle 1 Day 1 Visit 
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Vital signs 
• Lab sample collection for  
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
Biomarkers (blood) 


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Postdose 
• Dose administration – LD-AraC 
• Dose administration – ibrutinib 
• Dispense study drugs  
8.3.1.4. 
Cycle 1 Day 8 Visit  
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Laboratory sample collection for: 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
PK analysis  
Postdose 
• Dose administration – LD-AraC 
• Dose administration – ibrutinib 
• PK blood sample collection 
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min)    
 
6 hours (±1 hour)   
8.3.1.5. 
Cycle 1 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• ECOG status 
• Lab sample collection for 


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 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
8.3.1.6. 
Cycle 1 Day 22 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.1.7. 
Cycle 2 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspiration and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 


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Postdose 
• Dose administration – ibrutinib 
• Dose administration – LD-AraC 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs  
8.3.1.8. 
Cycle 2 Day 8 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for 
 
Hematology 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – LD-AraC 
8.3.1.9. 
Cycle 2 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.1.10. 
Cycle 2 Day 22 Visit  
Predose 
• Review of concomitant medications 


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• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.1.11. 
Cycle 3 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – LD-AraC 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.1.12. 
Cycle 3 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 


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Postdose 
• Dose administration – ibrutinib 
8.3.1.13. 
Cycle 4 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers(blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – LD-AraC 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.1.14. 
Cycle 4 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 


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8.3.1.15. 
Cycle 5 and Beyond, Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, 
then every 6 cycles thereafter) 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – LD-AraC 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.2. 
Treatment Visits - Ibrutinib Monotherapy Cohort 
8.3.2.1. 
Cycle 1 Day 1 Visit 
Predose 
• Review of medical history and demographics 
• Review of concomitant medications  
• Review of adverse events 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Reconfirm eligibility 
• Lab sample collection for:  
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
T/B/NK Cell count 
 
Biomarkers (blood) 


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 
PK analysis 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for at-home dosing 
• PK blood sample collection analysis at  
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min)    
 
6 hours (±1 hour)  
8.3.2.2. 
Cycle 1 Day 2 Visit 
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for: 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
PK analysis (Day 2 predose or 24 hours post Day 1 dose) 
Postdose 
• Dose administration – ibrutinib 
8.3.2.3. 
Cycle 1, Day 8 Visit  
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 


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 
Serum chemistry 
 
PK blood sample collection  
Postdose 
• Dose administration – ibrutinib 
• Post-dose PK blood sample collection at: 
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min) 
 
6 hours (±1 hour)  
8.3.2.4. 
Cycle 1 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
8.3.2.5. 
Cycle 1 Day 22 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 


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 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.2.6. 
Cycle 2 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspiration and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for at-home dosing 
8.3.2.7. 
Cycle 2 Day 8 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 


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8.3.2.8. 
Cycle 2 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.2.9. 
Cycle 2 Day 22 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical Exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.2.10. 
Cycle 3 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 


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• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for at-home dosing 
8.3.2.11. 
Cycle 3 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.2.12. 
Cycle 4 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 


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• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for at-home dosing 
8.3.2.13. 
Cycle 4 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.2.14. 
Cycle 5 and Beyond, Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, 
then every 6 cycles thereafter) 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for at-home dosing 


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8.3.3. 
Treatment Visits - Ibrutinib + Azacitidine Combination Cohort 
8.3.3.1. 
Ibrutinib Run-in Day 1 Visit 
Predose 
• Review of medical history and demographics 
• Review of current medications and any new medications since screening visit 
• Review of current signs/symptoms including any new untoward events since screening  
• Complete physical exam and weight  
• Vital signs 
• ECOG status 
• Reconfirm eligibility 
• Laboratory tests for: 
 
Hematology including differential 
 
Serum chemistry 
• Laboratory blood samples for: 
 
PK analysis  
 
T/B/NK 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Provide drug diary and dosing instructions to subject 
• Dispense study drug to subject for run-in and Cycle 1 
• PK blood sample collection at  
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min)  
 
6 hours (±1 hour)  
• Biomarker blood sample at 4 hours (±30 min)  
8.3.3.2. 
Cycle 1 Day 1 Visit 
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Vital signs 
• Lab sample collection for  
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 


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 
Serum chemistry 
 
Biomarkers (blood) 
 
PK analysis  
Postdose 
• Dose administration – azacitidine 
• Dose administration – ibrutinib 
• Dispense study drugs  
• PK blood sample collection at  
 
2 hours (±15 min)  
8.3.3.3. 
Cycle 1 Day 7 Visit  
Predose 
• Review of concomitant medications  
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Laboratory sample collection for: 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
PK analysis  
Postdose 
• Dose administration – ibrutinib 
• Dose administration – azacitidine  
• PK blood sample collection 
 
1 hour (±15 min)  
 
2 hours (±15 min)  
 
4 hours (±30 min)    
 
6 hours (±1 hour)   
8.3.3.4. 
Cycle 1 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 


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• Symptom directed physical exam 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
8.3.3.5. 
Cycle 1 Day 22 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Vital signs 
• Symptom directed physical exam 
• Lab sample collection for 
 
Hematology including differential (Subjects with platelet counts ≤25,000/µL will be 
required to have platelet assessment 3 times a week until the end of first treatment 
cycle) 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.3.6. 
Cycle 2 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspiration and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 


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 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – azacitidine 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs  
8.3.3.7. 
Cycle 2 Day 7 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for 
 
Hematology 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.3.8. 
Cycle 2 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.3.9. 
Cycle 2 Day 22 Visit  
Predose 
• Review of concomitant medications 


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• Review of adverse events 
• Review returned subject dosing diary 
• Symptom directed physical exam 
• Vital signs 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 
8.3.3.10. 
Cycle 3 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – azacitidine 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.3.11. 
Cycle 3 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 


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Postdose 
• Dose administration – ibrutinib 
8.3.3.12. 
Cycle 4 Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
T/B/NK cell count 
 
Biomarkers(blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – azacitidine 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.3.13. 
Cycle 4 Day 15 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
Postdose 
• Dose administration – ibrutinib 


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8.3.3.14. 
Cycle 5 and Beyond, Day 1 Visit  
Predose 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, 
then every 6 cycles thereafter) 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
Biomarkers (blood) 
Postdose 
• Dose administration – ibrutinib 
• Dose administration – azacitidine 
• Provide drug diary and dosing instructions to subject 
• Dispense study drugs 
8.3.4. 
Treatment Failure (TF) Visit 
• Review of concomitant medications 
• Review of adverse events 
• Complete physical exam 
• Vital signs 
• ECOG status 
• Bone marrow aspirate and biopsy including bone marrow smear slides  
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
Collection of CSF if CNS involvement is suspected 
 
T/B/NK 
 
Biomarkers (blood) 
 
PK sample (blood) upon collection of CSF  
8.3.5. 
End-of-Treatment (EOT) Visit 
An EOT visit should occur 30 days (±7 days) from the last dose of study drug or prior to the start 
of a new anticancer treatment. If a subject starts a new anticancer treatment less than 7 days after 


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the TF visit, only those procedures not conducted at the TF should be performed at the EOT 
visit. 
• Review of concomitant medications 
• Review of adverse events 
• Review returned subject dosing diary 
• Complete physical exam 
• Vital signs 
• ECOG status 
• ECG 
• Lab sample collection for 
 
Hematology including differential 
 
Serum chemistry 
 
Coagulation (PT, INR, aPTT) 
 
Urinalysis 
 
T/B/NK 
 
Biomarkers (blood) 
8.4. 
Follow-up Phase 
Once a subject has completed the End-of-Treatment Visit they will enter the Follow-up Phase.  
Subjects who withdraw from treatment for reasons other than TF will participate in ongoing 
response follow-up. 
8.4.1. 
Response Follow-up (RFU) 
The response follow-up period will begin when the subject withdraws for any reason other than 
TF, until the subject experiences a TF or starts an alternative anticancer therapy. During this 
period, subject will return to the clinic approximately every 3 months (±14 days) and the 
following procedures should be performed. 
• ECOG performance status 
• Bone marrow aspirate and biopsy including bone marrow smear slides (per investigator 
discretion) 
• Lab sample collection for 
 
Hematology including differential 
 
Biomarkers (blood) 
• Subsequent anticancer therapy 
8.4.2. 
Long-Term Follow-up (LTFU) 
Once subjects experience TF, relapse, or start use of alternative anticancer therapy (for subjects 
who have not withdrawn consent), they will be contacted approximately every 3 months 


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(±14 days) by clinic visit or telephone until death, subject withdrawal, lost to follow-up, or study 
termination by the Sponsor, whichever occurs first. 
• Survival status, including other malignancies 
• Subsequent anticancer therapy 
9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.  
9.2. 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• Treatment failure or no evidence of clinical benefit per investigator assessment 
• Unacceptable toxicity: an intercurrent illness or adverse event that prevents further 
ibrutinib administration. 
• Withdrawal of consent for treatment by subject 
• Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• Study termination by Sponsor 
• Subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo an End of 
Treatment Visit and be followed for treatment failure and survival.  
The Investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
treatment due to treatment failure.  These subjects should stay in the study to be followed for 
survival.  
9.3. 
Withdrawal from Study 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• Withdrawal of consent for follow-up observation by the subject 
• Lost to follow-up 
• Study termination by Sponsor 
• Death 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject.  The measures taken to follow up should be documented. 


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When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
• Reason for withdrawal; 
• Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits)  
10. STATISTICAL METHODS AND ANALYSIS  
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor.  A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below.  Specific details will be provided in the Statistical Analysis Plan.  
10.1. 
Demographics, Baseline Characteristics and Study Conduct 
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease burden, and number of prior therapies) will be 
summarized.  Summary statistics will include means, standard deviations, and medians for 
continuous variables and proportions for categorical variables. 
10.2. 
Endpoints   
10.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall remission rate (ORR).  The ORR is defined as the 
proportion of subjects who achieve either a complete remission (CR) or complete remission with 
incomplete blood recovery (CRi) as best response as assessed by the investigator according to 
the LeukemiaNet guidelines (Döhner 2010).  ORR will be calculated for the response evaluable 
population for each cohort separately.   
Response evaluable subjects are defined as subjects who had at least 1 post-baseline response 
assessment or any subjects who died due to an AML-related cause or were discontinued early 
due to an AML-related event without at least 1 post-baseline response assessment. 
10.2.2. 
Secondary Efficacy Endpoints 
The efficacy of 3 treatment cohorts (ibrutinib monotherapy, ibrutinib with LD-AraC, and 
ibrutinib with azacitidine) will be evaluated separately for relapse-free survival (RFS), event-free 
survival (EFS), overall survival (OS), and clinical benefit rate (CBR).   
For subjects achieving CR or CRi, relapse-free survival (RFS) will be calculated to determine 
durability.  RFS will be measured from the date criteria for remission are met (CR or CRi), 
whichever is recorded first, until the date of death or the earliest date of relapse is objectively 
documented.  


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EFS will be obtained for the response evaluable population.  EFS will be measured from the date 
of first dose to the date of treatment failure (failure to achieve at least a PR), relapse from CR or 
CRi, or death from any cause, whichever occurs first.  
For EFS and RFS, subjects who start subsequent anticancer therapy, who are event free and alive 
at the time of clinical cut-off, or who have unknown status will be censored at the date of the last 
disease assessment prior the start of subsequent therapy or the clinical cut-off time.  Subjects 
with no post-baseline disease assessment will be censored on the date of Day 1. 
OS will be measured from the time of first study drug administration until the date of death from 
any cause.  Data for subjects who have not died will be censored at the date of the last known 
contact.  The estimates will be calculated using the all treated population. 
Clinical benefit rate (CBR) defined as the proportion of subjects who achieve CR, CRi, 
morphologic leukemia-free state, or PR as best response as assessed by the investigator.  
CBR will be calculated for the response evaluable population for each cohort.   
10.3. 
Sample Size Determination 
The sample size of 6 or 9 subjects for safety review was based on clinical experience and 
conventional DLT studies.  
The sample size was calculated to detect a meaningful signal of clinical activity of each 
treatment cohort while minimizing risk of continuing enrollment under null conditions.  
The sample size was estimated for each treatment cohort without multiplicity adjustment.   
The sample size of 33 subjects was calculated to test the null hypothesis that the ORR of 
ibrutinib monotherapy is ≤5% (not clinically compelling) versus the alternative hypothesis that 
ORR will be ≥20%, with a significance level of 5%, and 80% power.   
The sample size of 34 subjects was calculated to test the null hypothesis that the ORR of 
ibrutinib plus LD-AraC or azacitidine is ≤15% (not clinically compelling) versus the alternative 
hypothesis that ORR will be ≥35%, with a significance level of 5%, and 80% power.    
10.4. 
Efficacy Analysis   
The primary efficacy endpoint is the ORR for each of each treatment cohort as defined by to the 
LeukemiaNet guidelines (Döhner 2010).  The point estimate of the rate and the corresponding 
exact binomial 95% confidence interval will be calculated individually for each treatment cohort 
on response evaluable population.  
The secondary efficacy endpoints, RFS, EFS, and OS, will be calculated using the Kaplan-Meier 
procedure for each cohort.  


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For CBR, the point estimate of the rate and the corresponding exact binomial 95% confidence 
interval will be calculated individually for the 3 treatment cohorts.  
10.5. 
Safety Analysis 
Analysis of safety data will be conducted on the all treated population, which includes enrolled 
subjects who receive at least 1 dose of ibrutinib.  The baseline value for safety assessments will 
be defined as the last value on or before the day of the first dose of study drugs if we do not 
specify.  The safety analyses will be based on the monitoring of adverse events, survival status, 
ECOG performance status, vital signs measurements, and clinical laboratory results. 
The safety variables to be analyzed include adverse events, clinical laboratory test results 
(hematology and chemistry), physical examination findings, and vital signs measurements.  
Exposure to ibrutinib first dose and reasons for discontinuation from study treatment will be 
tabulated.  In general, continuous variables will be summarized using descriptive statistics 
(n, mean, median, standard deviation and range).  Categorical variables will be summarized 
using frequencies and percentages.  No formal statistical testing is planned.  
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of adverse 
events; the relationship of adverse events to ibrutinib; and the action taken with respect to 
ibrutinib treatment due to adverse events. 
The verbatim terms used in the eCRF by Investigators to identify non-hematological adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent adverse events are those adverse events (including worsening of an existing 
event) occurring after the first dose of study drugs and within 30 days following the last dose of 
study drug or the first date starting new anticancer therapy, whichever is earliest; any adverse 
event that is considered study drug-related regardless of the start date of the event.  
All treatment-emergent adverse events will be included in the analysis.  For each adverse event, 
the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized.  The number and percent of subjects with treatment-emergent adverse events will 
be summarized according to intensity (NCI CTCAE, v4.03) and drug relationship as well as 
categorized by system organ class and preferred term.  Summaries, listings, datasets, or subject 
narratives may be provided, as appropriate, for those subjects who die, who discontinue 
treatment due to an adverse event, or who experience a severe or a serious adverse event. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry.  Local 
laboratory results will be standardized using the International System SI unit.  Selected 
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values will be graded using the NCI CTCAE v4.03. The worst toxicity grade during the study 
will be tabulated. 
Descriptive statistics will be provided for the values of selected clinical laboratory tests at each 
scheduled on-treatment evaluation including the final value.  Percent change from baseline to 
each scheduled on-treatment evaluation and to the final value will also be summarized.  
For selected variables, the mean value and mean percent change over time will be presented 
graphically. 
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided.  The worst toxicity grade 
during the study will be tabulated. 
10.6. 
Pharmacokinetic Analysis 
Bioanalytical data from this study will be used in noncompartmental PK analysis and also may 
be combined with data from other studies performed with ibrutinib in subjects with hematologic 
malignancies as part of a population PK analysis using nonlinear mixed effects models.  For the 
population PK analysis, covariates that could potentially correlate with plasma PK parameters 
will be evaluated.  The results of the population PK analyses (if performed) will be presented in a 
separate report. 
Plasma concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics.  All subjects and samples excluded from the analysis will be clearly 
documented in the Clinical Study Report. 
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point and PK parameters of ibrutinib and PCI-45227: including but not limited to 
Cmax, Tmax, AUClast, and t1/2. 
Mean plasma ibrutinib and PCI-45227 concentration time profiles will be plotted. 
10.7. 
Biomarker Analyses  
• Changes in peripheral T/B/NK count and profiling of immunophenotypes 
• BTK active site percent occupancy in peripheral blood cells  
• Changes in secreted protein levels (ie, chemokines, cytokines) 
• Identification of cytogenetic abnormalities, tumor mutations and other biomarkers 
associated with sensitivity or resistance to ibrutinib  
Clinically relevant biomarkers may be associated with clinical responses.  Changes in 
biomarkers over time will be summarized by treatment cohort.  Association between baseline 
levels and changes from baseline in select markers and response to treatment will be explored.   


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11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide.  The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. 
11.1. 
Definitions  
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an adverse event term but instead 
symptoms/clinical signs of disease progression may be reported.   
Adverse events may include, but are not limited to: 
• Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period.  
• Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• Pre-existing condition:  A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  


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Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs. 
• Diagnostic Testing and Procedures:  Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported. 
11.1.2. 
Serious Adverse Events 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
• Results in death (ie, the AE actually causes or leads to death). 
• Is life-threatening.  Life-threatening is defined as an AE in which the subject was at risk 
of death at the time of the event.  It does not refer to an event which hypothetically might 
have caused death if it were more severe.  If either the Investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• Requires inpatient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject or 
subject may require intervention to prevent one of the other outcomes listed in this 
definition.  Examples of such events are intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not result 
in hospitalization; or development of drug dependency or drug abuse. 
Given that the Investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the Investigator believes that 
the event is serious, the event will be considered serious. 
11.1.3. 
Severity Criteria (Grade 1-5) 
Definitions found in the CTCAE v4.03 will be used for grading the severity (intensity) of 
nonhematologic AEs.  The CTCAE v4.03 displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE not listed 
in the CTCAE v4.03, the following grading system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 


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• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
• Grade 5 (Death related to AE) – experiences which result in subject death 
11.1.4. 
Causality (Attribution)  
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures.  Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
11.2. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation. 


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11.3. 
Special Reporting Situations 
Special reporting situation on a Sponsor study may require expedited reporting and/or safety 
evaluation include, but are not limited to: 
• Overdose of any study drug 
• Suspected abuse/misuse of a study drug 
• Inadvertent or accidental exposure to a study drug 
• Medication error involving a product (with or without subject/subject exposure to the 
study drug, eg, name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF.  If any special 
reporting situation meets the criteria of an adverse event, it should be recorded on the adverse 
events eCRF.  If the adverse event is considered serious, it should be recorded on the adverse 
events eCRF as serious and should be reported on the Serious Adverse Event Report Form.  
The SAE Report Form should be sent via email or fax to Pharmacyclics Drug Safety or designee 
within 24 hours of awareness. 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
11.4.1. 
Assessment of Adverse Events 
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation timepoints during the study.  All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, detected 
through physical examination, clinically significant laboratory test, or other means, will be 
recorded in the subject’s medical record and on the Adverse Event CRF and, when applicable, on 
the Serious Adverse Event Report Form. 
Each recorded adverse event or serious adverse event will be described by its duration (ie, start 
and end dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to 
the investigational product, and any actions taken. 
11.4.2. 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be documented in the source documents from the 
time signed and dated ICF is obtained until 30 days following the last dose of study drug.  
SAEs will be reported to the Sponsor from the time of ICF signing.  Both serious and non-
serious AEs will be recorded in the eCRF from the first dose of study drug until 30 days after the 
last dose of study drug. 
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug.  Resolution information after 30 days should be 


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provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. (See Section 11.1.1) 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document.  All records will need to 
capture the details of the duration and the severity of each episode, the action taken with respect 
to the study drug, investigator’s evaluation of its relationship to the study drug, and the event 
outcome.  Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection").  Investigators must record in the CRF their opinion 
concerning the relationship of the adverse event to study therapy.  All measures required for 
adverse event management must be recorded in the source document and reported according to 
Sponsor instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  Autopsy, postmortem reports and death 
certificates must be forwarded to the Sponsor, or designee, as outlined above, if allowed per local 
regulatory guidelines. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a serious adverse event.  
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events (initial and follow-up information) will be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, 
within 24 hours of the discovery of the event or information.  Pharmacyclics may request 
follow-up and other additional information from the Investigator (eg, hospital 
admission/discharge notes and laboratory results).  The contact information (phone, email and 
fax) for Pharmacyclics Drug Safety can be found on the Serious Adverse Event Report Form and 
instructions. 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors unrelated to 
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• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.   
The investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.4.4. 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug.  A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months 
(90 days) after the last dose of study drug.  Any female subjects receiving study drug(s) who 
become pregnant must immediately discontinue study drug.  The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.   
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented.  Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported.  Any occurrence of pregnancy must 
be recorded on the Pregnancy Report Form Part I and sent via email or fax to Pharmacyclics 
Drug Safety, or designee, within 24 hours of learning of the event.  All pregnancies will be 
followed for outcome, which is defined as elective termination of the pregnancy, miscarriage, or 
delivery of the fetus.  For pregnancies with an outcome of live birth, the newborn infant will be 
followed until 30 days old by completing the Pregnancy Report Form Part II.  Any congenital 
anomaly/birth defect noted in the infant must be reported as a serious adverse event. 
11.4.5. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including follow-up for overall survival. 
11.4.6. 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor.  These events (regardless of seriousness) should be 


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reported on the Serious Adverse Event Report Form and sent via email or fax to Pharmacyclics 
Drug Safety, or designee, within 24 hours of awareness.   
11.4.6.1. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*.  Any treatment-
emergent serious adverse events of bleeding of any grade 
• Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher AE per 
CTCAE v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.6 above. 
12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS   
12.1. 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.  
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF.  


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12.3. 
Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.   
The Investigator or designee (designee must be listed on the Delegation of Authority log), 
must explain in terms understandable to the subject the purpose and nature of the study, 
study procedures, anticipated benefits, potential risks, possible AEs, and any discomfort 
participation in the study may entail.  This process must be documented in the subject’s source 
record.  Each subject must provide a signed and dated ICF before any study-related (nonstandard 
of care) activities are performed.  The original and any amended signed and dated consent forms 
must remain in each subject’s study file at the study site and be available for verification by 
study monitors at any time.  A copy of each signed consent form must be given to the subject at 
the time that it is signed by the subject. 
12.4. 
Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements.  This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, 
Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on GCP 
(ICH E6).   
12.5. 
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 12.3), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific HIPAA consent may be used).  The Investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Pharmacyclics and its 
designees, regulatory agencies, and IRBs/REBs/IECs.  As the study Sponsor, Pharmacyclics will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization.  It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject.  If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
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During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. 
Study Files and Record Retention 
The Investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects subsequently 
excluded from enrollment, the reason(s) for exclusion is to be recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 
transmitted to Pharmacyclics and notification of SAEs and related reports, source 
documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time.  Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 


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12.7. 
Case Report Forms and Record Maintenance 
CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents).  Authorized study site personnel (ie, listed on the Delegation 
of Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided.  The Investigator will ensure that the CRFs are accurate, 
complete, legible, and completed within a reasonable period of time.  At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The CRFs exists within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics or its authorized representative for this study.  Study staff will be appropriately 
trained in the use of CRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system.  Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail.  The Investigator attests that the information contained in the CRFs is true 
by providing electronic signature within the EDC system.  After database lock, the Investigator 
will receive a copy of the subject data (eg, paper, CD, or other appropriate media) for archiving 
at the study site. 
12.8. 
Investigational Study Drug Accountability 
Ibrutinib and any comparator used must be kept in a locked limited access room.  The study drug 
must not be used outside the context of the protocol.  Under no circumstances should the 
Investigator or other site personnel supply ibrutinib or comparator to other Investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from Pharmacyclics. 
Accountability records for ibrutinib and any comparator must be maintained and readily 
available for inspection by representatives of Pharmacyclics and are open to inspections by 
regulatory authorities at any time.  
An Investigational Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study: 
1. Study identification number (PCYC-1131-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib or comparator dispensed for that subject 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject 


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At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements.  If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product.  Before disposal/destruction, final drug accountability and reconciliation 
must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
12.9. 
Study Monitoring/Audit Requirements 
Representatives of Pharmacyclics or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone.  
The purpose of monitoring is to ensure that the study is conducted in compliance with the 
protocol, standard operating procedures (SOPs), and other written instructions and regulatory 
guidelines, and to ensure the quality and integrity of the data.  This study is also subject to 
reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice.  During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics, its designated agents and 
authorized employees of the appropriate Regulatory Authority to inspect the facilities used in 
this study and, for purposes of verification, allow direct access to the hospital or clinic records of 
all subjects enrolled into this study.  A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. 
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study.  All study-related documentation must be made available to the 
designated auditor.  In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study.  
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation.  
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
12.10. 
Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the 
Investigator before commencement of the study.  In summary, the Investigator will conduct the 


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study according to the current protocol; will read and understand the IB; will obtain 
IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study 
participant; will maintain and supply to the Sponsor or designee, auditors and regulatory 
agencies adequate and accurate records of study activity and drug accountability for study-
related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report SAEs 
to the Sponsor or designee and IRB/ REB/IEC according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments. 
12.11. 
Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted.  In summary, 
the Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug. 
12.12. 
Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each Investigator and Subinvestigator (as designated on the Form FDA1572) will 
provide a personally signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each 
Investigator will notify Pharmacyclics or its authorized representative of any relevant changes in 
financial disclosure information during the conduct of the study and for 1 year after the study has 
been completed. 
12.13. 
Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
The ICF will include a description treatment in the event of a study related injury and handling 
of the costs associated therewith, incorporating country-specific national regulations and/or local 
laws.  Financial compensation for lost wages, disability or discomfort due to the study is not 
available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 


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12.14. 
Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document.  
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF.  Written documentation of IRB/REB/IEC and required site approval must be 
received by Pharmacyclics before the amendment may take effect at each site.  Additionally 
under this circumstance, information on any change in risk and/or change in scope must be 
provided to subjects already actively participating in the study, and they must read, understand 
and sign each revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and 
Pharmacyclics. 
12.15. 
Publication of Study Results 
Pharmacyclics may use the results of this clinical study in registration documents for Regulatory 
Authorities in the US or abroad.  The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an Investigator.  In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient time to 
make appropriate comments before submission for publication. 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  The medical monitor, study 
director and/or lead statistician may also be included in the list of authors.  This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions. 
12.16. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, 
both the Sponsor and the Investigator will arrange discontinuation procedures.  In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
 


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target in acute myeloid leukemia. Blood. 2014;123:1229-38. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood 
cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187-205.  
Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the 
treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1990;8:272-9. 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell 
lymphoma. N Engl J Med. 2013;369:507-16. 
Yin JA, O'Brien MA, Hills RK, et al. Minimal residual disease monitoring by quantitative RT-PCR in 
core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom 
MRC AML-15 trial. Blood. 2012;120:2826-35. 
Zaitseva L, Murray MY, Shafat MS, et al. Ibrutinib inhibits SDF1/CXCR4 mediated migration in 
AML. Oncotarget. 2014;5:9930-8. 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 93 
14. APPENDICES 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 94 
Appendix 1: Schedule of Assessments – Ibrutinib + LD-AraC Combination Cohort  
Study Cycle 
Ibrutinib 
Run-in 
C1 
C2 
C3 
C4 
C5 & Beyond 
TF 
EOTa RFUb LTFU 
Study Day 
1 
2 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
1 
15 
1 
 
 
 
 
(±2 days) 
(±2 days) 
(±2 days) 
(±2 days) 
Any 
time (±7d) (±14 days) 
Study Drug Administration 
 
Ibrutinib (continuous) 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LD-AraC (for 10 days every 4 wks) 
Days  
1-10 
Days 
1-10 
Days 
1-10 
Days 
1-10 
Days 
1-10 
 
Procedure 
Screening 
Day -28 to -1 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Medical history & demographics 
X 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Review Concomitant Medicationsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
Review adverse eventsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam & Weighte  
X 
X 
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
 
Symptom directed physical exam 
  
  
  
  
X 
X 
X 
  
X 
 X 
X 
  
  
  
  
 
Vital signsf  
X 
X 
  
X 
X 
X 
X 
X 
X 
 X 
X 
X 
  
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
  
  
X 
X 
  
 X 
X 
  
X 
X 
X 
X 
X 
Triplicate 12-Lead ECGg 
X 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
  
X  
 
Bone marrow aspirate/biopsyh 
X 
  
  
  
  
  
X 
  
  
  
  
  
 X  
 X  
 X 
  
X 
Confirm eligibility 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Laboratory Assessment  
Hematologyi 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
  
Serum chemistryj 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
  
  
Coagulation (PT, INR, aPTT) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
  
Hepatitis serologiesk 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Urinalysisl 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Pregnancy test 
X 
 
Cerebrospinal fluidm 
X 
 
T/B/NK cell countn 
  
X 
  
  
  
  
X 
  
  
  
X 
X 
  
X 
X 
 
Biomarker - blood sampleo 
  
X 
  
X 
X 
X 
X  
X 
  
X 
X 
X 
X 
Biomarker - bone marrowp 
X 
X 
  
  
 X q 
  
X 
X 
X 
PK blood samplingr   
  
X 
X 
  
X 
  
  
  
  
  
  
(X)s 
  
 
Other 
Survival status, incl. other malignancies 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Subsequent Anticancer Therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Abbreviations:  C=cycle; D or d=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment visit; LTFU=Long-Term Follow Up; 
PO=oral; RFU=Response Follow Up; TF=treatment failure; (X) = optional 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 95 
Footnotes: 
a. 
An EOT visit will occur 30 days (±7) from the last dose of study drug or prior to the start of a new anticancer treatment. 
b. 
Subjects who discontinue for reasons other than TF will be followed every 3 months (±14 days) until TF or use of alternative anticancer treatment.   
c. 
Concomitant medications are collected from within 14 days before first dose through the 30 days after the last dose of study drug. 
d. 
See Section 11.4 for details regarding the reporting of AEs.   
e. 
A complete physical examination will include, at a minimum, the general appearance of the subject, height (may use prior height measurement if  available 
in source documents) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
lymphatic system, and nervous system.  
f. 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.   
g. 
12-lead ECG will be done in triplicate (≥1 minute apart).  The calculated Fridericia’s corrected QT interval (QTcF) average of the 3 ECGs must be 
<470 msec for eligibility.  Subjects should be in a supine position and resting for at least 10 minutes before obtaining the ECGs.  During the treatment 
period, ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or 
new onset dyspnea. A single ECG tracing will be performed at EOT. 
h. 
A unilateral bone marrow aspirate and biopsy will be done at Screening within 7 days before the first administration of study drug.  Bone marrow 
aspirate/biopsy will be required Cycle 2 Day 1 (±3 days), Cycle 4 Day 1 (±3 days), then every 3 cycles (±5 days) (ie, Cycles 7, 10, and 13), and every 
6 cycles (±5 days) thereafter until designation of treatment failure or withdrawal of consent. Subjects with prolonged pancytopenia and hypocellular bone 
marrow (ie, cellularity 5% or less without evidence of leukemia) at the Cycle 2 Day 1 assessment must undergo an additional bone marrow assessment on 
Day 42 (±3 days) after initiation of study treatment. 
i. 
Hematology includes complete blood count with differential and platelet counts. Subjects with platelet counts ≤25,000/µL at baseline or during the first 
cycle will be required to have platelet assessment 3 times a week until the end of first treatment cycle.  Thereafter, follow the Schedule of Assessment and 
hematological and dosing guidelines provided in Section 5.4.1.4). 
j. 
Serum chemistry:  Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate. 
k. 
Hepatitis C antibody, hepatitis B surface antigen and antibody and hepatitis B core antibody will be evaluated.  If hepatitis B core antibody or hepatitis 
B surface antigen is positive, then hepatitis B PCR to quantitate hepatitis B DNA must be performed.  DNA PCR needs to be confirmed negative (<29 U) 
prior to enrollment  in subjects who are hepatitis B core antibody or hepatitis B surface antigen positive.  For subjects who are hepatitis C antibody positive, 
hepatitis C PCR needs to be confirmed negative prior to enrollment.  
l. 
Urinalysis:  pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
m. 
In subjects who develop CNS progression, CSF will be obtained for PK, PD, and other disease related testing. 
n. 
T/B/NK cell count samples are to be collected before dosing at the protocol specified timepoints.  
o. 
Biomarker blood samples are to be collected before dosing at the protocol specified timepoints.  On Day 1 of the ibrutinib run-in, blood sample will be 
collected at pre-dose and 4 hours (±30 min) after dosing with ibrutinib.    
p. 
From the bone marrow biopsy, up to an additional 10 unstained slides and up to 20 mL aspirate samples will be collected for evaluation. 
q. 
Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, then every 6 cycles thereafter) 
r. 
Pharmacokinetic blood samples will be drawn according to the schedule Table 2. See Section 7.1.3.4 for more details regarding requested samples.  
s. 
An additional PK blood sampling at TF visit would be required if CSF is drawn.  
 
 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 96 
Appendix 2: Schedule of Assessments – Ibrutinib Monotherapy Cohort 
Study Cycle 
C1 
C2 
C3 
C4 
C5 & Beyond 
TF 
EOTa RFUb 
LTFU 
Study Day 
1 
2 
8 
15 
22 
1 
8 
15 
22 
1 
15 
1 
15 
1 
 
(±2 days) 
(±2 days) 
(±2 days) 
(±2 days) 
Any 
time 
(±7d) 
(±14 days) 
Study Drug Administration 
   
Ibrutinib (continuous) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Procedure 
Screening 
Day -28 to  -1 
  
Informed consent 
X 
 
Medical history & demographics 
X 
X 
 
Review concomitant Medicationsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse eventsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam & weighte 
(height C1D1 only) 
X 
X 
X 
X 
X 
 
X 
X 
X 
Symptom directed physical exam 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Triplicate 12-Lead ECGg 
X 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
X  
Bone marrow aspirate/biopsyh 
X 
X 
X 
 
X 
X 
X 
Confirm eligibility 
X 
X 
 
Laboratory Assessment 
Hematologyi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation (PT, INR, aPTT) 
X 
 
X 
 
Hepatitis serologiesk 
X 
 
 
Urinalysisl 
X 
 
X 
 
Pregnancy test 
X 
 
Cerebrospinal fluidm 
 
X 
T/B/NK cell countn 
X 
X 
X 
X 
 
X 
X 
Biomarker - blood sampleo 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Biomarker - bone marrowp  
X 
X 
X 
 
Xq 
X 
X 
PK blood samplingr  
X 
X 
X 
 
(Xs) 
Other 
Survival status, incl. other malignancies 
 
X 
Subsequent anticancer therapy 
 
X 
X 
Abbreviations:  C=cycle; D or d =day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment visit; LTFU=Long-Term Follow Up; PO=oral;  
RFU=Response Follow Up; TF=treatment failure; (X) = optional 
 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 97 
Footnotes: 
a. 
An EOT visit will occur 30 days.  (±7) from the last dose of study drug or prior to the start of a new anticancer treatment. 
b. 
Subjects who discontinue for reasons other than TF will be followed every 3 months (±14 days) until TF or use of alternative anticancer treatment.   
c. 
Concomitant medications are collected from within 14 days before first dose through the 30 days after the last dose of study drug. 
d. 
 See Section 11.4 for details regarding the reporting of AEs.   
e. 
A complete physical examination will include, at a minimum, the general appearance of the subject, height (C1D1 Visit only [may use prior height 
measurement if  available in source documents]) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system.  
f. 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.   
g. 
12-lead ECG will be done in triplicate (≥1 minute apart).  The calculated Fridericia’s corrected QT interval (QTcF) average of the 3 ECGs must be 
<470 msec for eligibility.  Subjects should be in a supine position and resting for at least 10 minutes before obtaining the ECGs. During the treatment period, 
ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset 
dyspnea. A single ECG tracing will be performed at EOT.  
h. 
A unilateral bone marrow aspirate and biopsy will be done at Screening or within 7 days before the first administration of study drug.  Bone marrow 
aspirate/ biopsy will be required Cycle 2 Day 1 (±3 days), Cycle 4 Day 1 (±3 days), then every 3 cycles (±5 days) (ie, Cycles 7, 10, and 13), and every 
6 cycles (±5 days) thereafter until designation of TF or withdrawal of consent. Subjects with prolonged pancytopenia and hypocellular bone marrow 
(ie, cellularity 5% or less without evidence of leukemia) at the C2D1 assessments must undergo an additional bone marrow assessment on Day 42 (±3 days) 
after initiation of study treatment. 
i. 
Hematology includes complete blood count with differential and platelet counts. Subjects with platelet counts ≤25,000/µL at baseline or during the first 
cycle will be required to have platelet assessment 3 times a week until the end of first treatment cycle. Thereafter, follow the Schedule of Assessment and 
hematological and dosing guidelines provided in Section 5.4.1.4). 
j. 
Serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate. 
k. 
Hepatitis C antibody, hepatitis B surface antigen and antibody and hepatitis B core antibody will be evaluated.  If hepatitis B core antibody or hepatitis 
B surface antigen is positive, then hepatitis B PCR to quantitate hepatitis B DNA must be performed.  DNA PCR needs to be confirmed negative (<29 U) 
prior to enrollment  in subjects who are hepatitis B core antibody or hepatitis B surface antigen positive.  For subjects who are hepatitis C antibody positive, 
hepatitis C PCR needs to be confirmed negative prior to enrollment.  
l. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
m. 
In subjects who develop CNS progression, CSF will be obtained for PK, PD, and other disease related testing. 
n. 
T/B/NK cell count samples are collected before dosing at the protocol specified timepoints.  
o. 
Biomarker blood samples are collected before dosing at the protocol specified timepoints.   
p. 
From the bone marrow biopsy, up to an additional 10 unstained slides and up to 20 mL aspirate samples will be collected for evaluation. 
q. 
Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, then every 6 cycles thereafter) 
r. 
Pharmacokinetic blood samples will be drawn according to the schedule Table 3.  See Section 7.1.3.4 for more details regarding requested samples.  
s. 
An additional PK blood sampling at TF visit would be required if CSF is drawn. 
 
 
 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 98 
Appendix 3: Schedule of Assessments – Ibrutinib + Azacitidine Combination Cohort (Cohort 3) 
Study Cycle 
Ibrutinib 
Run-in 
C1 
C2 
C3 
C4 
C5 & Beyond 
TF 
EOTa RFUb LTFU 
Study Day 
1 
1 
7 15 
22 
1 
7 
15 
22 
1 
15 
1 
15 
1 
 
 
 
 
(±2 days) 
(±2 days) 
(±2 days) 
(±2 days) 
Any 
time (±7d) (±14 days) 
Study Drug Administration 
Ibrutinib (continuous) 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Azacitidine (for 7 days every 4 wks) 
Days 
1-7 
Days 
1-7 
Days 
1-7 
Days 
1-7 
Days 1-7 
 
Procedure 
Screening 
Day -28 to -1 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Medical history & demographics 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Review Concomitant Medicationsc 
X 
X 
X X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
Review adverse eventsd 
X 
X 
X X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete Physical Exam & Weighte  
X 
X 
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
 
Symptom directed physical exam 
  
  
X 
X 
X 
  
X 
 X 
X 
  
  
  
  
 
Vital signsf  
X 
X 
X X 
X 
X 
X 
X 
 X 
X 
X 
  
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
  
X 
X 
  
 X 
X 
  
X 
X 
X 
X 
X 
Triplicate 12-Lead ECGg 
X 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
  
X  
 
Bone marrow aspirate/biopsyh 
X 
  
  
  
  
X 
  
  
  
  
  
 X  
 X  
 X 
  
X 
Confirm eligibility 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Laboratory Assessment  
Hematologyi 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
  
Serum chemistryj 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
  
  
Coagulation (PT, INR, aPTT) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
  
Hepatitis serologiesk 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Urinalysisl 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Pregnancy test 
X 
 
Cerebrospinal fluidm 
X 
 
T/B/NK cell countn 
  
X 
  
  
  
X 
  
  
  
X 
X 
  
X 
X 
 
Biomarker - blood sampleo 
  
X 
X 
X 
X 
X  
X 
  
X 
X 
X 
X 
Biomarker - bone marrowp 
X 
X 
  
  
 X  
  
X q 
X 
X 
PK blood samplingr   
  
X 
X X 
  
  
  
  
  
  
(X)s 
  
 
Other 
Survival status, incl. other malignancies 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Subsequent Anticancer Therapy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Abbreviations:  C=cycle; D or d=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment visit; LTFU=Long-Term Follow Up; 
PO=oral; RFU=Response Follow Up; TF=treatment failure; (X) = optional 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 99 
Footnotes: 
a. 
An EOT visit will occur 30 days (±7) from the last dose of study drug or prior to the start of a new anticancer treatment. 
b. 
Subjects who discontinue for reasons other than TF will be followed every 3 months (±14 days) until TF or use of alternative anticancer treatment.   
c. 
Concomitant medications are collected from within 14 days before first dose through the 30 days after the last dose of study drug. 
d. 
See Section 11.4 for details regarding the reporting of AEs.   
e. 
A complete physical examination will include, at a minimum, the general appearance of the subject, height (may use prior height measurement if  available 
in source documents) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
lymphatic system, and nervous system.  
f. 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.   
g. 
12-lead ECG will be done in triplicate (≥1 minute apart).  The calculated Fridericia’s corrected QT interval (QTcF) average of the 3 ECGs must be 
<470 msec for eligibility.  Subjects should be in a supine position and resting for at least 10 minutes before obtaining the ECGs.  During the treatment 
period, ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or 
new onset dyspnea. A single ECG tracing will be performed at EOT. 
h. 
A unilateral bone marrow aspirate and biopsy will be done at Screening within 7 days before the first administration of study drug.  Bone marrow 
aspirate/biopsy will be required Cycle 2 Day 1 (±3 days), Cycle 4 Day 1 (±3 days), then every 3 cycles (±5 days) (ie, Cycles 7, 10, and 13), and every 
6 cycles (±5 days) thereafter until designation of treatment failure or withdrawal of consent. Subjects with prolonged pancytopenia and hypocellular bone 
marrow (ie, cellularity 5% or less without evidence of leukemia) at the Cycle 2 Day 1 assessment must undergo an additional bone marrow assessment on 
Day 42 (±3 days) after initiation of study treatment. 
i. 
Hematology includes complete blood count with differential and platelet counts. Subjects with platelet counts ≤25,000/µL at baseline or during the first 
cycle will be required to have platelet assessment 3 times a week until the end of first treatment cycle.  Thereafter, follow the Schedule of Assessment and 
hematological and dosing guidelines provided in Section 5.4.1.4). 
j. 
Serum chemistry:  Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate. 
k. 
Hepatitis C antibody, hepatitis B surface antigen and antibody and hepatitis B core antibody will be evaluated.  If hepatitis B core antibody or hepatitis 
B surface antigen is positive, then hepatitis B PCR to quantitate hepatitis B DNA must be performed.  DNA PCR needs to be confirmed negative (<29 U) 
prior to enrollment in subjects who are hepatitis B core antibody or hepatitis B surface antigen positive.  For subjects who are hepatitis C antibody positive, 
hepatitis C PCR needs to be confirmed negative prior to enrollment.  
l. 
Urinalysis:  pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
m. 
In subjects who develop CNS progression, CSF will be obtained for PK, PD, and other disease related testing. 
n. 
T/B/NK cell count samples are to be collected before dosing at the protocol specified timepoints.  
o. 
Biomarker blood samples are to be collected before dosing at the protocol specified timepoints.  On Day 1 of the ibrutinib run-in, blood sample will be 
collected at pre-dose and 4 hours (±30 min) after dosing with ibrutinib.    
p. 
From the bone marrow biopsy, up to an additional 10 unstained slides and up to 20 mL aspirate samples will be collected for evaluation. 
q. 
Bone marrow aspirate and biopsy including bone marrow smear slides (Cycles 7, 10, 13, then every 6 cycles thereafter) 
r. 
Pharmacokinetic blood samples will be drawn according to the schedule Table 4.  See Section 7.1.3.4 for more details regarding requested samples.  
s. 
An additional PK blood sampling at TF visit would be required if CSF is drawn.  
 


IMBRUVICA® (ibrutinib) 
PCYC-1131-CA-Amendment 1 
15 January 2016 
Amendment 1 Final 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 100 
Appendix 4: ECOG Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed January 04, 2008. 
 


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Appendix 5: Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A are defined as follows. Refer to Section 6.2.1 on instructions for 
concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/.  
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone 
telithromycin 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem 
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
 
 


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Appendix 6: Response Criteria 
Category 
Definition 
Complete Remission 
(CR)* 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count > 1.0 x 109/L 
(1000/µL); platelet count >100 x 109/L (100 000/µL); independence of 
red cell transfusions 
CR with Incomplete 
Recovery (CRi) 
All CR criteria except for residual neutropenia (< 1.0 x 109/L [1000/µL]) 
or thrombocytopenia (<100 x 109/L [100 000/µL])  
Morphologic 
leukemia-free state 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
Partial Remission 
(PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5% to 25%; and decrease of pretreatment bone marrow 
blast percentage by at least 50% 
Relapse 
Bone marrow blasts > 5%; or reappearance of blasts in the blood; or 
development of extramedullary disease 
Reference:  Döhner 2010 
* All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 
nucleated cells in an aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 
days; flow cytometric evaluation may help to distinguish between persistent leukemia and 
regenerating normal marrow; a marrow biopsy should be performed in cases of dry tap, or if 
no spicules are obtained; no minimum duration of remission required.  
 


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Appendix 7: Child-Pugh Score for Subjects with Liver Impairment 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, et al . “Transection of the oesophagus for bleeding oesophageal 
varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 
 

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APPENDIX 9.1 
STATISTICAL ANALYSIS PLAN 
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Statistical Analysis Plan 
 
TITLE:  
A Multicenter Open-Label Phase 2a Study of 
Ibrutinib Monotherapy or in Combination with 
either Cytarabine or Azacitidine in Subjects with 
Acute Myeloid Leukemia 
PROTOCOL: 
PCYC-1131-CA 
 
 
 
 
DATE:   
02 August 2017 
The information in this document is considered privileged and confidential by Pharmacyclics 
LLC, and may not be disclosed to others except to the extent necessary to obtain Institutional 
Review Board approval and informed consent, or as required by Federal and State Laws.  
Persons to whom this information is disclosed must be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................3 
1.1. Study Objectives ............................................................................................................3 
1.2. Study Endpoints .............................................................................................................3 
1.3. Study Design ..................................................................................................................4 
1.4. Sample Size Considerations ...........................................................................................4 
2. 
GENERAL ANALYSIS CONSIDERATION ......................................................................5 
2.1. Analysis Populations ......................................................................................................5 
2.2. Analysis Conventions ....................................................................................................5 
3. 
SUBJECT INFORMATION..................................................................................................5 
3.1. Protocol Deviations ........................................................................................................5 
4. 
EFFICACY ..............................................................................................................................5 
4.1. Change from Protocol-defined Analysis ........................................................................5 
4.2. Overall Survival (OS) ....................................................................................................6 
5. 
SAFETY...................................................................................................................................6 
5.1. DLT Assessment ............................................................................................................6 
5.2. Adverse Events ..............................................................................................................6 
5.2.1. Treatment-emergent Adverse Events ...............................................................6 
5.2.2. Adverse Events of Special Interest ...................................................................6 
5.2.3. Other Malignancies ...........................................................................................7 
5.2.4. Other Safety Observations in AE Reporting ....................................................7 
5.2.5. Deaths ...............................................................................................................7 
5.3. Clinical Laboratory Tests ...............................................................................................7 
 
 
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1.
INTRODUCTION
This Phase 2a open-label, non-randomized U.S. multicenter study is designed to evaluate the 
safety and efficacy of ibrutinib monotherapy and in combination with low dose cytosine 
arabinoside (LD-AraC) or azacitidine in the treatment of subjects with Acute Myeloid Leukemia 
(AML).  
This statistical analysis plan (SAP) describes the statistical methodology of efficacy and safety 
for this study. This plan does not cover the pharmacokinetic (PK) or biomarker analyses. These 
analyses will be performed and reported by the DMPK Department and Biomarker group of 
Pharmacyclics, respectively. 
1.1.Stud y Objectives 
The primary objectives are to evaluate the efficacy of ibrutinib monotherapy or in combination 
with either LD-AraC or azacitidine in the treatment of AML using the overall remission rate 
(ORR, defined as the proportion of subjects achieving a complete remission (CR) or complete 
remission with incomplete marrow recovery (CRi)) according to the LeukemiaNet guidelines 
(Döhner 2010, Appendix 6 in Protocol Amendment 1.0) and to evaluate the safety and 
tolerability of ibrutinib monotherapy or in combination with either LD-AraC or azacitidine in 
subjects with AML.  
The secondary objectives are to evaluate clinical efficacy by assessing relapse-free survival 
(RFS), event-free survival (EFS) and overall survival (OS) and to evaluate clinical benefit 
defined as CR, CRi, morphologic leukemia-free state, and partial remission (PR). 
The exploratory objectives are to determine the PK of ibrutinib monotherapy or in combination 
with either LD-AraC or azacitidine in an AML population and to evaluate prognostic and 
predictive biomarkers relative to treatment outcomes (ie, BTK/pBTK, secreted proteins, gene 
expression profiling, mutational analysis). Exploratory objectives are outside the scope of this 
SAP. 
1.2.Stud y Endpoints 
Response criteria from the LeukemiaNet guidelines have been used by all investigators to assess 
efficacy outcomes. In accordance with the study protocol, the primary efficacy endpoint is 
defined as the ORR per investigator assessment of ibrutinib monotherapy and in combination 
with LD-AraC or azacitidine, respectively. The secondary efficacy endpoints include RFS for 
subjects who achieve a CR or CRi; EFS; OS and Clinical Benefit Rate (CBR; defined as the 
proportion of subjects achieving CR, CRi, morphologic leukemia-free state, or PR).  Safety 
endpoints include the safety and tolerability of ibrutinib monotherapy and in combination with 
LD-AraC or azacytidine. 
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1.3.Stud y Design 
A maximum of 101 subjects will be enrolled in 3 treatment cohorts. 
• Cohort 1 – ibrutinib monotherapy: ibrutinib 560 mg once daily on a continuous basis. Up to 
33 response evaluable subjects 
• Cohort 2 – ibrutinib + LD-AraC:  ibrutinib 560 mg once daily on a continuous basis plus low 
dose cytarabine. Up to 34 response evaluable subjects 
• Cohort 3 – ibrutinib + azacitidine: ibrutinib 560 mg once daily on a continuous basis plus IV 
azacitidine. Up to 34 response evaluable subjects 
 
The study will begin with safety run-in phase in Cohort 2 only.  Six subjects will receive 
ibrutinib at a dose level of 560 mg once daily on a continuing basis starting 2 days prior to the 
first cytarabine dose.  Assessment for dose limiting toxicities (DLTs) will continue for the first 
treatment cycle.  If 2 of the first 6 subjects experience DLT(s), 3 additional subjects will be 
assessed for DLT(s).  If 3 or more of the 9 subjects experience DLT(s), enrollment will be halted 
at the 560 mg dose level.  At sponsor’s discretion, a dose of 420 mg ibrutinib or lower (plus LD-
AraC) may be explored.  If less than 2 out of 6 subjects or less than 3 out of 9 subjects 
experience DLT(s), additional subjects will be enrolled in Cohort 1 or 2 at the discretion of the 
investigator. Efficacy parameters will be monitored closely. In the event response assessments 
suggest futility in the ibrutinib + AraC cohort, further enrollment in either cohort 1 or 2 will be 
closed and a new cohort of ibrutinib + azacitidine will be started. For Cohort 3 the same safety 
run-in principle as Cohort 2 (6+3 design) will be implemented.  Study treatment will continue in 
subjects who demonstrate a PR or better on their Cycle 2 Day 1 bone marrow assessment 
according to the LeukemiaNet guidelines or based on clinical benefit as determined by the 
treating physician.  Treatment may continue thereafter until unacceptable toxicity, treatment 
failure (TF), or withdrawal of consent.  Subjects treated in the ibrutinib monotherapy cohort who 
experience a documented TF or relapse will be permitted to add LD-AraC to ibrutinib per 
investigator discretion. 
1.4. Sample Size Considerations 
The sample size of 6 or 9 safety run-in subjects for safety review was based on clinical 
experience and conventional DLT studies. The total sample size was calculated to detect a 
meaningful signal of activity of each treatment regimen while minimizing risk of continuing 
enrollment under null conditions.  The sample size was estimated for each treatment cohort 
without multiplicity adjustment. The study will enroll approximately 101 subjects in total, 
including 33 response evaluable subjects for monotherapy and 34 response evaluable subjects for 
each combo therapy.  The sample size of 33 subjects was calculated to test the null hypothesis 
that the ORR of ibrutinib monotherapy is ≤5% (not clinically compelling) versus the alternative 
hypothesis that ORR will be ≥20%, with a significance level of 5%, and 80% power.  The 
sample size of 34 subjects was calculated to test the null hypothesis that the ORR of ibrutinib 
plus LD-AraC or ibrutinib plus azacitidine is ≤15% (not clinically compelling) versus the 
alternative hypothesis that ORR will be ≥35%, with a significance level of 5%, and 80% power.   
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2. GENERAL ANALYSIS CONSIDERATION 
2.1.Analysis Population s 
All treated population includes all enrolled subjects who received at least 1 dose of study drug in 
each study cohort.  The DLT population will include the first 6 to 9 safety run-in subjects who 
signed the informed consent form and were enrolled for the safety run-in period, and were 
evaluable for DLT. The DLT population will be used to summarize dose limiting toxicities in the 
first 6 to 9 subjects in the safety run-in period. No subgroup analysis will be performed. 
2.2.Analysis Convention s 
Descriptive statistics (mean, standard deviation or standard error, median, minimum, and 
maximum) will be used to summarize continuous variables. Categorical variables will be 
summarized by counts and percentages. Unless otherwise specified, exact 95% confidence 
intervals will be constructed for event rates or response rates. As appropriate, data collected on 
the electronic case report form (eCRF) will be presented in data listings upon request.  All 
statistical analyses will be performed using SAS® version 9.2 or later. 
3. SUBJECT INFORMATION 
All analyses in this section will be based on the all treated population for each treatment cohort 
unless otherwise specified, including subject disposition, demographics and baseline 
characteristics, baseline disease characteristics, prior AML therapies, concomitant medications 
including CYP3A inhibitors, and exposure to ibrutinib. 
3.1.Pr otocol Deviation s 
In general, protocol violations/deviations will be reviewed by the study team during the study, 
and important protocol deviations will be determined based on the review. The information on 
important protocol deviations will be generated based on the review outcome for all subjects by 
the clinical team. 
4. EFFICACY 
4.1.Chan ge from Protocol-defined Analysis  
The study was terminated early due to lack of efficacy. As such, none of the protocol-defined 
efficacy endpoints including primary efficacy endpoints and secondary efficacy endpoints listed 
in Sections 1.2 will be calculated except for OS. A subject listing with all the available response 
assessment data for all treated patients will be provided.  Overall survival will be analyzed as 
described in Section 4.2. 
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4.2.Over all Survival (OS) 
Overall survival is defined as the duration of time from the date of first study drug to the date of 
death from any cause. Subjects who are not known to have died at or prior to the database lock 
date will be censored at the date last known alive or database lock date, whichever occurs first.  
OS(day) = Date of death or censoring date – date of first dose of study drug + 1 
The date last known alive will be derived as the latest among dosing records, lab measurements, 
vital signs, assessment dates. The median OS and its 95% CI will be obtained using Kaplan-
Meier method.  Overall survival at landmark time points (e.g. 1,2,3 months and etc. from first 
ibrutinib date) will also be obtained from Kaplan-Meier method. 
5. SAFETY 
Adverse events, changes in clinical laboratory results from baseline, summary of vital signs and 
ECG values will be provided. All safety analyses will be based on all treated population (except 
for DLT evaluation which will be based on DLT population).  
5.1.DLT Assessment 
At the safety review meeting, DLTs will be assessed for the first 6 to 9 subjects in the DLT 
population. Listing of subjects for DLT assessment will be provided.  
5.2.Adver se Events 
Adverse events collected in the CRF (verbatim terms) by investigators will be coded to a 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The severity 
of adverse events is assessed in National Cancer Institute (NCI) common toxicity criteria for 
adverse events (CTCAE) Version 4.03. 
5.2.1. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events will be summarized by system organ class and preferred 
terms and by NCI toxicity grade. The same summary will be provided for treatment-related AEs, 
AEs leading to treatment discontinuation, AEs leading to treatment discontinuation for subjects 
who discontinued treatment due to AE, AEs leading to dose reduction and serious TEAEs.  
Adverse event overview on the incidences of all the above will be presented. 
5.2.2. 
Adverse Events of Special Interest 
5.2.2.1. 
Hemorrhagic Events 
Bleeding events: Identified by MedDRA Hemorrhage SMQ without lab SMQ. 
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Major hemorrhage: Defined as any bleeding event identified by Hemorrhage SMQ without lab 
SMQ that satisfies at least one of the following three criteria: Grade 3 or higher in severity, 
Serious AE or all grades of CNS hemorrhage.  
5.2.3. 
Other Malignancies 
Other malignancies are defined as new malignant tumors including categories non-melanoma 
skin cancer, melanoma skin cancer and other non-skin cancers. Both treatment-emergent adverse 
events of other malignancies and all other malignancies AEs reported during the study will be 
summarized.  
5.2.4. 
Other Safety Observations in AE Reporting 
Treatment-emergent adverse events including other cardiac arrhythmia (excluding atrial 
fibrillation), Interstitial Lung Disease events (ILD) and Severe Cutaneous Adverse Reactions 
(SCAR) will be summarized by preferred terms based on SMQ searches and/or medical monitor 
and safety scientist review. 
Summary of treatment-emergent adverse events including leukostasis, infections, tumor lysis 
syndrome (TLS), cytopenias, hypersensitivity, hepatic disorders and atrial fibrillation can be 
obtained from existing AE summary tables.  
5.2.5. 
Deaths  
Treatment-emergent adverse events leading to deaths will be summarized.   
5.3.Clinical Laborator y Tests 
All gradable laboratory parameters will be graded using the NCI CTCAE version 4.03. A 
summary of worst post-baseline toxicity grade will be provided. The events with Grade 3 and 4 
as the worst post-baseline toxicity grade will be also provided.  Only subjects whose grades 
worsened are counted in the numerator of percentage calculation while the denominator is all 
subjects in each treatment cohort all treated population. Liver function abnormality by Hy’s law 
will be summarized. Listing of white blood cell (WBC) count, platelet count, blood blasts (%) 
and abnormal cells will be presented.   
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