Clinical trial NCT02548962
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Bruton's Tyrosine Kinase PCI-32765 Pomalidomide Dexamethasone Relapsed Refractory Multiple Myeloma Ibrutinib
Sponsor: Pharmacyclics LLC.
Start date: 2016-03-01; Completion date: 2018-06-13
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1 is an open-label, dose finding, multicenter study of ibrutinib in combination with pomalidomide and dexamethasone in subjects with relapsed/refractory multiple myeloma.

Phase 2b is a randomized, double-blind, multicenter study of ibrutinib or placebo, in combination with pomalidomide and dexamethasone in subjects with relapsed/refractory multiple myeloma.

Detailed description:
Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic cells other than T cells and is necessary for downstream signal transduction from various hematopoietic receptors including the B cell receptor as well as some Fc, chemokine, and adhesion receptors, and is crucial for both B cell development and osteoclastogenesis. Although down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from many myeloma patients and some cell lines. Ibrutinib is a potent and specific inhibitor of Btk currently in Phase 2 and 3 clinical trials. The current study is designed and intended to determine the safety and efficacy of ibrutinib in combination with pomalidomide and dexamethasone in subjects with relapsed/refractory multiple myeloma.

Arms: arm 1: Ibrutinib PO+ Pomalidomide PO+ Dexamethasone PO arm 2: Ibrutinib PO+ Pomalidomide PO+ Dexamethasone PO arm 3: Placebo PO+ Pomalidomide PO+ Dexamethasone PO
Interventions: intervention 1: Ibrutinib intervention 2: Pomalidomide intervention 3: Dexamethasone intervention 4: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
Ibrutinib (PCI-32765) 
PCYC-1138-CA, Amendment 2 
13 February 2017 
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PROTOCOL 
 
 
TITLE: 
A Randomized Multicenter Study of Ibrutinib in Combination with 
Pomalidomide and Dexamethasone in Subjects with 
Relapsed/Refractory Multiple Myeloma 
PROTOCOL NUMBER: 
PCYC-1138-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
102,688 
EudraCT NUMBER: 
2015-002191-25 
SPONSOR MEDICAL 
MONITOR: 
Elizabeth Bilotti, MSN, MSJ, ANP-BC 
Pharmacyclics Switzerland GmbH 
Phone (US): 
+1 (408) 215 3400 
Phone (Ex-US): +41 (52) 556 0839 
Fax: 
+41 (76) 392 2152 
Email: 
ebilotti@ch.pcyc.com 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
Original Protocol Date: 
5 May 2015 
Amendment 1 Date: 
6 November 2015 
Amendment 2 Date: 
13 February 2017 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee.  This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics LLC. 
 
 


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PCYC-1138-CA, Amendment 2 
13 February 2017 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................8 
LIST OF IN-TEXT TABLES .......................................................................................................8 
LIST OF FIGURES .......................................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................19 
1.
BACKGROUND ............................................................................................................22
1.1. 
Multiple Myeloma .........................................................................................................22 
1.1.1. 
Existing Therapies and Unmet Need in Relapsed/Refractory Multiple Myeloma ........23 
1.1.2. 
BTK Inhibition as a Treatment Option for MM ............................................................24 
1.2. 
Investigational Product Name and Description .............................................................25 
1.2.1. 
Summary of Nonclinical Data .......................................................................................25 
1.2.1.1. 
Pharmacology ................................................................................................................25 
1.2.1.2. 
Safety Pharmacology and Toxicology ..........................................................................25 
1.2.2. 
Summary of Clinical Data .............................................................................................26 
1.2.2.1. 
Pharmacokinetics and Product Metabolism ..................................................................26 
1.2.3. 
Summary of Clinical Safety ..........................................................................................27 
1.2.3.1. 
Monotherapy Studies .....................................................................................................27 
1.2.3.2. 
Combination Therapy Studies .......................................................................................27 
1.2.4. 
Risks ..............................................................................................................................28 
1.2.4.1. 
Bleeding-related Events ................................................................................................28 
1.2.4.2. 
Atrial Fibrillation ...........................................................................................................28 
1.2.4.3. 
Cytopenias .....................................................................................................................28 
1.2.4.4. 
Diarrhea .........................................................................................................................29 
1.2.4.5. 
Infections .......................................................................................................................29 
1.2.4.6. 
Interstitial Lung Disease (ILD) .....................................................................................29 
1.2.4.7. 
Non-melanoma Skin Cancer .........................................................................................29 
1.2.4.8. 
Rash ...............................................................................................................................29 
1.2.4.9. 
Tumor Lysis Syndrome .................................................................................................29 
1.2.4.10. Hypertension .................................................................................................................30 
1.2.5. 
Summary of Clinical Data with Ibrutinib in MM ..........................................................30 
1.2.5.1. 
PCYC-1111-CA ............................................................................................................30 
1.2.5.2. 
PCYC-1119-CA ............................................................................................................31 
1.3. 
Pomalidomide Description ............................................................................................32 
1.3.1. 
Pharmacokinetics and Product Metabolism ..................................................................32 
1.3.2. 
Summary of Clinical Data for Pomalidomide and Dexamethasone in MM .................32 
1.3.3. 
Venous Thromboembolism (VTE) ................................................................................34 
1.3.4. 
Second New Cancers .....................................................................................................34 
1.4. 
Justification of Study Design and Dose Rationale ........................................................35 
2.
STUDY OBJECTIVE ...................................................................................................36
2.1. 
Primary Objective(s) .....................................................................................................36 
2.2. 
Secondary Objective(s) .................................................................................................36 


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PCYC-1138-CA, Amendment 2 
13 February 2017 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................8 
LIST OF IN-TEXT TABLES .......................................................................................................8 
LIST OF FIGURES .......................................................................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................19 
1. 
BACKGROUND ............................................................................................................22 
1.1. 
Multiple Myeloma .........................................................................................................22 
1.1.1. 
Existing Therapies and Unmet Need in Relapsed/Refractory Multiple Myeloma ........23 
1.1.2. 
BTK Inhibition as a Treatment Option for MM ............................................................24 
1.2. 
Investigational Product Name and Description .............................................................25 
1.2.1. 
Summary of Nonclinical Data .......................................................................................25 
1.2.1.1. 
Pharmacology ................................................................................................................25 
1.2.1.2. 
Safety Pharmacology and Toxicology ..........................................................................25 
1.2.2. 
Summary of Clinical Data .............................................................................................26 
1.2.2.1. 
Pharmacokinetics and Product Metabolism ..................................................................26 
1.2.3. 
Summary of Clinical Safety ..........................................................................................27 
1.2.3.1. 
Monotherapy Studies .....................................................................................................27 
1.2.3.2. 
Combination Therapy Studies .......................................................................................27 
1.2.4. 
Risks ..............................................................................................................................28 
1.2.4.1. 
Bleeding-related Events ................................................................................................28 
1.2.4.2. 
Atrial Fibrillation ...........................................................................................................28 
1.2.4.3. 
Cytopenias .....................................................................................................................28 
1.2.4.4. 
Diarrhea .........................................................................................................................29 
1.2.4.5. 
Infections .......................................................................................................................29 
1.2.4.6. 
Interstitial Lung Disease (ILD) .....................................................................................29 
1.2.4.7. 
Non-melanoma Skin Cancer .........................................................................................29 
1.2.4.8. 
Rash ...............................................................................................................................29 
1.2.4.9. 
Tumor Lysis Syndrome .................................................................................................29 
1.2.4.10. Hypertension .................................................................................................................30 
1.2.5. 
Summary of Clinical Data with Ibrutinib in MM ..........................................................30 
1.2.5.1. 
PCYC-1111-CA ............................................................................................................30 
1.2.5.2. 
PCYC-1119-CA ............................................................................................................31 
1.3. 
Pomalidomide Description ............................................................................................32 
1.3.1. 
Pharmacokinetics and Product Metabolism ..................................................................32 
1.3.2. 
Summary of Clinical Data for Pomalidomide and Dexamethasone in MM .................32 
1.3.3. 
Venous Thromboembolism (VTE) ................................................................................34 
1.3.4. 
Second New Cancers .....................................................................................................34 
1.4. 
Justification of Study Design and Dose Rationale ........................................................35 
2. 
STUDY OBJECTIVE ...................................................................................................36 
2.1. 
Primary Objective(s) .....................................................................................................36 
2.2. 
Secondary Objective(s) .................................................................................................36 


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2.3. 
Exploratory Objective(s) ...............................................................................................37 
2.4. 
Open-Label Sub-Study Treatment Arm C (Phase 2b) ...................................................37 
3. 
OVERVIEW OF STUDY DESIGN .............................................................................38 
3.1. 
Statement of Compliance ..............................................................................................42 
4. 
SUBJECT SELECTION ...............................................................................................42 
4.1. 
Inclusion Criteria ...........................................................................................................42 
4.1.1. 
Inclusion Criteria for Open-label Sub-study Arm C (Phase 2b) ...................................44 
4.2. 
Exclusion Criteria ..........................................................................................................44 
4.2.1. 
Exclusion Criteria for Open-Label Sub-Study Arm C (Phase 2b) ................................46 
5. 
TREATMENT OF SUBJECTS ....................................................................................46 
5.1. 
Phase 1 Dose Escalation and Stopping Rules ...............................................................46 
5.1.1. 
Definition of Dose Limiting Toxicity (DLT) ................................................................47 
5.2. 
Randomization and Blinding .........................................................................................48 
5.3. 
Treatment Regimens ......................................................................................................49 
5.3.1. 
Phase 1 ...........................................................................................................................49 
5.3.2. 
Randomized Phase 2b (Treatment Arms A and B) .......................................................49 
5.3.2.1. 
Treatment Arm A ..........................................................................................................50 
5.3.2.2. 
Treatment Arm B ...........................................................................................................50 
5.3.3. 
Open-Label Sub-Study (Treatment Arm C) ..................................................................50 
5.4. 
Ibrutinib or Placebo .......................................................................................................50 
5.4.1. 
Formulation, Packaging, and Storage of Ibrutinib or Placebo ......................................50 
5.4.2. 
Dose and Administration of Ibrutinib or Placebo .........................................................51 
5.4.3. 
Dose Hold, Reduction or Discontinuation of Ibrutinib or Placebo ...............................51 
5.4.4. 
Dose Modification of Ibrutinib or Placebo ....................................................................52 
5.4.5. 
Dose Modification for Hepatic Impaired Subjects ........................................................53 
5.5. 
Pomalidomide ................................................................................................................54 
5.5.1. 
Formulation, Packaging, and Storage of Pomalidomide ...............................................54 
5.5.2. 
Pomalidomide Prescribing Information (Applies to US/Canada Sites Only) ...............54 
5.5.3. 
Pomalidomide Drug Dispensing Requirements (Applies to Ex-US Sites Only) ..........55 
5.5.4. 
Dosage, Preparation and Administration of Pomalidomide ..........................................56 
5.5.4.1. 
Required Concomitant Medications and Procedures ....................................................56 
5.5.5. 
Dose Delay, Reduction or Discontinuation of Pomalidomide ......................................56 
5.5.6. 
Dose Modification of Pomalidomide During a Cycle ...................................................57 
5.6. 
Dexamethasone .............................................................................................................59 
5.6.1. 
Formulation, Packaging, and Storage of Dexamethasone .............................................59 
5.6.2. 
Dosage and Administration of Dexamethasone ............................................................59 
5.6.3. 
Dose Modification of Dexamethasone ..........................................................................60 
5.7. 
Overdose Instructions ....................................................................................................60 
5.7.1. 
Ibrutinib or Placebo .......................................................................................................60 
5.7.2. 
Pomalidomide ................................................................................................................60 
5.7.3. 
Dexamethasone .............................................................................................................61 
5.8. 
Criteria for Permanent Discontinuation of Study Treatment ........................................61 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES ...............................................61 
6.1. 
Concomitant Medications ..............................................................................................61 
6.1.1. 
Permitted Concomitant Medications .............................................................................61 
6.1.2. 
Medications to be Used with Caution ...........................................................................62 


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6.1.2.1. 
CYP3A Inhibitors/Inducers ...........................................................................................62 
6.1.2.2. 
Drugs that may Have Their Plasma Concentrations Altered by Ibrutinib ....................63 
6.1.2.3. 
QT Prolonging Agents ...................................................................................................63 
6.1.2.4. 
Concomitant Use of Antiplatelet Agents and Anticoagulants .......................................63 
6.1.3. 
Prohibited Concomitant Medications ............................................................................64 
6.2. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ............................64 
6.2.1. 
Minor Procedures ..........................................................................................................64 
6.2.2. 
Major Procedures ..........................................................................................................64 
6.2.3. 
Emergency Procedures ..................................................................................................64 
7. 
STUDY EVALUATIONS .............................................................................................65 
7.1. 
Screening/Administrative ..............................................................................................65 
7.1.1. 
Informed Consent ..........................................................................................................65 
7.1.2. 
Confirm Eligibility ........................................................................................................65 
7.1.3. 
Medical History and Demographics ..............................................................................65 
7.1.4. 
Venous Thromboembolism (VTE) Risk Assessment ...................................................65 
7.1.5. 
Prior and Concomitant Medications ..............................................................................66 
7.1.6. 
Adverse Events ..............................................................................................................66 
7.2. 
Assessments ...................................................................................................................66 
7.2.1. 
Eye-related Symptom Assessment ................................................................................66 
7.2.2. 
Physical Examination, Height, and Weight ...................................................................66 
7.2.3. 
Venous Thromboembolism (VTE) Monitoring ............................................................66 
7.2.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ............................67 
7.2.5. 
Vital Signs .....................................................................................................................67 
7.2.6. 
Patient-Reported Outcome (PRO) Assessment (Phase 2b only) ...................................67 
7.2.7. 
Follow-up for Other Malignancies ................................................................................67 
7.3. 
Clinical Laboratory Assessments ..................................................................................67 
7.3.1. 
Hematology ...................................................................................................................67 
7.3.2. 
Serum Chemistry ...........................................................................................................68 
7.3.3. 
Creatinine Clearance .....................................................................................................68 
7.3.4. 
Coagulation Studies .......................................................................................................68 
7.3.5. 
Hepatitis Serologies .......................................................................................................68 
7.3.6. 
Thyroid Function ...........................................................................................................68 
7.3.7. 
Pregnancy Test ..............................................................................................................68 
7.4. 
Diagnostic/Procedures ...................................................................................................69 
7.4.1. 
Electrocardiogram .........................................................................................................69 
7.5. 
Efficacy Assessments ....................................................................................................69 
7.5.1. 
Serum and Urine Protein Electrophoresis .....................................................................70 
7.5.2. 
Serum Free Light Chain Assay .....................................................................................70 
7.5.3. 
Serum and Urine Immunofixation .................................................................................70 
7.5.4. 
Quantitative Serum Immunoglobulins ..........................................................................70 
7.5.5. 
C-Reactive Protein and Serum β2-microglobulin .........................................................71 
7.5.6. 
Bone Radiologic Assessment ........................................................................................71 
7.5.7. 
Bone Marrow Aspirate and Biopsy ...............................................................................71 
7.6. 
Biomarker, Correlative and Special Studies ..................................................................72 
7.6.1. 
Pharmacokinetics ...........................................................................................................72 
7.6.2. 
Biomarkers ....................................................................................................................73 


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7.6.2.1. 
Genetic and Molecular Prognostic Markers ..................................................................73 
7.6.3. 
T/B/NK Cell Count (Phase 1 Only) ..............................................................................73 
7.7. 
Sample Collection and Handling ...................................................................................73 
7.8. 
Survival and Subsequent Anti-cancer Therapies ...........................................................74 
7.8.1. 
Survival .........................................................................................................................74 
7.8.2. 
Subsequent Anti-cancer Therapies ................................................................................74 
8. 
STUDY PROCEDURES ...............................................................................................74 
8.1. 
Overview .......................................................................................................................74 
8.2. 
Screening Phase .............................................................................................................74 
8.2.1. 
Screening Visit ..............................................................................................................74 
8.3. 
Treatment Phase ............................................................................................................75 
8.3.1. 
Cycle 1, Day 1 ...............................................................................................................76 
8.3.2. 
Cycle 1, Day 8 ...............................................................................................................77 
8.3.3. 
Cycle 1, Day 15 .............................................................................................................77 
8.3.4. 
Cycle 1, Day 22 .............................................................................................................78 
8.3.5. 
Cycle 2, Day 1 ...............................................................................................................78 
8.3.6. 
Cycle 2, Day 15 .............................................................................................................79 
8.3.7. 
Cycle 2, Days 22-28 ......................................................................................................80 
8.3.8. 
Cycles 3 and Beyond, Day 1 (odd cycles) .....................................................................80 
8.3.9. 
Cycle 3 and Beyond, Days 22-28 ..................................................................................81 
8.3.10. 
Cycle 4 and Beyond, Day 1 (even cycles) .....................................................................81 
8.3.11. 
Suspected PD Visit ........................................................................................................82 
8.3.12. 
End-of-Treatment Visit .................................................................................................83 
8.4. 
Follow-up Phase ............................................................................................................83 
8.4.1. 
Response Follow-up ......................................................................................................84 
8.4.2. 
Long-Term Follow-up ...................................................................................................84 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................84 
9.1. 
Completion ....................................................................................................................84 
9.2. 
Withdrawal from Study Treatment ................................................................................85 
9.3. 
Withdrawal from Study (Study Exit) ............................................................................85 
10. 
STATISTICAL METHODS AND ANALYSIS ..........................................................86 
10.1. 
Analysis Populations .....................................................................................................86 
10.1.1. 
Intent-to-Treat Population .............................................................................................86 
10.1.2. 
Response-Evaluable Population ....................................................................................86 
10.1.3. 
Safety Population ..........................................................................................................86 
10.1.4. 
Additional Analysis Populations ...................................................................................86 
10.2. 
Sample Size Determination ...........................................................................................86 
10.3. 
Subject Information .......................................................................................................87 
10.3.1. 
Demographic/Baseline Characteristics and Study Conduct ..........................................87 
10.4. 
Efficacy Analysis ..........................................................................................................87 
10.4.1. 
Primary Endpoint ..........................................................................................................87 
10.4.2. 
Secondary Endpoints .....................................................................................................88 
10.4.3. 
Efficacy Assessments by Investigator ...........................................................................88 
10.4.4. 
Exploratory Endpoints ...................................................................................................88 
10.5. 
Analysis Methods ..........................................................................................................88 
10.5.1. 
Analysis for Phase 1 ......................................................................................................88 


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10.5.2. 
Primary Efficacy Analyses ............................................................................................89 
10.5.3. 
Secondary Efficacy Analysis .........................................................................................89 
10.5.4. 
Exploratory Efficacy Analysis ......................................................................................90 
10.5.5. 
Open-Label Sub-study Treatment Arm C Efficacy Analysis (Phase 2b) ......................90 
10.5.6. 
Pharmacokinetics ...........................................................................................................90 
10.5.7. 
Biomarkers ....................................................................................................................91 
10.6. 
Safety Analysis ..............................................................................................................91 
10.6.1. 
Independent Review Committee (IRC) .........................................................................92 
10.6.2. 
Data Monitoring Committee .........................................................................................92 
10.6.3. 
Interim Analyses ............................................................................................................93 
10.6.4. 
Final Analysis ................................................................................................................93 
11. 
ADVERSE EVENT REPORTING ..............................................................................93 
11.1. 
Adverse Event Definitions and Classifications .............................................................93 
11.1.1. 
Adverse Events ..............................................................................................................93 
11.1.2. 
Serious Adverse Events .................................................................................................94 
11.1.3. 
Unexpected Adverse Events ..........................................................................................95 
11.1.4. 
Severity Criteria (Grade 1-5) .........................................................................................95 
11.1.5. 
Causality (Attribution) ..................................................................................................96 
11.2. 
Documenting and Reporting of Adverse Events ...........................................................96 
11.2.1. 
Special Reporting Situations .........................................................................................96 
11.2.2. 
Adverse Event Reporting Procedures ............................................................................96 
11.2.2.1. All Adverse Events ........................................................................................................96 
11.2.2.2. Expediting Reporting Requirements for Serious Adverse Events ................................97 
11.2.3. 
Other Malignancies .......................................................................................................98 
11.2.4. 
Pregnancy ......................................................................................................................98 
11.2.4.1. Pregnancy Reporting .....................................................................................................98 
11.2.5. 
Eye-Related Adverse Events .........................................................................................99 
11.2.6. 
Adverse Events of Special Interest ................................................................................99 
11.2.6.1. Major Hemorrhage ........................................................................................................99 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............99 
12.1. 
Regulatory and Ethical Compliance ..............................................................................99 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ..............................................................................100 
12.3. 
Informed Consent ........................................................................................................100 
12.4. 
Quality Control and Quality Assurance ......................................................................100 
12.5. 
Protected Subject Health Information Authorization ..................................................101 
12.6. 
Study Files and Record Retention ...............................................................................101 
12.7. 
Case Report Forms and Record Maintenance .............................................................102 
12.8. 
Investigational Study Drug Accountability .................................................................102 
12.9. 
Study Monitoring/Audit Requirements .......................................................................103 
12.10. 
Investigator Responsibilities .......................................................................................103 
12.11. 
Sponsor Responsibilities .............................................................................................104 
12.12. 
Financial Disclosure ....................................................................................................104 
12.13. 
Liability and Clinical Trial Insurance .........................................................................104 
12.14. 
Protocol Amendments .................................................................................................105 
12.15. 
Publication of Study Results .......................................................................................105 


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12.16. 
Study Discontinuation .................................................................................................105 
12.17. 
Study Completion ........................................................................................................105 
13. 
REFERENCES ............................................................................................................106 
14. 
APPENDICES ..............................................................................................................109 
 
LIST OF APPENDICES 
Appendix 1. 
Schedule of Assessments ...................................................................................110 
Appendix 2. 
ECOG Status Scores...........................................................................................115 
Appendix 3. 
Cockcroft-Gault Formula for Estimating Creatinine Clearance ........................116 
Appendix 4. 
Lines of Therapy ................................................................................................117 
Appendix 5. 
Inhibitors and Inducers of CYP3A .....................................................................118 
Appendix 6. 
QT Drugs by Risk Group ...................................................................................119 
Appendix 7. 
International Myeloma Working Group Response Criteria (Rajkumar 2011) ...123 
Appendix 8. 
Pomalidomide Pregnancy Prevention Risk Plan (For Ex-US Sites Only) .........125 
Appendix 9. 
International Staging System (ISS) for Myeloma Criteria .................................137 
Appendix 10. Child-Pugh Score ...............................................................................................138 
Appendix 11. Thromboembolism Risk Assessment .................................................................139 
Appendix 12. EQ-5D-5L Health Questionnaire .......................................................................140 
Appendix 13. EORTC QLQ-MY20 ..........................................................................................143 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Dosing Levels and Cohorts ..........................................................................................47 
Table 2: 
Ibrutinib or PlaceboDose Modification Guidance .......................................................53 
Table 3: 
Ibrutinib or PlaceboDose Modifications ......................................................................53 
Table 4: 
Dose Modification or Interruption for Pomalidomide Toxicity During a Cycle .........57 
Table 5: 
Dose Reduction of Pomalidomide ...............................................................................59 
Table 6: 
Dose Modification of Dexamethasone.........................................................................60 
Table 7: 
Pharmacokinetic Sample Schedule for Ibrutinib or Placebo and Pomalidomide with 
Dexamethasone ............................................................................................................72 
 
LIST OF FIGURES 
Figure 1: Phase 2b Study Design Schematic ...............................................................................41 
 
 


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SYNOPSIS 
Study Title 
A Randomized Multicenter Study of Ibrutinib in Combination with 
Pomalidomide and Dexamethasone in Subjects with Relapsed/Refractory 
Multiple Myeloma 
Protocol Number 
PCYC-1138-CA 
Study Phase 
1/2b 
Duration of Study: 
Approximately 4 years 
Centers 
Multicenter – International 
Population 
Relapsed/Refractory Multiple Myeloma 
Study Drugs 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
Pomalidomide will be supplied as hard gelatin capsules in strengths of 
4 mg, 3 mg, 2 mg and 1 mg capsules for PO administration. 
Dexamethasone will be available as tablets in various strengths for PO 
administration. 
Objectives 
Phase 1: 
Primary Objectives:  
• 
To determine the maximum tolerated dose (MTD)/maximum 
administered dose (MAD) and the Phase 2b dose of the 
ibrutinib, pomalidomide and dexamethasone combination. 
• 
To determine the safety and tolerability of ibrutinib in 
combination with pomalidomide and dexamethasone in subjects 
with relapsed/refractory multiple myeloma (MM). 
Secondary Objective: 
• 
Overall response rate (ORR) defined as ≥ partial response (PR) 
according to the International Myeloma Working Group 
(IMWG) response criteria (Rajkumar 2011) 
• 
Duration of response (DOR) 
• 
The clinical benefit rate (CBR) and its duration, defined 
as ≥ minimal response (MR) according to the IMWG response 
criteria (Rajkumar 2011) 
• 
To evaluate the pharmacokinetics (PK) of ibrutinib and 
pomalidomide when given in combination with dexamethasone. 
Phase 2b: 
Primary Objective: 
• 
To evaluate the effect of ibrutinib in combination with 
pomalidomide and dexamethasone compared to placebo in 
combination with pomalidomide and dexamethasone on 
progression-free survival (PFS), as assessed by the Independent 
Review Committee (IRC), in subjects with relapsed/refractory 
MM. 


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Secondary Objectives: 
To compare the treatment arms as assessed by both IRC and investigator 
in terms of the following: 
• 
ORR (≥PR; according to IMWG [Rajkumar 2011])  
• 
DOR  
• 
CBR (≥MR according to IMWG [Rajkumar 2011]) and its 
duration 
• 
Overall survival (OS) 
• 
Time-to-progression (TTP)  
In addition, 
• 
To evaluate the safety and tolerability of ibrutinib in 
combination with pomalidomide and dexamethasone. 
• 
To evaluate the pharmacokinetics (PK) of ibrutinib and 
pomalidomide when given in combination with dexamethasone. 
Exploratory Objectives: 
• 
To evaluate potential prognostic and predictive biomarkers 
relative to treatment outcomes (selected sites for Phase 1 and all 
sites for Phase 2b). 
• 
To assess biomarkers, (including gene expression profiles 
[GEP], secreted proteins, bone turnover and/or 
immunophenotypic) in subjects with relapsed/refractory MM 
(selected sites for Phase 1 and all sites for Phase 2b). 
To evaluate and compare the treatment arms in terms of the following: 
• 
Time-to-next-treatment (TTNT) (Phase 2b). 
• 
Patient-reported outcomes (PROs) and disease-related 
symptoms according to European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire for 
Multiple Myeloma (EORTC QLQ-MY20) and Euro QoL 
5 dimensions questionnaire (EQ-5D-5L) (Phase 2b). 
Open-Label Sub-Study Treatment Arm C (Phase 2b) 
• 
To evaluate the efficacy and safety of ibrutinib in combination 
with pomalidomide and dexamethasone in subjects who either 
have: 
o 
Less than a partial response (<PR) following at least 
112 days (4 x 28 day cycles) of pomalidomide and 
dexamethasone (regimen must not have included other 
anti-cancer agents) and are without evidence of progressive 
disease (PD)  
OR 
o 
Disease progression following an initial confirmed response 
of MR or better to the combination of pomalidomide and 
dexamethasone (regimen must not have included other 
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Study Design 
This study will be conducted in two Phases: 
Phase 1 will be an open-label, international, multicenter dose-finding 
study of the ibrutinib, pomalidomide and dexamethasone combination in 
subjects with relapsed/refractory MM who have received at least two 
prior lines of therapy, including lenalidomide (LEN) and either 
bortezomib or carfilzomib and have demonstrated disease progression on 
or within 60 days of completion of the most recent treatment regimen. 
Up to 18 subjects will be enrolled in order to determine the MTD/MAD 
and Phase 2b dose. 
The study will follow a 3+3+3 dose escalation design.  In the dose finding 
portion of the study, up to two dose levels may be explored. (Refer to 
Section 5.1 for details.) 
After enrollment completion of Phase 1, enrollment into Phase 2b may 
commence once the MTD/MAD is identified.  
Phase 2b will be conducted as a randomized, double-blind, international, 
multicenter study of ibrutinib or placebo in combination with 
pomalidomide and dexamethasone in subjects with relapsed/refractory 
MM who have received at least two prior lines of therapy, including 
lenalidomide (LEN) and either bortezomib or carfilzomib and have 
demonstrated disease progression on or within 60 days of completion of 
the most recent treatment regimen. 
Approximately 195 subjects will be randomized 1:1 between Arm A 
(ibrutinib in combination with pomalidomide and dexamethasone) and 
Arm B (placebo in combination with pomalidomide and dexamethasone) 
and stratified according to: 
• 
2-3 vs. ≥ 4 prior therapies 
• 
Last regimen (no immunomodulatory drug [IMiD]/proteasome 
inhibitor [PI] vs. IMiD or PI vs. IMiD and PI) 
• 
Age: ≤75 vs. > 75 years 
Open-Label Sub-Study Treatment Arm C (Phase 2b Only) will enroll 
up to 22 subjects to receive open-label ibrutinib in combination with 
pomalidomide and dexamethasone.  For more details regarding 
inclusion/exclusion criteria refer to Section 4. 
Subjects eligible for the randomized study portion (Arm A or Arm B) are 
not eligible for participation in the sub-study (Arm C).   
Inclusion Criteria 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
Disease Related 
1. 
Subjects with relapsed/refractory MM who have received at least two 
prior lines of therapy (Appendix 5) including LEN and either 
bortezomib or carfilzomib and have demonstrated disease 
progression on or within 60 days of the completion of the most 
recent treatment regimen.  
• 
Subjects must have received at least 2 cycles of treatment with 
LEN and either bortezomib or carfilzomib at the approved dose 
and schedule (maintenance will be excluded). 
2. 
Measurable disease defined by at least ONE of the following: 


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• 
Serum monoclonal protein (SPEP) ≥1 g/dL. 
• 
Urine monoclonal protein (UPEP) ≥200 mg by 24 hour urine. 
Laboratory 
• 
Adequate hematologic function independent of platelet 
transfusion and growth factor support for at least 7 days prior to 
Screening and dosing (Phase 1) or randomization/enrollment 
(Phase 2b), with the exception of pegylated G-CSF 
(granulocyte-colony stimulating factor pegfilgrastim) and 
darbopoeitin which require at least 14 days, defined as:  
o 
Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L).   
o 
Platelet count >75,000 cells/mm3 (75 x 109/L).  
o 
Hemoglobin ≥8.0 g/dL. 
• 
Adequate hepatic and renal function defined as: 
o 
Serum aspartate transaminase (AST) or alanine 
transaminase (ALT) ≤3.0 x upper limit of normal (ULN). 
o 
Serum creatinine <3.0 mg/dL AND Creatinine Clearance 
≥30 mL/min (by Cockcroft-Gault OR as measured by 
24 hour urine collection).  
o 
Total Bilirubin ≤2.0 mg/dL (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 on 
warfarin, then INR ≤3.0). 
Demographic 
• 
Men and women ≥ 18 years of age. 
• 
Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤2. 
Ethical/Other 
• 
US /Canada Sites Only: All study participants must be 
registered into the mandatory Pomalyst REMS™ or RevAid® 
program, and be willing and able to comply with the 
requirements of the Pomalyst REMS™ or RevAid® program as 
appropriate for the country in which the drug is being used.  
• 
US/Canada Sites Only: Female subjects of childbearing 
potential (FCBP)a must adhere to the scheduled pregnancy 
testing as required in the Pomalyst REMS™ or RevAid® 
program as appropriate for the country in which the drug is 
being used.   
• 
Ex-US Sites Only: Female subjects of childbearing potential 
(FCBP)a must have a negative serum or urine pregnancy test 
with a sensitivity of at least 25 mIU/mL within 10 – 14 days and 
again within 24 hours prior to starting Cycle 1 of 
pomalidomide.  All subjects must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal 
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• 
US/Canada Sites Only: Male subjects must agree to use a latex 
condom during sexual contact with a FCBP even if they have 
had a successful vasectomy.   
• 
Ex- US Sites Only: Male subjects must agree to use a latex 
condom during sexual contact with a FCBP even if they have 
had a successful vasectomy.  All subjects must be counseled at a 
minimum of every 28 days about pregnancy precautions and 
risks of fetal exposure.  See Appendix 8. 
• 
FCBP a and male subjects who are sexually active must use 
TWO acceptable methods of birth control, one highly 
effective method of birth control plus one additional effective 
method of birth control for at least 28 days prior to study 
treatment and during the study treatment period.  For female and 
male subjects, these birth control requirements must be adhered 
to for 90 days after the last dose of ibrutinib and pomalidomide, 
whichever is later.  Male subjects must agree to not donate 
sperm during the study treatment period and up to 90 days after 
the last dose of ibrutinib and pomalidomide, whichever is later. 
a. 
A female of childbearing potential (FCBP) is a female who: 1) has 
achieved menarche at some point; or 2) has not undergone a 
hysterectomy or bilateral oophorectomy; or 3) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule 
out childbearing potential) for at least 24 consecutive months (ie, has 
had menses at any time in the preceding 24 consecutive months). 
Exclusion Criteria: 
Disease-Related 
• 
Primary refractory disease defined as nonresponsive in patients 
who have never achieved a minimal response or better with any 
therapy. 
• 
History of plasma cell leukemia, primary amyloidosis, POEMS 
syndrome within 12 months prior to first administration of study 
treatment. 
Concurrent Conditions 
• 
Recent prior chemotherapy 
o 
Alkylators (eg, melphalan, cyclophosphamide) and/or 
anthracyclines <21 days prior to first administration of 
study treatment. 
o 
High dose corticosteroids, IMiDs or proteasome 
inhibitors <14 days prior to first administration of study 
treatment.  
o 
Monoclonal antibody <14 days prior to first administration 
of study treatment. 
• 
Prior exposure to Bruton’s tyrosine kinase (BTK) inhibitors. 
• 
Prior exposure to pomalidomide (except Treatment Arm C). 
• 
History of serious hypersensitivity reactions to prior 
thalidomide, lenalidomide or pomalidomide. 
• 
History of other malignancies, except:  


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o 
Malignancy treated with curative intent and with no known 
active disease present for ≥3 years before the first dose of 
study drug and felt to be at low risk for recurrence by 
treating physician. 
o 
Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease. 
o 
Adequately treated carcinoma in situ without evidence of 
disease.  
• 
Peripheral neuropathy Grade ≥2 with pain at Screening. 
• 
Concurrent systemic immunosuppressant therapy (eg, 
cyclosporine A, tacrolimus, etc., or chronic administration of 
>20 mg/day of prednisone or equivalent) within 28 days of the 
first dose of study treatment. 
• 
Recent infection requiring systemic treatment that was 
completed <7 days before the first dose of study treatment 
and/or uncontrolled active systemic infection. 
• 
Unresolved toxicities from prior anti-cancer therapy, defined as 
having not resolved to Common Terminology Criteria for 
Adverse Event (CTCAE, version 4.03), Grade ≤1 or to the 
levels dictated in the inclusion/exclusion criteria with the 
exception of alopecia. 
• 
Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia). 
• 
History of stroke or intracranial hemorrhage within 6 months 
prior to enrollment/randomization. 
• 
Known history of human immunodeficiency virus (HIV) or 
active with hepatitis C virus (HCV) or hepatitis B virus (HBV).  
Subjects who are positive for hepatitis B core antibody, hepatitis 
B surface antigen, or hepatitis C antibody must have a negative 
polymerase chain reaction (PCR) result before enrollment/ 
randomization.  Those who are PCR positive will be excluded. 
• 
Major surgery within 4 weeks of first dose of study treatment. 
• 
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. 
• 
Currently active, clinically significant hepatic impairment 
(≥ mild hepatic impairment according to the Child Pugh 
classification [Appendix 10]) 
• 
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 enrollment/randomization. 
• 
QTc ≥470 msec calculated using Fridericia formula (QTcF) at 


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Screening.  
• 
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. 
• 
Requires treatment with a strong cytochrome P450 (CYP) 3A 
inhibitor. 
• 
Women who are pregnant or breast-feeding. 
• 
Unwilling or unable to participate in all required study 
evaluations and procedures. 
• 
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 
Phase 1: 
In the dose finding portion of the study, up to two cohorts may be 
explored and ibrutinib dose escalation will follow the 3+3+3 design for 
MTD/MAD and the Phase 2b dose determination.    
Ibrutinib will be administered orally daily at a designated dose and will be 
initiated on Day 1 of the first cycle.  The starting dose will be that of 
Cohort 1 (560 mg).  Treatment will be continuous (without interruption) 
until disease progression or unacceptable toxicity.  Pomalidomide 4 mg 
will be administered orally daily on Days 1-21 of each 28-day (4 weeks) 
cycle  until disease progression or unacceptable toxicity.  Dexamethasone 
will be administered orally (PO) once weekly at an age-adjusted dose of 
either 40 mg or 20 mg on Days 1, 8, 15 and 22 of each 28-day (4 weeks) 
cycle until disease progression or unacceptable toxicity.  
 
Ibrutinib  
(PO) 
Pomalidomide 
(PO) 
Dexamethasone 
(PO)† 
Cohort -1 
(Dose Level -1) 
420 mg 
4 mg 
40 mg 
Cohort 1 
(Dose Level 1-) 
Starting Dose level 
560 mg 
4 mg 
40 mg 
Cohort 2 
(Dose Level 2) 
840 mg 
4 mg 
40 mg 
† Dose will be 20mg weekly in those >75 years of age 
After the MTD/MAD of ibrutinib is defined and the Phase 2b dose 
determined, enrollment into Phase 2b will commence.  In the event that 
Cohort -1 will be considered the Phase 2b dose, the Sponsor may choose 
not to continue with Phase 2b enrollment as outlined in the protocol.   
Phase 2b: 
Phase 2b will be conducted as a randomized, double-blind, international, 
multicenter study.  Eligible subjects will be randomized in a 1:1 ratio into 
2 arms to receive either ibrutinib in combination with pomalidomide and 
dexamethasone (Treatment Arm A) or placebo in combination with 


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pomalidomide and dexamethasone (Treatment Arm B).  The dose of 
ibrutinib in all arms will be based upon the MTD/MAD identified in 
Phase 1.  All treatment arms will receive ibrutinib or placebo in 
combination with pomalidomide and dexamethasone on the same 
schedule as Phase 1 (28-day cycles) until IRC confirmed disease 
progression or unacceptable toxicity. 
Randomized Treatment  
Treatment Arm A 
 
All Cycles 
Ibrutinib 
PO daily  
Pomalidomide 
4 mg PO daily Days 1-21 
Dexamethasone  
Age-adjusted dose, PO on Days 1, 8, 15 and 22 
Treatment Arm B 
 
All Cycles 
Placebo 
PO daily  
Pomalidomide 
4 mg PO daily Days 1-21 
Dexamethasone 
Age-adjusted dose, PO on Days 1, 8, 15 and 22 
Open-label Sub-study  
Treatment Arm C 
 
 
All Cycles 
Ibrutinib 
PO daily  
Pomalidomide 
4 mg PO daily Days 1-21 
Dexamethasone 
Age-adjusted dose, PO on Days 1, 8, 15 and 22 
Concomitant Therapy  
Refer to Section 6 for information on concomitant therapy. 
Safety Plan 
The safety of this study, including DLT assessment, will be monitored by 
an independent DMC and in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures.  Adverse events (AEs) and 
serious adverse events (SAEs) will be reviewed by the Sponsor on an 
ongoing basis to identify safety concerns. 
Statistical Methods and 
Data Analysis 
Phase 1: 
Phase 1 is based on a 3+3+3 dose escalation design described in the Study 
Design Section.  
The primary objectives are to determine the MTD/MAD and Phase 2b 
dose and to evaluate safety and tolerability of ibrutinib in combination 
with pomalidomide and dexamethasone.  Adverse events including DLTs, 
laboratory values, and dosing data will be listed and summarized by dose 
cohort. 
The Phase 1 efficacy endpoints are the ORR, DOR, and CBR according to 
the IMWG response criteria.  The point estimate of the ORR and the 
corresponding exact binomial 95% confidence interval (CI) will be 
calculated.  For DOR, the distribution of DOR based on investigator’s 
assessment of response will be provided using Kaplan-Meier estimates for 


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responders. The CBR (≥MR) and its duration will be analyzed similar to 
the analysis of ORR and DOR, respectively.  
Phase 2b: 
All efficacy analyses will be performed using the intent-to-treat (ITT) 
population.   
Primary Efficacy Analysis: 
PFS will be assessed by a set of written rules and formulae developed 
based on IMWG response criteria as assessed by the IRC and will be 
analyzed using the Kaplan-Meier method.  The two treatment arms (Arm 
A and Arm B) will be compared using stratified log-rank test, stratified by 
the number of prior lines of therapy, most recent line of therapy, and age.  
Secondary Efficacy Analysis: 
Overall response rate (ORR) will be compared using the Cochran-Mantel-
Haenszel chi-square test, stratified by the three stratification factors: 
number of prior lines of therapy, most recent line of therapy, and age.  
The distribution of DOR will be estimated using the Kaplan-Meier 
method similar to PFS.  Overall survival (OS) will be compared using 
stratified log rank test.  Survival rate at landmark points will be 
summarized based on Kaplan-Meier point estimates.   
Efficacy measurements such as PFS, ORR, DOR, and CBR (MR or 
better) will be analyzed separately based on the assessments by both IRC 
and investigator. 
Exploratory Efficacy Analysis: 
Descriptive statistics for change in scores from baseline to each 
assessment will be summarized for the PROs.  Other time to event 
analysis will be analyzed by the same method as PFS.  Categorical 
endpoints will be compared between two treatment arms using the 
Cochran-Mantel-Haenszel chi-square test, stratified by the stratification 
factors used.  
Open-label Sub-study Treatment Arm C 
The primary efficacy endpoint is the ORR according to the IMWG 
response criteria.  The hypothesis that the true ORR is ≤5% (H0) will be 
tested against ≥18% (Ha), based on the exact binomial test.  The point 
estimate of the rate and the corresponding exact binomial 95% CI will be 
calculated.  For DOR, the distribution of DOR will be provided using 
Kaplan-Meier estimates for responders. 
Safety Analysis: 
Phase 1 
All AEs experienced from the start of treatment through Cycle 2 Day 1 
pre-dose assessments will be evaluated by the independent DMC for the 
purpose of identifying any DLTs during the identification of the 
MTD/MAD.  In addition, detailed tabulation of safety data (AEs, clinical 
laboratory tests and other safety endpoints) will be summarized. 
Phase 2b 
Detailed tabulations of safety data (AEs, clinical laboratory tests and 
other safety endpoints) will be summarized by treatment arms for all 
subjects receiving the study drug.  Summary statistics will include means, 


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standard deviations, and medians for continuous variables and proportions 
for categorical variables.  Safety analysis for Treatment Arm C will be 
conducted similar but described separately and independent from the 
safety analysis conducted for the randomized portion of the study. 
In addition, a pooled safety analysis will be performed on all subjects 
receiving the combination of ibrutinib, pomalidomide and 
dexamethasone, which includes subjects in Phase 1 treated at the 
MTD/MAD, as well as those treated on Arms A and C of Phase 2b.  This 
will be conducted similar but described separately and independent from 
the safety analysis conducted for the randomized portion of the study.  
The end of the study will occur approximately 2 years after the last 
subject is randomized, or the Sponsor terminates the study, whichever 
comes first. 
Interim Analysis 
Two interim analyses will be conducted (Phase 2b only).  The first 
interim analysis is a non-binding futility analysis and will occur when 
approximately 50 PFS events (40%) have occurred, which is estimated to 
occur when approximately 129 subjects have been enrolled.  The second 
interim analysis for both efficacy and non-binding futility will occur when 
approximately 74 PFS events (60%) have occurred, which is estimated to 
happen when approximately 172 subjects have been enrolled.  
Subjects in Arm C will not be included in the interim analysis. 
Sample Size Determination 
Phase 1 
N= 9-18 
Phase 2b 
The primary endpoint is PFS as assessed by the IRC.  A sample size of 
approximately 195 eligible subjects will be enrolled to observe 124 PFS 
events in this study.  Assuming exponential survival distribution and 67% 
improvement in median PFS of ibrutinib combined with pomalidomide 
and dexamethasone over placebo combined with pomalidomide and 
dexamethasone (hazard ratio of 0.6), the study has at least 80% power to 
achieve an overall 1-sided statistical significance level of 2.5% with the 
above planned interim analyses.  For this calculation, the median PFS of 
5 months for placebo in combination with pomalidomide and 
dexamethasone and an average enrollment rate of 15 subjects per month 
were assumed. 
For the open-label sub-study Treatment Arm C of Phase 2, approximately 
22 subjects will be enrolled to provide 78% power at a 1-sided 
significance level of 0.1 to test a true response rate of ≤5% (H0) versus 
≥18% (Ha), based on the exact binomial test. 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase  
Ames 
bacterial mutagenicity assay 
AST 
Serum aspartate transaminase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BTK 
Bruton’s tyrosine kinase  
BUN 
blood urea nitrogen 
CBR 
Clinical benefit rate 
CFR 
Code of Federal Regulations 
CHO 
chromosome aberration assay  
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
complete response  
CT 
computed tomography 
CYP 
cytochrome P 
DCB 
duration of clinical benefit 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee  
DNA 
deoxyribonucleic acid 
DOR 
duration of response  
DVT 
deep vein thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EOT 
End-of-Treatment 
EORTC QLQ-MY20 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire for Multiple Myeloma 
EMR 
electronic medical records 
EQ-5D-5L 
Euro QoL 5 dimensions questionnaire 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GEP 
gene expression profiling 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL-6 
interleukin-6 
ILD 
interstitial lung disease 
IMiD(s) 
Immunomodulatory drug(s) 
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee  
ITT 
Intent-to-Treat 
IUD 
Device 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LEN 
Lenalidomide 
MAD 
maximum administered dose 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
MIP-1α 
macrophage inhibitory protein-1α  
MM 
multiple myeloma 
MR 
minimal response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCCN 
National Comprehensive Cancer Network 
NF-κΒ 
nuclear factor κB  
NK 
natural killer (cells) 
ORR 
overall response rate (ORR = CR + PR) 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PE 
pulmonary embolism 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os (oral) 
PPP 
Pregnancy Prevention Program 
PR 
partial response 
PROs 
patient reported outcomes 
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time 


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QTcF 
corrected QT interval (Fridericia formula) 
RBC 
red blood cells 
REB 
Research Ethics Board 
REMS™ 
Risk Evaluation and Mitigation Strategies 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
ASCT 
autologous stem cell transplantation 
SCARs 
severe cutaneous adverse reactions 
SD 
stable disease 
SEER 
Surveillance Epidemiology and End Results 
SJS 
Stevens-Johnson syndrome 
SLL 
small lymphocytic lymphoma 
SOPs 
standard operating procedures 
SPEP 
serum protein electrophoresis 
TEAE(s) 
treatment-emergent adverse event(s) 
TSH 
thyroid stimulating hormone  
TTNT 
time-to-next-treatment  
TTP 
time-to-progression 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
US 
United States 
VTE 
venous thromboembolism 
WBC 
white blood cells 
WM 
Waldenström’s Macroglobulinemia 
 
 


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1. 
BACKGROUND 
1.1. 
Multiple Myeloma 
Multiple myeloma (MM) is a plasma-cell malignancy that is associated with monoclonal 
immunoglobulin (M protein) production, osteolytic bone lesions, hypercalcemia, anemia, and 
renal failure.  The latest SEER (Surveillance Epidemiology and End Results) Cancer Statistics 
Review (Howlader 2014) reported that the age-adjusted incidence rate of MM in the United 
States (US) during 2007-2011 was 6.1/100,000.  The age-adjusted incidence rate was higher in 
male (7.7/100,000) than in female (4.9/100,000) population, higher in Blacks (12.2/100,000) 
than Whites (5.6/100,000) population, and higher in elder (65 years or older; 32.4/100,000) than 
younger (under 65 years; 2.3/100,000) population.  The median age of MM diagnosis was 
69 years of age.  In addition, the age-adjusted incidence rates increased overtime from 
4.9/100,000 in 1975 to 6.7/100,000 in 2011.  
Age-adjusted prevalence rate in 2011 was 22.6/100,000 (27.1/100,000 in male and 19.0/100,000 
in female), ending in an estimated 83,367 patients living with MM in the US. 
The 5-year survival rate among patients diagnosed with MM during 2004 – 2010 was 46.7%, 
which was significantly improved since 1975-1977 (24.6%).  Based on 2007-2011 data, the 
age-adjusted mortality rate due to MM in the US was 3.4/100,000 (4.3/100,000 in male and 
2.7/100,000 in female). 
Myeloma cell growth occurs within bones and specifically involves the bone marrow.  
Its clinical hallmarks include bone destruction, which may be manifested by lytic lesions, severe 
osteopenia, pathologic fractures and hypercalcemia, and impaired bone marrow function, which 
may result in anemia, thrombocytopenia, and neutropenia.  Bone destruction in particular is a 
major cause of severe and disabling morbidity in myeloma.  Bone lesions are present in the 
majority of patients at presentation and nearly all patients by the time the disease runs its course.  
Myeloma cells typically secrete 1 (or rarely more) monoclonal paraprotein (M-protein) molecule, 
which may be intact immunoglobulin (usually IgG or IgA; rarely IgD, E, or M) or free (κ or λ) 
light chains.  Examples of completely nonsecretory myeloma are rare.  Myeloma M-proteins can 
cause numerous complications including renal insufficiency, amyloidosis, hyperviscosity, and 
neuropathy.  The various direct and indirect destructive effects of myeloma cells render MM 
patients highly symptomatic and challenging to manage.  In addition, these patients are subject to 
greater morbidity and higher mortality compared to those with the more common subtypes of 
lymphoma.  
Myeloma cells are highly dependent upon the bone marrow microenvironment, including the 
presence of certain cytokines (eg, interleukin-6 [IL-6]), chemokines, macromolecules in the 
extracellular matrix, and supportive cells (stromal cells), for their growth and survival.  Crucial 
cytokines and chemokines are secreted into the microenvironment by bone marrow (BM) stromal 
cells, and some by the MM cells themselves.  Adhesion of MM cells to BM stromal cells triggers 
secretion of cytokines, which augment MM cell growth and survival and confers drug resistance 


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(Roodman 2010b).  Vascular endothelial growth factor, basic fibroblast growth factor–2, and 
other factors secreted by MM and/or BM stromal cells promote angiogenesis, and thereby further 
support tumor cell growth and survival.  More recently, much progress has been made in 
elucidating the role of osteoclasts in the development of lytic lesions and in reciprocally 
contributing to a microenvironment supportive of myeloma cell growth and progression.  
Multiple myeloma cells stimulate osteoclastogenesis by secretion of factors including receptor 
activator of nuclear factor κB (NF-κΒ) ligand (RANKL), IL-6, and macrophage inhibitory 
protein-1α (MIP-1α), while osteoclasts themselves may produce IL-6, as well as interact with 
stromal cells.  These interactions contribute to a favorable microenvironment for myeloma cell 
adhesion and proliferation (Kawano 1988, Roodman 2004, Aggarwal 2006, Roodman 2010a, 
Roodman 2010b, Roodman 2011). 
1.1.1. 
Existing Therapies and Unmet Need in Relapsed/Refractory Multiple Myeloma 
Although improvements in progression-free survival (PFS) and overall survival (OS) have 
occurred in the last decade, even with the best available approved agents, almost all subjects are 
known to eventually relapse.  In addition, patients that have relapsed and are refractory to 
standard backbone agents (ie proteasome inhibitors [PI] and immunomodulatory agents[IMiDs]), 
specifically lenalidomide and bortezomib, have a poor prognosis with median PFS and OS of 
5 months and 9 months respectively (Kumar 2012).  The choice of treatment and intensity is 
dependent upon patient age, co-morbidities, residual treatment related toxicities, and response to 
previous therapies.  Thus, no preferred regimen has been identified for the treatment of these 
patients and the therapeutic options for patients following first relapse are similar 
(Dimopoulos 2015).  
Current treatments for relapsed/refractory MM includes combination chemotherapy with 
regimens using proteasome inhibitors (bortezomib [Velcade®], carfilzomib [Kyprolis®]), 
immunomodulatory drugs (IMiDs) (thalidomide [Thalomid®], lenalidomide [REVLIMID®] and 
pomalidomide [Pomalyst®/Imnovid®]), alkylators (cyclophosphamide [Cytoxan®] and 
bendamustine [Treanda™]) and anthracyclines (liposomal doxorubicin [Doxil®]) with and 
without corticosteroids as well as the participation in a clinical trial assessing novel combinations 
and agents with novel mechanisms of action. 
Recently two agents, carfilzomib (Kyprolis®) and pomalidomide (Pomalyst®/Imnovid®), 
received approval specifically for the treatment of patients with relapsed/refractory disease after 
having received at least 2 prior treatments that must have included bortezomib and an 
immunomodulatory agent.  The pivotal study for carfilzomib, PX-171-003-A1 study 
(Siegel 2012), was a single-arm study of carfilzomib monotherapy in patients with relapsed and 
refractory MM.  Carfilzomib received Food and Drug Administration (FDA) approval based 
upon the ORR of 23.7% in a heavily pre-treated patient population (median 5 prior therapies).  
The median duration of response was 7.8 months with a median PFS and OS of 3.7 months and 
15.6 months, respectively.  The pivotal study for pomalidomide, MM-002 (Richardson 2014), 
was a randomized study comparing pomalidomide and dexamethasone to pomalidomide 
monotherapy.  Pomalidomide received FDA approval based upon the ORR of 33% in the 


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combination arm in a heavily pre-treated patient population (median 5 prior therapies).  
The median duration of response was 8.3 months with a median PFS and OS of 4.2 months and 
16.5 months respectively.  The results of the MM-003 trial which indicated a significant 
improvement of pomalidomide in combination with dexamethasone vs. high-dose 
dexamethasone in regards to ORR (23% vs. 4%), PFS (3.6 months vs. 1.8 months) and OS 
(12.4 months vs. 8 months) are reflected in the US and EU label for pomalidomide. 
1.1.2. 
BTK Inhibition as a Treatment Option for MM 
Bruton’s tyrosine kinase (BTK) plays a key role in the development and function of normal 
B cells through activation of the B-cell receptor (BCR) signaling pathway and mediates their 
biological activities such as growth, adhesion and migration.  BTK is also expressed in various 
B cell malignancies including chronic lymphocytic leukemia (CLL), mantle cell lymphoma 
(MCL) and Waldenström’s Macroglobulinemia (WM) and has been implicated in deregulated 
proliferation, homing to the tumor microenvironment and metastasis to other organs.  
While BTK expression is reduced in normal plasma cells, its expression in MM cell lines and 
primary patient samples is increased when assessed by both immunoblotting and gene expression 
profile analysis (Tai 2012; Bam 2013).  Up-regulation of BTK is seen across all disease settings 
of MM from MGUS to plasma cell leukemia, with no observed differences between samples 
across International Staging System (ISS) stages or MM subtypes (Elias 2013). 
There have been several reports describing the potential role of BTK in MM and the impact of its 
inhibition on their phenotypes in vitro and in vivo.  First, BTK is expressed in patient-derived 
MM samples and in established MM cell lines.  Second, genetic or pharmacological inhibition of 
BTK resulted in direct inhibition of cell growth, adhesion and migration induced by either 
intrinsic and/or extrinsic signal(s).  Third, BTK indirectly promote MM pathogenesis through 
stimulation of osteoclast development (osteoclastogenesis) and their functional activity of 
creating a MM tumor microenvironment induced by RANKL and M-CSF.  In experimental 
models of osteoclast functions/activities in vitro and in vivo, BTK inhibition by ibrutinib has 
been shown to inhibit the bone resorption and the release of osteoclast-derived tumor growth 
factors by osteoclasts. 
Yang et al recently reported that expression of BTK mRNA in MM cell lines and patient-derived 
MM cells is highly enriched in the CD138-fraction or a side population, a sub-population of cells 
that show higher efflux of DNA-binding dye Hoechst33342 (Jakubikova 2011), both of which 
are believed to contain stem-like cells with tumor-initiating potential, when compared to the 
CD138+ cells or main population (Yang 2015).  Increased BTK expression in such population of 
cells is associated with clonogenic growth, increased expression of pluripotent/embryonic stem 
cell genes, and potential resistance to many standard myeloma treatments.  In contrast, 
knockdown of BTK impeded these effects in vitro.  Furthermore, BTK inhibition with a small 
molecule in the xenograft model of MM reduced serum IgG2b levels and extended the survival 
of host animals (Yang 2015). 


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These preclinical study results for BTK inhibitors against MM cells clearly differentiate 
themselves from other established therapeutic agents and provide a scientific rationale for 
investigation of ibrutinib as a therapeutic option for MM as a new combination partner with a 
novel mechanism of action. 
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) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of B-cell malignancies. 
Ibrutinib has been approved in many regions including the United States (US) and European 
Union (EU), for indications including treatment of patients with mantle cell lymphoma (MCL) 
who have received at least 1 prior therapy, patients with chronic lymphocytic 
leukemia (CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with a deletion of the 
short arm of chromosome 17 (del17p), Waldenström’s macroglobulinemia (WM), and marginal 
zone lymphoma (MZL) who require systemic therapy and have received at least one prior 
anti-CD20-based therapy.  For the most up to date and comprehensive nonclinical and clinical 
information regarding ibrutinib background, safety, efficacy, and in vitro and in vivo preclinical 
activity, and toxicology of ibrutinib, refer to the latest version of the ibrutinib Investigator's 
Brochure (IB) and/or the applicable regional labeling information. 
1.2.1. 
Summary of Nonclinical Data 
1.2.1.1. 
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of BTK (Pan 2007).  In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position.  
When added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011). 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB. 
1.2.1.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested.  Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs.   
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 


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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 (area under the 
concentration-time curve [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 more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB.  
1.2.2. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB.  
1.2.2.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally with substantial intersubject variability.  The mean terminal 
plasma elimination half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to 
maximum plasma concentration (Tmax) of 2 hours.  Despite the doubling in mean systemic 
exposure when dosed with food, the favorable safety profile of ibrutinib allows dosing 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 
implying non-clinically relevant accumulation.  Less than 1% of ibrutinib is excreted in the 
urine. 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.   
 


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1.2.3. 
Summary of Clinical Safety 
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below.  For the most up to date and most comprehensive safety information regarding ibrutinib, 
please refer to the current ibrutinib IB.  Additional safety information may be available for 
approved indications in regional prescribing labels where the study is conducted (eg, USPI, 
SmPC). 
1.2.3.1. 
Monotherapy Studies 
Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy in 13 studies 
that have completed primary analysis or final analysis as of the 31 May 2016 cutoff date for the 
current ibrutinib IB update in B-cell malignancies are summarized below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318): 
Most frequently reported 
TEAEs ≥ 15% a   
Most frequently reported Grade 3 
or 4 TEAEs ≥ 3% b  
Most frequently reported Serious 
TEAEs ≥ 2% c   
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia  
Hypertension   
 
Anemia  
Diarrhea 
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract infection 
 
 
Thrombocytopenia    
 
 
Oedema peripheral    
 
 
a Source is Table 6 of ibrutinib IB (v10), b source is Table 8 of ibrutinib IB (v10), c source is Table 9 of ibrutinib 
IB (v10). 
1.2.3.2. 
Combination Therapy Studies 
Pooled safety data from a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in subjects with B-cell malignancies are briefly summarized 
below.  Therapies used in combination with ibrutinib in these studies, included 
BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), 
ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and 
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Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 
Most frequently reported 
TEAEs ≥ 20% a    
Most frequently reported Grade 3 
or 4 TEAEs ≥ 3% b 
Most frequently reported Serious 
TEAEs ≥ 2% c 
Neutropenia 
Neutropenia 
Pneumonia  
Diarrhea 
Thrombocytopenia 
Febrile neutropenia  
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anemia 
Anemia 
 
Pyrexia 
Fatigue 
 
 
Hypertension 
 
 
Diarrhea 
 
a Source is Table 10 of ibrutinib IB (v10), b source is Table 12 of ibrutinib IB (v10), c source is Table 13 of ibrutinib 
IB (v10). 
1.2.4. 
Risks 
1.2.4.1. 
Bleeding-related Events   
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia.  These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, subdural intracranial hemorrhage, and hematuria.  Use of ibrutinib in subjects requiring 
other anticoagulants or medications that inhibit platelet function may increase the risk of 
bleeding.  Subjects with congenital bleeding diathesis have not been studied.  See Section 6.1.2.4 
for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.2 for guidance on ibrutinib management with surgeries or procedures.  In an in vitro 
platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation 
were observed, refer to Section 6.1.2.4. 
1.2.4.2. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous 
history of atrial fibrillation.  Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea should be evaluated clinically, and if indicated, have 
an ECG performed.  For atrial fibrillation which persists, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidance (see Section 5.4.4). 
1.2.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 


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1.2.4.4. 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation.  These events are rarely severe.  Should symptoms be severe or prolonged 
follow the protocol dose modification guidance (see Section 5.4.4). 
1.2.4.5. 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy.  Some of these reported infections have been associated with 
hospitalization and death.  Consider prophylaxis according to standard of care in subjects who 
are at increased risk for opportunistic infections (reference Section 6.1.1).  Although causality 
has not been established, cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib.  Subjects should be monitored for symptoms (fever, 
chills, weakness, confusion) and appropriate therapy should be instituted as indicated. 
1.2.4.6. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib.  
Monitor subjects for pulmonary symptoms indicative of ILD.  Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.4.4). 
1.2.4.7. 
Non-melanoma Skin Cancer  
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.2.4.8. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  Most rashes were mild to moderate in severity.  Isolated cases 
of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib.  Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS.  Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate.  In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
1.2.4.9. 
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 
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1.2.4.10. 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib.  Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib.  Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
1.2.5. 
Summary of Clinical Data with Ibrutinib in MM 
1.2.5.1. 
PCYC-1111-CA 
PCYC-1111-CA is a multicenter Phase 2 study in subjects with relapsed or relapsed and 
refractory MM.  The primary objective of the study is to determine the efficacy of ibrutinib, both 
as a single agent and in combination with dexamethasone by assessing the clinical benefit rate 
(CBR).  The secondary objectives are to evaluate the efficacy of ibrutinib in this population as 
assessed by the duration of clinical benefit (DCB), ORR, duration of response (DOR), and the 
safety and drug PK.  The exploratory objectives are PFS, time-to-progression (TTP), and OS. 
Subjects were enrolled to one of four cohorts, with ibrutinib doses ranging from 420 mg/day 
(Cohort 1), 560 mg/day (Cohort 2), to 840 mg/day (Cohorts 3 and 4).  Ibrutinib is given in 
combination with weekly dexamethasone in Cohorts 2 and 4; addition of dexamethasone was 
permitted upon disease progression in Cohorts 1 and 3.  All cohorts have completed Stage 1 
enrollment.   
A total of 69 subjects were enrolled in Stage 1: 13 subjects in Cohort 1, 18 subjects in Cohort 2, 
18 subjects in Cohort 3 and 20 subjects in Cohort 4.  At the time of the interim analysis, Cohort 4 
(ibrutinib 840 mg/day in combination with weekly dexamethasone) met the Simon 2-stage 
enrollment expansion criteria (≥3 MRs in 18 evaluable subjects) with a CBR of 25% (5/20) 
(Vij 2014).  As of 20 September 2014 an additional 23 subjects were enrolled to Cohort 4 
(total n=43) with confirmation of the initial safety and activity seen in Cohort 4 Stage 1 
enrollment.   
As of 09 March 2015, a total of 92 subjects were enrolled across four dosing cohorts (420 mg – 
840 mg).  The most common treatment emergent adverse events (>15%) included diarrhea 
(52%), fatigue (41%), nausea (29%), anemia (27%), cough (22%), arthralgia (21%), muscle 
spasms (21%), dizziness (20%), insomnia (17%), upper respiratory tract infection (17%), back 
pain (15%), dyspnea (15%) and epistaxis (15%).  The most common Grade 3 and higher TEAEs 
(>5%) included anemia (15%), thrombocytopenia (9%), and pneumonia (7%).  
Forty-three out of 92 subjects were treated with ibrutinib at 840 mg in combination with weekly 
dexamethasone.  The observed safety profile at 840 mg and across the tested cohorts in this 
ongoing study did not indicate clinically meaningful differences and the overall obtained safety 
profile with ibrutinib alone or in combination is consistent with the reported treatment-emergent 
AEs detailed in the current version of the IB for ibrutinib.   


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1.2.5.2. 
PCYC-1119-CA 
PCYC-1119-CA is a multicenter Phase 1/2b study in subjects with relapsed or relapsed and 
refractory MM.  The primary objective of Phase 1 is to determine the maximum tolerated dose 
(MTD) of ibrutinib in combination with carfilzomib and with or without dexamethasone as well 
as to describe the toxicities associated with the combination.  The secondary objectives of this 
phase are to assess overall ORR and DOR.  In Phase 1 subjects are enrolled to one of three dose 
levels (5 cohorts), with ibrutinib doses ranging from 560 mg/day (Dose Levels 1 and 2) to 
840 mg/day (Dose Level 3) and carfilzomib doses ranging from 20/27 mg/m2 (Dose Level 1) to 
20/36 mg/m2 (Dose Levels 2 and 3).  Age-adjusted dexamethasone is given in combination with 
ibrutinib and carfilzomib in one cohort in Dose Level 2 and one in Dose Level 3 while the other 
cohorts are treated without dexamethasone.  Thirteen patients were enrolled in the dose 
escalation phase which was completed after 6 evaluable patients were treated at Dose Level 3 
(per protocol, the highest planned dose level).  No dose limiting toxicities (DLTs) were observed 
at the highest tested dose level, ibrutinib 840 mg/day in combination with carfilzomib 
20/36 mg/m2 and dexamethasone.  
As of 22 July 2015, a total of 43 subjects were enrolled and dosed in Phase 1: 13 subjects in dose 
escalation and 30 subjects in dose expansion cohorts. In the 40 subjects evaluable for safety and 
efficacy the most common treatment-emergent AEs (≥20%) included diarrhea (43%), 
constipation and fatigue (40% each), cough (38%), anemia (33%), thrombocytopenia, nausea and 
pyrexia (30% each), epistaxis and hypertension (28% each), dyspnea and headache (25%), 
hypokalemia (23%), upper respiratory tract infection (23%), insomnia, peripheral edema and 
urinary tract infection (20%).  There were 4 cases of renal failure acute reported, 2 occurred in 
the setting of disease progression and 2 occurred in the setting of infection (pneumonia and 
pseudomonal sepsis).  Of the two cases occurring in the context of disease progression one 
occurred following the initiation of subsequent anti-cancer treatment.  The most common 
Grade 3 and higher TEAEs in 3 or more subjects included hypertension (20%), anemia, 
pneumonia and thrombocytopenia (18% each), diarrhea and fatigue (13% each) and acute kidney 
injury, pyrexia and rash maculopapular (8% each). The overall response rate was 62%, including 
24% VGPR or better, and median DOR has not been reached (Chari 2015). 
The safety was assessed by an independent Data Monitoring Committee (DMC) and the 
observed safety profile across the three tested dose levels in this ongoing study did not indicate 
clinically meaningful differences. The overall obtained safety profile with ibrutinib in 
combination with carfilzomib with and without dexamethasone is consistent with the reported 
treatment-emergent AEs expected for these agents.  
Based upon the encouraging Phase 1 safety and efficacy data, Phase 2b commenced on 
09 February 2016 with the first patient dosed with the recommended Phase 2 dosing as follows: 
ibrutinib 840 mg daily, carfilzomib 20/36 mg/m2 on two consecutive days each week for three 
weeks of a 4-week cycle and dexamethasone (age adjusted dose) on two consecutive days each 
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1.3. 
Pomalidomide Description 
Pomalidomide, an analogue of thalidomide, is an immunomodulatory agent with antineoplastic 
activity.   
1.3.1. 
Pharmacokinetics and Product Metabolism 
Following administration of single oral doses of pomalidomide, the Cmax occurs at 2 and 3 hours 
postdose.  The systemic exposure (AUC) increases in an approximately dose proportional 
manner.  Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.  
Pomalidomide is a substrate for P-glycoprotein (P-gp) and is primarily metabolized in the liver 
by cytochrome 1A2 (CYP1A2) and CYP3A4.  The drug is eliminated with a median plasma 
half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients 
with MM.  The effect of CYP1A2 inhibitors, in the absence of a co-administered CYP3A4 and 
P-gp inhibitor, is unknown.  However, co-administration of fluvoxamine (a strong CYP1A2 
inhibitor) in the presence of ketoconazole (a strong CYP3A4 and P-gp inhibitor) to 12 healthy 
male subjects increased exposure (geometric mean AUCINF) to pomalidomide by 146% 
compared to pomalidomide administered alone.  Co-administration of pomalidomide with drugs 
that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure. 
Co-administration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) in 16 healthy male 
subjects resulted in an increased exposure (geometric mean AUCINF) to pomalidomide of 19% 
compared to pomalidomide administered alone.  Co-administration of carbamazepine to 
16 healthy male subjects decreased exposure (geometric mean AUCINF) to pomalidomide by 
21% compared to pomalidomide administered alone.  Co-administration of multiple doses of 
4 mg pomalidomide with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of 
CYP3A4) to patients with MM had no effect on the PK of pomalidomide compared with 
pomalidomide administered alone.  Pomalidomide does not inhibit or induce CYP450 enzymes 
or transporters in vitro. 
1.3.2. 
Summary of Clinical Data for Pomalidomide and Dexamethasone in MM 
Pomalidomide is currently approved for the treatment of relapsed/refractory MM at a 
recommended starting dose of 4 mg orally once daily for 21 days every 28 days in combination 
with dexamethasone 40 mg orally once weekly on Days 1, 8 15 and 22.  
A Phase 2 randomized trial (MM-002) evaluated the safety and efficacy of pomalidomide with 
and without low-dose dexamethasone in relapsed and refractory MM.  The study enrolled 
221 patients that were refractory to their most recent regimen and had received prior 
lenalidomide and bortezomib.  The median number of prior therapies was 5.  The outcomes for 
all treated patients in the combination arm included an ORR of 33% with a complete response 
(CR) rate of 3% and a median PFS and OS of 4.6 months and 14.4 months respectively.  These 
outcomes were consistent regardless of patient age (≤65 vs. >65 years).  In addition, in those 
patients refractory to lenalidomide and bortezomib (n=136), the ORR was 31%, with a median 
PFS of 3.8 months and a median OS of 13.4 months (Richardson 2014).  


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The most common TEAEs Grade 3 and 4 (>10%) were neutropenia (41%), anemia (22%), 
pneumonia (22%), thrombocytopenia (19%), fatigue (14%) and dyspnea (13%).  Adverse events 
(≥5%) leading to dose interruption were pneumonia (18%), neutropenia (9%), fatigue (8%), 
pyrexia (6%) and upper respiratory tract infection and thrombocytopenia (5%).  Adverse events 
(≥5%) leading to dose reduction was thrombocytopenia (5%).  Most common AEs leading to 
discontinuation included increased blood creatinine (n=1) and acute renal failure (n=1).  In the 
setting of thromobprophylaxis, any grade deep vein thrombosis (DVT) was seen in 2% 
(Richardson 2014).  
Twenty-nine patients had at least one dose reduction of pomalidomide while 2% discontinued 
treatment due to AEs.  Of note, dose reduction and/or interruption due to hematologic AEs were 
infrequent. 
A Phase 3 randomized trial (MM-003) has evaluated the safety and efficacy of pomalidomide in 
combination with dexamethasone in relapsed and refractory and advanced refractory MM.  
The study enrolled 455 patients that were refractory to their most recent regimen and had 
received prior lenalidomide, bortezomib and alkylator therapy.  The outcomes for all patients 
included an ORR of 31% with a CR rate of 1% and a median PFS and OS of 4.0 and 
12.7 months respectively.  For those patients refractory to both lenalidomide (LEN) and 
bortezomib (n=225), the ORR was 28%, with a median PFS of 3.7 months and a median OS of 
11.1 months (San Miguel 2013).  
The most common TEAEs (>15%) were infection/infestations (68%), anemia (52%), neutropenia 
(51%), fatigue (34%), thrombocytopenia (30%), pyrexia (27%), diarrhea (22%), constipation 
(22%), cough (20%), back pain (22%), dyspnea (20%), bone pain (17%), peripheral edema 
(17%), upper respiratory tract infection (16%), asthenia (16%) and muscle spasms (16%).  
The most common Grade 3 or 4 AEs were often hematologic in nature: neutropenia (48%), 
anemia (33%), thrombocytopenia (22%) and febrile neutropenia (10%).  Infections and 
infestations (34%) and pneumonia (14%) were the most frequent non-hematologic Grade 3 and 
higher AE. In the setting of thromboprophylaxis, any grade thromboembolism (DVT and PE) 
was seen in 2%, with 1% being Grade 3-4 (San Miguel 2013).  
Two hundred and one patients (67%) required at least one dose interruption, while 82 patients 
(27%) had at least one dose reduction.  Eleven patients (4%) discontinued treatment due to AEs. 
In addition, a Phase 3b single-arm, open-label trial (MM-010) has evaluated the safety and 
efficacy of pomalidomide in combination with low-dose dexamethasone in patients with 
refractory or relapsed and refractory MM.  The study enrolled 456 patients (at the time of the 
data cut-off) that were refractory to their most recent regimen, had previous lenalidomide and 
bortezomib failure and adequate alkylator therapy.  The outcomes for all evaluable patients with 
a median follow-up of 6.8 months included an ORR of 35% with a ≥VGPR response in 6% with 
a median DOR of 6 months.  Median PFS and OS in patients refractory to lenalidomide or 


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lenalidomide and bortezomib was 4.2 vs. 3.9 and 10.9 months for each, respectively 
(Dimopoulos 2014a).   
The most common Grade 3 or higher TEAEs were hematologic including neutropenia (39%), 
anemia (27%) and thrombocytopenia (19%). Grade 3-4 non-hematologic toxicities included 
pneumonia (11%), fatigue (5%) and hypercalcemia (4%).  Grade 3-4 DVT was 1% with 
prophylaxis.  Dose reductions of either pomalidomide or dexamethasone occurred in 28% of 
patients with 9% discontinuing due to TEAEs (Dimopoulos 2014a).  
Further subgroup analysis of safety and efficacy in the MM-010 trial by age (≤65 vs. >65 vs. ≤75 
vs. >75 years) revealed consistent activity and tolerability regardless of age (Palumbo 2014).  
Pomalidomide has a black box warning for embryo-fetal toxicity and venous and arterial 
thromboembolism. 
For the most comprehensive nonclinical and clinical information regarding pomalidomide, 
please refer to the current version of the pomalidomide Package Insert (PI) or SmPC (Summary 
of Product Characteristics).  
1.3.3. 
Venous Thromboembolism (VTE) 
Recent or active cancer is a recognized prothrombotic risk factor for increasing the risk of 
venous thromboembolism (VTE).  Increased plasma viscosity related to monoclonal 
paraproteinemia has been implicated as a risk factor for VTE in MM subjects.  Clinical studies 
have shown that thalidomide and lenalidomide in combination with dexamethasone or other 
chemotherapeutic agents increase the risk of VTE (Baz 2005; Weber 2007).  It appears that the 
risk of DVT in patients treated with pomalidomide may be lower than those reported with other 
immunomodulatory agents although this may be in part attributed to the mandatory 
thromboprophylaxis (San Miguel 2013).  Aspirin has been reported to be effective in reducing 
the incidence of DVT in MM subjects treated with thalidomide or lenalidomide (Baz 2005).  
In addition, guidance for the assessment of VTE risk and risk-based recommendations for 
anticoagulation use with pomalidomide is available (Dimopoulos 2014b).  
1.3.4. 
Second New Cancers 
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer.  In clinical studies of newly diagnosed MM, 
a higher number of second cancers were reported in subjects treated with induction therapy 
(treatment as first step to reducing number of cancer cells) and/or bone marrow transplant then 
lenalidomide for a long period of time compared to subjects treated with induction therapy 
and/or bone marrow transplant then placebo (a capsule containing no lenalidomide).  Four 
subjects on the MM-003 trial developed a second primary malignancy (2 invasive solid cancers 
and 2 basal-cell skin cancers) (San Miguel 2013).  Cases of acute myelogenous leukemia have 
been reported in subjects receiving pomalidomide as an investigational therapy outside of MM.  


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Patients should make their doctors aware of their medical history and any concerns they may 
have regarding their own increased risk of other cancers.  
For more complete safety information, refer to the current version of the pomalidomide PI or 
SmPC.   
1.4. 
Justification of Study Design and Dose Rationale 
Patients with MM that have relapsed and refractory disease that has been previously treated with 
an immunomodulatory agent and proteasome inhibitor represent a subset of patients known to 
have a poor prognosis.  The combination of pomalidomide and dexamethasone has not only an 
ORR that led to approval in this specific patient population, but also extends both PFS and OS 
beyond the expectations without this therapeutic option (Refer to Section 1.3.2).   
The approved dose of pomalidomide is 4 mg administered orally once daily for 21 days of a 
28 day cycle in combination with weekly dexamethasone per both the US and EU label.  
The approval of this dose and schedule was based upon the efficacy results showing an ORR of 
24%  in a heavily pre-treated relapsed/refractory patient population with a safety profile similar 
to that of other approved immunomodulatory agents. 
The rationale for the target dose of ibrutinib 840 mg orally once daily continuously in 
combination with dexamethasone 40 mg once weekly is based upon the clinical activity and 
acceptable safety profile in patients with relapsed or relapsed/refractory MM from two 
independent studies.  In PCYC-1111, ibrutinib doses ranging from 420 mg to 840 mg were 
evaluated both alone and in combination with dexamethasone with the highest clinical activity 
noted with ibrutinib 840 mg in combination with dexamethasone.  The clinical CBR was 26% 
(n=43) in comparison with 6% and 8% at lower dose levels and a trend towards improved PFS 
was observed.  In addition, the safety profile at 840 mg was consistent with that seen at lower 
dose levels.  In PCYC-1119, ibrutinib was tested at doses of 560 mg and 840 mg in combination 
with carfilzomib 20/36 mg/m2 with no dose limiting toxicities observed.  The highest dose level 
(840 mg) has been expanded with an ORR of >50% seen in the first 11 subjects, with early 
follow-up for the remaining 7 subjects enrolled.  The safety profile of the combination is 
consistent across cohorts and as expected based upon and in alignment with the known safety 
profile of the individual agents (Refer to Sections 1.2.5.1 and 1.2.5.2).   
The safety profile of the approved pomalidomide/dexamethasone schedule as well as that of 
ibrutinib 840 mg in combination with dexamethasone in MM suggests a minimal overlap of 
clinically relevant toxicities.  Due to the lack of safety data for the combination of ibrutinib with 
pomalidomide and dexamethasone a dose escalation will occur and the starting dose for this 
study will be ibrutinib 560 mg once daily in combination with the labeled dose and schedule of 
pomalidomide and dexamethasone. 
Evidence of synergy between ibrutinib and the immunomodulatory agent, lenalidomide, has been 
shown in both MM patient cells and in MM cell lines evidenced by an increased cytotoxicity of 


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malignant plasma cells (Rushworth 2013).  These observations were confirmed using apoptosis 
assays and showed that BTK inhibition by ibrutinib had no cytotoxic effects on primary 
monocytes suggesting that its effect is not due to non-specific cytotoxicity (Rushworth 2013). 
In addition, preclinical data suggest that both BTK inhibitors and immunomodulatory agents 
target the clonogenic side populations of CD138neg cells, with evidence of clonogenicity and the 
ability to restore the original population (Jakubikova 2011).  Evidence of BTK overexpression 
(BTKOE) has been identified in the CD138neg side population and was associated with the marked 
upregulation of several stem cell genes (ie, NANOG, MYC and SOX2).  Yang et al, also 
demonstrated that BTKOE side population cells contributed to blunted responses of MM cells 
when treated with widely used MM drugs (ie, bortezomib, doxorubicin and etoposide) as well as 
a significant survival advantage of BTKOE cells when compared to BTKWT (Yang 2015).  In 
addition, studies have also shown that lenalidomide is able to decrease both the amount and 
clonogenicity of side population cells as well as the ability to abrogate the beneficial role that 
adherence to the bone marrow stromal cells can have on the side populations viability and 
proliferation potential (Jakubikova 2011). 
The novel oral combination of ibrutinib in combination with pomalidomide and dexamethasone 
may be well tolerated with the potential to exploit synergistic effects on the both the main and 
side population of cells responsible for disease burden and relapse allowing for an opportunity to 
improve outcomes in a patient population with minimal therapeutic options and poor prognosis. 
2. 
STUDY OBJECTIVE 
2.1. 
Primary Objective(s) 
Phase 1:  
• 
To determine the MTD/maximum administered dose (MAD) and the Phase 2b dose of 
the ibrutinib, pomalidomide and dexamethasone combination. 
• 
To determine the safety and tolerability of ibrutinib in combination with pomalidomide 
and dexamethasone in subjects with relapsed/refractory MM. 
Phase 2b:  
• 
To evaluate the effect of ibrutinib in combination with pomalidomide and 
dexamethasone  compared to placebo in combination with pomalidomide and 
dexamethasone on PFS, as assessed by independent review committee (IRC), in 
subjects with relapsed/refractory MM. 
2.2. 
Secondary Objective(s) 
Phase 1:  
• 
Overall response rate (ORR) defined as ≥PR according to the International Myeloma 
Working Group (IMWG) response criteria (Rajkumar 2011) 


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• 
Duration of response (DOR) 
• 
The clinical benefit rate (CBR) and its duration, defined as ≥MR according to the 
IMWG response criteria (Rajkumar 2011)  
• 
To evaluate the PK of ibrutinib and pomalidomide when given in combination with 
dexamethasone 
Phase 2b:  
• 
To compare the treatment arms as assessed by both IRC and investigator in terms of the 
following: 
o ORR (≥PR; according to IMWG [Rajkumar 2011])  
o DOR  
o CBR (≥MR; according to IMWG [Rajkumar 2011]) and its duration 
o Overall survival (OS)  
o Time-to-progression (TTP)  
In addition, 
• 
To evaluate the safety and tolerability of ibrutinib in combination with pomalidomide 
and dexamethasone 
• 
To evaluate the PK of ibrutinib and pomalidomide when given in combination with 
dexamethasone 
2.3. 
Exploratory Objective(s) 
• 
To evaluate potential prognostic and predictive biomarkers relative to treatment 
outcomes (selected sites for Phase 1 and all sites for Phase 2b) 
• 
To assess biomarkers, (including gene expression profiles [GEP], secreted proteins, 
bone turnover and/or immunophenotypic) in subjects with relapsed/refractory MM 
(selected sites for Phase 1 and all sites for Phase 2b) 
To evaluate and compare the treatment arms in terms of the following: 
• 
Time-to-next-treatment (TTNT) (Phase 2b) 
• 
Patient-reported outcomes (PROs) and disease-related symptoms according to European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire for 
MM (EORTC QLQ-MY20) and Euro QoL 5 dimensions questionnaire (EQ-5D-5L) 
(Phase 2b) 
2.4. 
Open-Label Sub-Study Treatment Arm C (Phase 2b) 
• 
To evaluate the efficacy and safety of ibrutinib in combination with pomalidomide and 
dexamethasone in subjects who either have: 
o Less than a partial response (<PR) following at least 112 days (4 x 28 day cycles) of 
pomalidomide and dexamethasone (regimen must not have included other 
anti-cancer agents) and are without evidence of disease progression 
OR 


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o Disease progression following an initial confirmed response of MR or better to the 
combination of pomalidomide and dexamethasone (regimen must not have included 
other anti-cancer agents) 
3. 
OVERVIEW OF STUDY DESIGN 
The study will be conducted in two Phases. 
Phase 1 
Phase 1 will be an open-label, international, multicenter dose-finding study of the ibrutinib, 
pomalidomide and dexamethasone combination in subjects with relapsed/refractory MM who 
have received at least two prior lines of therapy, including LEN and either bortezomib or 
carfilzomib and have demonstrated disease progression on or within 60 days of completion of the 
most recent treatment regimen. 
Up to 18 patients will be enrolled in order to determine the MTD/MAD and the Phase 2b dose. 
In the dose finding portion of the study, up to two cohorts may be explored and will follow the 
3+3+3 dose escalation design.  The MTD/MAD will be defined as the highest dose level at 
which <33% (ie, 1 of 6 or 2 of 9) of subjects in a cohort experience a study treatment related 
DLT.  
In the event that Cohort -1 will be considered the Phase 2b dose, the Sponsor may choose not to 
continue with Phase 2b enrollment as outlined in the protocol.   
After enrollment completion of Phase 1, enrollment into Phase 2b may commence once the 
MTD/MAD is identified. 
Phase 2b 
Phase 2b will be conducted as a randomized, double-blind, international, multicenter study of 
ibrutinib or placebo in combination with pomalidomide and dexamethasone in subjects with 
relapsed/refractory MM who have received at least two prior lines of therapy, including LEN and 
either bortezomib or carfilzomib and have demonstrated disease progression on or within 
60 days of completion of the most recent treatment regimen. 
Approximately 195 subjects will be randomized 1:1 between Arm A (ibrutinib in combination 
with pomalidomide and dexamethasone) and Arm B (placebo in combination with pomalidomide 
and dexamethasone) and stratified according to: 
• 
2-3 vs. ≥ 4 prior therapies 
• 
Last regimen (no IMiD/PI vs. IMiD or PI vs. IMiD and PI) 
• 
Age: ≤75 vs. > 75 years 


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Open-Label Sub-Study Treatment Arm C (Phase 2b Only) will enroll up to 22 subjects to 
receive open-label ibrutinib in combination with pomalidomide and dexamethasone.  For more 
details regarding inclusion/exclusion criteria refer to Section 4. 
Subjects eligible for the randomized study portion (Arm A or Arm B) are not eligible for 
participation in the sub-study (Arm C).  
Both Phase 1 and Phase 2b of the study will include a Screening Phase, Treatment Phase and a 
Follow-up Phase. 
The Screening Phase assessments will be performed within 28 days prior to study treatment.  
Eligible subjects will have relapsed/refractory MM, having received at least 2 prior therapies 
including lenalidomide (LEN) and either bortezomib or carfilzomib, and have demonstrated 
disease progression on or within 60 days of completion of most recent treatment regimen 
(Rajkumar 2011).  Subjects who satisfy all the inclusion/exclusion criteria are eligible to enter 
the study. 
The Treatment Phase will extend from first dose of study treatment for Phase 1 and 
randomization (Arm A and Arm B) or enrollment (Arm C) for Phase 2b until the End-of-
Treatment (EOT) visit (which should occur 30 days from last dose of study drug or prior to the 
start of a new anti-cancer treatment).  Initiation of study treatment should occur within 28 days 
of consenting and Screening procedures, following approval by the Sponsor’s medical monitor 
for Phase 1 and 3 days of randomization/enrollment for Phase 2b.  Subjects enrolled in Phase 1 
will receive ibrutinib in combination with pomalidomide and dexamethasone according to 
Section 5.1.  Subjects in Arms A and B of Phase 2b will receive pomalidomide and 
dexamethasone per protocol design.  In addition, all subjects in Arms A and B, according to 
randomization, will receive oral study drug (ibrutinib or matching placebo), administered 
continuously. Subjects in Arm C will receive the combination of pomalidomide and 
dexamethasone per protocol design with oral ibrutinib administered daily.  All subjects will 
continue study treatment until criteria for permanent discontinuation of study drug are met 
(Section 5.8), such as disease progression (confirmed by IRC for Phase 2b), study drug is no 
longer tolerated by subject, or study end.  Further information on dosing is provided in Section 5.  
Efficacy evaluations will be performed as specified in Section 7.5.  Subjects with progressive 
disease (confirmed by IRC for Phase 2b) must discontinue all study treatment.  The 
Post-treatment Follow-up Phase will begin once a subject discontinues study treatment and will 
continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first.   
• 
The Response Follow-up Phase will occur for subjects who discontinue for reasons 
other than disease progression (ie, for AE or Investigator decision), and will include 
efficacy assessments at a minimum every 4 weeks ± 3 days until disease progression 
(confirmed by IRC for Phase 2b).  In Phase 2b this will continue regardless of initiation 
of subsequent anti-cancer treatment.  Subjects with confirmed progression will continue 
to be followed in the Long-term Follow-up Phase.   


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• 
The Long-term Follow-up Phase will occur for subjects with disease progression (by 
IRC for Phase 2b) and subjects will be followed for survival, subsequent anti-cancer 
therapy and other malignancies every 12 weeks ± 14 days until study end.   
An independent DMC will be formed and constituted according to regulatory agency guidelines.  
Detailed information regarding the composition of the DMC and detailed DMC procedures will 
be provided in a separate charter.  In Phase 1, the DMC will review safety data for DLT 
assessment during the dose finding portion in order to determine the MTD/MAD and the Phase 
2b dose.  In Phase 2b, the DMC will review the safety data periodically and may be responsible 
to perform the interim analysis, review the results and provide recommendations according to the 
charter. 
 
 


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Figure 1: 
Phase 2b Study Design Schematic 
 
 
Treatment Arm A  
 
STUDY DRUG:  
ibrutinib orally, once daily, 
continuously starting on Day 1 of 
Cycle 1 until IRC confirmed 
disease progression, unacceptable 
toxicity, or the study end 
 
COMBINATION THERAPY:  
Pomalidomide orally on Days 1-21 
of each Cycle 
Dexamethasone (age-adjusted) 
orally, weekly on Days 1, 8, 15, 22 
of each Cycle 
Treatment Arm B  
  
STUDY DRUG:  
Placebo orally, once daily, 
continuously starting on Day 1 of 
Cycle 1 until IRC confirmed disease 
progression, unacceptable toxicity, 
or the study end 
 
COMBINATION THERAPY:  
Pomalidomide orally on Days 1-21 
of each Cycle 
Dexamethasone (age-adjusted) 
orally, weekly on Days 1, 8, 15, 22 
of each Cycle 
 
Assess Subject Eligibility  
Randomization 
Screening Phase 
Within 28 days prior to start of study treatment 
Treatment Arm C 
(sub-study for subjects that are not eligible 
for the randomized study portion 
(Refer to Section 4.1.1.) 
 
STUDY DRUG:  
ibrutinib orally, once daily, continuously 
starting on Day 1 of Cycle 1 until IRC 
confirmed disease progression, 
or unacceptable toxicity, or the study end 
 
COMBINATION THERAPY: 
Pomalidomide orally on Days 1-21 of each 
Cycle 
Dexamethasone (age-adjusted) orally, weekly 
on Days 1, 8, 15, 22 of each Cycle 
Open-Label Enrollment 
Long-Term Follow-up Phase 
 
Following IRC confirmed disease 
progression: Follow-up for survival 
status, PRO assessments (minimum 
of 18 mos) and record first 
subsequent anti-MM therapy and 
other malignancies every 12 weeks 
Treatment Discontinuation 
Due to IRC confirmed disease progression 
or other reason for treatment discontinuation as 
outlined in Section 9 
Complete EOT Visit  
(30 days from last dose of study drug or prior to 
start of new anti-cancer treatment)  
Response Follow-up Phase 
 
Prior to IRC confirmed disease 
progression: Continue efficacy 
evaluations and PRO assessments 
(minimum of 18 mos)  
every 4 weeks 


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3.1. 
Statement of Compliance 
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonisation (ICH), Good Clinical Practice (GCP), Declaration of Helsinki, and 
all applicable national and local regulations governing clinical studies. 
4. 
SUBJECT SELECTION 
The inclusion and exclusion criteria for enrolling subjects on this study are described below.  
If there are any questions about the entry criteria, the Investigator should consult with the 
Medical Monitor before enrolling a subject in the study. 
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must meet all of the following inclusion 
criteria. 
Disease Related 
1. Subjects with relapsed/refractory MM who have received at least two prior lines of therapy 
(Appendix 4) including lenalidomide (LEN) and either bortezomib or carfilzomib and have 
demonstrated disease progression on or within 60 days of the completion of the most recent 
treatment regimen.  
• 
Subjects must have received at least 2 cycles of treatment with LEN and either 
bortezomib or carfilzomib at the approved dose and schedule (maintenance will be 
excluded).  
2. Measurable disease defined by at least ONE of the following: 
• 
Serum monoclonal protein (SPEP) ≥1 g/dL. 
• 
Urine monoclonal protein (UPEP) ≥200 mg by 24 hour urine.  
Laboratory 
3. Adequate hematologic function independent of platelet transfusion and growth factor support 
for at least 7 days prior to Screening and dosing (Phase 1) or randomization/enrollment 
(Phase 2b), with the exception of pegylated G-CSF (granulocyte-colony stimulating factor 
pegfilgrastim) and darbopoeitin which require at least 14 days , defined as: 
• 
Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L). 
• 
Platelet count >75,000 cells/mm3 (75 x 109/L). 
• 
Hemoglobin ≥8.0 g/dL. 
4. Adequate hepatic and renal function defined as: 
• 
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit 
of normal (ULN). 


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• 
Serum creatinine < 3.0 mg/dL AND Creatinine Clearance ≥30 mL/min (by 
Cockcroft-Gault estimation OR as measured by 24 hour urine collection). 
• 
Total Bilirubin ≤2.0 mg/dL (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin). 
5. PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN (unless on warfarin, then INR ≤3.0). 
Demographic 
6. Men and women ≥ 18 years of age. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
Ethical/Other 
8. All study participants must be registered into the mandatory Pomalyst REMS™ program or 
RevAid® program, and be willing and able to comply with the requirements of the Pomalyst 
REMS™  program or RevAid® program as appropriate for the country in which the drug is 
being used (for US/Canada sites only).   
9. Female subjects of childbearing potential (FCBPa) must adhere to the scheduled pregnancy 
testing as required in the Pomalyst REMS™ program or RevAid® program as appropriate for 
the country in which the drug is being used. (for US/Canada sites only).  
10. Female subjects of childbearing potential (FCBPa)  must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 
24 hours prior to starting Cycle 1 of pomalidomide.  All subjects must be counseled at a 
minimum of every 28 days about pregnancy precautions and risks of fetal exposure.  
See Appendix 8 (for ex-US sites only). 
11. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy (for US/Canada sites only). 
12. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  All subjects must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal exposure.  See Appendix 8 
(for ex-US sites only). 
13. FCBPa and male subjects who are sexually active must use TWO acceptable methods of birth 
control, one highly effective method of birth control plus one additional effective method of 
birth control for at least 28 days prior to study treatment and during the study treatment 
period.  For female and male subjects, these birth control requirements must be adhered to 
for 90 days after the last dose of ibrutinib and pomalidomide, whichever is later.  Male 
subjects must agree to not donate sperm during the study treatment period and up to 90 days 
after the last dose of ibrutinib and pomalidomide, whichever is later. 
a. 
A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point; or 2) has 
not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal  
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time in the preceding 24 consecutive months). 


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4.1.1. 
Inclusion Criteria for Open-label Sub-study Arm C (Phase 2b) 
To be enrolled in the sub-study, each potential subject must meet all inclusion criteria defined in 
Section 4.1.  IN ADDITION the following criteria must be met: 
Subject must have received pomalidomide in combination with dexamethasone (regimen must 
not have included other anti-cancer agents) as their most recent line of therapy and have: 
• 
Achieved less than a partial response (<PR) following at least 112 days (4 x 28 day 
cycles) and are without evidence of progression disease (PD) 
OR 
• 
Disease progression following an initial confirmed response of MR or better to the 
combination (according to IMWG response criteria; Rajkumar 2011)  
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must not have any of the following exclusion 
criteria: 
Disease-Related 
1. Primary refractory disease defined as nonresponsive in patients who have never achieved a 
minimal response or better with any therapy. 
2. History of plasma cell leukemia, primary amyloidosis, POEMS syndrome within 12 months 
prior to first administration of study treatment. 
Concurrent Conditions 
3. Recent prior chemotherapy: 
a. 
Alkylators (eg, melphalan, cyclophosphamide) and/or anthracyclines <21 days prior to 
first administration of study treatment. 
b. High dose corticosteroids, IMiDs or proteasome inhibitors <14 days prior to first 
administration of study treatment.  
c. 
Monoclonal antibody <14 days prior to first administration of study treatment. 
4. Prior exposure to BTK inhibitors. 
5. Prior exposure to pomalidomide (except Treatment Arm C). 
6. History of serious hypersensitivity reactions to prior thalidomide, lenalidomide or 
pomalidomide. 
7. History of other malignancies, except: 
a. 
Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician. 


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b.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease.
c.
Adequately treated carcinoma in situ without evidence of disease.
8. Peripheral neuropathy Grade ≥2 with pain at Screening.
9. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or
chronic administration of >20 mg/day of prednisone or equivalent) within 28 days of the
first dose of study treatment.
10. Recent infection requiring systemic treatment that was completed <7 days before the first
dose of study treatment and/or uncontrolled active systemic infection.
11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to
CTCAE (version 4.03), Grade ≤1 or to the levels dictated in the inclusion/exclusion criteria
with the exception of alopecia.
12. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
13. History of stroke or intracranial hemorrhage within 6 months prior to
enrollment/randomization.
14. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
(HCV) or hepatitis B virus (HBV).  Subjects who are positive for hepatitis B core antibody,
hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain
reaction (PCR) result before enrollment/randomization.  Those who are PCR positive will
be excluded.
15. Major surgery within 4 weeks of first dose of study treatment.
16. Any life-threatening illness, medical condition including uncontrolled Diabetes Mellitus, or
organ system dysfunction that, in the opinion of the investigator, could compromise the
subject’s safety or put the study outcomes at undue risk.
17. Currently active, clinically significant hepatic impairment (≥ mild hepatic impairment 
according to the Child Pugh classification [Appendix 10])
18. 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 enrollment/randomization.
•
QTc ≥470 msec calculated using Fridericia formula (QTcF) at Screening.
19. Unable to swallow capsules, malabsorption syndrome, disease significantly affecting
gastrointestinal function, resection of the stomach or small bowel, symptomatic
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
20. Requires treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor (see Appendix 5).
21. Women who are pregnant or breast-feeding.
22. Unwilling or unable to participate in all required study evaluations and procedures.


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23. 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).
4.2.1. 
Exclusion Criteria for Open-Label Sub-Study Arm C (Phase 2b) 
To be enrolled in the sub-study, each potential subject must not meet any exclusion criteria 
defined in Section 4.2 EXCEPT for exclusion criteria 5 which is related to prior pomalidomide 
and does not apply for the sub-study Arm C. 
5.
TREATMENT OF SUBJECTS
5.1. 
Phase 1 Dose Escalation and Stopping Rules 
Phase 1 will follow a 3+3+3 dose escalation design with 3-9 subjects treated at each dose level.  
Before determining the Phase 2b dose, at least 6 subjects will be treated at the MTD or highest 
dose level tested.  The DLT observation period includes Cycle 1 and all pre-dose assessments per 
protocol on Day 1 of Cycle 2.  The dose will be selected as the Phase 2b dose if the subject 
incidence of DLTs during the DLT observation of study treatment is <33% (ie, ≤1/6 or ≤2/9 
subjects with a DLT).  If there are ≥3 subjects with a DLT in Cohort 1, then the next lower dose 
level (Cohort -1) will be enrolled.  In the event that Cohort -1 will be considered the Phase 2b 
dose, the Sponsor may choose not to continue with Phase 2b enrollment as outlined in the 
protocol (for dose levels, see Table 1).   
Dose Escalation: A minimum of three subjects will be enrolled within each cohort.  The DMC 
will evaluate each individual cohort prior to any dose escalation or de-escalation (Table 1). 
Before applying the dose escalation rules, 3 subjects must have completed the first cycle of 
therapy and have been evaluated for toxicity as defined by the DLT observation period.  If no 
DLT is observed in the first three subjects, then dose escalation will take place.  If one of three 
subjects experience a study treatment-related DLT during the first treatment cycle, the same 
cohort will be expanded to six subjects, and if two of the six experience a DLT it will be 
expanded to 9 subjects. If 1/6 or 2/9 subjects experiences a study treatment related DLT during 
the first treatment cycle, dose escalation will occur and the next cohort may be enrolled. If at any 
time during a cohort, ≥3 subjects experience a study treatment related DLT, the MTD will have 
been exceeded, and additional enrollment within the cohort will cease. If there are 3 DLTs in 
Cohort 1, Cohort -1 will be enrolled. The MTD will be defined as the highest dose cohort at 
which <33% of subjects in a cohort experience a study treatment related DLT.  If the MTD is not 
reached, the maximum administered dose (MAD) will be established as the highest dose level 
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Table 1: 
Dosing Levels and Cohorts 
Dose Level 
Cohort 
Ibrutiniba 
Pomalidomideb 
Dexamethasonec 
-1 
-1 
420 mg once daily 
4 mg 
40 mg 
1 
(Starting Dose) 
1 
560 mg once daily 
4 mg 
40 mg 
2 
2 
840 mg once daily 
4 mg 
40 mg 
a. 
Ibrutinib will be administered PO starting on Day 1 of Cycle 1, dosing is continuous thereafter (without 
interruption). 
b. 
Pomalidomide will be administered PO on Days 1 – 21 of a 28-day cycle. 
c. 
Dexamethasone will be administered PO once weekly.  Dose will be 20 mg weekly in those >75 years of age  
Missed doses of ibrutinib, pomalidomide and dexamethasone will not be made up.  
Note:  In the dose finding portion, if a subject is non-compliant with the prescribed therapy or 
ends treatment within the first cycle for reasons other than study drug(s) related toxicity, 
ie, withdraws consent, they will be replaced.  Any subject that misses >5 doses of ibrutinib or 
>3 doses of pomalidomide for reasons other than toxicity during the first cycle will be replaced.  
The review and confirmation of DLTs will be performed by the independent DMC and the 
decision to proceed with either Phase 2 initiation or dose escalation/de-escalation will be made in 
collaboration with the Sponsor.  
5.1.1. 
Definition of Dose Limiting Toxicity (DLT) 
The assessment of DLT will follow the guidelines provided in the CTCAE (version 4.03).  
A DLT is defined as:   
Hematologic: 
• 
Grade 4 neutropenia (ANC <500/mm3) lasting for >7 days 
• 
Febrile neutropenia (ANC <1,000/mm3 with a fever ≥38.3ºC)  
• 
Grade 4 thrombocytopenia (<25,000/ mm3) that persists for >7 days, despite holding 
treatment  
• 
Grade 3 thrombocytopenia associated with Grade ≥2 bleeding or requiring RBC or 
>1 platelet transfusion 
Non-Hematologic: 
• 
Any Grade 3 or higher non-hematologic AE where relationship to study drug(s) cannot 
be ruled out  
• 
Grade ≥3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive care and 
persisting >7 days 
• 
Grade ≥3 rash if symptomatic and requiring systemic intervention other than drug hold; 
unless hold is for >7 days 
• 
Any Grade 4 or desquamating rash 


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• 
Treatment delay of any drug > 7 days for toxicity; unless toxicity can be solely 
attributed to pomalidomide 
5.2. 
Randomization and Blinding 
Subjects who satisfy all the inclusion/exclusion criteria are eligible to enter the study. 
Phase 1:  
Phase 1 is an open-label study; there will be no randomization or stratification of subjects. 
Phase 2b: 
After the subject has completed all baseline (Screening) procedures and satisfied all requirements 
of the inclusion/exclusion criteria, study site personnel will submit the Eligibility Worksheet 
(EW) to the Medical Monitor or Sponsor designee for approval.  In order to begin treatment, 
study personnel will register the subject into the IWRS to have drug assigned to that subject.  
The first dose of study drug should be administered after randomization, but no more than 
3 business days after the subject has been randomized by IWRS. 
Approximately 195 subjects will be randomized in a 1:1 ratio to the 2 treatment arms: 
• 
Treatment Arm A:  ibrutinib in combination with pomalidomide and dexamethasone  
• 
Treatment Arm B:  placebo in combination with pomalidomide and dexamethasone  
Central randomization will be implemented in this study.  Randomization will be stratified using 
the following stratification factors and subjects will be randomized in a 1:1 ratio to receive either 
ibrutinib in combination with pomalidomide and dexamethasone or placebo in combination with 
pomalidomide and dexamethasone:  
a. 
Number of prior systemic treatment regimens (2-3 vs. ≥4) 
b. Last regimen (no IMiD/PI vs. IMiD or PI vs. IMiD and PI) 
c. 
Age: ≤75 vs. > 75 years 
The IWRS will assign a unique treatment code, which will dictate the treatment assignment and 
matching study drug kit for the subject.  The requestor must use his or her own user 
identification and personal identification number when contacting the IWRS, and will then give 
the relevant subject details to uniquely identify the subject. 
Subjects eligible for open-label sub-study Arm C will be enrolled using the IWRS to obtain a 
unique treatment code. 
Blinding 
This is a double-blind study; therefore, subjects, investigators, and the Sponsor’s study team 
members will remain blinded to study treatment assignment.  The investigator will not be 
provided with randomization codes.  The codes will be maintained within the IWRS, which has 


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the functionality to allow the investigator to break the blind for an individual subject.Data that 
may potentially unblind the treatment assignment (ie, study drug plasma concentrations) will be 
handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized.  This may include making special provisions, such as segregating the data 
in question from view by the investigators, clinical team, or others as appropriate until the time 
of database lock and/or unblinding. 
Under normal circumstances, the blind should not be broken.  The blind should be broken only if 
specific emergency treatment/course of action would be dictated by knowing the treatment status 
of the subject.  In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS.  It is recommended that the investigator contact the Sponsor 
or its designee, if possible, to discuss the particular situation before breaking the blind.  
Telephone contact with the Sponsor or its designee will be available 24 hours per day, 7 days per 
week.  In the event the blind is broken, the Sponsor must be informed as soon as possible.  The 
date, time, and reason for the unblinding must be documented by the IWRS and in the source 
document.  The documentation received from the IWRS indicating the code break must be 
retained with the subject's source documents in a secure manner.  A subject whose treatment 
assignment has been unblinded may continue the study treatment if receiving clinical benefit, 
and the subject should continue to return for scheduled study evaluations.  The single-blind 
(ie, subject remains blinded to treatment assignment) should be maintained provided the 
subject’s safety is not compromised. 
At the time of the interim analysis, the randomization codes and, if required, the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim analysis.   
All subjects eligible for the sub-study Arm C will be treated in an open-label fashion.  
5.3. 
Treatment Regimens 
All eligible subjects will be treated with pomalidomide and dexamethasone. 
5.3.1. 
Phase 1 
Ibrutinib in combination with pomalidomide and dexamethasone will be administered according 
to the assigned cohort. 
5.3.2. 
Randomized Phase 2b (Treatment Arms A and B) 
During the conduct of the randomized study portion, subjects will be randomly assigned to 
treatment with either ibrutinib in combination with pomalidomide and dexamethasone (Arm A) 
or matching placebo in combination with pomalidomide and dexamethasone (Arm B).  The final 
dose level for conducting the Phase 2b portion will be determined by the Phase 1 MTD/MAD. 
Each cycle is 28-days in length.  Missed doses of ibrutinib and pomalidomide will not be made 
up.  During the conduct of the Phase 2b study portion, dose escalation of any agent (ibrutinib or 


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placebo, pomalidomide or dexamethasone) at any time will not be allowed. Treatment will 
continue until IRC confirmed disease progression or other reason for treatment discontinuation 
as outlined in Section 5.8. 
5.3.2.1. 
Treatment Arm A 
Ibrutinib: 
Phase 2b dose orally administered daily 
Pomalidomide: 
4 mg orally administered Days 1-21 of each 28-day cycle 
Dexamethasone: Age-adjusted dose orally administered weekly on Days 1, 8, 15 and 22 of 
each 28-day cycle 
5.3.2.2. 
Treatment Arm B 
Placebo: 
Matched placebo orally administered daily 
Pomalidomide: 
4 mg orally administered Days 1-21 of each 28-day cycle 
Dexamethasone: Age-adjusted dose orally administered weekly on Days 1, 8, 15 and 22 of 
each 28-day cycle 
5.3.3. 
Open-Label Sub-Study (Treatment Arm C) 
Ibrutinib: 
Phase 2b dose orally administered daily 
Pomalidomide: 
4 mg orally administered Days 1-21 of each 28-day cycle 
Dexamethasone: Age-adjusted dose orally administered weekly on Days 1, 8, 15 and 22 of 
each 28-day cycle 
All subjects treated in this sub-study will follow guidelines for ibrutinib or placebo dosing and 
toxicity management as described for the randomized treatment arms (Arm A and Arm B) in the 
protocol. 
5.4. 
Ibrutinib or Placebo 
All subjects in Phase 1 and those assigned to Treatment Arm A and Treatment Arm C in 
Phase 2b of this study will receive ibrutinib.  All subjects assigned to Treatment Arm B in 
Phase 2b of this study will be administered placebo.  All subjects taking ibrutinib or matching 
placebo will follow guidelines for ibrutinib dosing and toxicity management. 
5.4.1. 
Formulation, Packaging, and Storage of Ibrutinib or Placebo 
Ibrutinib or placebo capsules are provided as a hard gelatin capsule containing 140 mg of 
ibrutinib or placebo.  All formulation excipients are compendial and are commonly used in oral 
formulations.  Refer to the ibrutinib IB for a list of excipients.  


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The ibrutinib or placebo capsules will be packaged in opaque high-density polyethylene plastic 
bottles with labels bearing the appropriate label text to meet the applicable regulatory 
requirements.  All study drug will be dispensed in child-resistant packaging.   
Refer to the Pharmacy Manual for additional guidance on study drug storage, preparation and 
handling. 
5.4.2. 
Dose and Administration of Ibrutinib or Placebo 
The first dose of ibrutinib or placebo will be administered orally in the clinic on Cycle 1 Day 1, 
of the Treatment Phase, after which ibrutinib or placebo will be self-administered daily by the 
subjects on an outpatient basis. 
Ibrutinib or placebo will be dosed at the same time as pomalidomide and dexamethasone on the 
days of PK assessment. 
Ibrutinib or placebo is administered orally once daily with 8 ounces (approximately 240 mL) of 
water at approximately the same time each day.  The capsules should be swallowed intact and 
patients should not attempt to open capsules or dissolve them in water.  The use of strong 
CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the 
duration of the study (Section 6.1.2.1). 
If a dose is missed, 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. 
Ibrutinib or placebo dosing is continuous (without interruption) throughout the Treatment Phase.  
If Day 1 pomalidomide or dexamethasone dosing is delayed for toxicity that does not require 
ibrutinib or placebo to be held for toxicity, dosing of ibrutinib or placebo should continue.  If a 
Day 1 (of any Cycle) is delayed due to scheduling delays, ibrutinib or placebo dosing should 
continue. 
Treatment will continue until disease progression (confirmed by IRC for Phase 2b) or other 
reason for treatment discontinuation as outlined in Section 5.8.  
Dose modifications for toxicity are outlined in Section 5.4.4. 
Ibrutinib or placebo will be dispensed to subjects in bottles.  Unused ibrutinib or placebo 
capsules dispensed during previous visits must be returned and drug accountability records 
updated at the beginning of the next cycle.  Returned capsules must not be re-dispensed to 
anyone. 
5.4.3. 
Dose Hold, Reduction or Discontinuation of Ibrutinib or Placebo  
In order to continue ibrutinib or placebo at the start of a new cycle, the subject must not meet any 
of the criteria for ibrutinib or placebo dose modification (see Section 5.4.4). 


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Treatment with ibrutinib or placebo should be withheld for any unmanageable, potentially study 
drug-related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity meeting the criteria in Section 5.4.4.  Subjects who require full-dose of anticoagulant 
treatment (eg, warfarin or heparin) should have ibrutinib or placebo held until stable on 
anticoagulant therapy (Section 6.1.2.4).  Subjects that require an invasive procedure or surgery 
must have ibrutinib or placebo withheld according to the guidance in Section 6.2.  Any other 
clinically important events where dose delays may be considered appropriate by the Investigator 
should be discussed with the Medical Monitor. 
Ibrutinib or placebo may be withheld for a maximum of 28 consecutive days for toxicity.  
Ibrutinib or placebo should be discontinued in the event of an ibrutinib or placebo toxicity lasting 
more than 28 days, unless reviewed and approved by the Medical Monitor. 
5.4.4. 
Dose Modification of Ibrutinib or Placebo 
The dose of ibrutinib or placebo should be modified according to the dose modification 
guidelines in Table 4 if any of the following toxicities occur: 
•
Grade 4 neutropenia (ANC <500/µL) for more than 7 days.  Refer to Section 6 for
instruction regarding the use of growth factor support
•
Grade 3 thrombocytopenia (platelets <50,000/µL) in the presence of clinically
significant bleeding events
•
Grade 4 thrombocytopenia (platelets <25,000/µL)
•
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic
and/or anti-diarrheal therapy
•
Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib or placebo
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib or placebo treatment. 
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the 
thromboprophylaxis of atrial fibrillation (Section 6.1.2.4). 


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Table 2: 
Ibrutinib or PlaceboDose Modification Guidance 
Hematologic Adverse Events 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib or placebo until recovery to an ANC ≥750 µL or platelets >25,000 µL with 
no evidence of Grade ≥2 bleeding; may restart at original dose level 
Subsequenta 
Withhold ibrutinib or placebo until recovery to an ANC ≥750 µL or platelets >25,000 µL with 
no evidence of Grade ≥2 bleeding; may restart at 1 dose level lower (refer to  
Table 3) 
Non-Hematologic Adverse Events 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib or placebo until recovery to Grade ≤1 or baseline; may restart at original 
dose level 
Subsequenta 
Withhold ibrutinib or placebo until recovery to Grade ≤1 or baseline; may restart at 1 dose 
level lower (refer to  
Table 3) 
a Do not dose below 280 mg daily 
Table 3: 
Ibrutinib or PlaceboDose Modifications 
Starting Dose Level 
840 mg 
560 mg 
420 mg 
Dose Reduction Level 1 
700 mg 
420 mg 
280 mg 
Dose Reduction Level 2 
560 mg 
280 mg 
140 mg 
Dose Reduction Level 3 
420 mg 
Discontinue 
Discontinue 
Dose Reduction Level 4 
280 mg 
NA 
NA 
Dose Reduction Level 5 
Discontinue 
NA 
NA 
For required dose modification for hepatic impairment refer to Section 5.4.5 and for concomitant 
treatment with CYP3A inhibitors refer to Section 6.1.2.1. 
If ibrutinib or placebo is discontinued for toxicity, subject will end the Treatment Phase of the 
study. 
5.4.5. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant chronic 
hepatic impairment at the time of Screening (Child-Pugh class B or C) are excluded from study 
participation.  Refer to Appendix 10 for Child-Pugh classification. 
•
For subjects who develop mild liver impairment (Child-Pugh class A), the
recommended dose for ibrutinib or placebo is 280 mg daily (two capsules)
•
For subjects who develop moderate liver impairment (Child-Pugh class B), the
recommended dose is 140 mg daily (one capsule).
•
Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold
ibrutinib or placebo until resolved to moderate impairment (Child-Pugh class B) or


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better, and could be re-treated according to resolved hepatic conditions (ie, 140 mg or 
280 mg for moderate or mild impairment, respectively).   
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 5.4.4. 
5.5. 
Pomalidomide 
All subjects in both phases of this study will receive pomalidomide and will follow guidelines 
for pomalidomide dosing and toxicity management. 
Ex-US: Pomalidomide and Dexamethasone are considered standard of care for patients with  
Relapsed/Refractory Multiple Myeloma.  Pomalidomide and Dexamethasone as standard of care 
background therapy will be administered to all patients participating in this trial as per the EU 
guidelines.  Please reference Section 5.6 for additional information regarding Dexamethasone.  
5.5.1. 
Formulation, Packaging, and Storage of Pomalidomide 
Pomalidomide will be shipped to the pharmacy at the study site or to the subject directly in 
individual bottles or blister packs.  Bottles or blister packs will contain a sufficient number of 
capsules to last for one cycle of dosing.  Pomalidomide must be dispensed in the original 
packaging with the label clearly visible.  Only enough pomalidomide for 1 cycle of therapy 
may be provided to the subject each cycle. 
Pomalidomide will be available in strengths of 4 mg, 3 mg, 2 mg and 1 mg capsules and 
appropriate dose will be prescribed per protocol with modifications for toxicity.  
Ex-US: Commercially available Pomalidomide will be supplied as capsules for oral 
administration by Pharmacyclics LLC via Celgene Corporation.  The commercial material will 
be relabeled for clinical trial use. 
The Investigator or designee is responsible for taking an inventory of each shipment of 
pomalidomide received on the drug accountability form.   
Pomalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
5.5.2. 
Pomalidomide Prescribing Information (Applies to US/Canada Sites Only) 
Pomalidomide will be provided to research subjects in the US for the duration of their 
participation in this study through their insurance provider.  Pomalidomide  will be provided to 
research subjects in Canada for the duration of their participation in this study at no charge to 
them or their insurance providers.  Pomalidomide will be provided in accordance with the 
POMALYST REMS™ or RevAid® program of Celgene Corporation as appropriate for the 
country in which drug is being used.  Per standard POMALYST REMS™ or RevAid® program 
requirements, all physicians who prescribe pomalidomide for research subjects enrolled into this 
study, and all research subjects enrolled into this study, must be registered in and must comply 


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with all requirements of the POMALYST REMS™  or RevAid® program.  Prescriptions must be 
filled within 7 days for females of childbearing potential and 14 days for all other risk categories.  
Drug will be shipped on a per subject basis by the contract pharmacy to either the clinic site or 
the subject directly.  Only enough pomalidomide for one cycle of therapy will be supplied to the 
subject each cycle. 
5.5.3. 
Pomalidomide Drug Dispensing Requirements (Applies to Ex-US Sites Only) 
In investigational studies, pomalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to nurses, pharmacists and physicians).  These healthcare 
professionals will be trained by Celgene in requirements specific to counseling of subjects.  Each 
site is required to have two trained counselors at all times.  Once trained, these healthcare staff 
will counsel subjects prior to medication being dispensed to ensure that the subject has complied 
with all requirements including use of birth control and pregnancy testing (FCBP) and that the 
subject understands the risks associated with pomalidomide.  This step will be documented with 
a completed Education and Counseling Guidance Document (Appendix 8), and no drug will be 
dispensed until this step occurs.  Counseling includes verification with the subject that required 
pregnancy testing was performed and results were negative.  A pomalidomide Information Sheet 
(Appendix 8) will be supplied with each medication dispense. 
Pregnancy Testing 
Pregnancy tests for females of childbearing potential.  A FCBP is a female who: 1) has achieved 
menarche at some point; or 2) has not undergone a hysterectomy or bilateral oophorectomy; or 
3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule
out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in 
the preceding 24 consecutive months). 
Pregnancy tests must occur within 10–14 days and again within 24 hours prior to initiation of 
Cycle 1 of pomalidomide.  FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on pomalidomide therapy (including 
breaks in therapy); at discontinuation of pomalidomide and at Day 28 post the last dose of 
pomalidomide.  A FCBP with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on pomalidomide therapy (including breaks in 
therapy), at discontinuation of pomalidomide and at Day 14 and Day 28 post the last dose of 
pomalidomide (Appendix 8).  
Counseling 
All subjects must be counseled about pregnancy precautions, risks of fetal exposure and other 
risks.  The counseling must be done on Day 1 of each cycle (or at a minimum of every 28 days) 
throughout the entire duration of pomalidomide treatment, including dose interruptions, and at 
pomalidomide discontinuation.  The Education and Counseling Guidance Document must be 
completed by a trained counselor (Appendix 8). 


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5.5.4. 
Dosage, Preparation and Administration of Pomalidomide 
The first dose of pomalidomide will be administered orally in the clinic on Cycle 1 Day 1, of the 
Treatment Phase, after which pomalidomide will be self-administered daily by the subjects on 
Days 1-21 of each cycle. 
Pomalidomide will be dosed at the same time as ibrutinib or placebo and dexamethasone on the 
days of PK assessment. 
Pomalidomide can be taken with or without food and administered with water at approximately 
the same time each day.  The capsule should be swallowed intact and subjects should not attempt 
to chew capsules, open capsules or dissolve them in water.  Females of childbearing potential 
(FCBP) should not handle or administer pomalidomide unless they are wearing gloves. 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day.  If a 
dose is missed for the entire day, it should not be made up. 
Pomalidomide dosing during the Treatment Phase occurs on Days 1-21 each cycle followed by a 
mandatory 7-day drug-free interval.  If a Day 1 (of any Cycle) is delayed due to scheduling, 
instruct the subject that pomalidomide dosing should not be initiated until Day 1 assessments can 
occur. 
Treatment will continue until disease progression (confirmed by IRC for Phase 2b) or other 
reason for treatment discontinuation as outlined in Section 5.8.  
Dose modifications for toxicity are outlined in Section 5.4.5. 
For instructions regarding drug accountability and disposal/return of unused pomalidomide refer 
to the Pharmacy Manual.   
5.5.4.1. 
Required Concomitant Medications and Procedures 
For the current study, low-dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anti-coagulant will be given during the study to all subjects based upon risk 
assessed during the VTE assessment (refer to Appendix 11).  Choice of anticoagulant will be 
based upon investigator discretion (Appendix 11 is only provided as guidance ). 
Subjects who develop symptomatic DVT will be assessed and diagnosed objectively by Doppler 
ultrasonography or a comparable method.  
5.5.5. 
Dose Delay, Reduction or Discontinuation of Pomalidomide 
In order to initiate a new cycle of therapy with pomalidomide, the subject must have an ANC 
≥800/µL and a platelet count ≥30,000/µL and no pomalidomide related ≥ Grade 3 toxicity on 
Day 1.  If these two criteria are not met, a repeat assessment is to be performed at least weekly or 
more frequent per the Investigator’s decision.  The initiation of pomalidomide should be delayed 


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until the subject meets the above criteria at which time the subject will initiate drug without dose 
modification.   
If the treatment has been interrupted and the next cycle is delayed beyond 28 days after Day 1 of 
the prior cycle, then Day 1 of the next cycle will be defined as the first day that treatment is 
resumed. 
Once a cycle has initiated, if pomalidomide must be held for toxicity during dosing, omitted 
doses should not be made up and pomalidomide will not resume until Day 1 of the subsequent 
cycle, provided the subject meets the cycle initiation criteria above, with dose adjustments as per 
Table 4.   
Treatment with pomalidomide should be withheld for any potentially study drug-related 
non-hematological toxicity that is Grade 3 or higher in severity and any hematologic toxicity as 
described in Table 4.  In the event the subject is diagnosed with a thyroid condition, develops a 
rash or renal impairment (serum creatinine >3.0), refer to Table 4 for further instructions.   
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator should be discussed with the Medical Monitor. 
Pomalidomide may be withheld for a maximum of 28 consecutive days for toxicity.  
Pomalidomide treatment should be discontinued in the event of a pomalidomide related toxicity 
lasting more than 28 days, unless reviewed and approved by the Medical Monitor. 
5.5.6. 
Dose Modification of Pomalidomide During a Cycle  
The dose of pomalidomide should be modified according to the dose modification guidelines in 
Table 4 if any of the following toxicities occur: 
Table 4: 
Dose Modification or Interruption for Pomalidomide Toxicity During a 
Cycle 
Toxicity 
Intervention 
Neutropenia: 
• 
ANC <500/µL 
• 
Febrile neutropenia (ANC 
<1,000/µL with a single 
temperature of >38.3°C or a 
sustained temperature of ≥38°C for 
more than one hour) 
 
• 
Interrupt pomalidomide treatment for the remainder of the 
cycle 
• 
Reduce the dose of pomalidomide by one dose level 
(1 mg) at the start of the next cycle.  Do not initiate a new 
cycle until the subject meets cycle initiation criteria 
(see Section 5.5.5).  Do not dose below 1 mg daily. 


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Toxicity 
Intervention 
Thrombocytopenia: 
•
Grade 3 (decrease to <50,000/µL)
associated with Grade ≥2 bleeding, 
•
Grade 4 (decrease to <25,000/µL)
•
Interrupt pomalidomide treatment for the remainder of the
cycle
•
Reduce the dose of pomalidomide by one dose level
(1 mg) at the start of the next cycle.  Do not initiate a new
cycle until the subject meets cycle initiation criteria
(see Section 5.5.5).  Do not dose below 1 mg daily.
Rash: 
•
Grade 3 requiring the need for
intervention 
•
Interrupt pomalidomide treatment for the remainder of the
cycle.
•
Reduce the dose of pomalidomide by one dose level
(1 mg) at the start of the next cycle.  Do not initiate a new
cycle until the rash has resolved to ≤ Grade 1.
Rash: 
•
Any Grade desquamating
(blistering) 
•
Grade 4 non-blistering
•
Discontinue pomalidomide permanently
Constipation ≥ Grade 3 
•
Interrupt pomalidomide treatment for the remainder of the
cycle.  Initiate bowel regimen.
•
Reduce the dose of pomalidomide by one dose level
(1 mg) at the start of the next cycle.  Do not initiate a new 
cycle until the subject meets cycle initiation criteria
(see Section 5.5.5).  Do not dose below 1 mg daily.
Venous thromboembolism ≥ Grade 3 
•
Interrupt pomalidomide treatment for the remainder of the
cycle
•
Initiate therapeutic anticoagulation – see Section 6.1.2.4.
•
Resume pomalidomide without dose modification at the
start of the next cycle if the benefit of therapy on this
study outweighs the risk for bleeding.
Hypo/hyperthyroidism ≥ Grade 2 
•
Interrupt pomalidomide treatment for the remainder of the
cycle
•
Evaluate etiology and initiate appropriate therapy
•
Resume pomalidomide without dose modification at the
start of the next cycle at the discretion of the investigator. 
Do not initiate a new cycle until the subject meets cycle 
initiation criteria (see Section 5.5.5).
Serum creatinine >3.0 mg/dL 
•
Interrupt pomalidomide treatment.
•
Do not initiate a new cycle or resume treatment until the
serum creatinine is <3.0 mg/dL and resume without dose
modification.


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Toxicity 
Intervention 
Any other Grade 3/4 non-hematologic 
toxicities attributed to pomalidomide 
• 
Interrupt pomalidomide treatment for the remainder of the 
cycle. 
• 
Reduce the dose of pomalidomide by one dose level 
(1 mg) at the start of the next cycle.  Do not initiate a new 
cycle until the patient meets cycle initiation criteria 
(see Section 5.5.5).  Do not dose below 1 mg daily. 
 
Table 5: 
Dose Reduction of Pomalidomide 
Starting Dose Level 
4 mg 
Dose Reduction 1 
3 mg 
Dose Reduction 2 
2 mg 
Dose Reduction 3 
1 mg 
Dose Reduction 4 
Discontinue 
5.6. 
Dexamethasone 
All subjects in both phases of this study will receive dexamethasone and will follow guidelines 
for dexamethasone dosing and toxicity management. 
5.6.1. 
Formulation, Packaging, and Storage of Dexamethasone 
Dexamethasone tablets for oral administration are scored and available in multiple strengths.  
Store at 20° to 25°C.  Protect from moisture and light. 
US:  Commercially available Dexamethasone will be prescribed locally as standard of care. 
Ex-US: Commercially available Dexamethasone will be supplied by Pharmacyclics LLC.  
The commercial material will be relabeled for clinical trial use. 
5.6.2. 
Dosage and Administration of Dexamethasone 
The first dose of dexamethasone will be administered orally in the clinic on Day 1 of Cycle 1, of 
the Treatment Phase.  Dexamethasone will be administered once weekly ±2 days on Days 1, 8, 
15, and 22.  If at any time pomalidomide is discontinued due to toxicity, dosing with 
dexamethasone can continue in the absence of dexamethasone related toxicity.  
If the subject misses a dose, it can be taken as soon as possible on the same day or the following 
day with a return to the normal schedule.  If dexamethasone dosing requires a schedule 
adjustment of more than ±2 days contact the medical monitor to discuss. 
Treatment will continue until disease progression (confirmed by IRC for Phase 2b) or other 
reason for treatment discontinuation as outlined in Section 5.8.  


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Dose modifications for toxicity are outlined in Section 5.6.3.  
5.6.3. 
Dose Modification of Dexamethasone 
Treatment with dexamethasone should be withheld for any unmanageable Grade ≥3 
dexamethasone related toxicity and may be reduced for unmanageable Grade 2 toxicity.  
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator should be discussed with the Medical Monitor. 
Dexamethasone may be withheld for a maximum of 28 consecutive days for toxicity.  
Dexamethasone should be discontinued in the event of a toxicity lasting more than 28 days, 
unless reviewed and approved by the Medical Monitor. 
Table 6: 
Dose Modification of Dexamethasone 
 
≤75 years old 
>75 years old 
Starting Dose Level 
40 mg 
20 mg 
Dose Reduction 1 
20 mg 
12 mg 
Dose Reduction 2 
8 mg 
8 mg 
Dose Reduction 3 
Discontinue 
Discontinue 
5.7. 
Overdose Instructions 
5.7.1. 
Ibrutinib or Placebo 
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 11.2.1 for further information regarding special reporting situations as a result 
of overdose.  
5.7.2. 
Pomalidomide 
No specific information is available on the treatment of overdose with pomalidomide, and it is 
unknown whether pomalidomide or its metabolites are dialyzable.   
Patients who take more than the prescribed dose of pomalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 


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5.7.3. 
Dexamethasone 
In the event of an overdose, subjects should be closely monitored and given appropriate 
supportive treatment. In the case of acute overdosage, according to the subject’s condition, 
supportive therapy may include gastric lavage or emesis.   
5.8. 
Criteria for Permanent Discontinuation of Study Treatment 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless disease progression (confirmed by IRC for Phase 2b), 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. 
An EOT Visit (Section 8.3.12) is required for all subjects except for those subjects who have 
withdrawn full consent (see Section 9.3). 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
6.1. 
Concomitant Medications 
6.1.1. 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. 
Usage of antimicrobial prophylaxis in accordance with standard practice (eg, ASCO 
guidelines [Flowers 2013]) is permitted and should be considered in subjects who are at 
increased risk for opportunistic infections.   
Erythropoietic growth factors (eg, erythropoietin) and hematopoietic growth factors are allowed 
per institutional policy and in accordance with the ASCO guidelines (Smith 2006).  
Transfusional support (packed red blood cells and platelets) may be given in accordance with 
institutional policy.  The use of myeloid growth factors is encouraged when ANC is less than 
800/μL at the discretion of the treating physician.  Primary prophylaxis for the prevention of 
neutropenia is highly recommended in subjects who are at high risk based on age, medical 
history and disease characteristics.  In Phase 1: Erythropoietic and hematopoietic growth factors 
as well as transfusional support (platelets) should not be given during the DLT assessment 
window, but is permitted at the Investigator’s discretion if a subject experiences a hematologic 
DLT as per the criteria outlined. 
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 are 


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clinically indicated are permitted in addition to those administered as study treatment per 
protocol.   
6.1.2. 
Medications to be Used with Caution 
6.1.2.1. 
CYP3A Inhibitors/Inducers 
Ibrutinib 
Ibrutinib is metabolized primarily by CYP3A4.  Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure and therefore strong 
CYP3A inhibitors should be avoided.  
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, cobicistat, and 
posaconazole) must be used, reduce ibrutinib or placebo dose to 140 mg for the duration 
of the inhibitor use or withhold treatment temporarily (for 7 days or less).  Subjects 
should be monitored for signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, fluconazole, voriconazole, erythromycin, 
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, 
imatinib, verapamil, amiodarone, and dronedarone) is indicated, reduce ibrutinib or 
placebo to 280 mg for those subjects receiving 840 mg and to 140 mg for those subjects 
receiving doses below 840 mg for the duration of the inhibitor use.  
• 
No dose adjustment is required in combination with mild inhibitors.   
• 
Avoid grapefruit and Seville oranges during ibrutinib or placebo treatment, as these 
contain moderate inhibitors of CYP3A. 
Avoid concomitant use of systemic strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort).  Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix 5; for further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/.  
This website is continually revised and should be checked frequently for updates. 
Pomalidomide 
Pomalidomide is primarily metabolized by CYP1A2 and CYP3A.  Pomalidomide is also a 
substrate for P-glycoprotein (P-gp).  Pomalidomide exposure is increased when the drug is 
co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong 
CYP3A4/5 and P-gp inhibitor (ketoconazole).  Ketoconazole in the absence of a CYP1A2 
inhibitor does not increase pomalidomide exposure.  Avoid co-administration of strong CYP1A2 
inhibitors (e.g. ciprofloxacin and fluvoxamine).  If it is medically necessary to co-administer 
strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, 
pomalidomide dose should be reduced by 50%.  The effect of a CYP1A2 inhibitor in the absence 
of a co-administered CYP3A4 and P-gp inhibitor has not been studied.  Monitor for toxicities if 


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CYP1A2 inhibitors are to be coadministered in the absence of a co-administered CYP3A4 and  
P-gp inhibitor, and reduce dose if needed. 
Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction.  Patients 
should be advised that smoking may reduce the efficacy of pomalidomide.   
Co-administration of pomalidomide with drugs that are CYP1A2 inducers has not been studied 
and may reduce pomalidomide exposure. 
A comprehensive list of CYP1A2 inhibitors, inducers and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This website is continually revised and 
should be checked frequently for updates. 
6.1.2.2. 
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 or placebo.  
6.1.2.3. 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be avoided unless deemed medically 
necessary.  If there is no therapeutic alternative, these medications should be used with caution; 
periodic Electrocardiogram (ECG) and electrolyte monitoring should be considered.  
A comprehensive list of medications know to interfere with the QT interval may be found at 
www.QTdrugs.org (refer to Appendix 6).  This website is continually revised and should be 
checked frequently for updates. 
6.1.2.4. 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
Use ibrutinib or placebo with caution in subjects requiring anticoagulants or medications that 
inhibit platelet function.  In an in vitro platelet function study, inhibitory effects of ibrutinib on 
collagen-induced platelet aggregation were observed. Supplements such as fish oil and vitamin E 
preparations should be avoided during treatment with ibrutinib. Bleeding events of any grade, 
including bruising and petechiae, occurred in subjects treated with ibrutinib.  Subjects with 
congenital bleeding diathesis have not been studied.  Ibrutinib or placebo should be held at least 
3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding 
(see Section 6.2). 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation) 
should be monitored closely for signs and symptoms of bleeding and the risks and benefits of 
continuing ibrutinib treatment should be considered.     


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6.1.3. 
Prohibited Concomitant Medications 
Any non-study protocol related chemotherapy, anti-cancer immunotherapy or experimental 
therapy is prohibited while the subject is receiving study treatment.  Localized, hormonal, or 
bone sparing treatment for non-B-cell malignancies may be considered with approval of the 
Medical Monitor. 
The need for radiation therapy is considered to be a treatment failure.  However, an exception 
(that is, subjects allowed to remain in the treatment phase of the study) is made for radiation 
therapy to a pathological fracture site to enhance bone healing or to treat post-fracture pain that is 
refractory to narcotic analgesics because pathologic bone fractures do not by themselves fulfill a 
criterion for disease progression.  
The Sponsor should be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.2. 
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 peri-operative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib or placebo:   
6.2.1. 
Minor Procedures 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib or placebo should be held 
for at least 3 days prior to the procedure and should not be restarted for at least 3 days after the 
procedure.  For bone marrow biopsies that are performed while the subject is on ibrutinib or 
placebo, it is not necessary to hold ibrutinib or placebo for these procedures.   
6.2.2. 
Major Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib or 
placebo should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure and restarted at the discretion of the investigator when the surgical site is 
reasonably healed without serosanguineous drainage or the need for drainage tubes.   
6.2.3. 
Emergency Procedures 
For emergency procedures, ibrutinib or placebo 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. 


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7.
STUDY EVALUATIONS
7.1. 
Screening/Administrative 
All clinical screening assessments and routine laboratory must be performed within 28 days of 
the first administration of study drug. 
7.1.1. 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved ICF confirming his or her 
willingness to participate in this study before any study-specific screening procedures are 
performed.  Subjects in the US must also grant permission to use protected health information 
per the Health Insurance Portability and Accountability Act (HIPAA).  In addition, subjects must 
sign all approved ICF amendments per the site IRB/REB/IEC guidelines during the course of the 
study.  
7.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4).  Study site personnel 
will submit the Eligibility Worksheet to the Medical Monitor or Sponsor designee for approval to 
proceed with enrollment/randomization. 
7.1.3. 
Medical History and Demographics 
The subject’s relevant history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis and list of 
all prior anti-cancer treatments, dates administered, and responses to these treatments, will be 
recorded.  In addition, all prior venous thromboembolic events (VTE) and pulmonary embolisms 
(PE) that occurred will be collected as part of relevant medical history. 
7.1.4. 
Venous Thromboembolism (VTE) Risk Assessment 
The subject’s risk for development of VTE will be assessed at Screening and anytime thereafter.  
General risk factors for subjects with cancer include, but are not limited to: underlying disease, 
family history, age, obesity, immobilization, hormonal therapy, central venous catheter, recent 
DVT, gender, renal dysfunction and certain chemotherapy based regimens (Refer to 
Appendix 11 for guidance).  Clinical studies have shown that there is an increased risk of VTE 
with the use of immunomodulatory agents. 
For this study, low-dose aspirin, low molecular weight heparin or other equivalent 
antithrombotic or anti-coagulant will be given to all subjects and determined by the investigator 
following VTE risk assessment (refer to Appendix 11 for guidance).  Refer to Table 4 for dose 
modification in the event a VTE occurs while on treatment. 


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7.1.5. 
Prior and Concomitant Medications 
All medications from the signing of  ICF, or at least 14 days prior to first dose, through 30 days 
after the last dose of study treatment will be documented.  After a subject discontinues study 
treatment, the first subsequent anti-cancer therapy will be collected. 
7.1.6. 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 11.1.  The occurrence of an 
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 treatment until 30 days after 
the last dose of study treatment that meet the AE definition must be recorded as AEs in the 
eCRF.  Laboratory abnormalities or changes in vital signs designated as clinically significant by 
the Investigator will also be documentedas AEs.  Additional important requirements for AE and 
SAE reporting are explained in Section 11.2. 
7.2. 
Assessments 
7.2.1. 
Eye-related Symptom Assessment 
The subjects will be asked about eye-related symptoms at Screening and with all subsequent 
physical exams while on treatment. 
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subjects 
develop any eye-related symptoms of severity Grade ≥2 while on study treatment, an 
ophthalmologic evaluation/consult must be performed and the outcome must be reported on the 
ophthalmologic eCRF.  
7.2.2. 
Physical Examination, Height, and Weight 
The physical examination for Screening, Day 1 of every Cycle, Suspected PD or CR, and EOT 
visits will include, at a minimum, the general appearance of the subject, height (Screening Visit 
only, may use historical 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. 
A limited symptom-directed physical examination, including weight may be performed at all 
other time points.  Refer to Schedule of Assessments (Appendix 1). 
7.2.3. 
Venous Thromboembolism (VTE) Monitoring 
Clinical review of sign/symptoms for possible VTEs will be performed at every scheduled visit 
during study treatment, and at EOT.  Subjects who develop symptomatic DVT will be assessed 
and diagnosed objectively by Doppler ultrasonography or a comparable method per institutions 
standard of care.   


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7.2.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG performance index is found in Appendix 2.  The ECOG performance status will be 
assessed at time points specified in the Schedule of Assessments (Appendix 1).   
7.2.5. 
Vital Signs 
Vital signs will include blood pressure, heart rate, and body temperature and will be assessed at 
time points specified in the Schedule of Assessments (Appendix 1).  
7.2.6. 
Patient-Reported Outcome (PRO) Assessment (Phase 2b only) 
The PRO instruments, EQ-5D-5L and EORTC QLQ-MY20 (Appendix 12 and Appendix 13), 
will be administered in this study on Day 1 of Cycle 1 and every other cycle thereafter 
(eg, Cycle 3, Cycle 5, etc.), as well as at Suspected PD, EOT, and Follow-up visits (including a 
minimum of 18 months of  Long-Term Follow-up visits following IRC confirmed PD).  It is 
preferable that questionnaires be administered at the beginning of each visit prior to any 
procedures or physician assessments according to the Schedule of Assessments (Appendix 1).  
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome consisting of 
a 5-item questionnaire and a “thermometer” visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state) (EuroQol Group 1990).  The scores 
for the 5 separate questionnaires are categorical and should not be analyzed as cardinal numbers.  
The scores for the 5 dimensions are normalized to a single utility score ranging from 0 to 1, 
representing the general health status of the individual.  The United Kingdom weights will be 
used to generate patient utilities from the 5 dimensions of the EQ-5D-5L in this 
study (Appendix 12).  
The EORTC QLQ-MY20 (Appendix 13) is a 20-item questionnaire to assess the quality of life 
in MM patients (Stead 1999; Cocks 2007). 
7.2.7. 
Follow-up for Other Malignancies 
Occurrences of any new malignant tumors including solid tumors, skin malignancies and 
hematologic malignancies will be reported throughout study participation, including duration of 
study treatment and during any protocol specified follow-up periods including post-progression 
follow-up for overall survival, refer to Section 11.2.3. 
7.3. 
Clinical Laboratory Assessments 
7.3.1. 
Hematology 
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils 
and bands (if reported).  See time points specified in the Schedule of Assessments (Appendix 1).  
All assessments will be performed by the local laboratory. 


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7.3.2. 
Serum Chemistry 
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, LDH, phosphate, uric acid, magnesium.  See time points specified in 
the Schedule of Assessments (Appendix 1).  All assessments will be performed by the local 
laboratory. 
7.3.3. 
Creatinine Clearance 
Creatinine clearance will be calculated using either the Cockcroft-Gault method OR as measured 
by 24 hour urine collection (Appendix 3).  See time points specified in the Schedule of 
Assessments (Appendix 1). 
7.3.4. 
Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening.  All assessments will be performed by the local laboratory. 
In addition, assessments for those subjects on anticoagulation will be performed per investigator 
discretion according to local standard of care practices.   
7.3.5. 
Hepatitis Serologies 
Hepatitis serologies including Hepatitis C antibody, Hepatitis B surface antigen, and Hepatitis B 
core antibody will be evaluated at Screening.  If Hepatitis B core antibody, Hepatitis B surface 
antigen or Hepatitis C antibody is positive, then PCR to quantitate Hepatitis B/C must be 
performed and must be negative prior to randomization/enrollment.  Hepatitis Serologies will be 
analyzed by the local laboratory. 
7.3.6. 
Thyroid Function 
Thyroid stimulating hormone (TSH) will be used to evaluate thyroid function.  If abnormal, 
further testing should be performed as clinically appropriate.  Testing will be performed at 
Screening and at EOT visits by local laboratory.  Testing at additional time points may be 
performed at the Investigator’s discretion. 
7.3.7. 
Pregnancy Test 
A pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be done in accordance 
with Celgene Corporation’s POMALYST REMS™ program, RevAid® program, or global 
Pregnancy Prevention Program (PPP) guidelines for FCBP only (refer to Sections 5.5.2 and 
5.5.3).  If the pregnancy test is positive at Screening, the subject is not eligible.   
A FCBP is a female who: 1) has achieved menarche at some point; or 2) has not undergone a 
hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).  


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Pregnancy tests must occur within 10–14 days and again within 24 hours prior to initiation of 
Cycle 1 of pomalidomide.  A FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on pomalidomide therapy (including 
breaks in therapy); at discontinuation of pomalidomide and at Day 28 post the last dose of 
pomalidomide.  A FCBP with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on pomalidomide therapy (including breaks in 
therapy), at discontinuation of pomalidomide and at Day 14 and Day 28 following pomalidomide 
discontinuation.  
In order to allow for drug delivery in the US, pregnancy testing should be performed during 
Days 22-28 of each cycle.  A pregnancy test may be performed more frequently if required by 
local and national requirements. 
7.4. 
Diagnostic/Procedures 
7.4.1. 
Electrocardiogram 
Triplicate 12-lead ECGs will be taken (≥1 minute apart) at Screening only.  The ECGs should be 
performed prior to any blood samples being collected.  Any clinically significant abnormalities 
noted at Screening should be included in the medical history.  A single ECG tracing will be 
performed at Cycle 2 Day 1 and the EOT visit, and as clinically indicated. 
7.5. 
Efficacy Assessments 
Efficacy assessments will be performed every four weeks after the initiation of study treatment.  
Response assessments will be performed every four weeks and will be based upon the IMWG 
Response Criteria (Rajkumar 2011, refer to Appendix 7).  In Phase 1 assessments will be 
performed locally, in Phase 2b assessments will be performed by a central laboratory. 
All screening and Cycle 1 Day 1 efficacy assessments will include quantitative 
immunoglobulins, serum and urine electrophoresis, serum and urine immunofixation, and serum 
free light chain assay. 
After Cycle 1 Day 1 assessment, SPEP and UPEP (if measureable), and other parameters, as 
applicable, according to the IMWG response criteria will be measured and followed.  
At the Investigator’s discretion additional evaluations may be performed according to standard of 
care but they are not to be used for response assessment. 
If at any time CR is suspected, all assessment including quantitative immunoglobulins, serum 
protein electrophoresis and immunofixation, urine protein electrophoresis and immunofixation, 
serum free light chain, radiographic imaging (if applicable) and bone marrow biopsy 
(see Section 7.5.7) must be performed as per the IMWG response assessment guidelines. 
Any suspected case of disease progression should be reported to the Sponsor within 24 hours of 
awareness.  If disease progression is suspected solely based on the results of a single examination 


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or a single laboratory parameter (eg, SPEP or UPEP), this finding should be confirmed by a 
subsequent evaluation within no more than 4 weeks from the first finding.  Additional 
assessments should be performed at the discretion of the treating physician to confirm 
progressive disease if indicated (eg, radiographic imaging).  
In general, subjects should continue study treatment until progression is confirmed by a serial 
examination within 4 weeks from the first finding and confirmation by the IRC (Phase 2b).  
When disease progression has been confirmed (by the IRC for Phase 2b), study treatment should 
be withheld.  Following confirmed disease progression, subjects should continue to adhere to all 
other study-related procedures.  Whenever possible, subsequent anti-cancer therapy should be 
withheld until confirmed disease progression by the IRC for Phase 2b.  
7.5.1. 
Serum and Urine Protein Electrophoresis 
Samples will be collected at Screening, and prior to study treatment administration on Day 1 of 
Cycle 1.  Additional sample collection will occur every four weeks from first dose of study 
treatment per Section 7.5.  Refer to the Schedule of Assessments for additional timepoints 
(Appendix 1).  Samples will be analyzed centrally for Phase 2b. 
7.5.2. 
Serum Free Light Chain Assay 
Samples will be collected at Screening, and prior to study treatment administration on Day 1 of 
Cycle 1.  Additional sample collection on study is only required to confirm CR (conducted on 
the first observation that the subject has detectable M-protein) and then repeated at each 
subsequent assessment until disease progression per Section 7.5.  Refer to the Schedule of 
Assessments for additional timepoints (Appendix 1).  Samples will be analyzed centrally for 
Phase 2b.   
7.5.3. 
Serum and Urine Immunofixation 
Samples will be collected at Screening and prior to treatment administration on Day 1 of 
Cycle 1.  Repetitive serum and urine immunofixation on study is only required to confirm CR 
(conducted on the first observation that the subject has no detectable M-protein) and then 
repeated at each subsequent assessment until disease progression. Refer to the Schedule of 
Assessments for additional timepoints (Appendix 1).  Samples will be analyzed centrally for 
Phase 2b. 
7.5.4. 
Quantitative Serum Immunoglobulins 
Samples for serum immunoglobulins IgA, IgG and IgM will be collected at Screening, prior to 
study treatment administration on Day 1 of Cycle 1.  Additional sample collection will occur 
every four weeks from first dose of study treatment.  If clinically indicated, serum 
immunoglobulin IgD or IgE should also be collected at timepoints specified above.  Refer to the 
Schedule of Assessments for additional timepoints (Appendix 1).  Samples will be analyzed 
centrally for Phase 2b. 


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7.5.5. 
C-Reactive Protein and Serum β2-microglobulin 
Samples will be collected at Cycle 1, Day 1 only.  Samples will be analyzed centrally for 
Phase 2b. 
7.5.6. 
Bone Radiologic Assessment 
Skeletal Survey or Low-Dose Whole-Body CT Scan  
A radiologic assessment for evaluation of bone lesions is required.  Either a low-dose 
whole-body CT scan or a radiological skeletal survey including a lateral radiograph of the skull, 
antero-posterior and lateral views of the spine, and antero-posterior views of the pelvis, ribs, 
femora, and humeri will be performed.  Radiological assessment is to be done within 50 days 
prior to the first administration of study treatment.  Additional radiologic assessments may be 
performed at any time during the study, as determined necessary by the investigator.  
Plasmacytoma Evaluation 
Magnetic resonance imaging (MRI), computed tomography (CT) or positron emission 
tomography (PET)/CT scans are to be performed as clinically indicated.  If evidence of 
plasmacytoma noted on radiographic imaging at Screening, subsequent response assessments 
must include follow-up studies using the same imaging modality every 3 months. 
7.5.7. 
Bone Marrow Aspirate and Biopsy 
A unilateral bone marrow aspirate and biopsy will be obtained at Screening and submitted to a 
local laboratory to evaluate for morphology and document bone marrow involvement.  Subjects 
who have had a bone marrow biopsy within 90 days of first administration of study treatment 
may use those bone marrow results in lieu of the baseline bone marrow biopsy required for the 
study, however, the bone marrow aspirate will be required within 28 days of first administration 
of study treatment.     
Phase 1 Only: In addition, the screening bone marrow sample should have fluorescence in-situ 
hybridization (FISH) analysis performed locally.  The analysis should include at a minimum 
assessment of del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 (copy number) status, and should 
preferably also include 13q14 status (NCCN, version 4 2015).  FISH analysis should preferably 
be performed on samples that have been enriched for plasma cells (PCs).  If the FISH analysis 
has been performed within 90 days prior to the first administration of study treatment and 
includes all probes, it does not need to be repeated.  Any probes not analyzed per protocol within 
90 days of first administration of study treatment should be assessed during screening.  
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the Investigator’s Form FDA 1572.  De-identified copies of all FISH results must be provided 
to the Sponsor.  
If the subject’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved, an additional bone marrow aspirate and biopsy 


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should be obtained to confirm the CR.  Bone marrow for confirmation of CR should include 
staining for CD138 and κ/λ mono-clonality by immunohistochemistry (IHC) or 
immunofluorescence and will be assessed locally.  
Additional samples of bone marrow aspirate (6 mL) will be collected for biomarkers and other 
exploratory evaluations and submitted to a central lab at Screening and, if performed, at the time 
of CR and following confirmed PD (may be done at EOT or prior to a new anti-cancer therapy) 
(Section 7.6.2.1).  
Phase 2b: FISH will be performed by central laboratory using the bone marrow aspirate collected 
at Screening.  
7.6. 
Biomarker, Correlative and Special Studies 
7.6.1. 
Pharmacokinetics  
During treatment with ibrutinib or placebo in combination with pomalidomide and 
dexamethasone plasma concentrations of ibrutinib (PCI-32765), its metabolite PCI-45227 and 
pomalidomide will be determined using a validated analytical method on all patients in both 
Phase 1 and 2b.  Other potential metabolites of ibrutinib may be explored.  Plasma 
concentrations for 4-β-hydroxycholesterol, a marker of CYP3A induction, will be determined 
using a validated analytical method at time points specified in Table 7 below.  
Refer to the Schedule of Assessments (Appendix 1) and the Pharmacokinetic Sample 
Schedule (Table 7). 
 
Table 7: 
Pharmacokinetic Sample Schedule for Ibrutinib or Placebo and 
Pomalidomide with Dexamethasone 
Cycle 
Day 
Predoseb 
Time after ibrutinib or placebo and pomalidomide with 
dexamethasone dosinga 
1 hour 
(1h ± 15 min) 
2 hour  
(2 h ± 15 min) 
4 hour  
(4 h ± 30 min) 
6 hour 
(5 h to 8h) 
Screening 
NA 
W 
 
 
 
 
1 
15 
X, W 
X 
X 
X 
X, W 
2 
15 
X, W 
X 
X 
X 
X, W 
W= Additional samples will be collected at Screening and following time-points in relation to dexamethasone 
dosing described in the table for the analysis of 4-β-hydroxycholesterol (CYP3A induction marker) 
X = Pharmacokinetics timepoint for ibrutinib/placebo and pomalidomide 
a. 
Ibrutinib or placebo will be dosed at the same time as pomalidomide and dexamethasone. 
b. 
Samples for ibrutinib or placebo, pomalidomide, and 4-β-hydroxycholesterol should be collected 
approximately 24 (± 2 h) hours after previous study dose and approximately 30-60 minutes before ibrutinib 
or placebo, pomalidomide and dexamethasone administration.  
Refer to the Laboratory Manual for instructions on collecting and processing PK samples.  
On the day of the sampling visit, the clinical staff will instruct the subject to not take ibrutinib or 


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placebo, pomalidomide or dexamethasone before arrival at the clinic.  All three study drugs will 
be brought to the clinic and intake will be observed by clinic staff and time of last meal prior to 
administration of study treatment on Cycle 1 Day 15 and Cycle 2 Day 15 will be recorded. It is 
recommended that the clinical staff make reasonable effort with regards to subject dosing 
instructions during Cycles 1 and 2 to ensure appropriate collection times of the PK samples.  
The actual time (versus requested time) that each PK sample is drawn must be recorded using a 
24 hour format.   
7.6.2. 
Biomarkers 
7.6.2.1. 
Genetic and Molecular Prognostic Markers 
Cytokines, chemokines, bone metabolism biomarkers, and exploratory investigations of 
predictive biomarkers and mechanisms of resistance will be tested in blood and bone marrow. 
Serum CTX will be collected at Screening.  Samples will be collected on Day 1 of Cycle 1, and 
on Day 1 of every even Cycle, Suspected Disease Progression and EOT, and submitted to a 
central lab (refer to Appendix 1).  Testing will include (T/B/NK immunophenotyping, serum 
CTX) and other secreted proteins.  Serum CTX collection will require 12 hour fasting prior to 
collection.  Testing will be performed at a central laboratory.  Samples will be collected from all 
subjects.  
Samples may be tested to evaluate potential biomarkers related to disease response and 
investigate potential mechanisms of treatment resistance.  These samples may be characterized 
by technologies such as gene expression profiling, targeted sequencing for genomic alterations, 
and intracellular signaling pathway analysis.  Inhibition of BTK and other related kinases may 
also be explored.  These efforts may identify genes and pathways associated with primary or 
later development of resistance to ibrutinib and potentially identify biomarkers that could assist 
with future development of this compound.  Pharmacodynamic assays, (ie, BTK occupancy) may 
be performed to correlate results of biomarker assessments to the physiological effects of 
ibrutinib. 
7.6.3. 
T/B/NK Cell Count (Phase 1 Only) 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected predose at the time points specified in the Schedule of Assessments (Appendix 1.). 
7.7. 
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) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 


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7.8. 
Survival and Subsequent Anti-cancer Therapies 
7.8.1. 
Survival 
After disease progression, subjects will be contacted to assess survival status every 
12 weeks (± 14 days) from EOT Visit until death, subject withdrawal of full consent, lost to 
follow-up or study termination by Sponsor, whichever comes first.  At the time of the analysis 
and at study closure, a survival sweep will be conducted.  All subjects who are not known to 
have died or withdrawn consent prior to survival sweep will be contacted at that time. 
7.8.2. 
Subsequent Anti-cancer Therapies 
After study treatment is complete, the following information will be collected for the first 
subsequent anti-cancer therapy: 
• 
Receipt of first subsequent anti-cancer therapy 
• 
Indication for initiation of subsequent anti-cancer therapy  
Please Note:  If new anti-cancer treatment is initiated prior to IRC confirmed disease 
progression (for Phase 2b), Response Follow-up visits must continue to occur every 4 weeks 
(±3 days) following the End-of -Treatment visit per protocol. 
8. 
STUDY PROCEDURES 
8.1. 
Overview 
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase.  
The Schedule of Assessments (Appendix 1) summarizes the frequency and timing of efficacy, 
PK, biomarker, and safety measurements applicable to this study.  All subjects enrolled will 
undergo the same study procedures throughout the study unless otherwise noted. 
8.2. 
Screening Phase 
Screening procedures will be performed up to 28 days before Cycle 1, Day 1.  All subjects must 
first read, understand, and sign the IRB/IEC-approved ICF before any study-specific screening 
procedures are performed.  After signing the ICF, screening and being deemed eligible for entry, 
subjects will be enrolled/randomized in the study. 
8.2.1. 
Screening Visit 
The following procedures will be performed at the Screening Visit within 28 days prior to 
treatment unless otherwise noted: 
• 
Relevant medical history including demographic information 
• 
Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs  
• 
Record AEs since signing of the ICF 
• 
Perform a complete physical examination, including height and weight 


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• 
Eye-related symptom assessment  
• 
Evaluation of ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Obtain triplicate 12-lead ECG (≥1 minute apart) 
• 
Imaging by CT, MRI or PET/CT (if applicable) 
• 
Bone radiological assessment (may be performed within 50 days of C1D1) 
• 
Bone marrow biopsy and aspirate for FISH analysis (if not performed within 90 days 
prior to first dose of study drug) 
o An additional 6 mL to be sent to central lab for biomarker assessment 
(Section 7.5.7) 
• 
Venous thromboembolism (VTE) risk assessment 
• 
Obtain blood specimens for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation studies (PT/INR, aPTT) 
o Hepatitis serologies  
o Thyroid function (TSH)  
o Serum and urine protein electrophoresis (SPEP and UPEP) 
o Serum free light chain assay (sFLC) 
o Serum and urine immunofixation 
o Quantitative serum immunoglobulins (IgA, IgG, IgM and if clinically indicated, IgD 
or IgE) 
o Pharmacokinetic sample for 4-β-hydroxycholesterol  
o Serum CTX (requires 12 hour fasting) 
• 
Obtain urine or serum pregnancy test for women of childbearing potential within  
10–14 days prior to initiation of Cycle 1 of pomalidomide according to Section 7.3.7.  
• 
Creatinine clearance  
• 
Review inclusion and exclusion criteria to confirm subject eligibility 
• 
Pomalidomide counseling 
8.3. 
Treatment Phase 
Phase 1 
Initiation of study treatment should occur within 28 days of consenting and Screening 
procedures, following approval by the Sponsor’s medical monitor.  If laboratory tests are 
required to be collected on Cycle 1 Day 1, subject must continue to satisfy all eligibility criteria 
to begin treatment. 


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Phase 2b 
Following completion of the Screening Visit and once eligibility has been confirmed for 
treatment Arm A or Arm B, subjects will be randomized via an automatic IWRS or alternative 
system provided by the Sponsor.  Randomization should occur as close to the time of the 
expected first dose as possible, i.e. not more than 3 days prior to expected first dose with study 
drug.  Subjects considered refractory to pomalidomide and dexamethasone (refer to 
Sections 4.1.1 and 4.2.1) may be enrolled in Arm C via IWRS and receive ibrutinib in 
combination with pomalidomide and dexamethasone if the eligibility criteria as specified in 
Section 4 are satisfied. 
Study drug treatment with ibrutinib or placebo in combination with pomalidomide and 
dexamethasone should be continued until IRC confirmed disease progression, unacceptable 
treatment-related toxicity, or other reasons outlined in Section 9.2.  Local safety labs will be used 
to guide all dosing-related decisions.  In the event of clinically suspected disease progression, the 
subject should continue to receive study medication until disease progression is confirmed by the 
IRC, at the discretion of the Investigator.  
Refer to the Schedule of Assessments (Appendix 1) for a complete list of procedures to be 
performed at each scheduled study visit. 
8.3.1. 
Cycle 1, Day 1 
Subjects who are deemed eligible will return to the clinic on Cycle 1, Day 1.  Safety laboratory 
assessments performed within 48 hours prior to the first dose of study drug may be used for 
dosing.   
Pre-dose 
• 
PRO assessments (Phase 2b only)- preferable to be performed prior to any assessments 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology (C1D1 testing not required if done within 48 hours prior to the first 
dose of study drug) 
o Serum chemistry (C1D1 testing not required if done within 48 hours prior to the 
first dose of study drug) 
o SPEP/UPEP 
o Serum free light chain assay (sFLC) 
o Serum and urine immunofixation 


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o Quantitative Immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o T/B/NK cell counts  
o Biomarkers including Serum CTX (requires 12 hour fasting)  
o C-Reactive Protein and Serum β2-microglobulin 
• 
Review of AEs and concomitant medications 
• 
Obtain urine or serum pregnancy test for women of childbearing potential within 24 
hours prior to initiation of Cycle 1 of pomalidomide according to Section 7.3.7.  
• 
Review inclusion and exclusion criteria to confirm subject eligibility prior to dosing 
• 
Pomalidomide counseling 
Dosing and Postdose 
• 
Dispense ibrutinib (ibrutinib or placebo for Phase 2b) and pomalidomide 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone   
• 
Review of AEs and concomitant medications  
8.3.2. 
Cycle 1, Day 8 
Predose  
• 
Symptom directed physical exam including weight 
• 
VTE monitoring 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology  
• 
Review of AEs and concomitant medications  
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7. 
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone 
8.3.3. 
Cycle 1, Day 15 
Predose  
• 
Symptom directed physical exam including weight 
• 
VTE monitoring 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature) after  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 


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o Collect predose PK sample for ibrutinib and pomalidomide 
o Collect blood sample for 4-β-hydroxycholesterol before dexamethasone 
administration 
• 
Review of AEs and concomitant medications  
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7. 
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone 
• 
Blood sample collection for ibrutinib (ibrutinib or placebo for Phase 2b) and 
pomalidomide PK and 4-β-hydroxycholesterol (times from study drug dose): 
o 1 hour after dosing (for ibrutinib and pomalidomide PK) 
o 2 hours after dosing (for ibrutinib and pomalidomide PK) 
o 4 hours after dosing (for ibrutinib and pomalidomide PK) 
o 6 hours (window 5 to 8 hours) after dosing (for ibrutinib and pomalidomide PK and 
4-β-hydroxycholesterol) 
8.3.4. 
Cycle 1, Day 22 
Predose  
• 
Symptom directed physical exam including weight  
• 
VTE monitoring 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
• 
Review of AEs and concomitant medications  
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7. 
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b) and dexamethasone 
8.3.5. 
Cycle 2, Day 1 
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  


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• 
12-lead single ECG  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy Assessments as applicable per Section 7.5 
o T/B/NK cell counts  
o Biomarkers including Serum CTX (requires 12 hour fasting) 
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test every 28 days 
while on pomalidomide therapy (including breaks in therapy).   
o FCBP with irregular menstruation must have a pregnancy test every 14 days while 
on pomalidomide therapy (including breaks in therapy).   
• 
Review of AEs and concomitant medications 
• 
Pomalidomide counseling  
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone   
8.3.6. 
Cycle 2, Day 15 
Predose  
• 
Symptom directed physical exam including weight 
• 
VTE monitoring 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect a blood sample for the following laboratory test: 
o Hematology 
o Collect predose PK sample for ibrutinib and pomalidomide 
o Collect blood sample for 4-β-hydroxycholesterol before dexamethasone 
administration 
• 
Review of AEs and concomitant medications 
• 
Females with irregular menstruation must have a pregnancy test every 14 days while on 
pomalidomide therapy (including breaks in therapy).   


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Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone.   
• 
Blood sample collection for ibrutinib (ibrutinib or placebo for Phase 2b) and 
pomalidomide PK and 4-β-hydroxycholesterol (times from study drug dose): 
o 1 hour after dosing (for ibrutinib and pomalidomide PK) 
o 2 hours after dosing (for ibrutinib and pomalidomide PK) 
o 4 hours after dosing (for ibrutinib and pomalidomide PK) 
o 6 hours (window 5 to 8 hours) after dosing (for ibrutinib and pomalidomide PK and 
4-β-hydroxycholesterol) 
8.3.7. 
Cycle 2, Days 22-28 
In order to allow for drug delivery in the US, pregnancy testing can be done on Days 22-28 of 
each cycle. 
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test every 28 days 
while on pomalidomide therapy (including breaks in therapy).   
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on pomalidomide therapy (including breaks in therapy). 
• Continuous dosing of ibrutinib 
• Administration of dexamethasone (only on Day 22) 
8.3.8. 
Cycles 3 and Beyond, Day 1 (odd cycles) 
Predose  
• 
PRO assessments (Phase 2b only)- preferable to be performed prior to any assessments 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy Assessments as applicable per Section 7.5 
• 
Review of AEs and concomitant medications  


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• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test every 28 days 
while on pomalidomide therapy (including breaks in therapy).   
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on pomalidomide therapy (including breaks in therapy).  
• 
Pomalidomide counseling 
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone   
8.3.9. 
Cycle 3 and Beyond, Days 22-28 
In order to allow for drug delivery in the US, pregnancy testing can be done on Days 22-28 of 
each cycle. 
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test every 28 days 
while on pomalidomide therapy (including breaks in therapy).   
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on pomalidomide therapy (including breaks in therapy).   
• 
Continuous dosing of ibrutinib 
• 
Administration of dexamethasone (only on Day 22) 
8.3.10. 
Cycle 4 and Beyond, Day 1 (even cycles) 
Predose  
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy assessments as applicable per Section 7.5 
o T/B/NK cell counts 


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o Biomarkers including Serum CTX (requires 12 hour fasting) 
• 
Review of AEs and concomitant medications  
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test every 28 days 
while on pomalidomide therapy (including breaks in therapy).   
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on pomalidomide therapy (including breaks in therapy).   
• 
Pomalidomide counseling 
• 
Investigator response assessment  
Dosing and Postdose 
• 
Administration of ibrutinib (ibrutinib or placebo for Phase 2b), pomalidomide and 
dexamethasone    
8.3.11. 
Suspected PD Visit 
The Suspected PD visit should be performed at any time during the study, if based on clinical 
and/or laboratory evaluation, the Investigator suspects PD.  If a suspected PD visit is the first 
observation of PD, the subsequent confirmatory assessment must occur on or before the next 
protocol scheduled response assessment (refer to Section 7.5 for further details).  The following 
procedures will be performed: 
• 
PRO assessments (Phase 2b) – preferable to be performed prior to any assessments 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy assessments as applicable per Section 7.5 
o T/B/NK cell counts 
o Biomarkers including Serum CTX (requires 12 hour fasting)  
• 
Radiographic imaging; if applicable  
• 
Review of AEs and concomitant medications 
• 
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8.3.12. 
End-of-Treatment 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 anti-cancer treatment, whichever occurs first.  If the subject starts a new 
anti-cancer treatment less than 7 days after the Suspected PD visit, only those procedures not 
conducted at the Suspected PD visit should be performed at the EOT visit.  
The following procedures will be performed at the EOT visit: 
• 
PRO assessments (Phase 2b) – preferable to be performed prior to any assessments 
• 
Complete physical exam including weight 
• 
Eye-related symptom assessment  
• 
VTE monitoring 
• 
ECOG performance status 
• 
Obtain vital signs (including blood pressure, heart rate, and body temperature)  
• 
12-lead single ECG  
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy assessments as applicable per Section 7.5 
o T/B/NK cell counts  
o Biomarkers including Serum CTX (requires 12 hour fasting) 
o Thyroid function (TSH) 
• 
Bone marrow aspirate sample biomarker: 6 mL to be sent to central lab for biomarker 
assessment (may be done prior to the start of new anti-cancer therapy after PD is 
confirmed). 
• 
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.3.7 
o FCBP with regular or no menstruation must have a pregnancy test at discontinuation 
of pomalidomide and at Day 28 post the last dose of pomalidomide.   
o FCBP with irregular menstruation must have a pregnancy test at discontinuation of 
pomalidomide and at Day 14 and Day 28 after last dose of pomalidomide 
• 
Review of AEs and concomitant medications 
• 
Collect subject diary and any remaining drug from last cycle 
• 
Investigator response assessment, if applicable  
8.4. 
Follow-up Phase 
Once a subject has completed the EOT visit, he/she will enter the Follow-up Phase.  Subjects that 
withdraw from treatment for reasons other than PD will participate in ongoing Response Follow-up. 


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8.4.1. 
Response Follow-up  
Subjects who discontinue the study for reasons other than PD will be followed every 4 weeks 
(±3 days) until PD.  In Phase 2b, PD must be confirmed by the IRC. During this period, 
evaluations used for response assessment (ie labs, radiographic imaging, bone marrow biopsy) 
will be done per Investigator discretion. 
• 
PRO assessments (Phase 2b only) – preferable to be performed prior to any assessments 
• 
Collect blood samples for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Quantitative immunoglobulins (IgA, IgG and IgM and if clinically indicated, IgD or 
IgE) 
o Efficacy Assessments as applicable per Section 7.5  
• 
Survival status and new anti-cancer therapy 
• 
Investigator response assessment 
8.4.2. 
Long-Term Follow-up  
Once subjects progress (following IRC confirmed disease progression in Phase 2b), they will be 
contacted approximately every 12 weeks (±14 days) from EOT by clinic visit or telephone to 
assess survival.  The first subsequent anti-cancer therapy will be collected.  Subjects will be 
contacted until death, subject withdrawal, lost to follow-up, or study termination by the Sponsor, 
whichever occurs first to obtain the following: 
• 
PRO assessments (Phase 2b only) for a minimum of 18 months 
• 
Survival status and new anti-cancer therapy 
• 
Other malignancies 
Every effort should be made to administer the questionnaires for subjects who are followed by 
clinic visit.  At the time of the interim analysis and at study closure, a survival sweep will be 
conducted.  All subjects who are on study and not known to have died prior to the survival sweep 
will be contacted at that time. 
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.  


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9.2. 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• 
Confirmed progressive disease (by IRC for Phase 2b) 
• 
Unacceptable toxicity: an intercurrent illness or an AE that prevents further ibrutinib or 
placebo 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 EOT 
visit and be followed for progression (if applicable) and survival.  
The Investigator should notify the Sponsor if a subject discontinues study treatment due to 
disease progression and should provide documentation of disease progression for review by the 
Sponsor’s Medical Monitor.  If a subject shows signs of disease progression, the subject may 
continue study treatment until disease progression is confirmed (by IRC in Phase 2b).  
These subjects should remain in the study to be followed for survival.  
9.3. 
Withdrawal from Study (Study Exit) 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• 
Withdrawal of consent for follow-up observation by the subject 
• 
Lost to follow-up 
• 
Study termination by Sponsor 
• 
Death 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject.  The measures taken to follow up should be documented. 
When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
• 
Reason for withdrawal 
• 
Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits)  


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10. 
STATISTICAL METHODS AND ANALYSIS 
Statistical analysis will be performed by the Sponsor or under the authority of the Sponsor.  
A general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below.  Specific details will be provided in the Statistical Analysis Plan (SAP). 
10.1. 
Analysis Populations 
10.1.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all eligible subjects who are randomized into 
the Phase 2b portion of the study.  Eligible subjects are defined as all subjects who signed the 
ICF, with relapsed/refractory MM according to IMWG consensus criteria (Appendix 7), who had 
received at least two prior lines of therapy and had a baseline assessment.  The ITT population 
will be the primary population for all efficacy analyses. 
10.1.2. 
Response-Evaluable Population 
The response-evaluable population is defined as all enrolled subjects who received at least 1 dose 
of study treatment, and provided at least one post-baseline response (or disease) assessment.  
The response-evaluable population will be used for efficacy sensitivity analyses as described in 
the statistical analysis plan. 
10.1.3. 
Safety Population 
The safety population will consist of all enrolled subjects who received at least one dose of study 
treatment.  The safety population will be used for the analysis of safety data. 
10.1.4. 
Additional Analysis Populations 
Additional analysis population, which may be used in sensitivity analyses for primary and 
secondary efficacy objectives or analyses for exploratory objectives, will be defined in the 
statistical analysis plan. 
10.2. 
Sample Size Determination 
Phase 1: This is a standard 3+3+3 design to determine the MTD/MAD and the Phase 2b dose 
and toxicity profile of ibrutinib in combination with pomalidomide and dexamethasone.  Dose 
escalation will follow the 3+3+3 principle and up to 2 cohorts will be explored.  This study is not 
powered for comparison of treatment cohorts.  Up to 18 subjects will be enrolled into the Phase 1 
of the study. 
Phase 2b: A sample size of approximately 195 eligible subjects will be enrolled to observe 
124 PFS events in this study.  Two interim analyses including subjects in Treatment Arms A and 
B will be conducted.  The first interim analysis is a non-binding futility analysis and will occur 
when approximately 50 PFS events (40%) have occurred, which is estimated to happen when 
approximately 129 subjects have been enrolled.  The second interim analysis for both efficacy 
and non-binding futility will occur when approximately 74 PFS events (60%) have occurred, 


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which is estimated to happen when approximately 172 subjects have been enrolled.  The sample 
size is determined according to the Group Sequential Design.  For this calculation, the median 
PFS of 5 months for placebo in combination with pomalidomide and dexamethasone and an 
average enrollment rate of 15 subjects per month were assumed.  Assuming exponential survival 
distribution and 67% improvement in median PFS of ibrutinib in combination with 
pomalidomide and dexamethasone over placebo in combination with pomalidomide and 
dexamethasone (hazard ratio [HR] of 0.6), the study has at least 80% power to achieve an overall 
1-sided significance level of 2.5% with the above planned interim analyses. 
Both interim analyses will be performed by the DMC, and the Sponsor will remain blinded to the 
results.  As part of the second interim analysis, the Sponsor may request the DMC to assess the 
HR based on the interim PFS data, which may lead to an adaptation of the sample size. 
The adaptive plan and sample size increase rule will be detailed in the statistical analysis plan or 
a separate interim analysis plan. 
For the open-label sub-study Treatment Arm C of Phase 2b, 22 subjects will be enrolled to 
provide 78% power at a 1-sided  significance level of 0.1 to test a true response rate of ≤5% (H0) 
versus ≥ 18% (Ha), based on the exact binomial test.   
10.3. 
Subject Information 
The distribution of subjects for each of the analysis populations will be provided.  The number of 
subjects enrolled by each investigative site and country, dosed, and discontinued will be 
summarized.  Treatment discontinuation will be summarized according to the reasons for 
discontinuation.  Demographic and baseline vital sign variables will be summarized.  Baseline 
disease characteristics will also be summarized. 
10.3.1. 
Demographic/Baseline Characteristics and Study Conduct 
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease status, 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. 
Further, compliance parameters (including number of doses taken compared with number of 
doses that should have been taken), the reason for discontinuation, and concurrent treatments 
will also be similarly summarized.   
10.4. 
Efficacy Analysis 
10.4.1. 
Primary Endpoint  
The primary efficacy endpoint of the Phase 2b portion of this study is PFS, as assessed by the 
IRC.  Progression-free survival will be assessed on all subjects in the ITT population. 


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10.4.2. 
Secondary Endpoints  
• 
The ORR will be assessed by investigator (for Phase 1) and by IRC (for Phase 2b) 
according to the IMWG criteria and is defined as the proportion of subjects who achieve 
a PR or better over the course of the study. 
• 
The DOR is defined as the interval between the date of initial documentation of a 
response and the date of first documented evidence of progressive disease as assessed 
by investigator (for Phase 1) and by IRC (for Phase 2b), death, or date of censoring if 
applicable, for responders only.  Subjects who start new anti-cancer treatment before 
documentation of disease progression will be censored on the date of the last adequate 
disease assessment that is on or before the start date of new anti-cancer therapy.  
Responders are subjects in the ITT population who achieve PR or better according to 
the IMWG response criteria.  Non responders (≤MR) will be excluded from the analysis 
for DOR. 
• 
Clinical benefit rate (CBR) and its duration as assessed by investigator (for Phase 1) and 
by IRC (for Phase 2b) including subjects with minimal response (MR) or better 
according to the IMWG. 
• 
OS is defined as the time from date of randomization until date of death due to any 
cause.  Subjects who are known to be alive or whose survival status is unknown will be 
censored at the date last known to be alive.  Subjects who are completely lost to 
follow-up for survival after randomization will be censored at randomization date 
(Phase 2b). 
• 
TTP is defined as the time from the start of treatment until date of disease progression 
as assessed by IRC.  Subjects who die before disease progression due to  causes other 
than progression will be censored at the date of death (Phase 2b).  
10.4.3. 
Efficacy Assessments by Investigator 
Investigator-assessed PFS, ORR, DOR and CBR and its duration will be analyzed in a similar 
fashion as corresponding endpoints assessed by the IRC for Phase 2b.  
10.4.4. 
Exploratory Endpoints 
Exploratory endpoint analyses will be described in the SAP and may include the following: 
• 
Time-to-next-treatment (TTNT) (Phase 2b) 
• 
Patient reported outcomes (PROs) and disease-related symptoms according to EORTC 
QLQ-MY20 and EQ-5D-5L (Phase 2b) 
10.5. 
Analysis Methods 
10.5.1. 
Analysis for Phase 1 
The Phase 1 portion of this study is an algorithm-based dose-escalation design to find the 
MTD/MAD and the Phase 2b dose of  the ibrutinib,  pomalidomide and dexamethasone 
combination and to characterize the most frequent AEs experienced through Phase 1 and the 
DLTs.  Dose-limiting toxicities will be evaluated and will include all AEs experienced through 
Cycle 2 Day 1 pre-dose assessments.  


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The Phase 1 secondary efficacy endpoints are the ORR, DOR, and the CBR and its duration 
according to the IMWG response criteria.  The point estimate of the rate and the corresponding 
exact binomial 95% confidence interval (CI) will be calculated.  For DOR, the distribution of 
DOR as assessed will be provided using Kaplan-Meier method for responders.  The CBR (≥MR) 
and its duration will be analyzed similar to the analysis of ORR and DOR, respectively.  
10.5.2. 
Primary Efficacy Analyses 
Progression free survival is defined as the time from the date of randomization to IRC confirmed 
disease progression per IMWG response criteria or death from any cause, whichever occurs first. 
Subjects who withdraw from the study or are considered lost to follow-up without prior 
documentation of disease progression will be censored on the date of the last adequate disease 
assessment.  Subjects who are progression-free and alive at the time of clinical cut-off, or have 
unknown status will be censored on the date of the last adequate disease assessment.  For 
subjects without an adequate post-baseline disease assessment, PFS will be censored on the date 
of randomization.  Adequate disease assessment is defined according to the IMWG criteria. 
The analysis of PFS will be performed on Phase 2b subjects in the ITT population to compare 
PFS for the 2 treatment arms using a stratified log-rank test stratified by the number of prior 
lines of therapy (2-3 versus ≥4), last prior treatment (no proteasome inhibitor [PI] or 
immunomodulatory agent [IMiD] versus PI or IMiD versus PI and IMiD) and age (≤75 versus 
>75 years).  Distribution of PFS will be summarized for each treatment arm using the 
Kaplan-Meier estimate of median and its corresponding 95% CI.  The estimate of the hazard 
ratio and its corresponding 95% CI will be computed using a Cox proportional hazards model 
stratified by the randomization stratification factors, the number of prior lines of therapy 
(2-3 versus ≥4), last prior treatment (no PI/IMiD versus PI or IMiD versus PI and IMiD) and age 
(≤75 versus >75 years).  
10.5.3. 
Secondary Efficacy Analysis 
Overall response rate (ORR [PR or better]) as assessed by IRC, and its 95% CI will be 
calculated using normal approximation to the binomial distribution for the ITT population.  
Overall response rate will also be compared between 2 treatment arms (A and B) using the 
Cochran-Mantel-Haenszel chi-square test, stratified by the three stratification factors: number of 
prior lines of therapy, most recent line of therapy, and age.  
DOR will be analyzed for subjects who achieve response (PR or better) based on the response 
assessed by IRC during the study.  The distribution of DOR will be estimated using the 
Kaplan-Meier method similar to PFS. 
The CBR and its duration, including subjects with MR or better, will be analyzed similar to the 
analysis of ORR and DOR, respectively.  
PFS, ORR, DOR, CBR, and TTP will also be evaluated based on Investigator’s assessments. 


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OS will be analyzed in the ITT population to compare OS for the 2 treatment arms (A and B) 
using a stratified log-rank test, stratified by the number of prior lines of therapy, last prior 
treatment and age.  Distribution of OS will be summarized for each treatment arm using the 
Kaplan-Meier estimate of median and its corresponding 95% CI.  Survival rate at landmark 
points will be summarized based on Kaplan-Meier point estimates. 
All or some of the efficacy analyses may be performed based on the response-evaluable 
population as sensitivity analyses.  A sensitivity analysis of PFS may be conducted with 
censoring at subsequent therapy if initiated prior to a documented PD. 
10.5.4. 
Exploratory Efficacy Analysis 
The distribution of TTNT will be estimated using the Kaplan-Meier method.  Analysis method 
will be detailed in the SAP (Phase 2b). 
Descriptive statistics for change in scores from baseline to each assessment time point will be 
summarized for the PROs and disease-related symptoms according to EORTC QLQ-MY20 and 
EQ-5D-5L (Phase 2b). 
10.5.5. 
Open-Label Sub-study Treatment Arm C Efficacy Analysis (Phase 2b)  
The primary efficacy endpoint is the ORR as assessed by IRC according to the IMWG response 
criteria.  The hypothesis that the true ORR is ≤5% (H0) will be tested against ≥18% (Ha), based 
on the exact binomial test.  The point estimate of the rate and the corresponding exact binomial 
95% CI will be calculated.  For DOR, the distribution of DOR will be provided using 
Kaplan-Meier estimates for responders. 
10.5.6. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and its metabolite (PCI-45227) and pomalidomide will be 
determined using a validated analytical method.  Other potential metabolites of ibrutinib may be 
explored. 
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 of ibrutinib, covariates that could potentially correlate with plasma PK 
parameters will be evaluated.  Pharmacokinetic relationships to pharmacodynamic measures of 
efficacy or toxicity may also be explored.  The results of the population PK analyses will be 
presented in a separate report.   


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10.5.7. 
Biomarkers 
• 
Exploratory identification of gene expression profiles, signaling pathways or 
biomarkers that may predict sensitivity or resistance to ibrutinib.  
• 
Frequency of tumor mutations (or other molecular markers) between pre and post 
treatment tissue that may predict acquired resistance. 
Clinically relevant biomarkers of high penetrance with presence/absence of mutation may be 
highly associated with clinical response.  A Fisher Exact Test may be used to compare the 
clinical response rates between the mutant and wild-type populations for each biomarker. 
10.6. 
Safety Analysis 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who receive at least 1 dose of study treatment.  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.  
The safety variables to be analyzed include AEs, survival status, clinical laboratory test results 
(hematology and chemistry), ECOG performance status, physical examination findings, and vital 
signs measurements.  Exposure to study treatment and reasons for discontinuation from study 
treatment will be tabulated.  In general, continuous variables will be summarized using 
descriptive statistics (n, mean, median, standard deviation, standard error and range).  
Categorical variables will be summarized using frequencies and percentages. No formal 
statistical testing is planned.  
Phase 1 
All AEs experienced from the start of treatment through Cycle 2 Day 1 pre-dose assessments 
will be evaluated by the independent DMC for the purpose of identifying any DLTs during the 
identification of the MTD/MAD.  In addition, detailed tabulation of safety data (AEs, clinical 
laboratory tests and other safety endpoints) will be summarized. 
Phase 2b 
Detailed tabulations of safety data (AEs, clinical laboratory tests and other safety endpoints) will 
be summarized by treatment arms for all subjects receiving the study drug.  Summary statistics 
will include means, standard deviations, and medians for continuous variables and proportions 
for categorical variables. Safety analysis for Treatment Arm C will be conducted similar but 
described separately and independent from the safety analysis conducted for the randomized 
portion of the study. 
In addition, a pooled safety analysis will be performed on all subjects receiving the combination 
of ibrutinib, pomalidomide and dexamethasone, which includes subjects in Phase 1 treated at the 
MTD/MAD, as well as those treated on Arms A and C of Phase 2b.  This will be conducted 


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similar but described separately and independent from the safety analysis conducted for the 
randomized portion of the study. 
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of AEs; the 
relationship of AEs to study treatment; and the action taken with respect to study treatment due 
to AEs. 
The verbatim terms used in the eCRF by Investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and graded according to NCI CTCAE 
version 4.03.  Treatment-emergent adverse events are those AEs occurring after the first dose of 
study treatment and within 30 days following the last dose of study treatment (ibrutinib, 
pomalidomide, or dexamethasone, whichever occurs later), but before first dose date of 
subsequent anti-cancer therapy, whichever occurs first; any AE that is considered study drug-
related regardless of the start date of the event; or any AE that is present at baseline but worsens 
after the first administration of study treatment in severity or is subsequently considered 
drug-related by the Investigator.   
All TEAEs will be included in the analysis.  The number and percent of subjects with TEAEs 
will be summarized by system organ class and preferred term.  Drug related AEs, SAEs, Grade 
≥3 AEs, AEs leading to study treatment discontinuation, dose modification, or death, and events 
of special interest will be summarized and listed. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry.  
All laboratory values will be graded using the NCI CTCAE (version 4.03).  The worst toxicity 
grade during the study will be tabulated. 
10.6.1. 
Independent Review Committee (IRC) 
The IRC will be chaired by a physician with expertise in MM and the IRC will conduct 
progression and response evaluations.  The IRC assessment will incorporate central laboratory 
results and additional assessments (as indicated) based upon evaluations outlined in Section 7.5.  
Details regarding IRC activities will be outlined in a separate charter.  IRC is established to 
conduct response assessment centrally according to the IRC charter. 
10.6.2. 
Data Monitoring Committee 
The safety of this study will be monitored by an independent DMC.  In Phase 1 the DMC will 
review safety and efficacy data and advise on the Phase 2b dose.  In Phase 2b the DMC will 
review the safety data on an ongoing basis as well as the interim analysis results. 


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The independent DMC will be chaired by a physician with expertise in MM.  The DMC will 
review data and provide recommendations regarding stopping or continuing the trial in 
accordance with the DMC charter.  
10.6.3. 
Interim Analyses  
Both interim analyses will be unblinded and performed by the DMC, independent to the study 
team.  As part of the second interim analysis, the Sponsor may request the DMC to assess the HR 
based on the interim PFS data as assessed by the IRC, which may lead to an adaptation of the 
sample size.  The details of the crossing boundaries and adaptive plan including a sample size 
increase rule will be detailed in the SAP or a separate interim analysis plan.  
10.6.4. 
Final Analysis 
The final analysis for the PFS will occur when approximately 124 PFS events are observed as 
assessed by the IRC, or the Sponsor terminates the study, whichever comes first. 
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 
(SOPs) 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. 
Adverse Event Definitions and Classifications 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an AE term.  As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 


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Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered 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 MM 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 
eCRF) 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 
ICF is not considered an SAE, but rather a therapeutic intervention.  However, if during 
the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE.  Surgeries or 
interventions that were under consideration, but not performed before enrollment in the 
study, will not be considered serious if they are performed after enrollment in the study 
for a condition that has not changed from its baseline level.  Elective hospitalizations 
for social reasons, solely for the administration of chemotherapy, or due to long travel 
distances are also not SAEs. 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported. 
• 
Asymptomatic Treatment Related Lymphocytosis: This event should not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on 
study treatment and continue with all study-related procedures. 
11.1.2. 
Serious Adverse Events 
A SAE 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 patient was at risk 
of death at the time of the event.  It does not refer to an event which hypothetically 
might have caused death if it were more severe.  If either the Investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• 
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 


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• 
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 patient or patient may 
require intervention to prevent one of the other outcomes listed in this definition.  
Examples of such events are intensive treatment in an emergency department or at 
home for allergic bronchospasm, blood dyscrasias, or convulsion that does not result in 
hospitalization; or development of drug dependency or drug abuse. 
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. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the IB/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 IB referred only to elevated hepatic enzymes 
or hepatitis.  Similarly, cerebral thromboembolism and cerebral vasculitis would be 
“unexpected” (by virtue of greater specificity) if the IB/package insert listed only cerebral 
vascular accidents.  "Unexpected" also refers to AEs that are mentioned in the IB as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the study drug under investigation. 
11.1.4. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE version 4.03) will be used for grading the severity (intensity) AEs.  The CTCAE 
(version 4.03) 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 (version 4.03), the 
following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• 
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 


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11.1.5. 
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 Related: 
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. 
Documenting and Reporting of Adverse Events 
The Investigator is responsible for ensuring that all AEs and SAEs observed or reported during 
the study, as outlined in the prior sections, are recorded on the eCRF.  All SAEs must also be 
reported on the SAE Report Form and submitted to the Sponsor (see Section 11.2.2.2). 
11.2.1. 
Special Reporting Situations 
Special reporting situations on a Sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• 
Overdose of any study drug 
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to a study drug 
• 
Medication error involving a product (with or without subject/patient exposure to the 
study drug, eg, name confusion) 
Any special reporting situation that meets the criteria of an AE should be reported on the SAE 
Report Form.  The SAE Report Form should be sent via email or fax to Pharmacyclics Drug 
Safety or designee within 24 hours of awareness. 
11.2.2. 
Adverse Event Reporting Procedures 
11.2.2.1. 
All Adverse Events 
All subjects who receive at least one dose of study drug(s) will be considered evaluable for 
safety assessments.  All AEs whether serious or non-serious, will be documented from the time 
signed and dated ICF is obtained until 30 days following the last dose of study drug.  All SAEs 
will be reported to the Sponsor Drug Safety via an SAE reporting form and will be recorded in 


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the eCRF from the time of ICF signing.  Non-serious AEs will be recorded in the source 
documents from the time of ICF signing and will be recorded in the eCRF from the first dose of 
study drug(s).  
Serious adverse events occurring more than 30 days following the last dose of study drug should 
also be reported if considered related to any of the study drugs.  Resolution information after 
30 days should be provided. 
Progressive disease should NOT be reported as an AE, but instead symptoms/clinical signs of 
disease progression may be reported (See Section 11.1.1).   
All AEs, 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 (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection").  Investigators must record in the eCRF their opinion concerning 
the relationship of the AE to study therapy.  All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a SAE.  
11.2.2.2. 
Expediting Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent 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 SAEs 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 
• 
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• 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.   
The Investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.2.3. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported as SAEs, regardless of the treatment arm the subject is enrolled in.  
This includes any second primary malignancy, regardless of causal relationship to study drug[s], 
occurring at any time for the duration of the study, from the time of signing the informed consent 
to 5 years after the last study drug treatment. 
Events of second primary malignancy are to be reported using the SAE form; these events must 
also be documented in the appropriate page(s) of the eCRF and in the subject’s source 
documents.  Documentation of the diagnosis of the second primary malignancy must be provided 
at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, X-rays, 
CT scans, etc.). 
If observed, enter data in the corresponding eCRF. 
11.2.4. 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject or a male subject's partner, consent 
to provide follow-up information regarding the outcome of the pregnancy and the health of the 
infant until 1 year old will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of study drug.  A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of his consent to 90 days 
after the last dose of study drug.  Any female subjects receiving study drug(s) who become 
pregnant must immediately discontinue study treatment.  The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
11.2.4.1. 
Pregnancy Reporting 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented.  
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90 days after the last dose of study drug must be reported.  Any occurrence of pregnancy must be 
recorded on the Pregnancy Report Form Part I and submitted 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 1 year old by completing the Pregnancy Report Form Part II.  Any congenital anomaly/birth 
defect noted in the infant must be reported as a SAE. 
11.2.5. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF. 
11.2.6. 
Adverse Events of Special Interest 
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities 
by the Sponsor.  These events regardless of seriousness should be reported on the SAE Report 
Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, within 24 hours of 
awareness. 
11.2.6.1. 
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 event of bleeding of any grade.
•
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade.
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher AE per
CTCAE (version 4.03). 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.2.6 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. 


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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 ICF must also be approved by the IRB/REB/IEC before the implementation of 
changes in this study. 
The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF. 
12.3. 
Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.   
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail.  This process must be documented in the subject’s source record.  Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed.  The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time.  A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
12.4. 
Quality Control and Quality Assurance 
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 
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12.5. 
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 12.3), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used).  The Investigator or designee 
must explain to each subject that for the evaluation of study results, the subject’s protected health 
information obtained during the study may be shared with Pharmacyclics and its designees, 
regulatory agencies, and IRBs/REBs/IECs.  As the study Sponsor, Pharmacyclics will not use the 
subject’s protected health information or disclose it to a third party without applicable subject 
authorization.  It is the Investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each subject.  If a subject withdraws permission to use 
protected health information, it is the Investigator’s responsibility to obtain the withdrawal 
request in writing from the subject and to ensure that no further data will be collected from the 
subject.  Any data collected on the subject before withdrawal will be used in the analysis of study 
results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. 
Study Files and Record Retention 
The Investigator must keep a record of all subjects who have consented to enroll in the study.  
For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed investigator agreements (eg, Form FDA 1572 or 
equivalent) 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 eCRFs, and 
documentation of eCRF 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.  


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The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time.  Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
12.7. 
Case Report Forms and Record Maintenance 
Electronic 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 eCRFs designed for this study according to the 
completion guidelines that will be provided.  The Investigator will ensure that the eCRFs are 
accurate, complete, legible, and completed within a reasonable amount of time.  At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The eCRFs 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 eCRFs 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 eCRFs 
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 Pharmacyclics-supplied comparator used must be kept in a locked limited 
access room and must not be used outside the context of the protocol.  Under no circumstances 
should the Investigator or other site personnel supply ibrutinib and pomalidomide to other 
Investigators, subjects, or clinics or allow supplies to be used other than as directed by this 
protocol without prior authorization from Pharmacyclics. 


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Accountability records for ibrutinib and pomalidomide must be maintained and readily available 
for inspection by representatives of Pharmacyclics and are open to regular inspections by 
regulatory authorities at any time.  
An Investigational Drug Accountability Log must be used for drug accountability.   
For additional details on investigational study drug management, please refer to the Pharmacy 
Manual. 
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, 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 eCRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice.  If access to the EMR cannot be granted to the 
monitor, the site must ensure that all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects.  During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 
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 investigator agreements (eg, Statement of Investigator Form FDA 1572 or 
equivalent), both of which are signed by the Investigator before commencement of the study.  
In summary, the Investigator will conduct the study according to the current protocol; will read 


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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 Sub-Investigator (as designated on the investigator 
agreements [eg, Form FDA1572 or equivalent]) will provide a signed Financial Disclosure Form 
in accordance with § 21 CFR 54.  Each Investigator will notify Pharmacyclics or its authorized 
representative of any relevant changes during the conduct of the study and for 1 year after the 
study has been completed. 
12.13. Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
The ICF will include a description of treatment in the event of a study related injury and 
handling of the costs associated therewith, incorporating country-specific national regulations 
and/or local laws.  Financial compensation for lost wages, disability or discomfort due to the 
study is not available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 


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12.14. Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document.  
The amendment will be submitted to regulatory authorities as well as the IRB/REB/IEC together 
with, if applicable, a revised model ICF.  Written documentation of regulatory authority, 
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 
the increased risk and/or change in scope must be provided to subjects already actively 
participating in the study, and they must read, understand and sign any 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. 
12.17. Study Completion 
The end of study will occur approximately 2 years after the last subject is randomized into the 
Phase 2b portion of the study, or the Sponsor terminates the study, whichever comes first. 
 
 


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13. 
REFERENCES 
1. Aggarwal R, Ghobrial IM, Roodman GD. Chemokines in multiple myeloma. Exp Hematol 
2006;34:1289 1295. 
2. Bam R, Ling W, Khan S et al.  Role of Bruton’s tyrosine kinase in myeloma cell migration and 
induction of bone disease.  American Journal of Hematology 2013;88:463-471. 
3. Baz R, Li L, Marchant-Kottke K, et al.  The role of aspirin in the prevention of thrombotic 
complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.  
Mayo Clinic Proc 2005; 80: 1568-1574. 
4. Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation. Crit Rev 
Immunol. 2003;23:165–197. 
5. Chari A, Chabra S and Usmani S et al. Combination Treatment of the Bruton’s Tyrosine Kinase 
Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple 
Myeloma: Initial Results from a Multicenter Phase 1/2b Study. Blood. 2015; 126: Abstract 377. 
6. Child CG, Turcotte JG (1964) “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. pp. 50-64.   
7. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41. 
8. Cocks K, Cohen D, Wisløff F, Sezer O, Lee S, Hippe E, Gimsing P, Turesson I, Hajek R, Smith A, 
Graham L, Phillips A, Stead M, Velikova G, Brown J, EORTC Quality of Life Group:An 
international field study of the reliability and validity of a disease-specific questionnaire module (the 
QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 2007, 
43:1670-1678 
9. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, Published June 14, 2010 
10. Dimopoulos MA, Palumbo A and Weisel K et al.  Safety and Efficacy in the Stratus (MM-010) Trial, 
Single-Arm Phase 3b Study Evaluating Pomalidomide + Low-Dose Dexamethasone in Patients with 
Refractory or Relapsed and Refractory Multiple Myeloma. Blood 2014a;124(21):Abstract 80. 
11. Dimopoulos MA, Leleu X and Palumbo A et al. Expert panel consensus statement on the optimal use 
of pomalidomide in relapsed and refractory multiple myeloma. Leukemia 2014b;28:1573-1585. 
12. Dimopoulos MA, Richardson PG, Moreau P and Anderson KC. Current treatment landscape for 
relapsed and/or refractory multiple myeloma. Nature Reviews Clinical Oncology 2015;12:42-54. 
13. Elias L and Buggy J.  Bruton Tyrosine Kinase Expression in Multiple Myeloma. Haematologica 
2013;98(s1):Abstract P211 
14. EuroQol Group. EuroQol-a New Facility for the Measurement of Health-Related Quality of Life. 
Health Policy. 1990;16:199-208 
15. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of 
fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology 
clinical practice guideline. J Clin Oncol. 2013;31:794-810. 
16. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.  
Blood 2011; 117:6287-6296. 
17. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics 


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Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, 
based on November 2013 SEER data submission, posted to the SEER web site, April 2014. 
18. Investigator's Brochure. Ibrutinib. Version 10: 29 August 2016. Pharmacyclics LLC; Janssen 
Research & Development, LLC. 
19. Jakubikova J, Adamia S, Kost-Alimova M, et al. Lenalidomide targets clonogenic side population in 
multiple myeloma: pathophysiologic and clinical implications. Blood. 2011. 
20. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for 
human multiple myelomas. Nature 1988;332:83-85. 
21. Kumar SK, Lee JH, Labuerta JJ et al.  Risk of progression and survival in multiple myeloma 
relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working 
group study. Leukemia 2012;26:149-157. 
22. National Comprehensive Cancer Network (NCCN) Guidelines for multiple myeloma. Version 4 2015 
23. 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. 
24. Palumbo A, Rajkumar SV and Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-
associated thrombosis in myeloma. Leukemia 2008;22:414-423. 
25. Palumbo A, Dimopoulos MA and Weisel K et al.  Outcomes for Older Patients in Stratus (MM-010), 
a Single-Arm, and Phase 3b Study of Pomalidomide + Low-Dose Dexamethasone in Refractory or 
Relapsed and Refractory Multiple Myeloma. Blood 2014;124(21):Abstract 4770. 
26. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine 
kinase. ChemMedChem 2007;2:58-61. 
27.  Pomalyst®  (pomalidomide) prescribing information. Summit, NJ: Celgene Corporation; 2016. 
28. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R (1973). “Transection of the 
oesophagus for bleeding oesophageal varices”. The British journal of surgery, 60 (8): 646-649. 
29. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting 
of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 
2011;117:4691-5.  
30. Roodman GD, Choi SJ. MIP-1 alpha and myeloma bone disease. Cancer Treat Res 2004;118:83-100. 
31. Roodman GD. Pathogenesis of myeloma bone disease. J Cell Biochem 2010a;109:283-291. 
32. Roodman GD. Targeting the bone microenvironment in multiple myeloma. J Bone Miner Metab 
2010b;28:244-250. 
33. Roodman GD. Osteoblast function in myeloma. Bone 2011;48:135-140. 
34. Richardson PG, Siegel DS, Vij R et al.  Pomalidomide alone or in combination with low-dose 
dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study.  
Blood 2014:12(12):1826-32. 
35. Rushworth SA, Bowles KM, Barrera LN, et al. BTK inhibitor ibrutinib is cytotoxic to myeloma and 
potently enhances bortezomib and lenalidomide activities thorugh  NF-κB. Cell Signal 2013:  
106-112.  
36. San Miguel J, Weisel K, Moreau P et al.  Pomalidomide plus low-dose dexamethasone versus high-
dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): 
a randomized, open-label, phase 3 trial. Lancet 2013;14:1055-70. 


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37. Siegel DS, Martin T, Wang M et al.  A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in 
patient with relapsed and refractory multiple myeloma.  Blood 2012;120(14):2817-25. 
38. 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.  Journal of 
Clinical Oncology. 2006:24: 3187-205. 
39. Stead ML, Brown JM, Velikova G, Kaasa S, Wisløff F, Child JA, Hippe E, Hjorth  M, Sezer O, Selby 
P. Development of an EORTC questionnaire module to be used in health-related quality-of-life 
assessment for patients with multiple myeloma. European Organization for Research and Treatment 
of Cancer Study Group on Quality of Life. Br J Haematol. 1999 Mar;104(3):605-11.  
40. Summary of Product Characteristics. Imnovid® (previously Pomalidomide). 29 Sep 2016. Celgene 
Europe Ltd. 
41. Tai Y, Chang B, Kong S, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy 
targeting tumor in the bone marrow microenvironment in multiple myeloma.  
Blood 2012;120:1877-1887. 
42. US Food & Drug Administration. Guidance for Industry: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting. ICH-E2A. March 1995. 
43. Vij R, Huff C and Bensinger W et al.  Ibrutinib, Single Agent or in Combination with 
Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): 
Preliminary Phase 2 Results. Blood 2014;124(21):Abstract 31. 
44. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, et al.  Lenalidomide 
plus Dexamethasone for Relapsed Multiple Myeloma in North America.  N Engl J Med 2007; 357: 
21: 2133-2142. 
45. Yang Y, Shi J and Gu Z et al.  Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells 
from Multiple Myeloma. Cancer Research 2015;75(3):594-604. 


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14. 
APPENDICES 
 


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Appendix 1. 
Schedule of Assessments 
Phase 
Screening 
Phase 
Treatment Phase (28 days/cycle) 
Follow-Up Phase 
Study Cycle 
  
Cycles 1 
Cycles 2 
Cycles 3 and 
beyond 
Suspected 
PD Visit 
EOT 
Response Follow-up  Long-term Follow-up 
30-day 
(Until PD) 
Study Day 
  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Any  
time 
  
q4 weeks 
 q12 weeks 
Visit Window 
-28 days 
 
 
 
 
 
 
 
 
 
 
 
± 7 days 
± 3 days 
± 14 days 
Study Procedures 
Administrative 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Assessments  
Physical exam  
(Height at Screening only)a  
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
ECOG status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Eye-related Symptom Assessmentc 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
12-lead ECGd 
X 
 
 
 
 
X 
Additional tests may be performed at any time 
during participation in the study, as determined 
necessary 
X 
 
 
Imaging by CT,MRI or PET/CT, if 
applicablee 
X 
Subsequent response assessments must include follow-up studies 
 if evidence of plasmacytoma at Screening. 
 
Venous thromboembolism risk 
assessmentf 
X 
VTE risk assessment will be performed at any time during participation in the study as 
applicable 
 
 
Venous thromboembolism 
monitoring 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
PRO assessments (Ph 2b only)g 
X 
 
 
 
 
 
 
 
Xg 
 
 
 
X 
X 
X 
X 
Concomitant medications 
Continuous from informed consent, or at least 14 days prior to first dose, through 30 days after last 
dose of study treatment 
 
 
AEsh 
Continuous from informed consent to 30 days after last dose of study treatment 
 
 


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Phase 
Screening 
Phase 
Treatment Phase (28 days/cycle) 
Follow-Up Phase 
Study Cycle 
  
Cycles 1 
Cycles 2 
Cycles 3 and 
beyond 
Suspected 
PD Visit 
EOT 
Response Follow-up  Long-term Follow-up 
30-day 
(Until PD) 
Study Day 
  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Any  
time 
  
q4 weeks 
 q12 weeks 
Visit Window 
-28 days 
 
 
 
 
 
 
 
 
 
 
 
± 7 days 
± 3 days 
± 14 days 
Study Treatment Administration 
Ibrutinib or Placeboi 
Beginning C1D1, administer once a day, continuously 
 
 
Pomalidomidej 
Administer daily on Days 1-21 of each cycle 
 
 
Pomalidomide Counseling 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Dexamethasonek 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Efficacy Assessments 
Investigator Response Assessment 
(Refer to Appendix 7)l 
 
 
 
 
 
X  
 
 
 
X 
 
 
 
X 
X 
X 
 
Serum/Urine protein 
electrophoresis (SPEP/UPEP) m  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Serum free light chain assay 
(sFLC)n 
X 
X 
Additional tests may be performed to confirm CR 
 
 
 
Serum/Urine immunofixationo 
X 
X 
Additional tests may be performed to confirm CR 
 
 
 
Quantitative immunoglobulin 
X 
X 
X 
X 
X 
X 
X 
C-reactive protein and β2-
microglobulin  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone radiological asssessmentp 
X 
Additional tests may be performed, as determined necessary, at any time during participation in the study 
Bone marrow aspirate/biopsyq 
X 
Additional test may be performed to confirm CR 
 
 
 
Survival status and new anti-cancer 
therapyr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Laboratory Assessments 
Hematologys 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
Serum chemistryt 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 


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Phase 
Screening 
Phase 
Treatment Phase (28 days/cycle) 
Follow-Up Phase 
Study Cycle 
  
Cycles 1 
Cycles 2 
Cycles 3 and 
beyond 
Suspected 
PD Visit 
EOT 
Response Follow-up  Long-term Follow-up 
30-day 
(Until PD) 
Study Day 
  
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Any  
time 
  
q4 weeks 
 q12 weeks 
Visit Window 
-28 days 
 
 
 
 
 
 
 
 
 
 
 
± 7 days 
± 3 days 
± 14 days 
Creatinine Clearanceu 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT/INR, aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testv 
X 
- Female subjects with regular or no menstruation must have a pregnancy test weekly 
for the first 28 days & then every 28 days thereafter and at 28 days after last dose of 
pomalidomide. 
- Female subjects with irregular menstruation, must have a pregnancy test weekly for 
the first 28 days & then every 14 days thereafter and at Day 14 and Day 28 after last 
dose of pomalidomide. 
- FCBP with regular or no menstruation must have a pregnancy test at discontinuation 
of pomalidomide and at Day 28 post the last dose of pomalidomide 
- FCBP with irregular menstruation must have a pregnancy test at discontinuation of 
pomalidomide and at Day 14 and Day 28 after last dose of pomalidomide 
 
 
TSH w 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis serologiescc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers and Pharmacokinetic Assessments 
PK (See separate schedule)x 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood sample for 4-β-
hydroxycholesteroly 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate Biomarkersz 
X 
Additional test may be performed to confirm CR 
X 
 
Biomarkers: whole blood 
collection 
 
X 
 
 
 
X 
 
 
 
Day 1 of every even 
Cycle 
X 
X 
 
 
Biomarkers: serum CTXaa 
X 
X 
 
 
 
X 
 
 
 
Day 1 of every even 
Cycle 
X 
X 
 
 
T/B/NKbb 
 
X 
 
 
 
X 
 
 
 
Day 1 of every even 
Cycle 
X 
X 
 
 
AEs = adverse events; CT = computed tomography, EOT = End-of-Treatment Visit, ECG = electrocardiogram, FCBP = female of childbearing potential, MRI = magnetic resonance 
imaging, INR =  international normalized ratio, PD = progressive disease, PET = positron emission tomography, PK =  pharmacokinetics, PT =  prothrombin time, PTT = partial 
thromboplastin time, TSH = thyroid stimulating hormone.  


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a. At Screening, Day 1 of each Cycle, Suspected PD or CR, and EOT, Physical Exam should include: skin, eyes, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, lymphatic system, nervous system and weight.  At all other time points symptom-directed Physical Exam, including 
weight, is required. Height is required at Screening only. 
b. Vital signs (blood pressure, heart rate, and body temperature) will be assessed.  
c. Refer to Section 7.2.1 for additional information. 
d. Performed at Screening in triplicate, and a single tracing on Cycle 2 Day 1, and EOT.  Not required at subsequent cycles unless medically indicated. 
e. Magnetic resonance imaging (MRI), computed tomography (CT) or PET/CT scans are to be performed as clinically indicated.  If evidence of plasmacytoma 
noted on radiographic imaging at Screening, subsequent response assessments must include follow-up studies every 3 months.  Refer to Section 7.5.6. 
f. Refer to Section 7.1.4 for a description of the venous thromboembolism risk assessment. 
g. Collected at C1D1, Day 1 of every other cycle (eg, C3D1, C5D1, etc), Suspected PD, EOT, and Follow-up Visits (including a minimum of 18 months of  
Long-term Follow-up visits following IRC confirmed PD).  It is preferable that the questionnaires be administered at the beginning of each visit prior to any 
procedures or physician interactions.  
h. Adverse events are collected from the time the subject signs the ICF until 30 days following last dose of study treatment.  In addition to all routine AE 
reporting, all new malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as AEs for the duration of 
the study treatment and during any protocol-specified follow-up periods including post-progression follow-up for OS for up to 5 years after discontinuing 
treatment. 
i. Starting C1D1 subjects will be provided a dosing diary and dispensed ibrutinib or placebo to self-administer daily.  Subject is to return unused ibrutinib or 
placebo and completed diary at day 1 of each subsequent cycle. 
j. Pomalidomide will be administered orally daily on Days 1-21 of each Cycle and will continue until disease progression, unacceptable toxicity, or other 
protocol specified reason (refer to Section 9). 
k. Dexamethasone will be administered orally once weekly at an age-adjusted dose of either 40mg or 20mg on Days 1, 8, 15, 22 of each Cycle until disease 
progression or unacceptable toxicity.  If dexamethasone dosing requires a schedule adjustment of more than ± 2 days contact the medical monitor to 
discuss. 
l. Beginning C2D1, Investigator response assessments should be performed every 4 weeks, regardless of treatment delays. 
m.SPEP and UPEP will be collected at Screening and C1D1.  Samples will be submitted to a Central Laboratory (Phase 2b).  Refer to Section 7.5 for 
subsequent assessments.  If at any time CR is suspected, all assessments must be performed per IMWG guidelines. 
n. Required at Screening and Cycle 1 Day 1 and will be submitted to a Central Laboratory (Phase 2b).  Refer to Section 7.5 for subsequent assessments. If at 
any time CR is suspected, all assessments must be performed per IMWG guidelines.  
o. Required at Screening and Cycle 1 Day 1.  Additional test required to confirm CR, conducted at first observation of CR and then repeated at Day 1 of each 
cycle until progression.  
p. Either a low-dose whole-body CT or radiologic skeletal survey including the skull, antero-posterior and lateral views of the spine, and antero-posterior 
views of the pelvis, ribs, femora and humeri will be performed for evaluation of bone lesions.  Assessments to be done within 50 days of C1D1.  MRI, CT 
or PET/CT scans are to be performed if clinically indicated.  If evidence of plasmacytoma is noted on imaging at Screening, subsequent response 
assessments must include follow-up assessments every 3 months. 
q. To be submitted at Screening and confirmation of CR to a local laboratory to evaluate for morphology and document bone marrow involvement.  Bone 
marrow aspirate will be evaluated by FISH (Phase 1: performed locally; Phase 2b: performed centrally).  Refer to Section 7.5.7 for additional information.  


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r. After disease progression, subjects will be contacted to assess survival status approximately every 12 weeks (±14 days). 
After ibrutinib treatment is discontinued all information on first subsequent anti-cancer therapy will be collected  to include: start date and indication for 
initiation of subsequent anti-cancer therapy. 
s. Hematology (WBC, RBC, Hgb, Hct, platelet count, neutrophils, lymphocytes, monocytes, eosinophils, basophils and bands if reported).  C1D1 testing not 
required if done within 48 hours prior to the first dose of study drug. All assessments will be performed by the local laboratory.   
t. Chemistry (sodium, potassium, chloride, BUN/urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, 
LDH, phosphate, and uric acid, and magnesium).  C1D1 testing not required if done within 48 hours prior to the first dose of study drug. All assessments 
will be performed by the local laboratory. 
u. Creatinine clearance is only required during Screening.  
v. Must be done in accordance with Celgene POMALYST REMS™, RevAid®, or global Pregnancy Prevention Program (PPP) guidelines for females of 
childbearing potential (FCBP) only.  Serum or urine depending on site standard method.  If positive at Screening Visit, the subject is not eligible.  A FCBP 
is a female who: 1) has achieved menarche at some point; or 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at 
any time in the preceding 24 consecutive months).  Pregnancy tests must occur within 10–14 days and again within 24 hours prior to initiation of Cycle 1 of 
pomalidomide.  A FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on 
pomalidomide therapy (including breaks in therapy); at discontinuation of pomalidomide and at Day 28 post the last dose of pomalidomide.  A FCBP with 
irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on pomalidomide therapy (including breaks in 
therapy), at discontinuation of pomalidomide and at Day 14 and Day 28 following the last dose of pomalidomide.  To allow for drug delivery in the US, 
pregnancy testing can be done on Days 22-28 of each cycle. 
w.If abnormal, further testing should be performed as clinically appropriate.  Testing will be performed at Screening and at EOT visits by local laboratory.  
Testing at additional time points may be performed at the Investigator’s discretion. 
x. Assessments pre- and postdose Ibrutinib or placebo and pomalidomide, see Table 7.  Ibrutinib will be administered in the treatment center on C1D15 and 
C2D15.  Time of dose is to be recorded in the medical record for PK evaluation. For C1D15 and C2D15, record time of last meal prior to administration of 
study treatment.  
y. Blood sample for 4-β-hydroxycholesterol will be drawn at Screening, pre-dose on Cycles 1 and 2 Day 15, and 6 hrs postdose on Cycles 1-2 Day 15.   
z. An additional bone marrow aspirate (6 mL) to be collected for biomarker testing and submitted to a central lab at Screening, at the time of CR, and 
following confirmed PD (may be done at EOT or prior to the start of new anti-cancer therapy).  Refer to Section 7.5.7 for additional information.  
aa.Biomarker serum CTX collections require 12 hour fasting prior to collection. 
bb.T/B/NK must be collected predose (Phase 1 only). 
cc.Hepatitis serologies including Hepatitis C antibody, Hepatitis B surface antigen, and Hepatitis B core antibody will be evaluated at Screening.  If Hepatitis B 
core antibody, Hepatitis B surface antigen or Hepatitis C antibody is positive, then PCR to quantitate Hepatitis B/C must be performed and must be negative 
prior to randomization/enrollment.   
 


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


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Appendix 3. 
Cockcroft-Gault Formula for Estimating Creatinine Clearance 
 
 
Ccr = 
(140 – age) x Body Weight (kg) 
(Serum creatinine mg/dL) x 72 
 
Note: 
• 
Multiply by 0.85 for women 
• 
Use with caution in cirrhosis and muscle wasting 
• 
To convert µmol (micromoles)/L of creatinine to mg/dL, divide by 88.4. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41.  


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Appendix 4. 
Lines of Therapy 
 
According to the IMWG Consensus panel on uniform reporting criteria in clinical trials 
(Rajkumar 2011), a line of therapy consists of at least 1 or more cycles of a planned treatment 
regimen. This may consist of single-agent or combination therapy or a sequence of treatments 
administered in a planned manner. For example, a planned induction, followed by autologous 
stem cell transplant (ASCT) followed by maintenance is considered one line of therapy. A new 
line of therapy starts when a planned course is modified as a result of progression, relapse or 
toxicity or when a planned period of observation is interrupted by the need for additional 
treatment of the disease. Modification of drug doses or resuming therapy after holding will not 
be considered a new line of therapy provided that there was no evidence of progression of 
disease as defined in the “Response Criteria” section of this document. 
 
 


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Appendix 5. 
Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows.  Refer to Section 6.1.2.1 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 CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone  
telithromycin 
rifabutin  
boceprevir 
rifampin  
cobicistat 
St. John’s Wort  
mibefradil 
troglitazone  
posaconazolea 
 
telaprevir 
 
troleandomycin 
 
Moderate inhibitors: 
 
aprepitant 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
amiodarone 
 
amprenavir 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir 
 
dronedarone 
 
fosamprenavir 
 
imatinib 
 
voriconazolea 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
Chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
a. 
Classification based on internal data. 
 
 


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Appendix 6. 
QT Drugs by Risk Group  
QT-prolonging drugs grouped by risk of torsades, possible risk of torsades, and conditional risk 
of torsades are included in the tables below.  
Risk for Torsades de Pointes and/or QT prolongation 
Drugs that are generally accepted by the QTdrugs.org Advisory Board of the Arizona CERT to 
have a risk of causing torsades de pointes are listed below.  
Generic Name 
Class/Clinical Use 
Comments 
Amiodarone  
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males,TdP risk regarded as 
low 
Arsenic trioxide  
Anti-cancer / Leukemia 
 
Astemizole  
Antihistamine / Allergic rhinitis 
No Longer available in U.S. 
Bepridil  
Anti-anginal / heart pain 
Females>Males 
Chloroquine 
Anti-malarial / malaria infection 
 
Chlorpromazine  
Anti-psychotic/ Anti-emetic / 
schizophrenia/ nausea 
 
Cisapride 
GI stimulant / heartburn 
Restricted availability; 
Females>Males. 
Clarithromycin 
Antibiotic / bacterial infection 
 
Disopyramide  
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Dofetilide  
Anti-arrhythmic / abnormal heart 
rhythm 
 
Domperidone 
Anti-nausea / nausea 
Not available in the U.S. 
Droperidol  
Sedative;Anti-nausea / anesthesia 
adjunct, nausea 
 
Erythromycin  
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility 
Females>Males 
Halofantrine  
Anti-malarial / malaria infection 
Females>Males 
Haloperidol  
Anti-psychotic / schizophrenia, 
agitation 
When given intravenously (IV) or at 
higher-than- recommended doses, 
risk of sudden death, QT 
prolongation and torsades increases.  
Ibutilide 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Levomethadyl 
Opiate agonist / pain control, 
narcotic dependence 
 
Mesoridazine 
Anti-psychotic / schizophrenia 
 
Methadone 
Opiate agonist / pain control, 
narcotic dependence 
Females>Males 
Moxifloxacin  
Antibiotic / bacterial infection 
 
Pentamidine  
Anti-infective / pneumocystis 
pneumonia 
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Generic Name 
Class/Clinical Use 
Comments 
Pimozide 
Anti-psychotic / Tourette's tics 
Females>Males 
Probucol 
Antilipemic / Hypercholesterolemia 
No longer available in U.S. 
Procainamide  
Anti-arrhythmic / abnormal heart 
rhythm 
 
Quinidine 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Sotalol  
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Sparfloxacin  
Antibiotic / bacterial infection 
 
Terfenadine 
Antihistamine / Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Anti-psychotic / schizophrenia 
 
Revised:  06/06/2011. 
Printed:  02/24/2012. 
Source:  www.QTdrugs.org. 
 
Possible Risk for Torsades de Pointes and/or QT Prolongation 
Drugs that in some reports have been associated with torsades de pointes and/or QT prolongation 
but at this time lack substantial evidence for causing torsades de pointes are listed below. 
Generic Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Alpha1-blocker / Benign prostatic 
hyperplasia 
 
Amantadine 
Dopaminergic/Anti-viral / Anti-
infective/ Parkinson's Disease 
 
Atazanavir 
Protease inhibitor / HIV 
 
Azithromycin 
Antibiotic / bacterial infection 
 
Chloral hydrate 
Sedative / sedation/ insomnia 
 
Clozapine 
Anti-psychotic / schizophrenia 
 
Dolasetron 
Anti-nausea / nausea, vomiting 
 
Dronedarone 
Anti-arrhythmic / Atrial Fibrillation 
 
Escitalopram 
Anti-depressant / Major depression/ 
Anxiety disorders 
 
Felbamate  
Anti-convulsant / seizure 
 
Flecainide 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Foscarnet  
Anti-viral / HIV infection 
 
Fosphenytoin 
Anti-convulsant / seizure 
 
Gatifloxacin 
Antibiotic / bacterial infection 
 
Gemifloxacin 
Antibiotic / bacterial infection 
 
Granisetron 
Anti-nausea / nausea and vomiting 
 
Indapamide 
Diuretic / stimulate urine & salt loss 
 


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Generic Name 
Class/Clinical Use 
Comments 
Isradipine 
Anti-hypertensive / high blood 
pressure 
 
Lapatinib 
Anti-cancer / breast cancer, 
metastatic 
 
Levofloxacin 
Antibiotic / bacterial infection 
 
Lithium 
Anti-mania / bipolar disorder 
 
Moexipril/HCTZ  
Anti-hypertensive / high blood 
pressure 
 
Nicardipine  
Anti-hypertensive / high blood 
pressure 
 
Nilotinib 
Anti-cancer / Leukemia 
 
Octreotide  
Endocrine / acromegaly, carcinoid 
diarrhea 
 
Ofloxacin 
Antibiotic / bacterial infection 
 
Ondansetron 
Anti-emetic / nausea and vomiting 
 
Oxytocin 
Oxytocic / Labor stimulation 
 
Paliperidone 
Antipsychotic, atypical / 
Schizophrenia 
 
Perflutren lipid microspheres 
Imaging contrast agent / 
Echocardiography 
 
Quetiapine  
Anti-psychotic / schizophrenia 
 
Ranolazine 
Anti-anginal / chronic angina 
 
Risperidone  
Anti-psychotic / schizophrenia 
 
Roxithromycin* 
Antibiotic / bacterial infection 
*not available in the United States 
Sertindole 
Antipsychotic, atypical / Anxiety, 
Schizophrenia 
 
Sertindole 
Antipsychotic, atypical / Anxiety, 
Schizophrenia 
 
Sunitinib 
Anti-cancer / RCC, GIST 
 
Tacrolimus  
Immunosuppressant / Immune 
suppression 
 
Tamoxifen  
Anti-cancer / breast cancer 
 
Telithromycin 
Antibiotic / bacterial infection 
 
Tizanidine  
Muscle relaxant /  
 
Vardenafil 
phosphodiesterase inhibitor / 
vasodilator 
 
Venlafaxine  
Anti-depressant / depression 
 
Voriconazole 
Anti-fungal / anti-fungal 
 
Ziprasidone 
Anti-psychotic / schizophrenia 
 
Revised:  12/21/2011.  
Printed:  02/24/2012.  
Source:  www.QTdrugs.org. 


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Conditional Risk for Torsades de Pointes and/or QT Prolongation 
Drugs that, in some reports, have been weakly associated with torsades de pointes and/or QT 
prolongation but that are unlikely to be a risk for torsades de pointes when used in usual 
recommended dosages and in subjects without other risk factors (e.g., concomitant QT 
prolonging drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, 
concomitant drugs that inhibit metabolism) are listed below.  
Generic Name 
Class/Clinical Use 
Comments 
Amitriptyline 
Tricyclic Antidepressant / depression 
 
Ciprofloxacin 
Antibiotic / bacterial infection 
 
Citalopram 
Anti-depressant / depression 
 
Clomipramine 
Tricyclic Antidepressant / depression 
 
Desipramine 
Tricyclic Antidepressant / depression 
 
Diphenhydramine 
Antihistamine / Allergic rhinitis, 
insomnia 
 
Doxepin 
Tricyclic Antidepressant / depression 
 
Fluconazole 
Anti-fungal / fungal infection 
 
Fluoxetine  
Anti-depressant / depression 
 
Galantamine 
Cholinesterase inhibitor / Dementia, 
Alzheimer's 
 
Imipramine 
Tricyclic Antidepressant / depression 
 
Itraconazole 
Anti-fungal / fungal infection 
 
Ketoconazole 
Anti-fungal / fungal infection 
 
Nortriptyline 
Tricyclic Antidepressant / depression 
 
Paroxetine 
Anti-depressant / depression 
 
Protriptyline 
Tricyclic Antidepressant / depression 
 
Ritonavir 
Protease inhibitor / HIV 
 
Sertraline 
Anti-depressant / depression 
 
Solifenacin 
muscarinic receptor anatagonist / 
treatment of overactive bladder 
 
Trazodone 
Anti-depressant / Depression, insomnia 
 
Trimethoprim-Sulfa 
Antibiotic / bacterial infection 
 
Trimipramine 
Tricyclic Antidepressant / depression 
 
Revised:  03/30/2010.  
Printed:  05/25/2011.  
Source:  www.QTdrugs.org. 
 
Drugs on the QT Drug Lists are reviewed on an ongoing basis to assure the evidence is still 
appropriate for their placement on their respective list.  


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Appendix 7. 
International Myeloma Working Group Response Criteria 
(Rajkumar 2011) 
IMWG Response Criteria 
CATEGORY 
RESPONSE CRITERIA a 
Stringent complete 
response (sCR)   
CR as defined below plus all of the following: 
• 
Normal serum FLC ratio  
• 
Absence of clonal cells in bone marrow by IHC or immunofluorescence b 
Complete response 
(CR) 
• 
Negative immunofixation of the serum and urine  
• 
<5% plasma cells in bone marrow  
• 
Disappearance of any soft tissue plasmacytomas  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
normalization of FLC ratio 
Very good partial 
response (VGPR) 
• 
PR as defined below plus all of the following: 
• 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
• 
If at on study, serum measurable, ≥90% or greater reduction in serum 
M-component plus urine M-component <100 mg per 24 h  
Partial Response (PR) 
• 
One of the following: 
 If at on study, serum and urine measurable, a ≥50% reduction of serum 
M-protein and reduction in 24-h urinary M-protein by ≥90% or to 
<200 mg per 24 h  
 If at on study, only serum measurable (but urine not), a ≥ 50% reduction 
of serum M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24-h 
urinary M-protein by ≥90% or to <200 mg per 24 h  
• 
In addition to the above criteria, if a plasmacytoma present at baseline, 
≥50% reduction in the size of soft tissue plasmacytomas is also required 
Minimal Response 
(MR) 
• 
≥25% but ≤49% reduction of serum M-protein and reduction in 24h urine 
M-protein by 50-89% 
• 
In addition to the above criteria, if a plasmacytoma present at baseline,  
25-49% reduction in the size of soft tissue plasmacytomas is also required 
• 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response) 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
 
 


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IMWG Response Criteria 
CATEGORY 
RESPONSE CRITERIA a 
Progressive disease 
(PD) 
Any one or more of the following:  
• 
Increase of 25% from lowest value in d: 
 Serum M-component (absolute increase must be ≥0.5 g/dL)c  
 Serum M-component increase ≥1 g/dL, if starting M component 
was ≥5 g/dL 
 Urine M-component (absolute increase must be ≥200 mg/24 h) c 
Or any one or more of the following felt related to the underlying clonal 
plasma cell proliferative disorder 
 Development of new soft tissue plasmacytomas or bone lesions 
 Hypercalcemia (corrected serum calcium ≥11.5 mg/dL) 
a All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; CR and PR, MR and SD categories also require no known evidence of progressive or new bone lesions 
if radiographic studies were performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments need not be confirmed. 
b Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  ratio by IHC and/or 
immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/  of >4:1 or <1;2.  
c Positive immunofixation alone in a subject previously classified as CR will not be considered progression. 
d In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab 
error), that value will not be considered when determining the lowest value. 
Confirmation of Response Categories  
In order to be classified as a hematologic response, confirmation of serum monoclonal protein, and urine 
monoclonal protein (when primary determinant of response) results must be made by verification on two 
consecutive determinations.  Confirmation assessments may be performed at any time after the initial 
assessment.   
• 
Bone marrow aspirate/biopsy is only required to document CR.  However, a second confirmatory 
bone marrow is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements; however, if radiographic 
studies were performed there should be no evidence of progressive or new bone lesions. 
Measurable disease  
o Serum M-protein ≥1 g/dL  
o Urine M-protein ≥ 200 mg/24 h 
 
For Phase 2b the primary efficacy evaluations are based on IRC assessment.  The IRC assessment will 
incorporate assessments from the central laboratory and additional assessments (as indicated) based upon 
evaluations outlined in Section 7.5 Details regarding the IRC evaluation for response and progression will 
be outlined in a separate charter. 


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Appendix 8. 
Pomalidomide Pregnancy Prevention Risk Plan (For Ex-US Sites Only) 
1. Pomalidomide Pregnancy Prevention Plan for Subjects in Clinical Trials
The Pregnancy Prevention Plan (PPP) applies to all subjects receiving pomalidomide within a 
clinical trial. The following PPP documents are included:  
1. The Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 2) provides the following 
information:
•
Potential risks to the fetus associated with pomalidomide exposure
•
Definition of female of childbearing potential (FCBP)/female not of childbearing
potential (FNCBP)
•
Requirements for counseling of all subjects receiving pomalidomide about pregnancy
precautions and the potential risks of fetal exposure to pomalidomide
•
Acceptable birth control methods for both female subjects of childbearing potential
and male subjects receiving pomalidomide in the study
•
Pregnancy testing requirements for subjects receiving pomalidomide who are FCBP
2. The Pomalidomide Education and Counseling Guidance Document for each gender
(female and male; Section 3 and Section 4 respectively) must be completed and signed by
a trained counselor at the participating clinical center prior to each dispensing of
pomalidomide. A copy of this document must be maintained in the subject’s records for
each dispense.
3. The Pomalidomide Information Sheet Section 5 will be given to each subject receiving
pomalidomide. The subject must read this document prior to starting pomalidomide and
each time the subject receives a new supply of pomalidomide.
2. Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and
Acceptable Birth Control Methods
2.1.1. Risks Associated with Pregnancy 
Pomalidomide was teratogenic in both rats and rabbits when administered during the period of 
organogenesis. Pomalidomide is an analogue of thalidomide. Thalidomide is a known human 
teratogen that causes severe life-threatening human birth defects. If pomalidomide is taken 
during pregnancy, it can cause birth defects or death to an unborn baby. 
The teratogenic effect of pomalidomide in humans cannot be ruled out. Therefore, a pregnancy 
prevention program must be followed. 


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2.1.2. Definition of Females of Childbearing Potential 
A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a 
hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). 
2.1.3. Definition of Females Not of Childbearing Potential 
Females who do not meet the above definition of FCBP should be classified as FNCBP. 
2.2. 
Counseling 
2.2.1. Females of Childbearing Potential 
For a FCBP, pomalidomide is contraindicated unless all of the following are met (ie, all FCBP 
must be counseled concerning the following risks and requirements prior to the start of 
pomalidomide):  
• She understands the potential teratogenic risk to the unborn child 
• She understands the need for effective contraception, without interruption, 28 days 
before starting pomalidomide, throughout the entire duration of pomalidomide, 
during dose interruptions and for at least 28 days after the last dose of pomalidomide 
• She understands and agrees to inform the Investigator if a change or stop of method 
of contraception is needed 
• She must be capable of complying with effective contraceptive measures 
• She is informed and understands the potential consequences of pregnancy and the 
need to notify her study doctor immediately if there is a risk of pregnancy 
• She understands the need to commence pomalidomide as soon as it is dispensed 
following a negative pregnancy test 
• She understands and accepts the need to undergo pregnancy testing based on the 
frequency outlined in this plan (Section 2.4 of Appendix 8) and in the Informed 
Consent 
• She acknowledges that she understands the hazards pomalidomide can cause to an 
unborn fetus and the necessary precautions associated with the use of pomalidomide. 
The Investigator must ensure that a FCBP: 
• Complies with the conditions of the pregnancy prevention plan, including 
confirmation that she has an adequate level of understanding 
• Acknowledges the aforementioned requirements. 


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2.2.2. Females Not of Childbearing Potential 
For a FNCBP, pomalidomide is contraindicated unless all of the following are met (ie, all 
FNCBP must be counseled concerning the following risks and requirements prior to the start of 
pomalidomide):  
• She acknowledges she understands the hazards pomalidomide can cause to an unborn 
fetus and the necessary precautions associated with the use of pomalidomide. 
2.2.3. Males 
The effect of pomalidomide on sperm development is not known and has not been studied. 
The risk to an unborn baby in females of child bearing potential whose male partner is receiving 
pomalidomide is unknown at this time. Therefore, male subjects taking pomalidomide must meet 
the following conditions (ie, all males must be counseled concerning the following risks and 
requirements prior to the start of pomalidomide): 
• Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a FCBP 
• Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a FCBP 
• Understand the potential teratogenic risk if the subject donates semen or sperm. 
2.3. 
Contraception 
2.3.1. Female Subjects of Childbearing Potential 
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting pomalidomide; 2) while 
taking pomalidomide; 3) during dose interruptions; and 4) for at least 28 days after the last dose 
of pomalidomide.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate for 
the FCBP, she must be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the subject. The following are examples 
of highly effective and additional effective methods of contraception: 
• Examples of highly effective methods: 
− Intra-uterine device (IUD) 
− Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel]) 


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− Tubal ligation 
− Partner’s vasectomy 
• Examples of additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
Because of the increased risk of venous thromboembolism in subjects with MM taking 
pomalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a 
subject is currently using combined oral contraception the subject should switch to another one 
of the highly effective methods listed above. The risk of venous thromboembolism continues for 
4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive 
steroids may be reduced during co-treatment with dexamethasone.  
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia.  
2.3.2. Male Subjects 
Male subjects must practice complete abstinence (True abstinence is acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) or agree to use a condom during sexual contact with a pregnant female or a 
FCBP while taking pomalidomide, during dose interruptions and for at least 28 days after the last 
dose of pomalidomide, even if he has undergone a successful vasectomy.  
2.4. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP. 
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting pomalidomide. The first pregnancy test must be performed within 
10 to 14 days prior to the start of pomalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of pomalidomide. The subject may not receive 
pomalidomide until the study doctor has verified that the results of these pregnancy tests are 
negative. 
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking pomalidomide, at study discontinuation, and at Day 28 following the last dose of 
pomalidomide.  


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Females of childbearing potential with irregular menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 14 days while taking 
pomalidomide, at study discontinuation, and at Days 14 and 28 following the last dose of 
pomalidomide.  
2.5. 
Pregnancy Precautions for Pomalidomide Use 
2.5.1. Before Starting Pomalidomide 
Female Subjects of Childbearing Potential 
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting pomalidomide. The first pregnancy test must be performed within 
10 to 14 days prior to the start of pomalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of pomalidomide. The subject may not receive 
pomalidomide until the study doctor has verified that the results of these pregnancy tests are 
negative. 
Females of childbearing potential must use two reliable forms of contraception simultaneously, 
or practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact for at least 28 days before starting pomalidomide. 
Male Subjects 
Male subjects must agree to practice complete abstinence (True abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
[eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or agree to use a condom during sexual contact with a 
pregnant female or a FCBP while taking pomalidomide, during dose interruptions and for at least 
28 days after the last dose of pomalidomide, even if he has undergone a successful vasectomy.  
2.5.2. During and After Study Participation 
Female Subjects 
• Females of childbearing potential with regular or no menstrual cycles must agree to 
have pregnancy tests weekly for the first 28 days of study participation and then every 
28 days while taking pomalidomide, at study discontinuation, and at Day 28 
following the last dose of pomalidomide.  
• Females of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 
14 days while taking pomalidomide, at study discontinuation, and at Days 14 and 
28 following the last dose of pomalidomide.  


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• At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control if not committing to complete abstinence, or 
confirm commitment to complete abstinence. 
• If a FCBP considers the need to change or to stop a method of contraception, the 
Investigator must be notified immediately. 
• Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days.  
• If pregnancy or a positive pregnancy test does occur in a subject, pomalidomide must 
be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a subject misses her period or 
if her pregnancy test or her menstrual bleeding is abnormal. Pomalidomide must be 
discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding while taking pomalidomide and for 
at least 28 days after the last dose of pomalidomide. 
Male Subjects 
• Must practice complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or use a condom during sexual contact with a 
pregnant female or a FCBP while receiving pomalidomide, during dose interruptions 
and for at least 28 days after the last dose of pomalidomide, even if he has undergone 
a successful vasectomy. 
• Must not donate semen or sperm while receiving pomalidomide, during dose 
interruptions or for at least 28 days after the last dose of pomalidomide. 
• Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days. 
• If pregnancy or a positive pregnancy test does occur in the partner of a male subject 
while taking pomalidomide, the Investigator must be notified immediately. 
2.5.3. Additional Precautions 
• Subjects should be instructed to never give pomalidomide to another person. 
• Subjects should be instructed to return any unused capsules to the study doctor. 
• Subjects should not donate blood while receiving pomalidomide, during dose 
interruptions and for at least 28 days after the last dose of pomalidomide. 
• No more than a 28-day pomalidomide supply may be dispensed with each cycle of 
pomalidomide.  
 
 


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3. Pomalidomide Education and Counseling Guidance Document for Female Subjects 
To be completed prior to each dispensing of pomalidomide. 
Protocol Number: ____________________________________________ 
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy) 
Check one risk category: 
 FCBP (Female of childbearing potential): a female who: 1) has achieved menarche 
(first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of 
both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time during the preceding 24 consecutive months) 
 NOT FCBP 
3.1. 
Female of Childbearing Potential: 
I have verified and counseled the subject regarding the following: 
 Potential risk of fetal exposure to pomalidomide: A teratogenic potential of 
pomalidomide in humans cannot be ruled out. If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are 
advised to avoid pregnancy while taking pomalidomide. Females of childbearing 
potential must agree not to become pregnant while taking pomalidomide.  
That the required pregnancy tests performed are negative. 
 The subject confirmed that she is using TWO reliable methods of birth control at the 
same time, or complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) from heterosexual contact (at least 28 days 
prior to receiving pomalidomide, while receiving pomalidomide, during dose 
interruptions and for at least 28 days after the last dose of pomalidomide).  
One highly effective method and one additional method of birth control must be used 
AT THE SAME TIME. The following are examples of highly effective and 
additional effective methods of contraception: 
− Examples of highly effective methods: 
− Intra-uterine device (IUD) 
− Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel]) 
− Tubal ligation 
− Partner’s vasectomy 


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− Examples of additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
 The subject confirmed that even if she has amenorrhea she must comply with advice 
on contraception. 
 Pregnancy tests before, during administration of pomalidomide and at the last dose of 
pomalidomide, even if the subject agrees not to have reproductive heterosexual 
contact. 
 Frequency of pregnancy tests to be done: 
− Two pregnancy tests will be performed prior to receiving pomalidomide, one 
within 10 to 14 days, and a second within 24 hours of the start of pomalidomide. 
− Every week during the first 28 days of this study and a pregnancy test every 
28 days while the subject is taking pomalidomide if menstrual cycles are regular.  
− Every week during the first 28 days of this study and a pregnancy test every 
14 days while the subject is taking pomalidomide if menstrual cycles are 
irregular. 
− If the subject missed a period or has unusual menstrual bleeding.   
− When the subject is discontinued from the study and at Day 28 after the last dose 
of pomalidomide if menstrual cycles are regular. If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at Days 14 and 
28 after the last dose of pomalidomide. 
 The subject confirmed that she will stop taking pomalidomide immediately in the 
event of becoming pregnant and to call her study doctor as soon as possible.  
 The subject confirmed that she has not and will not breastfeed a baby while taking 
pomalidomide and for at least 28 days after the last dose of pomalidomide. 
 The subject has not and will never share pomalidomide with anyone else. 
 The subject has not and will not donate blood while taking pomalidomide, during 
dose interruptions and for at least 28 days after the last dose of pomalidomide. 
 The subject has not and will not break, chew, or open pomalidomide capsules at any 
point. 
 The subject confirmed that she will return unused pomalidomide capsules to the study 
doctor. 
I have provided the Pomalidomide Information Sheet to the subject. 
 


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3.2. 
 Female Not of Childbearing Potential (Natural Menopause for at Least 24 
Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy): 
I have verified and counseled the subject regarding the following: 
 Potential risk of fetal exposure to pomalidomide: A teratogenic potential of 
pomalidomide in humans cannot be ruled out. If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. 
 The subject has not and will never share pomalidomide with anyone else. 
 The subject has not and will not donate blood while taking pomalidomide, during 
dose interruptions and for at least 28 days after the last dose of pomalidomide. 
 The subject has not and will not break, chew, or open pomalidomide capsules at any 
point. 
 The subject confirmed that she will return unused pomalidomide capsules to the study 
doctor. 
I have provided the Pomalidomide Information Sheet to the subject. 
Do Not Dispense Pomalidomide if: 
• The subject is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The subject states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence from heterosexual contact) at least 28 days prior 
to receiving pomalidomide, while receiving pomalidomide and during dose 
interruptions. 
• The subject stated that she has or does not want to adhere to pregnancy 
precautions outlined within this PPP. 
 
Counselor Name (Print): ____________________ 
 
Counselor Signature: _______________________Date: _____/_____/_____(dd/mmm/yyyy) 
 
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.** 
 
 
 
 


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4. Pomalidomide Education and Counseling Guidance Document for Male Subjects 
To be completed prior to each dispensing of pomalidomide. 
Protocol Number: ____________________________________________ 
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy) 
 
I have verified and counseled the subject regarding the following: 
 Potential risk of fetal exposure to pomalidomide: A teratogenic potential of pomalidomide in 
humans cannot be ruled out. If pomalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby. 
 The subject confirmed that he has practiced complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and 
withdrawal are not acceptable methods of contraception.) or used a condom when engaging 
in sexual contact (including those who have had a vasectomy) with a pregnant female or 
FCBP, while taking pomalidomide, during dose interruptions and for at least 28 days after 
the last dose of pomalidomide. 
 The subject confirmed that he has not impregnated his female partner while in the study. 
 The subject confirmed that he will notify his study doctor if his female partner becomes 
pregnant and the female partner of a male subject taking pomalidomide confirmed that she 
will call her healthcare provider immediately if she becomes pregnant. 
 The subject has not and will never share pomalidomide with anyone else. 
 The subject confirmed that he has not donated and will not donate semen or sperm while 
taking pomalidomide or during dose interruptions and that he will not donate semen or sperm 
for at least 28 days after the last dose of pomalidomide. 
 The subject has not and will not donate blood while taking pomalidomide, during dose 
interruptions and for at least 28 days after the last dose of pomalidomide. 
 The subject has not and will not break, chew, or open pomalidomide capsules at any point. 
 The subject confirmed that he will return unused pomalidomide capsules to the study doctor. 
I have provided the Pomalidomide Information Sheet to the subject. 
Do Not Dispense Pomalidomide if: 
• 
The subject stated that he has or does not want to adhere to pregnancy precautions 
outlined within this PPP. 
Counselor Name (Print): ____________________ 
Counselor Signature: _______________________ Date: _____/_____/_____(dd/mmm/yyyy) 
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.** 


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5. Pomalidomide Information Sheet  
For subjects enrolled in clinical research studies  
Please read this Pomalidomide Information Sheet before you start taking pomalidomide and each 
time you get a new supply. This Pomalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment.   
What is the most important information I should know about pomalidomide? 
Pomalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Pomalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects. Pomalidomide has not been tested in pregnant 
women but may also cause birth defects. Pomalidomide was found to cause birth defects 
when tested in pregnant rats and rabbits. 
If you are a female who is able to become pregnant: 
• Do not take pomalidomide if you are pregnant or plan to become pregnant 
• You must practice complete abstinence from sexual contact with a male or use 
two reliable, separate forms of effective birth control at the same time:  
− for 28 days before starting pomalidomide 
− while taking pomalidomide  
− during breaks (dose interruptions) of pomalidomide  
− for at least 28 days after the last dose of pomalidomide  
• You must have pregnancy testing done at the following times: 
− within 10 to 14 days prior to the first dose of pomalidomide 
− 24 hours prior to the first dose of pomalidomide  
− weekly for the first 28 days 
− if you have regular menstrual periods: every 28 days after the first month  
− if you have irregular menstrual periods: every 14 days after the first month 
− if you miss your period or have unusual menstrual bleeding 
− 28 days after the last dose of pomalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular) 
• Stop taking pomalidomide if you become pregnant while taking pomalidomide 
− If you suspect you are pregnant at any time during the study, you must stop 
pomalidomide immediately and immediately inform your study doctor. Your 
study doctor will report all cases of pregnancy to Celgene Corporation. 


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• Do not breastfeed while taking pomalidomide and for at least 28 days after the 
last dose of pomalidomide 
• The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not able to become pregnant: 
In order to ensure that an unborn baby is not exposed to pomalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a male: 
The effect of pomalidomide on sperm development is not known and has not been 
studied. The risk to an unborn baby in females whose male partner is receiving 
pomalidomide is unknown at this time.  
• Male subjects (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or a 
female that can become pregnant: 
− While you are taking pomalidomide  
− During breaks (dose interruptions) of pomalidomide  
− For at least 28 days after the last dose of pomalidomide   
• Male subjects should not donate sperm or semen while taking pomalidomide, 
during breaks (dose interruptions) and for at least 28 days after the last dose of 
pomalidomide.  
• If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to Celgene Corporation. Your partner should call their healthcare 
provider immediately if they become pregnant. 
1. All subjects: 
• Do not share pomalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
• Do not donate blood while you take pomalidomide, during breaks 
(dose interruptions) and for at least 28 days after the last dose of pomalidomide.  
• Do not break, chew, or open pomalidomide capsules at any point. 
• You will get no more than a 28-day supply of pomalidomide at one time. 
• Return unused pomalidomide capsules to your study doctor. 
Additional information is provided in the ICF and you can ask your study doctor for more 
information. 
 
 


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Appendix 9. 
International Staging System (ISS) for Myeloma Criteria 
Stage 
Criteria 
Stage 1 
β2-microglobulin <3.5 mg/dL 
Albumin ≥3.5g/dL 
Stage 2 
Neither 1 or 3 
Stage 3 
β2-microglobulin ≥5.5 mg/dL 
 
 
 


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Appendix 10. 
Child-Pugh Score 
Measure 
1 Point 
2 Points 
3 Points 
Total bilirubin, μmol/L 
(mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
PT INR 
<1.7 
1.71-2.30 
>2.3 
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:  
Child CG, Turcotte JG (1964) “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. pp. 50-64.   
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R (1973). “Transection of the oesophagus for 
bleeding oesophageal varices”. The British journal of surgery, 60 (8): 646-649. 
 
 


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Appendix 11. 
Thromboembolism Risk Assessment  
Individual Risk Factors 
Myeloma-related Risk 
Factors 
Myeloma Therapy 
Obesitya 
Diagnosis 
High-dose dexamethasoneb 
Previous venous thromboembolism 
Hyperviscosity 
Doxorubicin 
Central Venous catheter or pacemaker 
 
Multiagent chemotherapy 
Associated Disease 
• 
Cardiac disease 
• 
Chronic Renal Disease 
• 
Diabetes 
• 
Acute Infection 
• 
Immobilization 
 
 
Surgery 
• 
General Surgery 
• 
Any anesthesia 
• 
Trauma 
 
 
Medications 
• 
Erythropoietin 
 
 
Blood Clotting Disorders 
 
 
a. Obesity was defined as body mass index ≥30kgm-2  
b. ≥480 mg per month 
 
ACTIONS: 
• 
If no risk factor or any one risk factor is present: Aspirin 81-325 mg once daily 
• 
If two or more risk factors are present: LMWH (equivalent of enoxaparin 40 mg once daily) or full-dose 
warfarin (target INR 2-3) 
• 
If any Myeloma Therapy conditions apply: LMWH (equivalent of enoxaparin 40 mg once daily) or full-dose 
warfarin (target INR 2-3) 
 
Palumbo A, Rajkumar SV and Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-
associated thrombosis in myeloma. Leukemia 2008;22:414-423. 
 
 


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Appendix 12. 
EQ-5D-5L Health Questionnaire 
 
 
 


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Appendix 13. 
EORTC QLQ-MY20 
 
 
 


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SAP_001.pdf: 
 
PCYC-1138-CA 
Statistical Analysis Plan 
Page 1 of 12 
 
Version 2.0 
Proprietary and Confidential 
 
 
 
 
 
Statistical Analysis Plan 
 
 
A Randomized Multicenter Study of Ibrutinib in Combination with Pomalidomide and Dexamethasone in 
Subjects with Relapsed/Refractory Multiple Myeloma 
 
 
PCYC-1138-CA 
 
 
June 26, 2018 
Version 2.0 
 
 
The information in this document is considered privileged and confidential by Pharmacyclics LLC, and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review Board 
approval and informed consent, or as required by Federal and State Laws.  Persons to whom this 
information is disclosed must be informed that this information is privileged and confidential and that it 
should not be further disclosed. 
 
 
 
 
 








 
PCYC-1138-CA 
Statistical Analysis Plan 
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Version 2.0 
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Statistical Analysis Plan Approval 
 
Protocol Number:   
PCYC-1138-CA 
Protocol Title: 
A Randomized Multicenter Study of Ibrutinib in Combination 
with Pomalidomide and Dexamethasone in Subjects with 
Relapsed/Refractory Multiple Myeloma 
SAP Version:  
2.0 
Date: 
26JUN2018 
By signing below, all parties accept that the analysis methods and data presentations are 
acceptable and that this document is final. 
 
 
 
 
 
 
 
 
   
 
 
 
 
Yihua Lee, PhD 
 
 
   
 
Date (ddMMMyyyy) 
Associate Director, Biostatistics 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Edyta Dobkowska, MD 
 
 
  
Date (ddMMMyyyy) 
Medical Director, Clinical Science 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Thorsten Graef, MD      
 
               
Date (ddMMMyyyy) 
Head of Oncology 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Claire Tsao, PhD 
 
 
 
  
Date (ddMMMyyyy) 
Senior Director, Biostatistics 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Andreas Terjung 
  
               
   
Date (ddMMMyyyy)  
Senior Director, Regulatory Affairs 
 
 
____________________________________ 
__________________________ 
Harnisha Dalwadi, PhD 
 
 
 
Date (ddMMMyyyy) 
Senior Director, Medical Writing  
 
 
 
 
26Jun2018




 
PCYC-1138-CA 
Statistical Analysis Plan 
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Version 2.0 
Proprietary and Confidential 
 
Statistical Analysis Plan Approval 
 
Protocol Number:   
PCYC-1138-CA 
Protocol Title: 
A Randomized Multicenter Study of Ibrutinib in Combination 
with Pomalidomide and Dexamethasone in Subjects with 
Relapsed/Refractory Multiple Myeloma 
SAP Version:  
2.0 
Date: 
26JUN2018 
By signing below, all parties accept that the analysis methods and data presentations are 
acceptable and that this document is final. 
 
 
 
 
 
 
 
 
   
 
 
 
 
Yihua Lee, PhD 
 
 
   
 
Date (ddMMMyyyy) 
Associate Director, Biostatistics 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Edyta Dobkowska, MD 
 
 
  
Date (ddMMMyyyy) 
Medical Director, Clinical Science 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Thorsten Graef, MD      
 
               
Date (ddMMMyyyy) 
Head of Oncology 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Claire Tsao, PhD 
 
 
 
  
Date (ddMMMyyyy) 
Senior Director, Biostatistics 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
Andreas Terjung 
  
               
   
Date (ddMMMyyyy)  
Senior Director, Regulatory Affairs 
 
 
____________________________________ 
__________________________ 
Harnisha Dalwadi, PhD 
 
 
 
Date (ddMMMyyyy) 
Senior Director, Medical Writing  
 
 
 
 
29 June 2018


 
PCYC-1138-CA 
Statistical Analysis Plan 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................. 4 
1 
INTRODUCTION ............................................................................................. 5 
1.1 
Study Design – Phase 1..................................................................................................5 
1.2 
Objective/Endpoints of Study – Phase 1 ........................................................................6 
 
Primary Objective .............................................................................................6 
 
Secondary Endpoints ........................................................................................6 
1.3 
Sample Size Determination ............................................................................................6 
1.4 
Planned Analysis ............................................................................................................6 
 
Final Analysis ...................................................................................................6 
2 
GENERAL ANALYSIS CONSIDERATION ................................................. 6 
2.1 
Analysis Sets ..................................................................................................................6 
3 
SUBJECT INFORMATION ............................................................................. 8 
3.1 
Subject Disposition ........................................................................................................8 
3.2 
Demographics and Baseline Characteristics ..................................................................8 
3.3 
Concomitant Medications ..............................................................................................8 
3.4 
Extent of Exposure to Study Treatment .........................................................................8 
4 
ANALYSIS FOR ENDPOINTS ....................................................................... 9 
5 
SAFETY ASSESSMENTS .............................................................................. 10 
6 
CHANGES IN PROTOCOL PLANNED ANALYSIS ................................ 11 
7 
REFERENCES ................................................................................................. 12 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
CBR 
clinical benefit rate 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCB 
Duration of Clinical Benefit  
DOR 
duration of overall response 
Hgb 
hemoglobin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minimal response 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PCYC 
Pharmacyclics 
PD 
progressive disease 
PR 
partial response 
PT 
preferred term 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse events 


 
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1 
INTRODUCTION 
The Study PCYC-1138-CA consisted of a Phase 1 and a Phase 2 part.  After completion of the 
Phase 1 part, in which 11 subjects received study treatment, the sponsor decided to not pursue an 
indication for treatment of patients with multiple myeloma with ibrutinib and therefore terminate 
the study early. Thus, this statistical analysis plan (SAP) is to define only the key study elements 
for the Phase 1 part of the study including variable definitions, and statistical methods for 
analysis of data in evaluation of efficacy and safety.  Analyses of pharmacokinetics data will be 
addressed in a separate document. Biomarker analysis will not be performed due to early 
termination of the study. Throughout this SAP, “study treatment” and “study drug” are used 
interchangeably. 
Analysis methods specified in this document take precedence over those described in the study 
protocol should there be any difference.  
1.1 
Study Design – Phase 1  
The Phase 1 part of the study was an open-label, international, multicenter dose-finding study of 
the ibrutinib, pomalidomide and dexamethasone combination in subjects with relapsed/refractory 
multiple myeloma (MM). Up to 18 patients were to be enrolled in order to determine the 
maximum therapeutic dose/maximum administered dose (MTD/MAD). In the dose finding 
portion of the study, up to 2 cohorts were to be explored (Table 1). The study followed a 3+3+3 
dose escalation design. The MTD/MAD was defined as the highest dose level at which <33% (ie, 
≤ 1 of 6 or ≤ 2 of 9) of subjects in a cohort experience a study treatment related dose limiting 
toxicity (DLT). 
Table 1: Dosing Levels and Cohorts 
Dose Level 
Cohort 
Ibrutiniba 
Pomalidomideb 
Dexamethasonec 
-1 
-1 
420 mg once daily
4 mg
40 mg 
1 
(Starting Dose) 
1 
560 mg once daily 
4 mg 
40 mg 
2 
2 
840 mg once daily 
4 mg 
40 mg 
a. Ibrutinib was administered PO starting on Day 1 of Cycle 1, dosing was continuous thereafter (without 
interruption). 
b. Pomalidomide was administered PO on Days 1 – 21 of a 28-day cycle. 
c. Dexamethasone was administered PO once weekly. The dose was reduced to 20 mg weekly in those >75 years of 
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1.2 
Objective/Endpoints of Study – Phase 1  
 
Primary Objective  
o To determine the MTD)/ MAD of the ibrutinib, pomalidomide and dexamethasone 
combination. 
 
o To determine the safety and tolerability of ibrutinib in combination with pomalidomide 
and dexamethasone in subjects with relapsed/refractory MM. 
 
Secondary Endpoints 
o Overall response rate (ORR): partial response (PR) or better, per the International 
Myeloma Working Group (IMWG) response criteria (Rajkumar 2011)1,2,3  
o Duration of Response (DOR) 
o The clinical benefit rate (CBR) and its duration, defined as ≥ minimal response (MR) 
according to the IMWG response criteria 
o To evaluate the pharmacokinetics (PK) of ibrutinib and pomalidomide when given in 
combination with dexamethasone   
1.3 
 Sample Size Determination 
Phase 1: This was a standard 3+3+3 design to determine the MTD/MAD and toxicity profile of 
ibrutinib in combination with pomalidomide and dexamethasone.  Dose escalation were to 
follow the 3+3+3 principle and up to 2 cohorts were to be explored.  This study was not powered 
for comparison of treatment cohorts.  Up to 18 subjects were to be enrolled into the Phase 1 part 
of the study. 
1.4 
Planned Analysis 
 
Final Analysis  
The final analysis for the clinical study report will be conducted when all Phase 1 subjects have 
exited PCYC-1138-CA study.  The sponsor decided not to perform the Phase 2 part of the study 
following a decision not to pursue an indication for multiple myeloma for ibrutinib. 
2 
GENERAL ANALYSIS CONSIDERATION 
Subjects will be analyzed and summarized for safety and other selected endpoints.   
2.1 
Analysis Sets 
o Safety Population 
The safety population include subjects who have received any dose of study treatment. 


 
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o Response-Evaluable Population 
The response-evaluable population is defined as subjects who are in safety population 
and provided at least one post-baseline response (or disease) assessment.  All subjects in 
safety population received at least 1 post-baseline response assessment. 
 


 
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SUBJECT INFORMATION  
3.1 
Subject Disposition 
The disposition tables will include the following summaries. 
 Analysis population 
 Study Treatment Disposition and Discontinuation  
 Study Status, Duration of Treatment and Study Exit  
Time on study is defined as the interval between the date of first dose and the date of last known 
to have been alive. The Kaplan-Meier method will be used to estimate the median time on study 
with subjects who died being censored at death date. 
3.2 
Demographics and Baseline Characteristics 
Subject demographics, baseline characteristics and baseline disease characteristics will be 
summarized with descriptive statistics for the safety population. 
3.3 
Concomitant Medications 
Medications will be coded to Anatomical Therapeutic Chemical (ATC) class and the preferred 
drug name (hereafter referred as “preferred name”) per World Health Organization drug 
dictionary.  Listings will be provided to present the data. 
 
Concomitant CYP3A inhibitors and inducers taken any time while on study treatment (i.e., from 
the date of first dose through the date of last dose of the study treatment) will be summarized by 
ATC class and preferred term (PT). Each subject will be counted once for each PT, and each 
ATC class.     
3.4 
Extent of Exposure to Study Treatment 
Exposure to the 3 study drugs will be summarized for the safety population.  Descriptive 
statistics will be provided for the following data for each of the 3 drugs unless otherwise 
specified: treatment duration (month) and number (%) of subjects with dose reduction due to 
adverse events (AEs).     


 
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ANALYSIS FOR ENDPOINTS 
Analysis of secondary endpoints (Table 2) will be conducted on the safety population.   
Table 2:  Definitions and Analyses for Secondary Endpoints 
 
Endpoint 
Definition 
Analysis Method  
Secondary endpoints: 
 
 
Overall Response 
Rate (ORR) 
 
 
 
The proportion of subjects achieving a 
best overall response of PR or better 
per investigator assessment per IMWG 
at or prior to initiation of subsequent 
anticancer therapy 
ORR will be estimated and the 
corresponding 2-sided 95% exact 
binomial confidence interval will be 
calculated. 
 
 
 
Duration of 
Response (DOR) 
The time interval between the date of 
initial documentation of a response and 
the date of first documented evidence 
of PD, death, or date of censoring for 
the subjects not progressed/died. The 
censoring date is the last adequate 
tumor assessment date. 
A listing will be provided. 
 
 
 
Clinical Benefit 
Rate (CBR) 
The proportion of subjects achieving a 
best overall response of MR or better 
per investigator assessment per IMWG 
at or prior to initiation of subsequent 
anticancer therapy 
CBR will be estimated and the 
corresponding 2-sided 95% exact 
binomial confidence interval will be 
calculated. 
 
Note: DOR; duration of response; PD: disease progression; PR: partial response; MR: minimal response; 
IMWG: International Myeloma Working Group. 
 


 
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SAFETY ASSESSMENTS 
Safety data will be summarized for safety population unless otherwise indicated. Table 3 
summarizes the safety analyses to be carried out. AEs will be coded in accordance with the 
Medical Dictionary for Regulatory Activities (MedDRA). Severity of AEs were graded by the 
investigator according the NCI Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v4.03. A listing will be provided to indicate dose-limiting toxicity (DLT). 
In general, the treatment-emergent period is defined as the period from the date of the first dose 
of study treatment up to 30 days after the date of the last dose of study treatment or the day 
before initiation of subsequent anticancer therapy, whichever comes first. Treatment emergent 
AEs are those events that occur or worsen during the treatment-emergent period or that are 
related to the study treatment or events with a complete missing onset date but with a resolution 
date during the treatment phase.  
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE v4.03.  
Table 3:  Summary of Safety Assessments 
 
Assessment Type 
Definition   
Analysis Methods 
 
AE 
TEAEs, SAEs, non-serious TEAE, grade 3 
or worse TEAEs, related TEAEs, TEAEs 
leading to treatment discontinuation, TEAEs 
leading to dose reduction, TEAEs leading to 
death, protocol- defined events of special 
interest and other safety observations 
Descriptive summary 
statistics and/or listings 
Lab 
Worst post-baseline toxicity grade for 
selected CTCAE gradable hematology and 
chemistry.  Abnormalities in creatinine 
clearance, uric acid, and liver function  
Descriptive summary 
statistics and/or listings 
Vital Signs and other 
Observations Related to 
Safety 
SBP, DBP, weight, heart rate, new or 
worsened eye-related symptoms 
Descriptive summary 
statistics and/or listings 
Dose Limiting Toxicity 
(DLT) 
DLT 
Listing 
TEAE: treatment-emergent adverse event; SAE= serious adverse event; SBP: systolic blood pressure; DBP: 
diastolic blood pressure; CTCAE= Common Terminology Criteria for Adverse Events.  
 


 
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CHANGES IN PROTOCOL PLANNED ANALYSIS 
The following modifications to the protocol “Statistical Methods and Analysis” section is made 
due to the decision by sponsor to terminate the study early. 
1) Phase 2 part of the study was not initiated, therefore, the analysis for Phase 2 will not be 
performed. 
2) Biomarker analysis will not be performed due to early termination of the study. 
3) The secondary endpoint of the duration of clinical benefit response will not be performed 
due to the early termination of the study.  
 
 
 
 


 
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7 
REFERENCES 
1. Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug 
approvals for myeloma. Leukemia 2008; 22(2):231-239. 
2. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for 
multiple myeloma. Leukemia 2006; 20(9):1467-1473. 
3. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 
1. Blood 2011; 117(18): 4691-4695.