Clinical trial NCT01478581
Conditions: Multiple Myeloma
Keywords: PCI-32765 Multiple Myeloma Relapsed Refractory Multiple Myeloma Bruton's Tyrosine Kinase
Sponsor: Pharmacyclics LLC.
Start date: 2012-03-01; Completion date: 2018-08-01
Enrollment: 92 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine the efficacy of PCI-32765, both as a single agent and in combination with dexamethasone, in subjects with relapsed or relapsed and refractory Multiple Myeloma (MM)

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. PCI 32765 is a potent and specific inhibitor of Btk currently in Phase 2 clinical trials. The current study is designed and intended to determine the effects of PCI-32765 in subjects with MM.

Arms: arm 1: PCI-32765 420 mg per day arm 2: PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week arm 3: PCI-32765 840 mg per day arm 4: PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week
Interventions: intervention 1: PCI-32765 intervention 2: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
PCI-32765 (Ibrutinib) 
PCYC-1111-CA, Amendment 6 
 18 April 2016 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 1 
PROTOCOL 
Title: 
A Multicenter Phase 2 Study of the Bruton’s Tyrosine 
Kinase (Btk) Inhibitor, PCI-32765, in Subjects with 
Relapsed or Relapsed and Refractory Multiple Myeloma 
Protocol Number: 
PCYC-1111-CA 
IND Number: 
102688 
Study Drug: 
PCI-32765 
Sponsor: 
Pharmacyclics LLC  
995 East Arques Avenue 
Sunnyvale, CA 94085-4521 
Medical Monitor: 
Elizabeth Bilotti, MSN 
(408) 215-3400
Original Protocol Date: 
04 November 2011
Amendment 1 Date: 
05 September 2012
Amendment 2 Date:  
03 December 2012
Amendment 2.1 Date: 
16 January 2013
Amendment 3 Date: 
11 February 2013
Amendment 4 Date: 
14 March 2014
Amendment 5 Date: 
25 August 2015
Amendment 6 Date: 
18 April 2016
CONFIDENTIALITY STATEMENT 
This document is a confidential communication of Pharmacyclics LLC provided to clinical investigators, study 
centers, associated individuals, and the like under the terms of existing confidentiality agreements. For example, 
this document may be disclosed to appropriate Investigational Review Boards under the condition that they maintain 
confidentiality consistent with their application procedures. Your acceptance and use of this document is subject to 
the condition that no information contained herein will be published or disclosed without first obtaining written 
approval from Pharmacyclics LLC. If you do not agree to this condition, please return the document to 
Pharmacyclics LLC at the above address. 


PCI-32765 (Ibrutinib) 
PCYC-1111-CA, Amendment 6 
 18 April 2016 
Pharmacyclics LLC 
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PROTOCOL APPROVAL PAGE 
I have carefully read Protocol PCYC-1111-CA entitled “A Multicenter Phase 2 Study of the 
Bruton’s Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects with Relapsed or Relapsed and 
Refractory Multiple Myeloma.”  Amendment 6.  I agree to conduct this study as outlined herein 
and in compliance with good clinical practice (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that Pharmacyclics LLC (the Sponsor) and the Institutional Review 
Board (IRB) must approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
of Pharmacyclics LLC.  All data pertaining to this study will be provided to Pharmacyclics LLC.  
The policy of Pharmacyclics LLC requires that any presentation or publication of study data by 
clinical investigators be reviewed by Pharmacyclics LLC before release, as specified in the 
protocol. 
 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 
 
 


PCI-32765 (Ibrutinib) 
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STUDY SYNOPSIS 
Title: 
A Multicenter Phase 2 Study of the Bruton’s Tyrosine Kinase (Btk) Inhibitor, 
PCI-32765, in Subjects with Relapsed or Relapsed and Refractory Multiple 
Myeloma 
Protocol Number: 
PCYC-1111-CA 
Phase: 
2 
Duration of Study: 
Approximately Five Years  
Indication: 
Relapsed or relapsed and refractory multiple myeloma (MM) 
Study Drug and 
Comparator: 
PCI-32765 (ibrutinib) p.o. hard gelatin capsule and Dexamethasone p.o.  
No comparator is used in this study. 
Objectives: 
The primary objective of this study is to determine the efficacy of PCI-32765, 
both as a single agent and in combination with dexamethasone, in subjects with 
relapsed or relapsed and refractory MM as measured by the clinical benefit 
response rate (CBR), defined as the proportion of subjects who achieve 
stringent complete response (sCR), complete response (CR),very good partial 
response (VGPR), partial response (PR), or minimal response (MR) as 
assessed by the modified International Myeloma Working Group (IMWG) 
response criteria.  
Secondary objectives are to evaluate the efficacy of PCI-32765 in this 
population as assessed by the duration of clinical benefit (DCB; ≥MR), 
objective response rate (ORR; ≥PR), duration of objective response (DOR), 
and the safety and drug pharmacokinetics (PK).  
Exploratory objectives are to evaluate progression-free survival (PFS), 
time to progression (TTP), overall survival (OS). 
Study Design: 
This is a Phase 2, open-label, nonrandomized, multi-cohort, multicenter Simon 
2-stage study designed to assess the safety and efficacy of PCI-32765 in 
subjects with relapsed or relapsed and refractory MM.  
Treatment of PCI-32765 420 mg once daily in the original protocol 
(hereafter referred to as Cohort 1) was designed to detect a meaningful signal 
of activity while minimizing risk of continuing enrollment under null 
conditions.  Amendment 1 was designed to further explore the optimal regimen 
by increasing doses of PCI-32765 and/or by routine combination with low dose 
dexamethasone.   
Stage 1: 
• 
Up to eighteen (18) subjects will be enrolled to each Cohort 2, 3, 
and 4, for a maximum total of 54 subjects. 
• 
Stage 1 enrollment to Cohorts 3 and 4 may begin concurrently after 
Cohort 2 Stage 1 enrollment is complete.  If there is concurrent 
enrollment, Sponsor will implement centralized assignments into 
cohorts. 
 
 
 
 


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Stage 2: 
• 
If ≥ 3 CBRs are observed within Cohorts 2, 3, or 4 in Stage 1, 
the Cohort(s) may be selected for expansion for up to a total of 
enrollment of 43 subjects or until observing ≥ 8 CBRs, whichever 
occurs earlier. 
• 
If there is concurrent Stage 2 enrollment to more than 1 Cohort at any 
given time, Sponsor will implement centralized assignments into 
cohorts. 
Sponsor maintains the prerogative to select regimen which gives optimal 
efficacy and safety results at interim analysis for further development while 
suspend other cohorts at any time. 
The expected total enrollment including Cohort 1 is between 67 (minimal) 
and 164 subjects. 
The dose cohorts are summarized in the table below.   
Cohort 
PCI-32765 
(mg/day) 
Dexamethasone
Planned 
First Stage 
Enrollment
CBR 
Criteria 
for First 
Stage 
Total Enrollment 
(First and Second
Stages) 
1 
420 
Upon PD, 
40 mg once 
weekly is 
allowed† 
11* 
≥ 2 
35 
2 
560 
40 mg once 
weekly 
18 
≥ 3 
43 
3 
840 
Upon PD, 
40 mg once 
weekly is 
allowed† 
18 
≥ 3 
43 
4 
840 
40 mg once 
weekly 
18** 
≥ 3 
43 
* n=11 planned for Cohort 1 First Stage, n=13 were enrolled. The decision for 
second stage expansion will be based on the number of CBR in the first 11 subjects.  
** n=18 planned for Cohort 4 First Stage, n=20 were enrolled. The decision for 
second stage expansion will be based on the number of CBR in the first 18 subjects 
†For Cohorts 1 and 3 subjects who have confirmed PD, and who are clinically stable, 
without significant worsening of symptoms or hematologic status (ie, meet all entry 
criteria for the study in regard to symptoms and hematology), will be eligible to 
receive dexamethasone 40 mg orally once per week in addition to continued 
treatment with PCI-32765, at the discretion of the investigator.  
Disease progression (PD) and response assessment will be performed by the 
investigators using the modified IMWG response criteria (Appendix 5). 
Subjects will otherwise continue on study drug until PD, withdrawal of 
consent, or until discontinuation of study drug due to an adverse event (AE).  
Continued treatment with study drug will be allowed for as long as a subject 
receives benefit. 
 


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Subjects who discontinue study drug without PD will be followed for response 
until PD or start use of alternative antineoplastic therapy.  Subjects who 
discontinue treatment due to PD will be followed for survival. 
Major Inclusion/ 
Exclusion Criteria: 
Refer to Section 5.0 for the complete list of inclusion/exclusion criteria.  
Major Inclusion Criteria: 
Disease related: 
1. Diagnosis of symptomatic MM (as defined by modified IMWG criteria, 
refer to Appendix 3) with measurable disease, defined here as having at 
least one of the following: 
• 
Serum monoclonal (M protein) ≥ 0.5 g/dL as determined by serum 
protein electrophoresis (SPEP). 
• 
Urine M-protein (UPEP) ≥ 200 mg/24 hrs. 
• 
Serum free light chain (FLC) assay:  involved FLC level ≥ 10 mg/dL 
(≥ 100 mg/L) provided serum FLC ratio is abnormal. 
2. Relapsed or relapsed and refractory MM after receiving at least 2, but no 
more than 5, previous lines of therapy, 1 of which must be an 
immunomodulator (eg, Revlimid®, thalidomide).   
• 
Refractory myeloma (to most recent treatment) is defined as disease 
that is nonresponsive while on treatment or progressive disease within 
60 days after the completion of the preceding treatment.  
Nonresponsive disease is defined as either failure to achieve minimal 
response or development of progressive disease while on therapy. 
o Subjects considered refractory to their most recent line of therapy 
will be ineligible if the most recent line included an 
immunomodulatory drug and proteasome inhibitor. 
• 
Relapsed myeloma is defined as the occurrence of any of the following 
after most recent treatment:  
o > 25% increase in M-protein from the lowest value obtained while 
on treatment (absolute increase must be ≥ 0.5g/dL by SPEP, 
≥ 200 mg/24h by UPEP), or ≥ 10mg/dL by sFLC, or 
o increase in the size and number of lytic bone lesions recognized on 
radiographs (compression fractures per se do not constitute a 
relapse). 
Demographic: 
3. Men and women ≥ 18 years of age. 
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. 
5. Life expectancy of ≥ 12 weeks. 
Ethical/Other: 
6. Ability to understand and willingness to sign a written informed consent 
form. 
7. Ability to adhere with the study visit schedule and other protocol 
procedures. 
 
 


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Major Exclusion Criteria: 
Disease Related: 
41. Subjects must not have primary refractory disease defined as disease that is 
nonresponsive in subjects who have never achieved a MR or better with 
any therapy. 
9. Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin 
changes (POEMS) syndrome, osteosclerotic myeloma, or Crow-Fukase 
syndrome.  
10. Plasma cell leukemia.  
11. Primary amyloidosis.  
12. Must not have had any cancer-directed systemic therapy including 
chemotherapy, immunomodulator or proteosome inhibitor within 3 weeks 
OR corticosteroid (> 10 mg/day prednisone equivalent systemic exposure) 
within 2 weeks, of the first dose of study drug.  
13. Radiotherapy within 21 days of Cycle 1 Day 1.  However, if the radiation 
portal was localized to single lesion or fracture site and covered by ≤ 5% 
of the bone marrow reserve (by investigator estimate), the subject may be 
enrolled irrespective of the end date of radiotherapy.  
14. Treatment with an anticancer antibody within 6 weeks of first dose of 
study drug.  
15. Concurrent enrollment in another therapeutic investigational clinical study, 
or treatment with an investigational agent within the 3 weeks prior to 
beginning study drug or 5 drug half-lives.  
16. Prior treatment with PCI-32765 or any other protein kinase inhibitory drug 
or drug targeting the B cell receptor signal transduction pathway.  
Laboratory: 
17. Absolute neutrophil count < 750 cells/μL (0.75 x 109/L) independent of 
growth factor support.  
18. Platelet count < 50,000 cells/μL (50 x 109/L) independent of transfusion 
support.  
19. Serum aspartate transaminase or alanine transaminase ≥ 3.0 x upper limit 
of normal (ULN).  
20. Total bilirubin > 2.5 x ULN, unless due to Gilbert’s syndrome.  
21. Creatinine > 2.5 mg/dL. 
Concurrent Conditions: 
23. Major surgery within 2 weeks of the first dose of study drug.  
24. Concomitant therapy with denosumab (bisphosphonate is allowed).  
26. Currently active, clinically significant cardiovascular disease such as 
uncontrolled or symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, any Class 3 or 4 
cardiac disease as defined by the New York Heart Association Functional 
Classification, or evidence of QT prolongation (QTc > 470 msec).  
27. Unable to swallow capsules or disease significantly affecting 
gastrointestinal function, such as malabsorption syndrome, resection of the 


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stomach or small bowel, or complete bowel obstruction.  
28. History of prior malignancy, with the exception of the following:  
a. Malignancy treated with curative intent and with no known active 
disease present for more than 3 years prior to screening and felt to be 
at low risk for recurrence by treating physician; 
b. Adequately treated non-melanoma skin cancer or lentigo maligna 
without current evidence of disease; or 
c. Adequately treated breast or cervical carcinoma in situ without current 
evidence of disease.  
29. Peripheral neuropathy Grade ≥ 2 on clinical examination within 14 days 
prior to enrollment.  
30. Uncontrolled diabetes mellitus.  
31. Currently active systemic fungal, bacterial, viral, or other infection not 
controlled (defined as exhibiting ongoing signs/symptoms related to the 
infection and without improvement, despite appropriate antibiotics or other 
treatment).  
32. Use of antibiotics for treatment of infection within 7 days prior to first dose 
of study drug.  
33. Known history of infection with human immunodeficiency virus (HIV) or 
history of active infection with hepatitis C virus (HCV) or hepatitis B virus 
(HBV) or any uncontrolled active systemic infection.  
34. History of stroke or intracranial hemorrhage within 6 months prior to the 
first dose of study drug.  
39. Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon). 
40. Requires treatment with strong CYP3A4/5 inhibitors (see 1Appendix 2) 
Ethical/Other: 
35. Subject is pregnant or breastfeeding.  
36. Will not agree to use highly effective contraception (eg, condoms, 
implants, injectables, combined oral contraceptives, some intrauterine 
devices [IUDs], sexual abstinence, or sterilized partner) during the study 
and for 30 days after the last dose of study drug.  (Note:  applies to women 
of child-bearing potential or men with female partners of child-bearing 
potential only.) 
37. Any other 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.  
38. Any medical or psychiatric condition that, in opinion of investigator, could 
interfere with the subject’s ability to give informed consent, compliance, 
or treatment.  
Endpoints: 
Primary Endpoint: 
The primary endpoint of the study is the CBR, defined as the proportion of 
subjects achieving an MR or better, by modified IMWG criteria (Appendix 5). 
 
 


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Secondary Endpoints: 
Safety: 
• 
Safety parameters including the incidences and types of clinical 
adverse events, laboratory variables, and vital signs measurements 
Efficacy: 
• 
Duration of clinical benefit (DCB)  
• 
Objective response rate (ORR) 
• 
Duration of objective response (DOR) 
Pharmacokinetics: 
• 
Plasma PK of PCI-32765 and metabolite PCI-45227 
Exploratory Endpoints: 
• 
Progression-free survival (PFS) 
• 
Time to Progression (TTP) 
• 
Overall survival (OS)  
Exploratory Analyses: 
• 
Prognostic and predictive biomarkers and genetics relative to treatment 
outcomes.  
Safety Plan: 
This study will be monitored in accordance with the Sponsor’s 
pharmacovigilance committee procedures.  Adverse events and serious adverse 
events (SAEs) will be reviewed internally on an ongoing basis to identify 
safety concerns.  The study's investigators and data coordinators are 
responsible for entering the data and safety of this study, including 
implementation of the stopping rules for efficacy.  All sites are required to use 
the eCRFs provided by the study sponsor. All sites will be monitored on an 
ongoing basis by the study sponsor.  Safety data is monitored in accordance 
with the sponsor's Pharmacovigilance Committee procedures. Adverse events 
and SAEs will be reviewed internally on an ongoing basis to identify safety 
concerns. 
Study Drug: 
Cohorts 1 and 3 Single Agent:  PCI-32765 will be administered orally once 
daily at dosages of 420 mg (3 x 140-mg capsules, Cohort 1) and 840 mg 
(6 x 140-mg capsules, Cohort 3).  
Upon PD and meeting the criteria described above, administration of 
dexamethasone 40 mg once weekly is allowed at investigator's discretion. 
Cohorts 2 and 4 (PCI-32765/Dexamethasone Combinations):  PCI-32765 
will be administered orally once daily at dosages of 560 mg (4 x 140-mg 
capsules, Cohort 2) and 840 mg (6 x 140-mg capsules, Cohort 4).  
Dexamethasone 40 mg will be administered orally once weekly (starting Day 4 
of Cycle 1). 
Cohort 4 Expansion (PCI-32765/Dexamethasone Combination):  
PCI-32765 will be administered orally once daily at a dose of 840 mg  
(6 x 140 mg capsules).  Dexamethasone 40 mg will be administered orally 
once weekly, starting Day 8 of Cycle 1, following the completion of the 7 hour 
postdose PK sample collection. 
One cycle is defined as 28 days of intended treatment. 


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Concomitant Therapy 
and Clinical Practice: 
Permitted Concomitant Therapy 
Antiemetics or other standard supportive agents are permitted as clinically 
indicated.  Hematopoietic growth factors are permitted per ASCO Guidelines55.  
Short courses (<14 days) of corticosteroids (at dosages equivalent to 
prednisone ≤20 mg per day) for treatment of non-cancer-related medical 
reasons are permitted. 
Prohibited Concomitant Therapy 
Any chemotherapy, other myeloma-targeted therapy including “IMiDs” 
(eg, lenalidomide) and proteosome inhibitors (eg, bortezomib), anticancer 
immunotherapy and corticosteroids are prohibited.  Experimental therapy and 
radiotherapy to treat the underlying myeloma disease are also prohibited. 
Refer to 1Appendix 2 for guidance on drugs that are CYP P450 inhibitors. 
Refer to Section 6.8.1.3 for guidance on concomitant use of anticoagulants. 
Statistical Methods: 
Subjects who meet the stated eligibility requirements will be enrolled in the 
study.   
Full enrollment to Cohort 1 will be contingent upon Simon 2-stage design rules 
with a target sample size of 35 evaluable subjects based on meeting interim 
efficacy endpoints ie, if ≥ 2 CBRs are observed among the first 11 subjects 
within this cohort.  This cohort is designed to test the null hypothesis that the 
CBR of PCI-32765 monotherapy at a dose of 420 mg/day is ≤ 10% (not 
clinically compelling) versus the alternative hypothesis that CBR will be 
≥ 30%, at a 1-sided significance level of 5%, with 85% power.  An interim 
analysis for futility will be performed when 11 subjects have been enrolled and 
have evaluable response data (ie, completed 6 treatment cycles and the Cycle 
7 Day 1 assessments OR have discontinued treatment) or earlier if two or more 
subjects have documented CBR, defined as a MR or better.  Further enrollment 
to Cohort 1will be halted if there are fewer than 2 CBRs observed among these 
11 subjects, or if deemed by sponsor.  Upon meeting the futility threshold, 
the second stage will enroll up to a total of 35 subjects.  
Up to 18 subjects will be enrolled to Cohorts 2, 3, and 4.  First stage 
enrollment will not be contingent upon results in the other cohorts.  
Full enrollment to Cohorts 2, 3, and 4 will be contingent upon Simon 2-stage 
design rules with a sample size of up to 43 evaluable subjects based on meeting 
interim efficacy endpoints, ie, if ≥ 3 CBRs are observed among the first 
18 subjects within the subject cohort.  This design has 80% power to reject the 
null hypothesis of CBR ≤ 10%, at a 1-sided significance level of 5%. 
Observation of ≥ 8 CBRs within an expanded cohort of up to 43 subjects will 
be considered consistent with the alternative hypothesis of CBR rate ≥ 25%.  
The enrollment of that cohort may be closed early for success once 8 CBRs 
observed. 
This study design is not powered or intended to allow direct comparison of 
CBR among the cohorts.  Results of this study will inform alternative 
directions for future combination and single-agent development in alternative 
MM study populations.   
The final analyses will occur upon study completion.  
 
 


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TABLE OF CONTENTS 
1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................18 
2.0 
INTRODUCTION .........................................................................................................18 
2.1 
Overview of the Disease ..................................................................................................18 
2.2 
PCI-32765 (Ibrutinib) Background .................................................................................19 
2.3 
Btk and Multiple Myeloma .............................................................................................20 
2.4 
Summary of Relevant Nonclinical and Clinical Data .....................................................22 
2.4.1 
Nonclinical Studies with PCI-32765 ...............................................................................22 
2.4.1.1  Pharmacology ..................................................................................................................22 
2.4.1.2  Toxicology .......................................................................................................................23 
2.4.1.3  Carcinogenesis, Mutagenesis, Impairment of Fertility ....................................................23 
2.4.2 
Summary of Clinical Safety of PCI-32765 .....................................................................23 
2.4.2.1  Monotherapy Studies .......................................................................................................24 
2.4.2.2  Combination Therapies ...................................................................................................24 
2.4.3 
Risks ................................................................................................................................25 
2.4.3.1  Atrial Fibrillation .............................................................................................................25 
2.4.3.2  Bleeding-related Events ...................................................................................................25 
2.4.3.3  Cytopenias .......................................................................................................................25 
2.4.3.4  Diarrhea ...........................................................................................................................25 
2.4.3.5  Infections .........................................................................................................................25 
2.4.3.6  Interstitial Lung Disease (ILD) .......................................................................................25 
2.4.3.7  Non-melanoma skin cancer .............................................................................................26 
2.4.3.8  Rash .................................................................................................................................26 
2.4.3.9  Tumor Lysis Syndrome ...................................................................................................26 
2.4.4 
Clinical Pharmacokinetics ...............................................................................................26 
2.4.5 
PCYC-1111-CA Stage 1 Summary .................................................................................26 
2.5 
Rationale for Study Design and Dose .............................................................................27 
3.0 
STUDY OBJECTIVES .................................................................................................29 
3.1 
Primary Objective ............................................................................................................29 
3.2 
Secondary Objectives ......................................................................................................29 
3.3 
Exploratory Objectives ....................................................................................................29 
3.4 
Exploratory Analyses ......................................................................................................29 
4.0 
STUDY DESIGN ...........................................................................................................29 
4.1 
Description of Study ........................................................................................................29 
4.1.1 
Study Summary Flow Diagram .......................................................................................31 
4.2 
Endpoints .........................................................................................................................31 
4.2.1 
Primary Endpoint .............................................................................................................31 


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4.2.2 
Secondary Endpoints .......................................................................................................31 
4.2.3 
Exploratory Endpoint ......................................................................................................32 
4.3 
Correlative Assessments on Bone Marrow Aspirate .......................................................32 
4.4 
Statement of Compliance ................................................................................................32 
5.0 
SELECTION OF SUBJECTS ......................................................................................33 
5.1 
Major Inclusion Criteria ..................................................................................................33 
5.2 
Major Exclusion Criteria .................................................................................................34 
6.0 
TREATMENT OF SUBJECTS ....................................................................................36 
6.1 
Randomization and Blinding ...........................................................................................36 
6.2 
Formulation, Packaging, and Storage ..............................................................................36 
6.3 
Dosage and Administration .............................................................................................36 
6.3.1 
PCI-32765 ........................................................................................................................36 
6.3.2 
Dexamethasone ................................................................................................................37 
6.3.3 
Combination of PCI-32765 and Dexamethasone Dosing ...............................................38 
6.3.3.1  For Subjects with PD (Cohorts 1 and 3) ..........................................................................38 
6.3.3.2  Concurrent Dosing of PCI-32765/Dexamethasone Combination (Cohorts 2 and 4) ......38 
6.3.3.3  Concurrent Dosing of PCI-32765/Dexamethasone Combination (Cohort 4 expansion) 38 
6.4 
Early Cellular Mobilization .............................................................................................38 
6.5 
Criteria for Holding or Adjusting Study Drug Dose .......................................................38 
6.5.1 
Criteria for Holding PCI-32765 .......................................................................................38 
6.5.2 
Dose Modification for Hepatic Impaired Subjects ..........................................................40 
6.5.3 
Criteria for Holding or Adjusting Dexamethasone .........................................................40 
6.6 
Criteria for Permanent Discontinuation of Study Drug ...................................................40 
6.6.1 
Withdrawal of Consent ....................................................................................................40 
6.7 
Concomitant Therapy ......................................................................................................41 
6.7.1 
Permitted Concomitant Therapy ......................................................................................41 
6.7.2 
Prohibited Concomitant Therapy ....................................................................................41 
6.7.3 
Guidelines for PCI-32765 Management with Surgeries or Procedures ..........................41 
6.7.3.1  Minor Surgical Procedures ..............................................................................................41 
6.7.3.2  Major Surgical Procedures ..............................................................................................41 
6.7.3.3  Emergency Procedures ....................................................................................................42 
6.8 
Precautions ......................................................................................................................42 
6.8.1 
Medications to be Used with Caution .............................................................................42 
6.8.1.1  Concomitant Use of CYP Inhibiting/Inducing Drugs .....................................................42 
6.8.1.2  Drugs That May Have Their Plasma Concentrations Altered by PCI-32765 .................42 
6.8.1.3  Concomitant Use of Antiplatelet Agents and Anticoagulants .........................................43 
6.8.2 
Reproductive Toxicity .....................................................................................................43 
6.8.3 
Overdose Instructions ......................................................................................................43 


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7.0 
STUDY PROCEDURES ...............................................................................................44 
7.1 
Description of Procedures ...............................................................................................44 
7.1.1 
Screening Assessments ....................................................................................................44 
7.1.2 
Assessments During Treatment .......................................................................................46 
7.1.3 
Safety Follow-up Visit ....................................................................................................50 
7.1.4 
Follow-up for Progression and Survival ..........................................................................50 
7.2 
Missed Evaluations ..........................................................................................................50 
7.3 
Study Completion ............................................................................................................51 
8.0 
STATISTICAL METHODS OF ANALYSIS .............................................................51 
8.1 
General Considerations ...................................................................................................51 
8.1.1 
Response Assessment ......................................................................................................51 
8.2 
Definition of Analysis Populations .................................................................................51 
8.3 
Endpoint Data Analysis ...................................................................................................52 
8.3.1 
Demographic/Baseline Characteristics and Study Conduct ............................................52 
8.3.2 
Primary Efficacy Endpoint ..............................................................................................52 
8.3.3 
Secondary/Exploratory Efficacy Endpoints ....................................................................52 
8.3.3.1  Duration of Clinical Benefit (DCB) ................................................................................52 
8.3.3.2  Objective Response Rate (ORR) .....................................................................................52 
8.3.3.3  Duration of Response (DOR) ..........................................................................................52 
8.3.4 
Exploratory Endpoint ......................................................................................................53 
8.3.4.1  Progression-free Survival (PFS) ......................................................................................53 
8.3.4.2  Time to Progression (TTP) ..............................................................................................53 
8.3.4.3  Overall Survival (OS) ......................................................................................................53 
8.3.5 
Safety Endpoint ...............................................................................................................53 
8.3.6 
Pharmacokinetics .............................................................................................................53 
8.3.7 
Exploratory Analyses ......................................................................................................54 
8.4 
Handling of Missing Data ...............................................................................................54 
8.5 
Determination of Sample Size .........................................................................................54 
8.5.1 
Cohort 1 ...........................................................................................................................54 
8.5.2 
Cohorts 2-4 ......................................................................................................................55 
8.6 
Interim Analysis ..............................................................................................................55 
8.7 
Final and Follow-up Analyses .........................................................................................56 
9.0 
ASSESSMENT OF SAFETY .......................................................................................56 
9.1 
Safety Monitoring ............................................................................................................56 
9.2 
Definitions .......................................................................................................................56 
9.2.1 
Adverse Events ................................................................................................................56 
9.2.2 
Serious Adverse Event ....................................................................................................57 


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9.2.3 
Severity ............................................................................................................................58 
9.2.4 
Causality ..........................................................................................................................58 
9.2.5 
Unexpected Adverse Events ............................................................................................59 
9.3 
Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators ....................................................................................................................59 
9.3.1 
Adverse Event Reporting Period .....................................................................................59 
9.3.2 
Assessment of Adverse Events ........................................................................................59 
9.3.3 
Expedited Reporting Requirements for Serious Adverse Events ....................................60 
9.3.4 
Events of Special Interest ................................................................................................60 
9.3.4.1  Major Hemorrhage ..........................................................................................................60 
9.3.5 
Pregnancy ........................................................................................................................60 
9.3.6 
Other Malignancies .........................................................................................................61 
9.4 
Reporting of Serious Adverse Events by Sponsor ..........................................................61 
10.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............61 
10.1 
Institutional Review Board and Independent Ethics Committee ....................................62 
10.2 
Informed Consent ............................................................................................................62 
10.3 
Protected Subject Health Information Authorization ......................................................62 
10.4 
Subject Screening Log .....................................................................................................63 
10.5 
Source Documentation Requirements .............................................................................63 
10.6 
Case Report Forms ..........................................................................................................63 
10.7 
Study Monitoring/Audit Requirements ...........................................................................64 
10.8 
Investigational Study Drug Accountability .....................................................................64 
10.9 
Financial Disclosure ........................................................................................................65 
10.10 
Availability and Retention of Records ............................................................................65 
10.11 
Protocol Amendments .....................................................................................................66 
10.12 
Use of Information and Publication ................................................................................67 
11.0 
REFERENCES ..............................................................................................................68 
12.0 
APPENDICES ................................................................................................................72 
LIST OF TABLES 
Table 1:  Treatment Cohorts and Planned Enrollment ................................................................ 30 
Table 2:  Drug Discontinuation Actions for Subjects on PCI-32765 .......................................... 39 
Table 3:  Intrasubject Dose De-escalation by Assigned Daily Dose ........................................... 39 
Table 4:  PK Sample Schedule for All Subjects - Cycle 1 .......................................................... 47 
Table 5:  PK Sample Schedule for Cohorts 1 and 3 Subjects Starting Dexamethasone after 
PD ................................................................................................................................. 48 
Table 6:  PK Sample Schedule for Cohorts 4 Expansion ............................................................ 48 


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LIST OF APPENDICES 
Appendix 1. 
ECOG and Karnofsky Performance Status Scores ............................................... 73 
Appendix 2. 
Inhibitors and Inducers of CYP3A ....................................................................... 74 
Appendix 3. 
Multiple Myeloma Diagnostic Criteria ................................................................. 75 
Appendix 4. 
Schedule of Assessments ...................................................................................... 77 
Appendix 5. 
Disease Response Assessment by Modified IMWG Criteria43,44 ......................... 80 
Appendix 6. 
Child-Pugh Score for Subjects with Liver Impairment ........................................ 83 
 
 


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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
allo-SCT 
allogeneic transplantation  
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time  
ASCT 
autologous hematopoietic stem cell transplantation  
AST 
aspartate transaminase 
AUC 
area under the curve 
BCR 
B cell receptor 
BM 
bone marrow 
Btk 
Bruton’s tyrosine kinase 
CBC 
complete blood count  
CBR 
clinical benefit rate 
CD3, 4, 8 etc. 
Cluster Designation 3, 4, 8, etc. 
CFR 
Code of Federal Regulations 
CLL 
chronic lymphocytic leukemia 
CR 
complete response or complete remission 
CRAB 
Calcium elevation, renal insufficiency, anemia hemoglobin, and lytic bone lesions or 
osteoporosis 
CRF 
Case Report Form 
CT 
computed tomography scans 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
C-terminal cross-linking protein of type-1 collagen 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DCB 
duration of clinical benefit 
DLBCL 
diffuse large B cell lymphoma 
DOR 
duration of (objective) response  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FACT/GOG-Ntx 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group 
Neurotoxicity 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization  
FL 
follicular lymphoma 


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Abbreviation 
Definition 
FLC 
free light chain 
GCP 
good clinical practice 
GEP 
gene expression profile 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
Hgb 
hemoglobin 
HI 
hematologic improvement  
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFE 
immunofixation 
IL-6 
interleukin-6 
IMWG 
International Myeloma Working Group 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRF 
independent review facility 
KO 
Knock-out (mice) 
LD 
low dose 
LPL 
lymphoplasmacytic lymphoma 
LTFU 
Long-term follow-up 
MCL 
mantle cell lymphoma 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MIP-1α 
macrophage inhibitory protein-1α 
MM 
multiple myeloma 
MNC 
mononuclear cells  
MRI 
Magnetic resonance imaging  
MR 
minimal response 
M-protein 
monoclonal protein 
NTX 
N-terminal cross-linking protein of type-1 collagen 
OC 
Osteoclast 
ORR 
objective response rate 
OS 
overall survival 
PCI-32765 p.o. 
oral formulation of PCI-32765 (study drug) provided in hard gelatin capsules also 
known as “PCI-32765 p.o. hard gelatin capsule” 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease/disease progression 


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Abbreviation 
Definition 
PE 
physical examination 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
p.o. 
per os (oral) 
POEMS 
syndrome 
polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes 
syndrome 
PP 
per-protocol  
PR 
partial response or partial remission 
PT 
prothrombin time 
QTc 
corrected QT interval 
RANKL 
receptor activator of nuclear factor κB ligand 
RNASeq 
RNA sequencing 
RFU 
Response follow-up 
SAE 
serious adverse event 
sCR 
stringent complete response 
SD 
stable disease 
SEER 
surveillance epidemiology and end result  
SFLC 
Serum free light chain 
SLL 
small lymphocytic lymphoma 
SPEP 
serum protein electrophoresis 
t1/2 
half life 
tmax 
time to maximum drug concentration 
TTP 
time to progression 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
VGPR 
very good partial response 
WES 
Whole Exome Sequencing 
WM 
Waldenström macroglobulinemia 
Xid 
X-linked immunodeficiency 
XLA 
X-linked agammaglobulinemia 
 
 


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1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Prior to study initiation, the Principal Investigator at each site must provide to Pharmacyclics 
LLC (Pharmacyclics) a protocol signature page, a fully executed and signed Form Food and 
Drug Administration (FDA) 1572, a current curriculum vitae and license, and a Financial 
Disclosure Form.  Financial Disclosure Forms, licenses, and current curricula vitae must also be 
completed for all subinvestigators listed on Form FDA 1572 who will be directly involved in the 
treatment or evaluation of subjects in this study. 
The study will be administered and monitored by employees or representatives of Pharmacyclics 
in accordance with all applicable regulations.  Clinical research associates will monitor each site 
on a periodic basis and perform verification of source documentation for each subject.  
Pharmacyclics’ Safety Department will be responsible for ensuring timely reporting of expedited 
Serious Adverse Event (SAE) reports to regulatory agencies, ethics committees, and 
investigators, as applicable by local regulations. 
2.0 
INTRODUCTION 
2.1 
Overview of the Disease 
Multiple myeloma (MM) is a disseminated malignant proliferation of plasma cells and 
plasmacytoid cells.1  Its yearly United States (US) age-adjusted incidence of 5.4/100,000 is 
comparable to that of chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL; 5.7/100,000), which in turn is second only to diffuse large B cell lymphoma 
(DLBCL; 6.9/100,000) among lymphoid malignancy subtypes.  Its most recently estimated 
(Surveillance Epidemiology and End Results [SEER]) population based 5-year survival of 37.7% 
is inferior to those of CLL/SLL (77.1%) and DLBCL (59%).2  MM is thus one of the most 
significant areas of unmet medical need, in terms of survival and incidence, among lymphoid 
malignancies.  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.  


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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.3  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 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.3-8 
Historically, the available treatments for MM were based upon alkylators (melphalan or 
cyclophosphamide), anthracyclines, dexamethasone, or vincristine in various combinations.  
Typically, 50% to 70% of subjects achieved an objective response to these regimens with little, 
if any, impact upon survival.  Current regimens include lenalidomide, thalidomide, bortezomib, 
and liposomal doxorubicin.  These regimens commonly also incorporate high- or low-dose 
dexamethasone, and may also include melphalan for patients who are not transplant candidates.  
Front-line therapy for most patients generally includes bortezomib and/or lenalidomide.1 
Survival following failure to these 2 agents is extremely poor.9 
High-dose alkylating agent chemotherapy, with or without total body irradiation, followed by 
autologous hematopoietic stem cell transplantation (ASCT) can achieve high (40%) complete 
response rates and a similar percentage of partial responses.10  ASCT has become a widely 
accepted management option for many, if not most, patients.10-14  Syngeneic or allogeneic 
transplantation (allo-SCT or BMT) is performed less frequently, but patients can remain 
progression free at long intervals post transplant.11,15-20  Once a patient relapses after single or 
tandem high-dose therapies and bone marrow transplantations, there may not be an acceptable 
therapeutic option. 
2.2 
PCI-32765 (Ibrutinib) Background 
PCI-32765 (ibrutinib; IMBRUVICA®) is a first-in-class, potent, orally administered covalently-
binding inhibitor of Bruton’s tyrosine kinase (Btk) for the treatment of B-cell malignancies.   
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, patients with chronic lymphocytic leukemia (CLL) including CLL with a deletion of the 


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short arm of chromosome 17 (del17p) or a TP53 mutation, and patients with Waldenström’s 
Macroglobulinemia.  Ibrutinib is currently under investigation in other various indications as a 
single agent and in combinations.   
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigen.  Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways.53  
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from 
mutations and translocations acquired during normal B-cell development.54  Several lines of 
evidence suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies.   
The role of Btk in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease 
X-linked immunodeficiency, both caused by a mutation in the Btk gene.  These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B-cells.  The Btk 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer 
(NK) cells, but the selective effect of Btk mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells.21   
Data from Study PCYC-04753 demonstrate that although PCI-32765 is rapidly eliminated from 
the plasma after oral administration, once daily dosing with PCI-32765 is adequate to sustain 
maximal pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg.  In Study 
PCYC-04753, the Btk occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 
560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration.   
For the most comprehensive nonclinical and clinical information regarding PCI-32765 
background, safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of 
PCI-32765, refer to the latest version of the PCI-32765 Investigator's Brochure (IB).  
2.3 
Btk and Multiple Myeloma 
Although Btk is markedly down-regulated in normal plasma cells, it is highly expressed in the 
malignant cells from many myeloma patients and some cell lines.  Chauhan et al,22 showed that 
Btk mRNA expression was 2.3-fold increased in 6 MM patient specimens compared to normal 
human marrow precursors.  Kong et al,23 noted increased expression in 84% of primary myeloma 
samples and among some cell lines, especially ANBL-6 and INA-6, both of which are IL-6 
dependent.  Bam et al,24 reported expression particularly among cases within the MF gene 


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expression profile (GEP) grouping, and also commonly in cases within the DC-1, DC-2, HY, 
and LB subgroups.25,26  Multiple myeloma cells with the MF GEP are known to be particularly 
dependent upon micro-environmental interactions and integrin β7-based adherence to the bone 
marrow stroma.27  These cases tend to be clinically aggressive.  The DC-2 GEP subtype often 
carries t(11;14) (q13, q32), which involves the same chromosomes and bands as the 
characteristic translocation of mantle cell lymphoma (MCL), albeit with differing breakpoints.  
This subtype tends to have a lymphoplasmacytic cytology, rather than purely plasmacytic 
cytology, and to express multiple markers associated with BCR or its function, including CD20, 
CD79a, VPREB, and PAX5.28  Since inhibition of stromal adherence is an important mechanistic 
feature of PCI-32765 activity and since PCI-32765 has significant clinical activity in MCL and 
lymphoplasmacytic lymphoma (LPL), it is reasonable to anticipate clinical activity in MM, 
especially in subtypes with such features.  
The ability of PCI-32765 to inhibit osteoclast (OC) development and function, as well as micro-
environmental interactions, is a further basis to test this drug in MM patients.  As specialized 
mature cells of the myelomonocytic lineage, OCs are known to express Btk.  Although neither 
Xid mice nor XLA patients have a clear clinical defect related to loss of Btk function, recent 
observations have shown that Btk is nonetheless important in OC function and development.  
Monocytic OC precursor cells from Xid mice are defective in multinucleate osteoclast formation 
in response to RANKL.29  Btk/TEC knockout (KO) mice (but not Btk KO mice) have 
osteopetrotic bones associated with defective osteoclast formation.30  XLA patients have a 
similar defect in OC formation in vitro, which has been suggested to be masked in vivo by higher 
than normal levels of regulatory cytokines.31  PCI-32765 has been found to inhibit production of 
human OC from progenitors in vitro as well as cytokine and chemokine secretion.  Erosion of 
human bone chips by myeloma xenografts in SCID mice was furthermore inhibited by 
PCI-32765 treatment, as was progression of the tumor itself.23 
In contrast to its activity in vivo systems, PCI-32765 was found to exert only limited apoptotic or 
growth inhibitory effects in suspension in vitro cultures of MM patient samples or cell lines that 
have been tested at clinically relevant (ie, submicromolar) levels.23  This has often been similarly 
noted when in vitro cell lines corresponding to other lymphoproliferative diseases with known 
clinical sensitivity to PCI-32765 have been tested.  PCI-32765 mechanism of action is apparently 
related to cells micro-environmental interactions, which may include engagement of the BCR or 
other receptors.  Adaptation to in vitro suspension growth by definition selects for independence 
of specific micro-environmental interactions. 
The putative myeloma stem cell or cancer regenerating cell as identified by Matsui32 was found 
to be enriched in the CD138neg subfraction of both MM patient samples and cell lines.  This 
functionally defined cell was further found to have phenotypic features generally consistent with 
a memory B cell phenotype, including BCR component and associated marker proteins, 
and small cell lymphoid morphology.  Two groups have independently reported increased Btk 
expression in cell subfractions (CD138neg or CXCR4+) and expect them to be enriched for this 


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colony forming population,23,24 compared to the bulk population of MM cells.  Consistent with 
this observation, Matsui found PCI-32765 to be inhibitory to in vitro colony formation by 
CD138neg cells (but not growth of CD138+ cells in bulk culture) from 5/5 patient samples tested 
at concentrations as low as 10 nM.33  A selective effect of PCI-32765 on the self-renewing 
subpopulation would further explain the difficulty of documenting inhibition of short-term 
cultures of predominantly CD138+ non-fractionated cells.  Such a selective effect could be 
advantageous for clinical use, as putative stem cells tend to be resistant to conventional 
antineoplastic agents. 
In summary, PCI-32765 is hypothesized to have potentially important clinical activity in MM by 
virtue of inhibitory demonstrated effects upon (1) OC function and development resulting in 
bone destruction, (2) micro-environmental interactions important for MM cell adherence and 
growth, and (3) MM repopulating cell growth.   
2.4 
Summary of Relevant Nonclinical and Clinical Data 
For the most comprehensive nonclinical and clinical information regarding PCI-32765, 
please refer to the current version of the IB.  
2.4.1 Nonclinical Studies with PCI-32765 
2.4.1.1 
Pharmacology 
PCI-32765 was designed as a selective and irreversible inhibitor of the Btk protein,34 in vitro, 
PCI-32765 is a potent inhibitor of Btk activity (IC50 = 0.39 nM).  The irreversible binding of 
PCI-32765 to cysteine-481 in the active site of Btk results in sustained inhibition of Btk and 
enhanced selectivity over other kinases that do not contain a cysteine at this position.  When 
added directly to human whole blood, PCI-32765 inhibited signal transduction from the BCR 
and blocked activation of B cells (IC50 = 80 nM).  Inhibition of B cell activation by PCI-32765 in 
peripheral blood mononuclear cells was measured by quantifying the level of the cell surface 
marker CD69 following stimulation of the BCR with anti-immunoglobulin antibodies.  
Continuous exposure to 10 nM PCI-32765 for 18 hours resulted in the complete prevention of 
up-regulation of CD69, whereas up-regulation of CD69 induced by T cell receptor stimulus was 
blocked only by continuous exposure to 10 µM PCI-32765, indicating that PCI-32765 is more 
than 1000-fold selective for inhibition of antigen receptor signaling in B cells over T cells.35  
PCI-32765 arrested cell growth and induced apoptosis in human B cell lymphoma cell lines in 
vitro and inhibited tumor growth in vivo in xenograft models.35  In mice, tumor growth inhibition 
was demonstrated at dose levels where no overt toxicity was observed, as measured by body 
weights.  In addition, PCI-32765 was efficacious in a mouse model of collagen-induced arthritis, 
a disease whose pathogenesis involves B cell activation. 


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Binding of PCI-32765 to the active site of Btk (Btk occupancy) was demonstrated in vivo in rat 
and dog blood mononuclear cells, mouse splenocytes, and xenograft tumor cells using a 
pharmacodynamic assay, which uses a specially designed Btk-binding fluorescent probe.  
The probe binds irreversibly to the active site of Btk, enabling fluorescent detection of labeled 
Btk protein.  The presence of PCI-32765 bound to the Btk active site precludes probe binding, 
thus reducing the fluorescence probe signal.  In mice, 50% of the Btk active sites in splenocytes 
were occupied 3 hours following a single oral dose of PCI-32765 at 5 mg/kg.  Mice orally 
administered PCI-32765 30 mg/kg had complete Btk active-site occupancy in splenocytes, 
which persisted for approximately 12 hours postdose.  In dogs, a single oral dose of 10 mg/kg 
resulted in complete occupancy of Btk measured in peripheral blood mononuclear cells 
(PBMCs).  The complete occupancy persisted for ≥ 24 hours with partial recovery by 48 hours 
postdose.  PCI-32765 added to human blood (ex vivo) led to complete Btk occupancy 
(IC50= 100 nM) and inhibition of B cell activation measured by CD69 expression. 
2.4.1.2 
Toxicology 
Four-week safety studies in rats (2.5, 40, and 300 mg/kg/day for males and 2.5, 40, and 
150 mg/kg/day for females) and dogs (1.5, 24, and 150 mg/kg/day) have been performed.  At the 
respective highest dosage, minor to mild clinical signs and histopathologic findings were noted.   
A cardiac study in radiotelemetry-monitored dogs (single doses of 24 and 150 mg/kg) also has 
been performed.  Lower heart rates were observed from 1 to 6 hours postdose, consistent with 
prolongation of the RR interval.  No treatment-related prolongation of the corrected QT interval 
(QTc) was observed. 
2.4.1.3 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with PCI-32765. 
PCI-32765 was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with PCI-32765 have not been conducted in animals.  In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
2.4.2 Summary of Clinical Safety of PCI-32765 
A brief summary of safety data from monotherapy and combination therapy studies is provided 
in below. For more comprehensive safety information please refer to the current version of the 
IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC).   


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2.4.2.1 
Monotherapy Studies 
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
 
2.4.2.2 
Combination Therapies 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below. Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone).  
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 
Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
  


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2.4.3 Risks 
2.4.3.1 
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.  For atrial fibrillation which persists, consider the risks and benefits 
of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 6.5.1). 
2.4.3.2 
Bleeding-related Events 
There are reports of hemorrhagic events in subjects treated with ibrutinib, both with and without 
thrombocytopenia.  These include minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria.  Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.  
Subjects with congenital bleeding diathesis have not been studied.  See Section 6.8.1.3 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See 
Section 6.7.3 for guidance on ibrutinib management with surgeries or procedures.   
2.4.3.3 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
2.4.3.4 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation.  These events are rarely severe.  These events are rarely severe.  Should 
symptoms be severe or prolonged follow the protocol dose modification guidelines 
(see Section 6.5.1).  
2.4.3.5 
Infections  
Fatal and non-fatal infections have occurred with ibrutinib therapy.  At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE).  The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis.  Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients 
treated with ibrutinib.  
2.4.3.6 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD.  Should symptoms develop follow 
the protocol dose modification guidelines (see Section 6.5.1). 


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2.4.3.7 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
for the appearance of non-melanoma skin cancer. 
2.4.3.8 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to 
moderate in severity.   
2.4.3.9 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy.  Subjects at risk of TLS are those 
with comorbidities and/or risk factors such as high tumor burden prior to treatment, increased 
uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre‐existing kidney 
abnormalities. 
2.4.4 Clinical Pharmacokinetics 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability. The 
mean half life (t1/2) of ibrutinib  ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours. Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food. Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not considered clinically 
relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose 
exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 
patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or 
patients on dialysis have not been studied. Following single dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects 
with normal liver function. A higher proportion of Grade 3 or higher adverse reactions were 
reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function. 
2.4.5 PCYC-1111-CA Stage 1 Summary 
As of 31 December 2013, 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.   


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The observed safety profile across the four 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 PCI-32765.   
Efficacy data collection is ongoing with 19 subjects still on treatment and 4 subjects treated for 
more than 6 cycles.  The Simon 2-stage enrollment expansion criteria were met for Cohort 4 with 
4 confirmed minimal responses (MR) and 9 subjects remaining on treatment. 
2.5 
Rationale for Study Design and Dose 
This study is based upon the biology of Btk and its inhibition in MM from preclinical laboratory 
studies conducted (Section 2.4.1).  PCI-32765 is hypothesized to have potentially important 
clinical activity in MM by virtue of demonstrated inhibitory effects upon (1) OC function and 
development resulting in bone destruction, (2) micro-environmental interactions important for 
MM cell adherence and growth, and (3) MM repopulating cell growth.  The extremely broad 
activity noted in early phase clinical studies of PCI-32765 in a wide range of B cell 
malignancies, including LPL/WM and MCL, is also supportive of exploring clinical effects in 
MM subjects.   
This multi-cohort study follows a 2-stage design among previously treated subjects, with dosing 
in the first cohort consisting of 420 mg per day PCI-32765 (3 x 140-mg capsules) administered 
once daily without interruption.  Pharmacodynamic analysis in a Phase 1 study PCYC-04753 and 
Phase 2 study PCYC-1102-CA revealed complete Btk active-site occupancy at doses of 
2.5 mg/kg and above, including the 420 mg continuous dosing cohort.  The highest dose safely 
explored in the Phase 1 study was 12.5 mg/kg, and extensive experience has been gained at doses 
of 8.3 mg/kg as well as at fixed doses of 560 and 840 mg/day in a number of studies.  
No maximum tolerated dose (MTD) was established in studies conducted at these doses.  In a 
subsequent Phase 1b/2 study of CLL/SLL dosed with 420 vs 840 mg/day (PCYC-1102-CA), 
neither responses nor toxicity was significantly different between the two arms.  Therefore, 
a substantial margin of safety has been established for dosing at 420 (up to 840) mg/day.  
The safety profile of PCI-32765 observed to date does not suggest the likelihood of exacerbation 
of pre-existing cumulative toxicities typical in this previously treated population.  
Thirteen subjects with MM were enrolled to Cohort 1 of this study from March to June 2012 and 
further accrual was on hold as per the protocol stipulated interim analysis, until responses among 
these subjects can be fully evaluated.  Evidence of anti-tumor activity in this population, as well 
as effects upon bone turnover and cytokine levels in some subjects supports that further dose 
ranging is indicated.  In Amendment 1, additional cohorts have been added to explore both 
higher doses and the routine addition of dexamethasone; the rationales for these changes are 
summarized as follows: 


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While 420 mg/day is the dose that has been applied in Phase 2 and Phase 3 studies of CLL/SLL, 
a higher dose of 560 mg/day is used in Phase 2 studies of the more aggressive NHL subtypes 
DLBCL and MCL.  There are several rationales for considering higher doses in some settings 
including:  1) expectation of higher rates of mutations of Btk and related signaling molecule 
genes in more aggressive diseases with greater chromosomal instability;  2) differing levels of 
tissue exposure or cellular penetration;  3) possible PK differences among individuals in different 
disease populations;  and 4) possible further activity benefit from inhibition of other kinase 
targets (e.g. BLK, BMX, ITK) at higher drug exposure levels.   
Dexamethasone 40 mg p.o. weekly (termed “low dose or LD dexamethasone”) is added to the 
treatment of subjects in Cohorts 1 and 3 with evidence of early disease progression (PD) with the 
goal of short-term stabilization to potentially allow more gradually developing responsiveness to 
PCI-32765 to emerge, while all subjects in Cohorts 2 and 4 will have dexamethasone added 
during the first cycle.  Myeloma regimens are commonly augmented with dexamethasone, which 
often appears to improve response to other agents.  More specifically, Btk expression was found 
to be up-regulated at both the protein and mRNA levels in MM1R dexamethasone-resistant cells 
compared to the sensitive parent line MM1S, suggesting a possible role of Btk in the mechanism 
of dexamethasone resistance.22  Dexamethasone has been noted to be markedly synergistic with 
PCI-32765 in vitro growth inhibition of lymphoma cell lines (Pharmacyclics, unpublished data).  
PCI-32765 exhibited protection against in vitro dentine pit formation, a commonly used model of 
osteoporosis, stimulated by dexamethasone.23  The dose of dexamethasone selected for this part 
of the study corresponds to that used in the LD combination with lenalidomide.  This dose was 
found to have superior safety and comparable activity to high-dose dexamethasone in 
combination with lenalidomide.39  High-dose dexamethasone alone in relapsed populations 
studied as controls for bortezomib and lenalidomide pivotal studies have had consistently limited 
activity:  ORR = 19% to 23%, CR = < 1% to 4%, and TTP = 3.5 to 4.7 months [Revlimid® and 
Velcade® package inserts].  The PCYC-1111-CA study eligibility selects a more heavily 
pretreated population compared to the Revlimid® and Velcade® pivotal studies.  Thus, in an 
analysis of the APEX trial data, ORR and median TTP to high dose dexamethasone among 
bortezomib-naïve patients previously treated with thalidomide was significantly decreased to 
10% and 2.8 months, respectively.50  These numbers are likely to more accurately reflect an 
upper limit to the expected single agent activity of low-dose dexamethasone in the more heavily 
pre-treated population entering the current study. 
PCI-32765 inhibited cytokine production and osteoclast development and function in vitro as 
well as bone destruction in vivo (Section 2.4.1).  Biomarkers of bone turnover40 and cytokine and 
chemokine levels4,6-8,41 will be obtained during the study.  Increased peripheral blood tumor cell 
mobilization or trafficking has been frequently observed both in CLL and non-CLL 
non-Hodgkin’s lymphoma subjects treated with PCI-32765.42  Peripheral blood levels of CD138+ 
cells, and their pattern of CD45 and CD38 expression, will therefore be measured among 
subjects treated in this study.   


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Refer to the IB for additional information. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to determine the efficacy of PCI-32765, both as a single 
agent and in combination with dexamethasone, in subjects with relapsed or relapsed and 
refractory MM as measured by clinical benefit response rate (CBR), defined as the proportion of 
subjects who achieved stringent complete response (sCR), complete response (CR), very good 
partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the 
modified International Myeloma Working Group (IMWG) response criteria. 
3.2 
Secondary Objectives 
Secondary objectives are to evaluate the efficacy of PCI-32765 in this population as assessed by 
the following: 
• Duration of clinical benefit (DCB)  
• Objective response rate (ORR) 
• Duration of objective response (DOR) 
• Safety (assessed by reporting of SAEs, AEs, and treatment-related discontinuations) 
• Pharmacokinetics (assessed by sampling and testing for drug and metabolite levels at 
designated time points)  
3.3 
Exploratory Objectives 
• Progression-free survival (PFS) 
• Time to progression (TTP) 
• Overall survival (OS) 
3.4 
Exploratory Analyses 
• Prognostic and predictive biomarkers and genetics relative to treatment outcomes. 
4.0 
STUDY DESIGN 
4.1 
Description of Study 
This is a Phase 2, open-label, nonrandomized, multi-cohort, multicenter Simon 2-stage study 
designed to assess the safety and efficacy of PCI-32765 in subjects with relapsed or relapsed and 
refractory MM.   
Treatment of PCI-32765 420 mg once daily in the original protocol (hereafter referred to as 
Cohort 1) was designed to detect a meaningful signal of activity while minimizing risk of 
continuing enrollment under null conditions.  Amendment 1 was designed to further explore the 


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optimal regimen by increasing doses of PCI-32765 and/or by routine combination with low dose 
dexamethasone.   
Cohorts 1 and 3 test activity of PCI-32765 monotherapy; Cohorts 2 and 4 test PCI-32765 in 
combination with LD dexamethasone.   
Stage 1:   
• Up to eighteen (18) subjects will be enrolled to each Cohort 2, 3 and 4, for a maximum 
total of 54 subjects.   
• Stage 1 enrollment to Cohorts 3 and 4 may begin concurrently after Cohort 2 Stage 1 
enrollment is complete.  If there is concurrent enrollment, Sponsor will implement 
centralized assignments into cohorts.  
Stage 2: 
• If ≥ 3 CBRs are observed within Cohorts 2, 3, or 4 in Stage 1, the cohorts(s) may be 
selected for expansion for up to a total enrollment of 43 subjects or until observing 
≥ 8 CBRs, whichever occurs earlier. 
• If there is concurrent Stage 2 enrollment to more than 1 cohort at any given time, 
Sponsor will implement centralized assignments into cohorts. 
Sponsor maintains the prerogative to select regimen, which gives optimal efficacy and safety 
results at interim analysis for further development while suspend other cohorts at any time. 
The expected total enrollment is between 67 (minimal) and 164 subjects.  Dosages and regimens 
by cohort are summarized in Table 1. 
Table 1: 
Treatment Cohorts and Planned Enrollment 
Cohort 
PCI-32765 
(mg/day) 
Dexamethasone 
Planned 
First Stage 
Enrollment 
CBR 
Criteria for 
First Stage 
Total Enrollment 
(First and Second 
Stages) 
1 
420 
Upon PD, 40 mg once 
weekly is allowed† 
11* 
≥ 2 
35 
2 
560 
40 mg once weekly 
18 
≥ 3 
43 
3 
840 
Upon PD, 40 mg once 
weekly is allowed† 
18 
≥ 3 
43 
4 
840 
40 mg once weekly 
18** 
≥ 3 
43 
*  n=11 planned for Cohort 1 First Stage, n=13 were enrolled.  The decision for second stage expansion will be 
based on the number of CBR in the first 11 subjects. 
**  n=18 planned for Cohort 4 First Stage, n=20 were enrolled.  The decision for second stage expansion will be 
based on the number of CBR in the first 18 subjects. 
† For Cohorts 1 and 3 subjects who have confirmed PD, and who are clinically stable, without significant 
worsening of symptoms or hematologic status (ie, meet all entry criteria for the study in regard to symptoms and 
hematology), will be eligible to receive dexamethasone 40 mg orally once per week in addition to continued 
treatment with PCI-32765, at the discretion of the investigator. 


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Subjects are allowed to continue study drug as long as the subject is clinically stable (SD or 
better) and the subject is not experiencing any unacceptable toxicity.  Subjects in the 
monotherapy cohorts (1 and 3) who have PD confirmed as required by definition in Appendix 5, 
and without significant worsening of symptoms or hematologic status (ie, meet all entry criteria 
for the study in regard to symptoms and hematology), will be eligible to receive dexamethasone 
40 mg p.o. once per week in addition to continued treatment with PCI-32765, at the discretion of 
the investigator.  Otherwise, subjects having PD will be removed from study. 
A flowchart summary of the PCYC-1111-CA study design is provided in Section 4.1.1.  
For a complete description of procedures refer to Study Procedures (Section 7.0). 
4.1.1 Study Summary Flow Diagram 
 
¾ In Stage 1 enrollment, up to 18 subjects will be enrolled to each Cohort 2, 3 and 4. 
¾ Stage 1 enrollment to Cohorts 3 and 4 may begin concurrently after Cohort 2 Stage 1 enrollment 
is complete. 
¾ If there is concurrent enrollment to more than 1 Cohort (Stage 1 or 2), Sponsor will implement 
centralized treatment assignments. 
¾ Sponsor maintains the prerogative to select regimen which gives optimal efficacy and safety 
results at interim analysis for further development while suspend other cohorts at any time. 
4.2 
Endpoints 
4.2.1 Primary Endpoint 
The primary endpoint of the study is the CBR, defined as the proportion of subjects achieving an 
MR or better as assessed by investigator per modified IMWG criteria (Appendix 5).43,44 
4.2.2 Secondary Endpoints 
The secondary endpoints for this study are as follows: 


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Safety:  
• Safety parameters including the incidences and types of clinical adverse events, 
laboratory variables, and vital signs measurements 
Efficacy: 
• Duration of clinical benefit (DCB)   
• Objective response rate (ORR) 
• Duration of objective response (DOR) 
Pharmacokinetics: 
• Plasma PK of PCI-32765 and metabolite PCI-45227  
4.2.3 Exploratory Endpoint 
• Progression-free survival (PFS) 
• Time to progression (TTP) 
• Overall survival (OS) 
4.3 
Correlative Assessments on Bone Marrow Aspirate 
Exploratory analysis of bone marrow aspirate samples are planned to be performed on all 
subjects in Cohort 4 expansion to investigate possible mechanisms of treatment sensitivity and 
resistance.   
Bone marrow aspirate specimens will be collected prior to start of dosing, if CR is suspected and 
at progression.  The sample obtained at progression may be at any time from when progression 
occurs, and the patient is taken off treatment, up to the start of a different treatment.   
The bone marrow aspirate will be analyzed centrally using fluorescence in-situ hybridization 
(FISH) and the analysis may include, but is not limited to the following probes: t(11;14), t(4;14), 
t(14;16), del 13q and del 17p.  The remaining bone marrow aspirate specimen will undergo flow 
cytometry analysis and may be processed by CD138+ enrichment.  If sufficient sample is 
available it will be used for the following assessments:  Whole Exome Sequencing (WES), 
RNA sequencing (RNASeq), and gene alteration analysis. 
Instructions for collection, processing, and shipping will be in the Laboratory Manual 
accompanying this protocol.   
4.4 
Statement of Compliance 
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonization (ICH) GCP, Declaration of Helsinki, and all applicable national 
and local regulations governing clinical studies. 


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5.0 
SELECTION OF SUBJECTS 
5.1 
Major Inclusion Criteria 
Disease Related 
1. Diagnosis of symptomatic MM (as defined by modified IMWG criteria, refer to Appendix 3) 
with measurable disease, defined here as having at least one of the following: 
• Serum monoclonal protein (M-protein) ≥ 0.5 g/dL as determined by serum protein 
electrophoresis (SPEP) 
• Urine protein electrophoresis (UPEP) ≥ 200 mg/24 hrs 
• Serum free light chain (FLC) assay:  involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) 
provided serum FLC ratio is abnormal 
2. Relapsed or relapsed and refractory MM after receiving at least 2, but no more than 5, 
previous lines of therapy, 1 of which must be an immunomodulator (eg, Revlimid®, 
thalidomide).51  
• Refractory myeloma (to most recent treatment) is defined as disease that is nonresponsive 
while on treatment or progressive disease within 60 days after the completion of 
preceding treatment.  Nonresponsive disease is defined as either failure to achieve 
minimal response or development of progressive disease while on therapy. 
o Subjects considered refractory to their most recent line of therapy will be ineligible if 
the most recent line included an immunomodulatory drug and proteasome inhibitor.  
• Relapsed myeloma is defined as the occurrence of any of the following after most recent 
treatment:   
o > 25% increase in M-protein from the lowest value obtained while on treatment 
(absolute increase must be ≥ 0.5 g/dL by SPEP, ≥ 200 mg/24h by UPEP or 
>10 mg/dL by serum FLC); or 
o increase in the size and number of lytic bone lesions recognized on radiographs 
(compression fractures per se do not constitute a relapse). 
Demographic 
3. Men and women ≥ 18 years of age. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
5. Life expectancy of ≥ 12 weeks. 
Ethical/Other 
6. Ability to understand and willingness to sign a written informed consent form (ICF). 


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7. Ability to adhere with the study visit schedule and other protocol procedures. 
5.2 
Major Exclusion Criteria 
Disease Related 
41. Subjects must not have primary refractory disease defined as disease that is nonresponsive in 
subjects who have never achieved a MR or better with any therapy. 
9. Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) 
syndrome, osteosclerotic myeloma, or Crow-Fukase syndrome.  
10. Plasma cell leukemia.  
11. Primary amyloidosis. 
12. Must not have had any cancer-directed systemic therapy including chemotherapy, 
immunomodulator or proteosome inhibitor within 3 weeks OR corticosteroid (> 10 mg/day 
prednisone equivalent systemic exposure) within 2 weeks, of the first dose of study drug.  
13. Radiotherapy within 21 days of Cycle 1 Day 1.  However, if the radiation portal was 
localized to single lesion or fracture site and covered by ≤ 5% of the bone marrow reserve 
(by investigator estimate), the subject may be enrolled irrespective of the end date of 
radiotherapy.  
14. Treatment with an anticancer antibody within 6 weeks of first dose of study drug.  
15. Concurrent enrollment in another therapeutic investigational clinical study, or treatment with 
an investigational agent within 3 weeks prior to beginning study drug or within 5 drug 
half-lives.  
16. Prior treatment with PCI-32765 or any other protein kinase inhibitory drug or drug targeting 
the BCR signal transduction pathway. 
Laboratory 
17. Absolute neutrophil count (ANC) < 750 cells/μL (0.75 x 109/L) independent of growth factor 
support.  
18. Platelet count < 50,000 cells/μL (50 x 109/L) independent of transfusion support.  
19. Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 3.0 x upper limit of 
normal (ULN).  
20. Total bilirubin > 2.5 x ULN, unless due to Gilbert’s syndrome.  
21. Creatinine > 2.5 mg/dL.  


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Concurrent Conditions 
23. Major surgery within 2 weeks of the first dose of study drug.  
24. Concomitant therapy with denosumab (bisphosphonate is allowed).  
26. Currently active, clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months 
of screening, any Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification, or evidence of QT prolongation (QTc > 470 msec).  
27. Unable to swallow capsules or disease significantly affecting gastrointestinal function, 
such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel 
obstruction.  
28. History of prior malignancy, with the exception of the following:  
a. Malignancy treated with curative intent and with no known active disease present for more 
than 3 years prior to screening and felt to be at low risk for recurrence by treating physician; 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without current 
evidence of disease; or 
c. Adequately treated breast or cervical carcinoma in situ without current evidence of disease. 
29. Peripheral neuropathy Grade ≥ 2 on clinical examination within 14 days prior to enrollment.  
30. Uncontrolled diabetes mellitus.  
31. Currently active systemic fungal, bacterial, viral, or other infection not controlled (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment).  
32. Use of antibiotics for treatment of infection within 7 days prior to first dose of study drug.  
33. Known history of infection with human immunodeficiency virus (HIV) or history of active 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active 
systemic infection.  
34. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of 
study drug. 
39. Requires anticoagulation with warfarin or a vitamin K antagonist (eg, phenprocoumon).  
40. Requires treatment with strong CYP3A4/5 inhibitors (see 3Appendix 2). 


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Ethical/Other 
35. Subject is pregnant or breastfeeding.  
36. Will not agree to use highly effective contraception (eg, condoms, implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or 
sterilized partner) during the study and for 30 days after the last dose of study drug.  
(Note:  applies to women of childbearing potential or men with female partners of 
childbearing potential only.) 
37. Any other 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.  
38. Any medical or psychiatric condition that, in opinion of investigator, could interfere with the 
subject’s ability to give informed consent, compliance, or treatment. 
6.0 
TREATMENT OF SUBJECTS 
6.1 
Randomization and Blinding 
This is an open-label study.  Subjects will not be blinded to study drug nor will they be randomly 
assigned to a treatment group.  Enrolled subjects will receive open-label PCI-32765 capsules. 
6.2 
Formulation, Packaging, and Storage 
PCI-32765 is provided in hard gelatin capsules containing 140 mg of PCI-32765.  The capsules 
are packaged in opaque high-density polyethylene plastic bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies.  The drug product is 
manufactured for Pharmacyclics LLC, by a contract manufacturer.  All formulation excipients 
are compendial and are commonly used in oral formulations.  
The recommended storage condition for PCI-32765 capsules is 15 to 25°C; excursions permitted 
to 30°C.  Refer to the IB for additional information regarding the drug product to be used in this 
study. 
If a drug shipment arrives damaged, or if there are any other drug complaints, please refer to the 
pharmacy study binder for further instructions.  
6.3 
Dosage and Administration  
6.3.1 PCI-32765 
PCI-32765 140-mg capsules are intended to be administered orally once daily with 8 ounces 
(approximately 240 mL) of water (avoid grapefruit or Seville orange juice due to CYP450 3A4/5 
inhibition).  The capsules should be swallowed intact and subjects should not attempt to open 


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capsules or dissolve them in water.  Subjects should refrain from taking the study drug on the 
morning of study visits designated for PK sampling until seen at the site (see Section 7.1.2).  
One cycle of treatment is once-daily administration of PCI-32765 for 28 days.  
Dosages are as follows: 
Cohort 
PCI-32765 (mg/day) 
Dexamethasone 
1 
420 (3 capsules) 
Upon PD, 40 mg once weekly is allowed 
2 
560 (4 capsules) 
40 mg once weekly 
3 
840 (6 capsules) 
Upon PD, 40 mg once weekly is allowed 
4 
840 (6 capsules) 
40 mg once weekly 
Subjects will continue on study drug until PD, withdrawal of consent, or until discontinuation of 
study drug due to an AE.  Subjects may continue study drug as long as the subject is deriving 
clinical benefit (SD or better) and the subject is not experiencing any unacceptable toxicity. 
PCI-32765 capsules should be taken at approximately the same time each day.  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 missed dose will not be made up and must be returned to the site at the 
next scheduled visit.   
A subject diary will be used to aid with study drug administration compliance. 
Only enough PCI-32765 capsules to supply subject until the next study visit should be dispensed 
with the exception of Cycle 1 where enough PCI-32765 capsules for the entire cycle can be 
dispensed.  Unused PCI-32765 capsules dispensed during previous visits must be returned and 
drug accountability records (Section 10.8) updated according to the schedule in Appendix 4. 
Returned capsules must not be re-dispensed to the same subject or to another subject. 
Investigators are prohibited from supplying PCI-32765 capsules to any subject not properly 
enrolled in this study or to any physician or scientist except those designated as subinvestigators 
on Form FDA 1572.  The investigator must ensure that subjects receive PCI-32765 capsules only 
from personnel who fully understand the procedures for administering the study drug. 
6.3.2 Dexamethasone 
Subjects receiving dexamethasone will receive 40 mg orally once per week.  Dexamethasone 
may be taken as either a single dose in the morning or as divided doses over the course of the 
day. 


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6.3.3 Combination of PCI-32765 and Dexamethasone Dosing  
6.3.3.1 
For Subjects with PD (Cohorts 1 and 3) 
At the discretion of the investigator and after Cycle 1, subjects in Cohorts 1 and 3 who have PD 
and who are clinically stable, without significant worsening of symptoms or hematologic status 
(ie, meet all entry criteria for the study in regard to symptoms and hematology), will be eligible 
to receive dexamethasone 40 mg orally once per week in addition to continued treatment with 
PCI-32765.  PD should be confirmed or have repeat laboratory samples collected prior to 
addition of dexamethasone.  Dexamethasone administration may commence at any time during a 
PCI-32765 cycle.  Blood samples for PK should be obtained during the initial cycle with added 
dexamethasone (Cohort 1 and 3 only), according to Section 7.1.2.  
6.3.3.2 
Concurrent Dosing of PCI-32765/Dexamethasone Combination 
(Cohorts 2 and 4) 
PCI-32765 will be administered orally once daily at dosages of 560 mg (Cohort 2) and 840 mg 
(Cohort 4).  Dexamethasone 40 mg will be administered orally once weekly, starting Day 4 of 
Cycle 1.  The rationale for this timing is to 1) prevent toxicity from dexamethasone confounding 
safety and tolerability as might occur if administered concurrently on Day 1, and 2) to allow 
intra-subject assessment of impact of dexamethasone on PCI-32765 PK. 
6.3.3.3 
Concurrent Dosing of PCI-32765/Dexamethasone Combination 
(Cohort 4 expansion) 
PCI-32765 will be administered orally once daily at a dose of 840 mg (6 x 140 mg capsules).  
Dexamethasone 40 mg will be administered orally once weekly, starting Day 8 of Cycle 1, 
following completion of the 7 hour postdose PK sample collection. 
6.4 
Early Cellular Mobilization 
Administration of PCI-32765 to subjects with other lymphoproliferative diseases has been 
associated with mobilization of tumor cells from tissue to peripheral blood.42,45,46  This effect 
begins in some cases within hours of the first administration and has been maximal within 
weeks.  It has been often accompanied by rapid symptomatic improvement.  It is therefore 
possible that increased MM cells will appear in the blood samples collected early on in the 
treatment of subjects during this study.  If such a phenomenon occurs, continued observation or 
treatment should be discussed with the medical monitor.  Note:  an increase in the presence of 
circulating plasma cells in peripheral blood in the absence of other indicators of active disease is 
not an indicator of PD. 
6.5 
Criteria for Holding or Adjusting Study Drug Dose 
6.5.1 Criteria for Holding PCI-32765 
Dosing will be held for any of the following conditions: 


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• Grade 4 ANC (< 500/µL) for > 7 days (neutrophil growth factors are permitted). 
• Grade 3 Platelets (< 50,000/µL)in the presence of clinically significant bleeding 
• Grade 4 Platelets (< 25,000/µL) 
• Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal anti-emetic 
and/or antidiarrheal therapy). 
Any other related grade 4 toxicities and any unmanageable nonhematologic Grade 3 toxicities.  
Table 2: 
Drug Discontinuation Actions for Subjects on PCI-32765 
 
Action to be taken - Hematologic Adverse Events 
• May resume therapy once ANC ≥750, follow dose modification guidelines below after first occurrence 
• May resume therapy once platelets >25,000 and no evidence of clinically significant bleeding, follow dose 
modification guidelines below after first occurrence 
Occurrence 
Action to be Taken - Non-hematologic Adverse Events 
First 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original dose level 
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower (ie, 
Phase 1: 420 mg/day for 560 mg /day cohort; or 700 mg/day for 840 mg/day cohort or Phase 2b: 
reduce daily dose by 1 capsule/day) 
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower (ie, 
Phase 1: 280 mg/day for 560 mg/day cohort; or 560 mg/day for 840 mg/day cohort or Phase 2b: 
reduce daily dose by 2 capsules/day) 
Fourth 
Discontinue study drug* 
*If study drug is discontinued for toxicity, subject will end the Treatment Phase of the study. 
Changes must be recorded in the Dosage Administration section of the case report form (CRF). 
Table 3: 
Intrasubject Dose De-escalation by Assigned Daily Dose 
Assigned Daily Dose 
420 mg 
(3 x 140 mg) 
560 mg 
(4 x 140 mg) 
840 mg 
(6 x 140 mg) 
Dose De-escalation Level 1 
280 mg 
(2 x 140 mg) 
420 mg 
(3 x 140 mg) 
700 mg 
(5 x 140 mg) 
Dose De-escalation Level 2 
140 mg 
(1 x 140 mg) 
280 mg 
(2 x 140 mg) 
560 mg 
(4 x 140 mg) 
 
If complete resolution or improvement of the toxicity to Grade 1 or to baseline values is achieved 
within 28 days, the investigator may elect to have the subject restart treatment with study drug.  
If the toxicity takes more than 28 days to resolve, then discussion with the medical monitor is 
required prior to the subject restarting treatment with study drug.  Upon restarting treatment with 
study drug, the investigator may elect to reduce the subject’s dose of study drug by 1 dose level, 
or by 2 dose levels if previously dose reduced, if the toxicity is considered likely related to study 
drug and likely to recur at the subject’s current daily dose.  Otherwise, study drug should be 
restarted at their current daily dose.  


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6.5.2 Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver.  For subjects who develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for ibrutinib is to a level of 280 mg 
daily (two capsules).  For subjects who develop moderate liver impairment while on study 
(Child-Pugh class B), the recommended dose reduction is to a level of 140 mg daily (one 
capsule).  Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study 
drug until resolved to moderate impairment (Child-Pugh class B) or better.  Monitor subjects for 
signs of toxicity and follow dose modification guidance as needed (Refer to Appendix 6). 
6.5.3 Criteria for Holding or Adjusting Dexamethasone 
Up to three successive dose reductions of dexamethasone, from 40 mg to 20, 8, and 4 mg per 
week per investigator discretion, may be instituted for related toxicity which is unmanageable by 
supportive measures.  Failure to tolerate 4 mg per week should lead to discontinuation of drug.  
Specific acute toxicities commonly noted with dexamethasone and other corticosteroids include 
upper gastrointestinal (dyspepsia, ulcer, gastritis), neurologic (confusion, mood alteration, 
insomnia), edema, hyperglycemia, and muscular weakness.   
6.6 
Criteria for Permanent Discontinuation of Study Drug 
Investigators are encouraged to keep a subject who is experiencing clinical benefit (refer to 
Section 4.1) in the study unless significant toxicity puts the subject at risk or routine 
noncompliance puts the study outcomes at risk.  If the subject meets any of the following criteria, 
then withdrawal from the study treatment is mandatory: 
• Subject has confirmed PD. 
• Subject has an intercurrent illness or AE that prevents further PCI-32765 capsule 
administration. 
• Subject decides to withdraw from study or becomes pregnant. 
• Subject is noncompliant with study procedures and/or scheduled evaluations. 
• Subject requires a prohibited concomitant medication or bone marrow transplant. 
• Investigator considers withdrawal to be in the best interest of the subject. 
• Pharmacyclics requires that the subject withdraw or Pharmacyclics and/or regulatory 
authorities terminate the study. 
• Subject completes the study. 
• Subjects who withdraw for any reason after receiving the first dose of PCI-32765 will not 
be replaced.  Subjects who withdraw prior to the first dose of PCI-32765 may be 
replaced. 
6.6.1 Withdrawal of Consent 
If a subject withdraws consent, it should be defined in the medical record if the subject 
withdraws consent to treatment and all further contact or if the subject withdraws partial consent, 


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ie, they no longer wish to receive treatment, but will participate in the Safety Follow Up Visit 
and/or Long term Follow up. 
6.7 
Concomitant Therapy 
6.7.1 Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted.  Use of hematopoietic growth factors is permitted in accordance with ASCO 
guidelines52.  
Short courses (<14 days) of corticosteroids (at dosages equivalent to prednisone ≤20 mg per day) 
for treatment of non-cancer-related medical reasons are permitted. 
6.7.2 Prohibited Concomitant Therapy 
Any chemotherapy, other myeloma-targeted therapy including “IMiDs” (eg, lenalidomide) and 
proteasome inhibitors (eg, bortezomib), anticancer immunotherapy, or corticosteroids are 
prohibited.  Experimental therapy and radiotherapy to treat the underlying myeloma disease are 
prohibited. 
Refer to Section 6.8.1.1 for guidance on drugs that are CYP P450 inhibitors. 
Refer to Section 6.8.1.3 for guidance on use of anticoagulants. 
6.7.3 Guidelines for PCI-32765 Management with Surgeries or Procedures 
PCI-32765 may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied during the perioperative period for subjects who require surgical 
intervention or an invasive procedure while receiving PCI-32765: 
6.7.3.1 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) PCI-32765 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 PCI-32765, it is not 
necessary to holdCI-32765.   
6.7.3.2 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, PCI-32765 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.   


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6.7.3.3 
Emergency Procedures 
For emergency procedures, PCI-32765 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. 
6.8 
Precautions 
For complete information on precautions refer to the IB. 
6.8.1 Medications to be Used with Caution 
6.8.1.1 
Concomitant Use of CYP Inhibiting/Inducing Drugs 
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong CYP3A4 or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
• 
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must 
be used, reduce ibrutinib dose to 140 mg or withhold treatment for the duration of 
inhibitor use.  Subjects should be monitored for signs of ibrutinib toxicity.  
• 
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 
ibrutinib to 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.  For subjects who are 
already on moderate CYP3A inhibitor concomitantly with ibrutinib without significant 
toxicity the investigator may consider the overall risk-benefit to determine if a dose 
reduction of ibrutinib is appropriate.  Avoid grapefruit and Seville oranges during 
ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Section 6.3.1). 
• 
No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort).  Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in 3Appendix 2. 
For further information, please refer to the current version of the IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/.  
This website is continually revised and should be checked frequently for updates.  
6.8.1.2 
Drugs That May Have Their Plasma Concentrations Altered by PCI-32765  
In vitro studies indicated that PCI-32765 is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  PCI-32765 is not expected to have systemic drug-drug 
interactions with P-gp substrates.  However, it cannot be excluded that PCI-32765 could inhibit 
intestinal P-gp after a therapeutic dose.  There is no clinical data available.  Therefore, to avoid a 


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potential interaction in the GI track, narrow therapeutic range P-gp substrates such as digoxin 
should be taken at least 6 hours before or after PCI-32765 
6.8.1.3 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
Warfarin or other vitamin K antagonists should not be administered concomitantly with 
PCI-32765.  Supplements such as fish oil and vitamin E preparations should be avoided.  
Use PCI-32765 with caution in subjects requiring other anticoagulants or medications that inhibit 
platelet function.  Subjects with congenital bleeding diathesis have not been studied.  Ibrutinib 
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 6.7.3).   
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg. atrial fibrillation), 
consider the risk and benefit of continuing PCI-32765 treatment.  If therapeutic anticoagulation 
is clinically indicated, treatment with ibrutinib should be held and not be restarted until the 
subject is clinically stable and has no signs of bleeding.  Subjects should be observed closely for 
signs and symptoms of bleeding.  No dose reduction is required when study drug is restarted. 
6.8.2 Reproductive Toxicity 
Reproductive toxicity studies have not been conducted with PCI-32765.  Therefore, women of 
childbearing potential, who are sexually active, must use highly effective contraception (as listed 
in Section 5.2) during the study and for 30 days after the last dose of study drug.  Men who are 
sexually active, must use highly effective contraception during the study and for 90 days 
(3 months) after the last dose of PCI-32765.  Subjects should promptly notify the investigator if 
they, or their partner, become pregnant during this period.  If a female subject becomes pregnant 
during the treatment period, she must discontinue study drug immediately.  Pregnancy in a 
female subject or a male subject’s partner must be reported in the same manner as an SAE 
(Section 9.3.5). 
6.8.3 Overdose Instructions 
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose.  Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as an SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose (Section 9.3.3).   
There is no specific experience in the management of ibrutinib overdose in patients.  No MTD 
was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day 
(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 9.3 for further information regarding AE reporting.  


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7.0 
STUDY PROCEDURES 
The Schedule of Assessments is provided in Appendix 4. 
Descriptions of the scheduled evaluations are outlined below and complete information on study 
drug and dosing is provided in Section 6.0. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments.  Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated. 
7.1 
Description of Procedures 
7.1.1 Screening Assessments 
All routine laboratory and clinical screening assessments must be performed within 21 days 
before the first administration of study drug, unless otherwise indicated (longer windows 
allowed for baseline radiologic studies).  All study-specific assessments that are not part of 
standard-of-care must be done after subjects sign the ICF. 
The following are required: 
Confirmation of Eligibility:  Perform all necessary procedures and evaluations to document that 
the subject meets each eligibility criterion (Section 5.0).  De-identified copies of measurable 
disease as documented by SPEP, serum FLC and UPEP is required prior to enrollment. 
Multiple myeloma diagnosis will be confirmed as well as the stage at original diagnosis47 and 
current disease status (relapsed or relapsed and refractory) will be documented if all requisite 
clinical results are available.  Please refer to the study manual for a more detailed description of 
the enrollment procedures. 
Medical History:  Collect and record the subject’s complete medical history through review of 
medical records and by interview.  Concurrent medical signs and symptoms must be documented 
to establish baseline severities.  A disease history, including the date of initial diagnosis and list 
of all prior anticancer treatments, and responses and duration of response to these treatments, 
also will be recorded. 
Concomitant Medications and Therapy:  All concomitant medications and procedures will be 
collected within 14 days prior to the start of study drug.  Prior use of denosumab and 
bisphosphates should also be recorded. 
Physical Examination, Vital Signs, Height, and Weight:  The screening physical examination 
(PE) will include, at a minimum, the general appearance of the subject, height (screening only) 


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and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, nervous system, and lymphatic system. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be assessed 
after the subject has been resting in the sitting position for at least 3 minutes. 
ECOG Performance Status:  The ECOG index is provided in 3Appendix 1. 
Electrocardiogram:  Subjects should be in the supine position for at least 10 minutes 
prior to the Screening ECG; 12-lead ECGs should be done in triplicate (≥ 1 minute apart).  
The calculated QTc average of the 3 ECGs must be < 470 msec for eligibility. 
Neuropathy and Bone Pain Assessments:  Subjects will complete questionnaires for 
neuropathy and bone pain at screening. 
Bone Marrow Aspirate and Biopsy:  A unilateral bone marrow aspirate and biopsy 
documenting percent marrow involvement will be done at screening.  Bone marrow aspiration 
and biopsy are to be evaluated for morphology locally.  Samples will be sent to a central 
laboratory for further evaluation.  Refer to Section 4.3 for a list of correlative assessments to be 
performed. 
Testing will be performed at the study center’s local laboratory or other clinical laboratory 
listedon the investigator’s Form FDA 1572. De-identified copies of all bone marrow 
aspirate/biopsy results must be provided to the Sponsor. 
Other Laboratory Tests:  Hematology and serum chemistry are part of the screening 
procedures to ensure eligibility.  For a description of these tests, refer to Section 7.1.2. 
Urinalysis:  Screening urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, 
and glucose.  Testing will be performed at the study center’s local laboratory or other clinical 
laboratory listed on the investigator’s Form FDA 1572. 
Urine Pregnancy Test:  Pregnancy tests are required only for women of childbearing potential.  
If positive, pregnancy must be ruled out by ultrasound to be eligible for participation in the 
study. 
Coagulation Studies:  Measurement of PT, INR, and aPTT are part of the screening procedures.  
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the investigator’s Form FDA 1572. 
Bone Radiological Assessment:  A radiologic skeletal survey for evaluation of bone lesions is 
required.  Magnetic resonance imaging (MRI) and computed tomography scans are to be 
performed as clinically indicated, ie, for subjects with known plasmacytoma.  Bone radiological 
assessment includes a lateral radiograph of the skull, antero-posterior and lateral views of the 


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spine, and antero-posterior views of the pelvis, ribs, femora, and humeri.  Bone radiological 
assessments are to be done within 30 days prior to the first dose of study drug. 
Myeloma Specific Tests:  Myeloma-specific tests will be performed on or within 14 days prior 
to Cycle 1 Day1.  Serum and urine protein electrophoresis are part of the screening procedures to 
ensure eligibility, and quantitative immunoglobulins.  Serum Free Light Chain (Freelite®), 
immunofixation (IFE), and β2-microglobulin are required as baseline tests.  For a description of 
these tests, refer to Section 7.1.2.  Testing will be performed at the study center’s local laboratory 
or other clinical laboratory listed on the investigator’s Form FDA 1572. 
Plasmacytoma Evaluation:  Presence of plasmacytomas using standard techniques should be 
evaluated at screening. 
7.1.2 Assessments During Treatment 
Subjects have scheduled study visits on Days 1, 2, 8, 15, and 22 of Cycle 1.  Thereafter, study 
visits will occur once per cycle on Day 1 (±2 days) of each cycle, continuing through Cycle 12 
unless otherwise indicated.  After Cycle 12, study visits will occur once every 2 cycles 
(ie, Cycle 12, 14, 16, etc).  Refer to the Schedule of Assessments (Appendix 4) for a complete 
list of procedures performed at each of the scheduled study visits.  
Concomitant Medications and Therapy:  Concomitant medications and therapy will be 
recorded at each visit; refer to Section 6.7. 
Adverse Events:  The definition for an AE is provided in Section 9.2.1.  All medical 
occurrences from the time of the first administration of study drug that meet this definition must 
be recorded.  Important additional requirements for reporting SAEs are included in Section 9.3.3.  
Adverse events will be recorded at each visit, or as they occur during the treatment period. 
Physical Examination, Vital Signs, and Weight:  Symptom-directed PEs will be performed 
during the treatment period.  Vital signs and weight (refer to Section 7.1.1) will be measured and 
recorded at each study visit unless otherwise indicated.   
ECOG Performance Status:  The ECOG will be measured and recorded at each study visit 
unless otherwise indicated.  The ECOG index is provided in 4Appendix 1. 
Neuropathy and Bone Pain Assessments:  Subjects will complete questionnaires for 
neuropathy and bone pain on Day 1 of Cycles 2, 4, 6, 8, 10, and 12.  Neuropathy and bone pain 
assessments are not required after Cycle 12. 
Bone Marrow Aspirate and Biopsy:  A unilateral bone marrow aspirate and biopsy 
documenting percent marrow involvement will be repeated as necessary to document response 
status as clinically indicated.  Analysis of bone marrow for confirmation of CR should include 
staining for CD138 and κ/λ mono-clonality by immunohistochemistry or immunofluorescence. 


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A unilateral bone marrow aspirate sample will also be collected following confirmed disease 
progression and can be performed any time prior to the start of a new antineoplastic treatment.  
Refer to Section 4.3 for description of testing. 
Hematology:  Hematology parameters will be measured on Days 1, 2, 8 and 15 of Cycle 1.  
Thereafter, blood samples for these tests will be collected at each study visit unless otherwise 
indicated.  Hematology parameters must include complete blood count (CBC) with differential  
and platelet counts.  Testing will be performed at the study center’s local laboratory or other 
clinical laboratory listed on the investigator’s Form FDA 1572. 
Serum Chemistry:  Serum chemistry parameters will be measured on Days 1, 2, 8, and 15 of 
Cycle 1.  Thereafter, blood samples for these tests will be collected at each study visit unless 
otherwise indicated.  Chemistry parameters must include albumin, alkaline phosphatase, ALT, 
AST, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate 
dehydrogenase, magnesium, phosphate, potassium, sodium, total bilirubin, total protein, and uric 
acid.  Testing will be performed at the study center’s local laboratory or other clinical laboratory 
listed on the investigator’s Form FDA 1572. 
Pharmacokinetics:  Refer to the laboratory binder for instructions on collecting and processing 
these samples.  All subjects regardless of cohort will have PK samples collected and processed as 
described in the tables below.  Additional PK samples will be collected for subjects in Cohort 1 
and Cohort 3 who have started dexamethasone.  The actual time (versus requested time) at which 
each sample is drawn must be recorded using a 24-hour format.  The same clock should be used 
for recording the time of dosing.  Refer to the laboratory manual for instructions on collecting 
and processing these samples. 
Table 4: 
PK Sample Schedule for All Subjects - Cycle 1 
 
 
 
Postdosea 
Cycle 
Day 
Predose 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
7 h (± 1 h) 
24 h (± 4 h) 
1 
1 
X 
X 
X 
X 
X 
X 
 
8 
X 
X 
X 
X 
X 
 
 
15 
X 
 
X 
 
 
 
 
22 
X 
 
X 
 
 
 
a. Record actual time of sample collection. 
 


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Table 5: 
PK Sample Schedule for Cohorts 1 and 3 Subjects Starting Dexamethasone 
after PD 
 
 
 
Postdosea 
Cycle 
Day 
Predose 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
7 h (± 1 h) 
24 h (± 4 h) 
X 
3 or 4 
X 
X 
X 
X 
X 
X 
 
11 or 12 
X 
X 
X 
X 
X 
 
a. Record actual time of sample collection. 
 
Table 6: 
PK Sample Schedule for Cohorts 4 Expansion 
 
 
 
Postdosea 
Cycle 
Day 
Predose 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
7 h (± 1 h) 
24 h (± 4 h) 
1 
1 
Xb 
X 
X 
X 
X 
X 
 
8c 
Xb 
X 
X 
X 
Xc  
 
2 
1d 
Xb 
X 
X 
X 
Xb  
 
a. Record actual time of sample collection. 
b. Additional samples will be collected at screening and following time-points described in the table for the 
analysis of 4-β-hydroxycholesterol (CYP3A induction maker) 
c. On C1D8 Dexamethasone will be administered after the 7 hr postdose PK draw  
d. On C2D1 Dexamethasone may be given concomitantly with PCI-32765 
The actual time (versus requested time) at which each PK sample is drawn must be recorded 
using a 24-hour format.  The same clock should be used for recording the time of dosing. 
Bone Radiological Assessment:  Repeated bone radiological assessments on study are not 
mandated by the protocol, but should follow institutional guidelines.  Bone radiological 
assessment includes 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. 
Myeloma-Specific Tests43,48:  Myeloma-specific tests include M-protein quantification by SPEP 
and UPEP, as well as quantitative immunoglobulins, Serum Free Light Chain (Freelite®), 
and β2-microglobulin.  UPEP is performed on a timed urine collection and should be recorded 
normalized to 24 hours.  Urine creatinine determinations should be performed as well as UPEP 
on all urines collected for M-protein quantification. 
Myeloma-specific protein tests will be obtained at the beginning of each cycle.  These will 
include SPEP, UPEP, or SFLC (if measurable disease is present at baseline by these methods), 
quantitative immunoglobulins and β2-microglobulin.  If the M-protein is not measurable by 
either SPEP or UPEP that test may be omitted at subsequent visits.  If the M- protein is or 
becomes immeasurable by both methods, Serum Free Light Chain (Freelite®) determinations will 
additionally be performed at all visits thereafter.  Testing will be performed at the study center’s 
local laboratory or other clinical laboratory listed on the investigator’s Form FDA 1572. 


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Measurable disease parameters (by serum and urine) must be repeated on Cycle 1 Day 1 prior 
to study drug administration unless performed within 5 days prior to the start of treatment.  
After Cycle 1, myeloma specific protein tests may be performed within ±2 days of Day 1 of 
subsequent cycles. 
Cytokines and Chemokines:  Blood samples for serum cytokine and chemokine measurement 
will be collected on Days 1, 2, 8, and 15 of Cycle 1 and Day 1 of Cycles 2, 3, 4, 6 and 10.  
Testing will include IL-6, SDF-1, RANKL and MIP-1α.  Centralized testing will be performed at 
Pharmacyclics LLC using overnight shipped samples.  
Peripheral Blood Immunophenotyping by Flow Cytometry:  Blood samples for 
immunophenotyping of peripheral blood mononuclear cells will be collected on Days 1, 2, 8, 
and 15 of Cycle 1 and on Day 1 of Cycles 2, 3, 4, 6 and 10.  Markers may include, but are not 
limited to, CD138, CD19, CD3, CD45, and CD38.  Centralized testing will be performed at 
Pharmacyclics LLC using overnight shipped samples.  Refer to the laboratory manual for 
instructions on collecting and processing these samples. 
Tests of Bone Turnover:  Bone turnover measurements will occur on Cycle 1 Days 1 and 15, 
Cycles 2, 3, and 4 Day 1; thereafter, they will be performed on Day 1 of the even numbered 
cycles.  Testing will include serum C-terminal cross-linking protein of type-1 collagen 
(serum CTX, CPT Code: 82523) and urinary N-terminal cross-linking peptide of type-1 collagen 
(urinary NTX, CPT Code: 82523; 82570).  Testing will be performed at a central laboratory.  
Refer to the laboratory manual for instructions on collecting and processing these samples. 
Confirmation of Responses:  Starting with Cycle 2, subjects will be evaluated for disease 
response criteria as detailed in Appendix 5.  Some or all of the following assessments may be 
required to confirm the response categories MR, PR, VGPR, CR, and sCR: 
• M-protein evaluations: 
¾ UPEP and SPEP  
¾ Serum IFE 
¾ Serum FLC 
• Plasmacytoma evaluation 
• Bone radiological assessment 
• Bone marrow aspiration and biopsy 
• Serum chemistries including calcium and albumin 
Plasmacytoma Evaluation:  Subjects with an extra-medullary plasmacytoma that is known or 
detected at baseline should be monitored throughout the study using the same technique used to 
evaluate at screening or baseline.  Therefore, a subcutaneous plasmacytoma that is readily 
measurable on physical examination should be followed by repeated physical examination, 


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with a CT or other clinically appropriate imaging study required only as needed to document CR.  
Follow-up of a deeply situated extra-medullary plasmacytoma should be in accordance with 
institutional guidelines, an appropriate imaging study is required to document a clinical response 
of PR or better. 
7.1.3 Safety Follow-up Visit 
Each subject should be followed for 30 (±7) days after the last dose of PCI-32765 or prior to the 
start of a new antineoplastic treatment to monitor for resolution or progression of AEs and to 
document the occurrence of any new AEs.  The procedures required at the Safety Follow-up visit 
are presented in the Schedule of Assessments (Appendix 4). 
A bone marrow aspirate sample at the time of confirmed progression may be collected during the 
Safety Follow-up visit or at any time prior to the start of a new antineoplastic treatment.  Refer to 
Section 4.3 for description of testing. 
7.1.4 Follow-up for Progression and Survival 
Subjects who discontinue from the study treatment for reasons other than PD will be followed 
for Response Follow-up (RFU) approximately every 2 months until PD or start use of alternative 
antineoplastic therapy.  During this period, the following tests may be performed at the 
investigator’s discretion as standard of care: 
• M-protein evaluations: 
¾ UPEP and SPEP 
¾ Serum IFE 
¾ Serum FLC 
¾ quantitative immunoglobulins 
• Plasmacytoma evaluation 
• Bone radiological assessment 
• Serum chemistries including calcium and albumin 
A bone marrow aspirate sample at the time of confirmed progression will be collected during this 
period prior to the start of a new antineoplastic treatment.  Refer to Section 4.3 for description of 
testing. 
A minimum of one Long Term Follow Up visit will be performed. Further Long-term Follow-up 
assessments will no longer be collected.  
7.2 
Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled date 
as possible.  An exception is made when rescheduling becomes, in the investigator’s opinion, 


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medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation.  
In that case, the missed evaluation should be abandoned. 
7.3 
Study Completion 
The expected duration of this study is approximately 5 years.  The study is considered completed 
when the last active subject discontinues PCI-32765 and completes the Safety Follow-up visit or 
rolls over to another study, whichever occurs first.  
8.0 
STATISTICAL METHODS OF ANALYSIS 
8.1 
General Considerations 
This study is designed to assess the efficacy and safety of PCI-32765 both as a single agent and 
in combination with dexamethasone in subjects with relapsed and relapsed and refractory MM.   
For subjects in Cohorts 1 and 3, subjects will be on PCI-32765 monotherapy and may convert to 
PCI-32765 and dexamethasone combination therapy at the discretion of the investigator after a 
confirmed PD on PCI-32765 monotherapy.  Thus the efficacy endpoints (DCB, ORR, DOR, 
PFS, TTP) will be presented and distinguished as with and without dexamethasone for subjects 
in Cohorts 1 and 3, when applicable. 
8.1.1 Response Assessment 
Response assessments will be made by the investigators using the modified IMWG response 
criteria (Appendix 5).43,44  Confirmation of investigator-assessed responses by an independent 
review committee (IRC) may be done as a supportive assessment.  The method of independent 
review will be governed by an IRC charter. 
8.2 
Definition of Analysis Populations 
The following definitions will be used for the efficacy and safety analysis sets. 
• Modified ITT population:  All enrolled subjects who receive ≥ 1 dose of study drug. 
• Safety analysis population:  All enrolled subjects who receive ≥ 1 dose of study drug. 
• Response evaluable population:  All enrolled subjects who receive ≥ 1 dose of study 
drug and undergo ≥ 1 response assessment after start of treatment. 
Unless otherwise specified, the Modified ITT population will be the primary population used for 
analyzing the efficacy endpoints.  The response evaluable population will be used for sensitivity 
analysis for efficacy.  The Safety analysis population will be used for analyzing the safety 
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8.3 
Endpoint Data Analysis 
8.3.1 Demographic/Baseline Characteristics and Study Conduct 
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease burden, and number of prior therapies) will be 
summarized.  Summary statistics will include means, standard deviations, and medians for 
continuous variables and proportions for categorical variables.   
Further, compliance parameters (including number of doses taken compared with number of 
doses that should have been taken) and concurrent treatments will also be similarly summarized. 
8.3.2 Primary Efficacy Endpoint 
The primary endpoint of the study is the CBR, defined as the proportion of subjects achieving a 
MR or better as assessed by investigator per modified IMWG criteria (Appendix 5).43,44 
The primary efficacy analysis will be performed in the Modified ITT population.  CBR and its 
corresponding 2-sided 90% exact binomial confidence interval will be calculated.  For subjects 
in Cohorts 1 and 3, CBR will be calculated during PCI-32765 monotherapy period as primary 
analysis.  CBR across the whole study course (including PCI-32765 and dexamethasone 
combination therapy period) will be calculated and presented as secondary analysis.   
8.3.3 Secondary/Exploratory Efficacy Endpoints 
8.3.3.1 
Duration of Clinical Benefit (DCB) 
Duration of clinical benefit (DCB) will include only subjects with confirmed responses 
(MR or better).  DCB will be calculated from the first observation of response to the time of PD, 
with death from causes other than progression censored.  Kaplan-Meier methodology will be 
used to estimate DOR and corresponding quartiles (including the median).  A 2-sided 95% 
confidence interval will be provided for the median DOR. 
8.3.3.2 
Objective Response Rate (ORR) 
Objective response rate (ORR) is defined as the proportion of subjects achieving CR 
(including sCR) + PR (including VGPR) as assessed by investigator per modified IMWG 
criteria.  ORR and its corresponding 2-sided 90% exact binomial confidence interval will be 
calculated.  
8.3.3.3 
Duration of Response (DOR) 
Duration of response (DOR) will include only subjects with confirmed responses (PR or better).  
DOR will be calculated from the first observation of response to the time of PD, with death from 
causes other than progression censored.  Kaplan-Meier methodology will be used to estimate 
DOR and corresponding quartiles (including the median).  A 2-sided 95% confidence interval 
will be provided for the median DOR. 


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8.3.4 Exploratory Endpoint 
8.3.4.1 
Progression-free Survival (PFS) 
Progression-free survival (PFS) is defined as the duration from start of the treatment to PD or 
death (regardless of cause of death), whichever comes first.  Kaplan-Meier methodology will be 
used to estimate event-free curves and corresponding quartiles (including the median).  A 2-sided 
95% confidence interval will be provided for the median PFS. 
8.3.4.2 
Time to Progression (TTP) 
Time to progression (TTP) is defined as the duration from start of treatment to PD, with deaths 
from causes other than progression censored.  Kaplan-Meier methodology will be used to 
estimate TTP and corresponding quartiles (including the median).  A 2-sided 95% confidence 
interval will be provided for the median TTP. 
8.3.4.3 
Overall Survival (OS) 
Overall survival (OS) is defined as the duration from first study drug administration until the 
date of death from any cause.  Subjects who are known to be alive as of data analysis cutoff date 
will be censored at their date last known alive.  Kaplan-Meier methodology will be used to 
estimate OS curves and corresponding quartiles (including the median).  A 2-sided 95% 
confidence interval will be provided for the median OS. 
8.3.5 Safety Endpoint 
Safety summaries will include tabulations in the form of tables and listings.  The frequency 
(number and percentage) of treatment-emergent AEs will be reported by MedDRA® System 
Organ Class and Preferred Term.  Additional AE summaries will include AE frequency by 
AE severity and by relationship to study drug. 
Adverse events requiring permanent discontinuation of study drug will be summarized 
separately, both overall and by AE severity and by relationship to study drug.   
The incidence of clinically significant abnormal laboratory values and vital signs will be 
summarized.   
8.3.6 Pharmacokinetics  
Plasma concentrations of PCI-32765 and metabolite PCI-45227) will be determined using a 
validated analytical method.  Other potential metabolites of PCI-32765 may be explored. 
Bioanalytical data from this study will be used in noncompartmental PK analysis and also may 
be pooled with data from other studies performed with PCI-32765 in subjects with hematologic 
malignancies as part of a population PK analysis using nonlinear mixed effects models.  For the 
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will be evaluated.  Pharmacokinetic relationships to PD measures of efficacy or toxicity may also 
be explored.  The results of the population PK analyses will be presented in a separate report. 
Plasma concentration for 4-β-hydroxycholesterol, a marker of CYP3A4 induction, will be 
determined using a validated analytical method at screening, pre-dose on Cycle 1 Days 1, 8, 
and Cycle 2 Day 1 for subjects in Cohort 4 expansion only.  4-β-hydroxycholesterol will be 
summarized using descriptive statistics. 
8.3.7 Exploratory Analyses  
Samples of whole blood and bone marrow will be collected and may be subjected to Biomarker 
assays which will compare the expression levels of proteins and genetic profile of a subject’s 
cancer cell genes prior and at the end of treatment.  These findings may offer some insight to the 
effects that the study drugs has on Multiple Myeloma which can help researchers identify 
changes in key biomarkers to monitor disease status of patients and may offer a method to better 
categorize the disease.  If there is evidence that study drug stops working, tests will be performed 
to determine the mechanism of resistance that the tumor cells have adapted to prevent response 
to study drug treatment.  Some of these samples may be stored and tested later, as defined in the 
informed consent, as new and more sensitive assays are developed. 
8.4 
Handling of Missing Data 
Every effort will be made to collect all data.  However, despite best efforts, it may be inevitable 
that missing or incomplete data are reported.  All missing or partial data will be presented in the 
subject data listing, as they are recorded on the CRF.   
Subjects lost to follow-up (or who dropped out) will be included in statistical analyses up to the 
point of their last evaluation.  Unless otherwise specified, no imputation of values for missing 
data will be performed.  Details of handling missing data will be included in the Statistical 
Analysis Plan. 
8.5 
Determination of Sample Size 
Cohort 1 was designed to detect a meaningful signal of activity while minimizing risk of 
continuing enrollment under null conditions.  Cohort 2-4 is designed to further explore the 
optimal regimen.  The sample size was estimated for each cohort without multiplicity 
adjustment. 
8.5.1 Cohort 1  
Subjects who meet the stated eligibility requirements will be enrolled in the study.   
Full enrollment to Cohort 1 will be contingent upon Simon 2 stage design rules with a target 
sample size of 35 evaluable subjects based on meeting interim efficacy endpoints, ie, if 
≥ 2 CBRs are observed among the first 11 subjects within Cohort 1.  This study cohort is 
designed to test the null hypothesis that the CBR of PCI-32765 monotherapy at a dose of 


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420 mg/day is ≤ 10% (not clinically compelling) versus the alternative hypothesis that CBR will 
be ≥ 30% at a 1-sided significance level of 5%, with 85% power.  Observation of ≥ 7 CBRs 
within an expanded cohort of 35 subjects will be considered consistent with the alternative 
hypothesis of CBR rate ≥ 30%. 
Although the design described above is setup to detect cohort specific CBRs of 30%, CBRs as 
low as 20% is still considered clinically meaningful, as the drug may be developed in 
combination therapy and/or in less heavily pre-treated populations.  With this 2-stage design, 
the probability to continue enrolling subjects for the second stage is approximately 0.68 if the 
true CBR rate is 20%.  
8.5.2 Cohorts 2-4 
Simon optimal 2-stage study design is utilized in Cohorts 2, 3, and/or 4. 
Up to eighteen subjects will be enrolled to each subsequent cohort (2-4).  Stage 1 enrollment to 
Cohorts 2, 3, and 4 will not be contingent upon results of preceding cohorts.  Full enrollment to 
Cohort 2, 3, and 4 will be contingent upon Simon 2-stage design rules with a sample size of  up 
to 43 evaluable subjects based on meeting interim efficacy endpoints, ie, if ≥ 3 CBRs are 
observed among the first 18 subjects within the subject cohort.  This design has 80% power to 
reject the null hypothesis of CBR ≤ 10%, at a 1-sided 5% significance level.  Observation of ≥ 8 
CBRs within an expanded cohort of up to 43 subjects will be considered consistent with the 
alternative hypothesis of CBR rate ≥ 25%.  The enrollment of that cohort may be closed early for 
success once 8 CBRs observed. 
Sponsor maintains the prerogative to select regimen that gives optimal efficacy and safety results 
at interim analysis for further development and suspend other cohorts at any time. 
This study design is not powered or intended to allow direct comparison of  percent CBR among 
the cohorts.  Results of this study will inform alternative directions for future combination and 
single agent development in alternative MM study populations.   
8.6 
Interim Analysis 
Each cohort will perform a futility interim analysis when stage 1 enrollment target met (Cohort 1 
11 subjects, Cohorts 2-4 18 subjects) and either all enrolled subjects have evaluable response 
data (ie, completed 6 treatment cycles and the Cycle 7 Day 1 assessments or have discontinued 
treatment) or the number of clinical benefit responders met stage 2 enrollment expansion criteria 
(≥ 2 for Cohort 1, ≥ 3 for Cohorts 2-4), whichever earlier.  Further enrollment will be halted until 
the cohort meet stage 2 enrollment expansion criteria.  All enrolled subjects will be followed to 
further assess their responses.  Enrollment may resume earlier while waiting for the confirmation 
of response of the last clinical benefit responder. 


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8.7 
Final and Follow-up Analyses 
The final analysis will occur upon study completion.  The study is considered completed when 
the last active subject discontinues PCI-32765 and completes the Safety Follow-up Visit or rolls 
over to another study, whichever occurs first.  
9.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of 
protocol-specified hematology, clinical chemistry, urinalysis, and other laboratory variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
9.1 
Safety Monitoring 
The study's investigators and data coordinators are responsible for entering the data and safety of 
this study, including implementation of the stopping rules for efficacy.  
All sites are required to use the eCRFs provided by the study sponsor.  All sites will be 
monitored on an ongoing basis by the study sponsor.  
Safety data is monitored in accordance with the sponsor's Pharmacovigilance Committee 
procedures.  Adverse events and serious adverse events will be reviewed internally on an 
ongoing basis to identify safety concerns. 
9.2 
Definitions   
9.2.1 Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an 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. 
For the purposes of this clinical study, AEs include only treatment-emergent events that are 
either new or represent detectable exacerbations of pre-existing conditions.  
Disease progression is not an AE; rather it may be the cause of an AE.  Adverse events that occur 
due to disease progression must be reported as all other treatment emergent AEs.  “Disease 
progression” should never be an AE. 
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. 


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• Adverse events experienced by the subject through the completion of final study 
procedures. 
• Adverse events 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 (Section 9.3.1). 
• Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered an AE: 
• Pre-existing Condition:  A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• Preplanned 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 that 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 therapy, or due to long travel distances are also not 
considered 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. 
9.2.2 Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  “Severity” (or intensity) refers to the 
grade of an AE, whereas “serious” is a regulatory definition. 
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
• results in death (ie, the AE actually causes or leads to death). 
• is life-threatening (“life-threatening” is defined as an AE in which the subject was at risk 
of death at the time of the event.  It does not refer to an event that hypothetically might 
have caused death if it were more severe.  If either the investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening). 
• requires inpatient hospitalization > 24 hours or prolongation of existing hospitalization. 
• results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• is a congenital anomaly/birth defect. 
• is an important medical event that may not result in death, be immediately life-threatening 
or require hospitalization but may be considered an SAE when, based upon appropriate 
medical judgment, in the event may jeopardize the subject or may require medical or 


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surgical 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 convulsions that do 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. 
9.2.3 Severity 
Definitions found in the CTCAE v4.0 will be used for grading the severity (intensity) of AEs.  
The CTCAE v4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for 
each referenced AE.  Should a subject experience any AE not listed in the CTCAE v4.0, 
the following grading system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences that are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities. 
• Grade 2 (Moderate AE) – experiences that introduce some level of inconvenience or 
concern to the subject, and that may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures. 
• Grade 3 (Severe AE) – experiences that 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 that cause the subject to be in 
imminent danger of death. 
• Grade 5 (Death related to AE) – experiences that result in subject death. 
9.2.4 Causality 
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: 
Unrelated: 
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. 
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. 
Definitely Related: 
The AE is clearly related to use of the investigational product. 


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9.2.5 Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the IB 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 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. 
9.3 
Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the electronic CRF (eCRF).  
All SAEs also must be reported on the SAE form (Section 9.3.3). 
9.3.1 Adverse Event Reporting Period 
The AE reporting period for this study begins with the first dose of study drug  and ends 30 days 
following the last dose of study drug.  SAEs occurring after 30 days following the last dose of 
study drug should also be reported to the Sponsor if considered related to study drug.  If an SAE 
is present at the Safety Follow-up visit, the SAE (and associated AEs and concomitant 
medications) should be followed to resolution or until the investigator assesses the subject as 
stable or the subject is lost to follow-up or withdraws consent.  Resolution/stable means the 
subject has returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the event. 
If a death occurs within 30 days after the last dose of study drug (even if the Safety Follow-up 
visit has already occurred), the death must be reported to the Sponsor as an SAE. 
9.3.2 Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study.  All AEs and SAEs, whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through PE, clinically significant laboratory testing, 
or other means, will be recorded in the subject’s medical record and on the AE eCRF and, 
when applicable, on an SAE form. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the investigational product 
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9.3.3 Expedited Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on an SAE form and will be 
emailed or faxed 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 (email/fax) for Pharmacyclics Drug Safety can be found on the SAE 
Report Form. 
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.  The primary cause of death on the 
autopsy report should be the term reported.  Autopsy and postmortem reports must be forwarded 
to Pharmacyclics Drug Safety, or designee, as outlined above. 
If study drug is discontinued due to an SAE, this information must be included in the SAE 
report. 
9.3.4 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) will be reported to the Sponsor within 
24 hours of awareness following the procedure described above for SAEs (Section 9.3.3) and 
will require enhanced data collection.  All Events of Special Interest will be submitted 
without a serious criterion selected if no other serious criterion is met. 
9.3.4.1 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. 
• Any treatment-emergent serious adverse events of bleeding of any grade 
• Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or higher AE per 
CTCAE. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 9.3.4 above. 
9.3.5 Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur (including female partners of male subjects), consent to 
provide follow-up information regarding the outcome of the pregnancy and the health of the 
infant until 30 days old will be requested. 


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A female subject must immediately inform the investigator if the subject becomes pregnant from 
the time of consent to 30 days after the last dose of study drug or a male subject must 
immediately inform the investigator if the subject’s partner becomes pregnant from the time of 
consent to 3 months after the last dose of study drug.  Any female subjects receiving PCI-32765 
capsules who become pregnant must immediately discontinue the use of study drug.  
The investigator should counsel the subject, discussing any risks of continuing the pregnancy and 
any possible effects on the fetus. 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented.  
Report any pregnancy that occurs in a subject or subject’s partner from the time of consent to 
30 days after the last dose of study drug.  Record any occurrence of pregnancy on the Pregnancy 
Report Form Part I and email or fax to Pharmacyclics Drug Safety, or designee, within 24 hours 
of learning of the event.  The pregnant female will be followed for outcome, which is defined as 
elective termination of the pregnancy, miscarriage, or delivery of the fetus.  For pregnancies with 
an outcome of live birth, the newborn infant will be followed until 30 days old by completing the 
Pregnancy Report Form Part II.  Any congenital anomaly/birth defect noted in the infant must be 
reported as a SAE. 
9.3.6 Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies are to be reported for the duration of study including 
the post-progression follow-up period for overall survival. 
9.4 
Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs), and Principal Investigators will be notified of SAEs in accordance with applicable 
requirements (eg, GCPs, ICH guidelines, national regulations, and local requirements).   
10.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Pharmacyclics retains the right to terminate the study and remove all study materials from a 
study site at any time.  Specific circumstances that may precipitate such termination are: 
• Unsatisfactory subject enrollment with regard to quality or quantity 
(eg, < 12 subjects enrolled within 12 months of starting the study). 
• Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects and maintain adequate study records. 
• Inaccurate, incomplete and/or late data recording on a recurrent basis. 
• The incidence and/or severity of AEs in this or other studies indicate a potential health 
hazard caused by the study treatment. 


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10.1 
Institutional Review Board and Independent Ethics Committee 
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/IEC for review and approval before study initiation.  Amendments to the 
protocol and ICF must also be approved by the IRB/IEC before the implementation of changes in 
this study. 
The investigator is responsible for providing the IRB/IEC with any required information before 
or during the study, such as SAE expedited reports or study progress reports. 
The IRB/IEC must comply with current 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/IEC letter that grants formal 
approval and (2) a copy of the IRB/IEC-approved ICF.  
10.2 
Informed Consent  
The ICF and process must comply with the United States 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, the study 
procedures, anticipated benefits, potential risks, the possible adverse effects, and any discomfort 
participation in the study may entail.  Each subject must provide a signed and dated ICF before 
any study-related (nonstandard of care) activities are performed (such as screening).  
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. 
10.3 
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 10.2), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific Health Insurance Portability and Accountability Act 
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/IECs.  
As the study sponsor, Pharmacyclics will not use the subject’s protected health information or 


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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. 
10.4 
Subject Screening Log 
The investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study.  For those subjects subsequently excluded 
from enrollment, record the reason(s) for exclusion. 
10.5 
Source Documentation Requirements 
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.  Source 
documentation for this study will include, but not be limited to, worksheets, hospital and/or 
clinic or office records documenting subject visits including study and other treatments or 
procedures, medical history and PE information, laboratory and special assessments results, 
pharmacy records, drug accountability records, and medical consultations (as applicable). 
10.6 
Case Report Forms 
Electronic case report forms 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 form) 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 as soon as reasonably possible.  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 


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investigator will receive a copy of the subject data (eg, paper, CD-ROM or other appropriate 
media) for archiving at the study site. 
10.7 
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 as well 
as any appropriate communications by mail, fax, email, or telephone.  The purpose of monitoring 
is to ensure that the study is conducted in compliance with the protocol, standard operating 
procedures (SOPs), and other written instructions and regulatory guidelines, and to endure the 
quality and integrity of the data.  This study is also subject to reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents at reasonable times and upon reasonable notice.  
During the review of source documents, every effort will be made to maintain the anonymity and 
confidentiality of all subjects during this clinical study.  However, because of the experimental 
nature of this treatment, the investigator agrees to allow the IRB/IEC, representatives of 
Pharmacyclics, its designated agents, and authorized employees of the appropriate regulatory 
agencies 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 on the ICF and permission from 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. 
10.8 
Investigational Study Drug Accountability 
PCI-32765 capsules must be kept in a locked limited access room.  The study drug must not be 
used outside the context of the protocol.  Under no circumstances should the investigator or other 
site personnel supply PCI-32765 capsules to other investigators, subjects, or clinics or allow 
supplies to be used other than as directed by this protocol without prior authorization from 
Pharmacyclics. 
PCI-32765 capsules accountability records must be maintained and readily available for 
inspection by representatives of Pharmacyclics and are open to inspections by regulatory 
authorities at any time.  


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Each shipment of PCI-32765 capsules will contain a Clinical Supplies Shipping Receipt Form 
(CSSF) that must be appended to the site’s drug accountability records.  Additionally a Drug 
Reorder Form for requesting more PCI-32765 capsules is provided in the pharmacy manual.  If it 
is used, the Drug Reorder Form must also be included in the site’s drug accountability records.   
Contents of each shipment must be visually inspected to verify the quantity and document the 
condition of PCI-32765 capsules.  Then the designated recipient completes and signs the CSSF.  
A copy of the signed CSSF must be faxed or mailed to Pharmacyclics at the fax number/mailing 
address listed on the form. 
An Investigational Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study: 
1. study identification number (PCYC-1111-CA). 
2. subject identification number. 
3. lot number(s) of PCI-32765 capsules dispensed for that subject. 
4. date and quantity of drug dispensed. 
5. any unused drug returned by the subject. 
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements.  If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product.  Before disposal/destruction, final drug accountability and reconciliation 
must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
10.9 
Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each investigator and subinvestigator (as designated on the Form FDA 1572) 
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. 
10.10 Availability and Retention of Records 
The investigator and other appropriate study staff are responsible for maintaining all essential 
documentation relevant to the study.  Essential documentation includes, but is not limited to, the 


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IB, signed protocols and amendments, IRB/IEC approval letters (dated), signed Form FDA 1572 
and Financial Disclosure, signed ICFs (including subject confidentiality information), drug 
dispensing and accountability records, shipping records of investigational product and study-
related materials, signed (electronically), dated and completed CRFs, and documentation of CRF 
corrections; SAE forms transmitted to Pharmacyclics and notification of SAEs and related 
reports, source documentation, normal laboratory values; decoding procedures for blinded 
studies; curricula vitae for study staff, all relevant correspondence, and other documents 
pertaining to the conduct of the study. 
Subject identity information will be maintained for 15 years.  All other essential documentation 
will be retained by the investigator for at least 2 years after the date the last marketing 
application is approved for the drug for the indication for which it is being investigated and until 
there are no pending or contemplated marketing applications; or, if no application is to be filed 
or if the application is not approved for such indication, until 2 years after formal discontinuation 
of clinical development of the drug.  
The investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, 
electrocardiogram 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 return 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. 
10.11 Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document.  The 
amendment will be submitted to the IRB/IEC together with, if applicable, a revised model ICF.  
Written documentation of IRB/IEC 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 study. 


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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. 
10.12 Use of Information and Publication  
All information, including but not limited to information regarding PCI-32765 or the Sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, 
prior clinical data, formulation information) supplied by the Sponsor to the investigator and not 
previously published, and any data generated as a result of this study, are considered confidential 
and remain the sole property of the Sponsor.  The investigator agrees to maintain this 
information in confidence and use this information only to accomplish this study, and will not 
use it for other purposes without the Sponsor’s prior written consent. 
The investigator understands that the information developed in the clinical study will be used by 
the Sponsor in connection with the continued development of PCI-32765, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies.  To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the Sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the Sponsor and 
will contain CRF/eCRF data from all investigational sites that participated in the study.  
Recruitment performance or specific expertise related to the nature and the key assessment 
parameters of the study will be used to determine a coordinating investigator.  Any work created 
in connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the Sponsor as author and owner of copyright in such work. 
The Sponsor shall have the right to publish such data and information without approval from the 
investigator.  If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to the Sponsor for review at least 60 days before submission for 
publication or presentation.  Authorship of publications resulting from this study will be based 
on the guidelines on authorship, such as those described in the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, which state that the named authors must have 
made a significant contribution to the design of the study or analysis and interpretation of the 
data, provided critical review of the paper, and given final approval of the final version.


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11.0 
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4. Aggarwal R, Ghobrial IM, Roodman GD. Chemokines in multiple myeloma. Exp Hematol 
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5. Roodman GD. Osteoblast function in myeloma. Bone 2011;48(1):135-140. 
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7. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 
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10. Schlossman RL, Anderson KC. Bone marrow transplantation in multiple myeloma. 
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11. Bensinger WI. Role of autologous and allogeneic stem cell transplantation in myeloma. 
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17. Giralt, S. Update on non-myeloablative stem cell transplantation for hematologic 
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multiple myeloma cells using oligonucleotide arrays. Oncogene 2002;21(9):1346-1358. 
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Blocks Osteoclastogenesis and Inhibits In Vivo Human Multiple Myeloma Growth via 
Significant Downregulation of Cytokines and Chemokines in the Bone Marrow 
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24. Bam R, Pennisi A, Li X, et al. Bruton's Tyrosine Kinase (Btk) Is Indispensable for Myeloma 
Cell Migration towards SDF-1 and Induction of Osteoclastogenesis and Osteolytic Bone 
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25. Saintigny P, Zhang L, Fan YH, et al. Gene expression profiling for molecular classification 
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28. Hoyer JD, Hanson CA, Fonseca R, Greipp PR, Dewald GW, Kurtin PJ. The 
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34. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's 
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PCI-32765 blocks B cell activation and is efficacious in models of autoimmune disease and 
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tolerable in patients with poor risk CLL: interim results from a Phase IB/II study. Ann Oncol 
2011;22(4):iv123-iv124. Presented at the 11th International Conference on Malignant 
Lymphoma 2011, Switzerland. 
37. Byrd JC, Blum JA, Burger SE, et al. Activity and tolerability of the Bruton's tyrosine kinase 
(Btk) inhibitor  in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL): Interim results of a phase Ib/II study. 2011 ASCO Annual Meeting. Abstract 
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39. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed 
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Leukemia 2010;24(10):1700-1712. 
41. Zannettino AC, Farrugia AN, Kortesidis A, et al. Elevated serum levels of stromal-derived 
factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in 
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42. Chang BF, Magadala P, Huang,MM, Buggy BJ, Elias L. Egress of CD19+CD5+ cells into 
the Peripheral Blood following Treatment with Bruton Tyrosine Kinase Inhibitor, 
PCI-32765, in Mantle Cell Lymphoma Patients, in American Society of Hematology2011. 
43. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for 
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approvals for myeloma. Leukemia 2008;22(2):231-239. 
45. Burger JA, O’Brien S, Fowler N, et al. The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, 
Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic 
Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 
Studies. Blood (ASH Annual Meeting Abstracts) 2010;116(21):57. 
46. Pollyea DA, Smith S, Fowler N, et al. A Phase I Dose Escalation Study of the Btk Inhibitor 
PCI-32765 in Relapsed and Refractory B Cell Non-Hodgkin Lymphoma and Use of a Novel 
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47. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple 
myeloma. J Clin Oncol 2005;23(15):3412-3420. 
48. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard 
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50. Vogl DT, Stadtmauer EA, Richardson PG, et al. Impact of prior therapies on the relative 
efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory 
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51. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
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1. Blood. 2011;117(18):4691-5.  
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53. Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation.  
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differentiation.  Nat Rev Immunol 2002; 2: 920–932. 
 
 


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12.0 
APPENDICES 
 
 
 


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Appendix 1. ECOG and Karnofsky Performance Status Scores 
% 
Karnofsky Performance Status 
Status 
Eastern Cooperative Oncology Group 
(ECOG) Performance Status 
100 
Normal; no complaints; no 
evidence of disease. 
0 
Fully active, able to carry on all predisease 
performance without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature, 
e.g., light housework, office work. 
70 
Care for self.  Unable to carry on 
normal activity or do active work. 
60 
Requires occasional assistance but 
is able to care for most of his or 
her needs. 
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. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
30 
Severely disabled; hospitalization 
is indicated though death not 
imminent. 
20 
Hospitalization necessary; very 
sick; active supportive treatment 
necessary. 
4 
Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 
 
 
 


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Appendix 2. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows.  Refer to Section 6.8.1.1 on 
instructions for concomitant use of CYP3A inhibitors or inducers with PCI-32765.  Further information 
can be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone 
telithromycin 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem 
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
 
 


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Appendix 3. Multiple Myeloma Diagnostic Criteria 
Subject must have been previously diagnosed with multiple myeloma (MM) based on either 
standard diagnostic criteria49 or by the International Myeloma Working Group Diagnostic 
(IMWG) Criteria.43  In addition, at least 1 of the “CRAB” conditions must be met for 
documentation of symptomatic myeloma requiring systemic therapy,43 along with either disease 
diagnostic criteria: 
Standard Criteria49 
Any of the following sets of criteria will confirm the diagnosis of MM: 
1. Any 2 of the major criteria. 
2. Major criterion 1 plus minor criteria b, c, or d. 
3. Major criterion 3 plus minor criteria a or c. 
4. Minor criteria a, b, and c; or criteria a, b, and d. 
Major Criteria 
a) Plasmacytomas on tissue biopsy. 
b) Bone marrow plasmacytosis (>30% plasma cells). 
c) Monoclonal immunoglobulin spike on serum electrophoresis immunoglobulin G (IgG) 
> 3.5 g/dL or immunoglobulin A (IgA) > 2.0 g/dL; kappa or lambda light chain excretion 
> 1g/day on 24-hour urine protein electrophoresis. 
Minor Criteria 
a. Bone marrow plasmacytosis (10% to 30% plasma cells). 
b. Monoclonal immunoglobulin present, but of lesser magnitude than given under major 
criteria. 
c. Lytic bone lesions. 
d. Normal (non-M protein) IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL. 
 
 


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IMWG Criteria for MM Requiring Systemic Therapy43 
Monoclonal protein (M-component) present in the serum and/or urinea plus monoclonal plasma 
cells in the bone marrow ≥ 10% and/or presence of a biopsy-proven plasmacytoma  
CRAB criteria of the IMWG,43 1 or more required for diagnosis of symptomatic myelomab 
[C] Calcium, serum ≥ 11.5 mg/dL or > upper limit of normal  
[R] Renal:  serum creatinine > 2 mg/dL 
[A] Anemia:  hemoglobin < 10 g/dL or 2 g < normal 
[B] Lytic Bone lesions, severe osteoporosis, or pathologic fracturesc 
a 
If no monoclonal protein is detected (non-secretory disease), then > 30% monoclonal bone marrow plasma 
cells and/or a biopsy-proven plasmacytoma required for IMWG diagnosis; however subjects with non-
secretory myeloma are not eligible to participate in this study. 
b 
A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy.  
Such dysfunction is sufficient to support classification of myeloma if proven to be myeloma related.  
c 
If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining 
criteria, then > 30% plasma cells are required in the bone marrow. 
 


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Appendix 4. Schedule of Assessments 
Study Cycles (28 day) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11
Beginning Cycle 12 
Continue assessments until Progressive Disease 
SFUb RFUc LTFUd
Cycle Days 
1 
2 
8 15 22
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
 
Procedures 
Screeninge 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X
X
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Assessment 
 
X 
X 
X
X
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examinationf, Vital 
Signsg, and ECOG 
X 
X 
 
As clinically 
necessary 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Electrocardiogramh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropathy and Bone Pain 
Assessments 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xi 
X 
 
 
Bone Marrow Aspiration/Biopsyj 
X 
 
 
 
 
 
Repeat as necessary to document response status as clinically indicated 
XJ 
XJ 
 
Laboratory Assessments 
 
 
Hematologyk 
X 
X 
X 
X
X
 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistryl 
X 
X 
X 
X
X
 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysism 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine Pregnancy Testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Coagulation: PT, INR, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PKo 
 
X 
X 
X
X
X 
 
Repeat PK in the event that dexamethasone is added to treatment 
(Cohorts 1 and 3 only) 
 
 
 
PK for Cohort 4 expansion 
 
X 
X 
X
 
 
X 
 
 
 
 
4-β-hydroxycholesterol levels for 
Cohort 4 expansion 
X 
X 
 
X
 
 
X 
 
 
 
 
Disease Assessments 
 
 
Bone Radiological Assessmentp 
X 
 
 
Repeat as necessary to document response status and as clinically indicated 
Xp 
Xp 
 
Β2-Microglobulins 
X 
X 
 
 
 
 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Quantitative Serum 
Immunoglobulins (IgG, A, M)q 
X 
X 
 
 
 
 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum IFE 
X 
X 
 
 
 
 
Repeat as necessary to document response status  
as clinically indicated  
X 
X 
 
continued 


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Study Cycles (28 day) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Beginning Cycle 12 
 
SFUb RFUc LTFUd
Cycle Days 
1 
2 
8 
15
22
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
 
 
Disease Assessments 
(continued) 
Screeninge 
 
 
Serum Free Light Chain 
(Freelite®) 
X 
X 
 
 
Repeat every cycle if M protein initially or becomes not measurable  
by protein electrophoresis 
X 
X 
 
M-Protein (SPEP or UPEP)r 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cytokines/Chemokinest 
 
X 
X
X 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
Peripheral Blood Cellular 
Immunophenotypingt 
 
X 
X
X 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
Bone Turnover Tests (serum 
CTX and urine NTX) 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Confirmation of Responseu 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Plasmacytoma Evaluations 
X 
As clinically indicatedv 
Xv 
Xv 
 
Long-term Follow-up Status 
 
 
 
 
 
X 
Abbreviations: aPTT = activated partial thromboplastin time; CR = complete response; CT = computed tomography, CTX = C-terminal cross-linking protein of type-1 
collagen; ECG = electrocardiogram; FLC = free light chain; IFE = immunofixation; Ig = immunoglobulin; INR = international normalized ratio; ECOG = Eastern Cooperative 
Oncology Group; LTFU = long-term follow-up; MM = multiple myeloma; MR = minimal response; NTX = N-terminal cross-linking protein of type-1 collagen; PD = 
progressive disease; PE = physical examination; PEP = protein electrophoresis; PR = partial response; PT = prothrombin time; RFU = response follow-up; sCR = stringent 
complete response; SFU = safety follow-up; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; VGPR = very good partial response.  
a. 
Study visits will occur every other cycle beginning Cycle 12 (ie Cycle 12, 14, 16, etc). 
b. 
The Safety Follow-up visit will occur 30 days (±7 days) from the last dose of study drug or prior to the start of a new anticancer therapy.  If subject withdraws consent to 
treatment, subject may still participate in safety follow-up.  
c. 
Subjects who permanently discontinue from the study for reasons other than PD will be followed every 2 months until PD or use of alternative antineoplastic therapy. 
During this period, myeloma assessment will be done per investigator discretion as referenced in Section 7.1.4.  
d. 
Subjects who progress or start use of alternative antineoplastic therapy will be contacted every 3 months by clinic visit or telephone, to assess survival and the use of 
alternative antineoplastic therapy.  If subject withdraws consent to treatment, subject may still participate in long-term follow-up.  Per amendment 5, after  completing a 
minimum of one Long-term Follow-up visit, further Long-term Follow-up assessments will no longer be collected.  
e. 
Screening assessments must be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
f. 
The screening PE will include, at a minimum, the general appearance of the subject and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, nervous system, and lymphatic system. Symptom-directed PEs will be performed thereafter. 
g. 
Vital signs (blood pressure, pulse, respiratory rate, and body temperature) will be assessed after the subject has been resting in the sitting position for at least 3 minutes, 
height (screening only) and weight. 
h. 
Subjects should be in the supine position for at least 10 minutes prior to the Screening ECG; 12-lead ECGs should be done in triplicate (≥ 1 minute apart). The calculated 
QTc average of the 3 ECGs must be < 470 msec for eligibility. 
i. 
Neuropathy assessment and bone pain assessment are not required after Cycle 12. 


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j. 
A unilateral bone marrow aspirate and biopsy documenting percent marrow involvement will be done at screening.  Bone marrow aspiration and biopsy are to be 
evaluated for morphology locally.  Samples will be sent to a central laboratory for further evaluation.  Refer to Section 4.3 for a list of correlative assessments to be 
performed.  Bone marrow for confirmation of CR should include staining for CD138 and κ/λ  clonality by immunohistochemistry or immunofluorescence. A unilateral 
bone marrow aspirate sample will be collected at the time of suspected CR.  It will also be collected following confirmed disease progression and will be performed any 
time prior to the start of a new antineoplastic treatment. 
k. 
Hematology includes complete blood count with differential and platelet counts. 
l. 
Serum chemistry includes albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, 
glucose, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, total bilirubin, total protein, and uric acid. 
m. 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
n. 
Pregnancy tests are required only for women of childbearing potential.  If positive, pregnancy must be ruled out by ultrasound to be eligible for participation in the study. 
o. 
PK time points: Please refer to Section 7.1.2 for tables summarizing PK collection timepoints for each specific cohort 
p. 
Bone radiological assessment includes 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. Repeated bone radiological assessment on study is not managed by the protocol, but should follow institutional guidelines. 
q. 
Quantitative serum immunoglobulin: IgG, IgM, and IgA by nephelometry. 
r. 
Myeloma protein tests will be performed at screening, predose Cycle 1 Day 1 and at the beginning of each subsequent cycle and include M-protein quantification by 
serum protein electrophoresis, a timed urine collection for urine M-protein quantification by urine protein electrophoresis (when urinary M protein has been detectable), 
immunofixation (IFE), quantitative immunoglobulins and β2-microglobulin.  Cycle 1 Day 1 SPEP required, other tests may be omitted if performed within 5 days prior to 
Day 1 as screening tests.  Creatinine excretion should also be measured on all 24 hour urine collections. If the M protein initially or becomes non-measurable by both 
SPEP and UPEP, serum free light chain determinations will additionally be performed.  
s. 
β2-microglobulin will also be tested at screening, predose Cycle 1 Day 1, and at the beginning of each cycle. Cycle 1 Day 1 β2-microglobulin may be omitted if 
determined within 5 days prior to Day 1 as screening test. 
t. 
Blood shipped overnight to Pharmacyclics LLC 
u. 
Response to treatment. Some or all of the following assessments may be required to confirm the response categories of MR, PR, VGPR, CR, and sCR according to 
Appendix 5.  M protein evaluations including UPEP, SPEP, IFE, and serum FLC; plasmacytoma evaluation, bone radiological assessment; bone marrow aspiration and 
biopsy; and serum chemistries including calcium and albumin. 
v. 
If present at baseline, plasmacytomas should be followed per institutional guidelines, using the same techniques, if possible, used at screening or at baseline to assess the 
plasmacytoma(s).  Measurements need to be incorporated in the response assessment (Appendix 5).  
 


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Appendix 5. Disease Response Assessment by Modified IMWG Criteria43,44 
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 immunohistochemistry 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)e 
• 
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  
• 
If at on study, the only measurable non-bone marrow parameter was FLC, 
≥90% or greater reduction in the difference between involved and 
uninvolved free light chain levels
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  
 If at on study, the only measurable non-bone marrow parameter was 
FLC, a ≥50% decrease in the difference between involved and 
uninvolved FLC levels   
 If at on study, the bone marrow was only measurable parameter, ≥50% 
reduction in bone marrow plasma cells is required in place of M-
protein, provided baseline percentage was ≥30% 
• 
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 g: 
 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 
 If at on study, the only measurable non-bone marrow parameter 
was FLC, the difference between involved and uninvolved FLC 
levels (absolute increase must be >10 mg/dL) c  
 Bone marrow plasma cell percentage (absolute % must be ≥10%)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 (≥11.5 mg/dL)
Relapse from CR or 
sCR d 
Subject who has achieved confirmed CR who has any one or more of 
the following: 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of ≥5% plasma cells in the bone marrow f 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion, or hypercalcemia)
a All response categories require two consecutive assessments made at any time before the institution of any new 
therapy; complete response 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 immunohistochemistry 
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 This category will ONLY be used to analyze disease free survival 
e This response category is not available for those subjects being followed by bone marrow only. 
f  Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
g 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. 


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Confirmation of Response Categories  
In order to be classified as a hematologic response, confirmation of serum monoclonal protein, 
serum immunoglobulin free light chain (when primary determinant of response) 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 or sCR, except for subjects with bone 
marrow plasmacytosis evaluable disease only, where a bone marrow is required to document all 
response categories including progression. 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 ≥0.5 g/dL  
o Urine M-protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥10 mg/dL provided serum FLC ratio is abnormal 
 
The serum free light chain (sFLC) assay is of particular use in monitoring response to therapy in subjects 
who have oligo-secretory or non-secretory disease and should be used in assessing response only if the 
baseline serum and/or urine M proteins are not “measurable” as above, and the baseline level of the 
involved FLC is “measurable.” When using this assay, it is important to note that the sFLC levels vary 
considerably with changes in renal function and in subjects with renal insufficiency, the levels of both the  
kappa and lambda may remain elevated, but the ratio normalizes with achievement of CR. Thus, both the 
level of the involved and the uninvolved sFLC isotype (ie, the involved/uninvolved ratio or 
involved-uninvolved difference) should be considered in assessing response. Subjects included on the 
study on the basis of sFLC alone (ie, no measurable serum/urine m-spike) should be the only ones who 
are evaluated using sFLC response criteria. The others should follow usual criteria and ignore sFLC 
results with the exception of defining stringent complete response. 
 
 


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

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Statistical Analysis Plan 
Protocol PCYC-1111-CA 
A Multicenter Phase 2 Study of the Bruton’s Tyrosine Kinase (Btk) 
Inhibitor, PCI-32765, in Subjects with Relapsed or Relapsed and 
Refractory Multiple Myeloma 
Version:   
4.0 
Version Date: 
17 June  2016 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics, LLC. that must not be disclosed 
to anyone other than the recipient study staff and members of the institutional review board/ethics 
committee.  This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics, LLC. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS  .................................................................................................................. 2 
REVISION HISTORY  ...................................................................................................................... 4 
ABBREVIATIONS  ........................................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................... 7 
1.1. 
PROTOCOL NUMBER AND TITLE ............................................................................................. 7 
1.2. 
STUDY OBJECTIVES ................................................................................................................ 7 
1.2.1. 
Primary Objective ................................................................................................................... 7 
1.2.2. 
Secondary Objectives .............................................................................................................. 7 
1.2.3. 
Exploratory Objectives ........................................................................................................... 8 
1.2.4. 
Exploratory Analyses .............................................................................................................. 8 
1.3. 
STUDY DESIGN ....................................................................................................................... 8 
2. 
STUDY ENDPOINTS ............................................................................................................ 10 
2.1. 
PRIMARY ENDPOINT ............................................................................................................. 10 
2.2. 
SECONDARY ENDPOINTS ...................................................................................................... 10 
2.3. 
EXPLORATORY ENDPOINTS .................................................................................................. 10 
3. 
SAMPLE SIZE CONSIDERATIONS .................................................................................... 11 
3.1. 
COHORT 1 ............................................................................................................................. 11 
3.2. 
COHORTS 2-4 ........................................................................................................................ 11 
4. 
STUDY POPULATIONS AND ANALYSIS SETS ................................................................ 12 
5. 
ANALYTIC DEFINITIONS .................................................................................................... 12 
5.1. 
STUDY DAY AND DURATION OF TREATMENT ....................................................................... 12 
5.2. 
TIME ON STUDY .................................................................................................................... 13 
5.3. 
BASELINE ............................................................................................................................. 13 
5.4. 
DISEASE STATUS .................................................................................................................. 13 
5.5. 
DISEASE STAGE .................................................................................................................... 13 
5.6. 
ECOG AND KARNOFSKY PERFORMANCE STATUS SCORES ................................................... 13 
5.7. 
TREATMENT-EMERGENT PERIOD .......................................................................................... 14 
5.8. 
AVERAGE DOSE AND RELATIVE DOSE INTENSITY ................................................................ 14 
5.9. 
CALCULATION OF LABORATORY VALUES ............................................................................ 15 
5.10. 
OTHER GENERAL DEFINITIONS ............................................................................................. 15 
6. 
MISSING DATA HANDLING ................................................................................................ 16 
6.1. 
GENERAL APPROACH ........................................................................................................... 16 


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6.2. 
MISSING AND INCOMPLETE DATA ........................................................................................ 16 
6.2.1. 
Efficacy Variables ................................................................................................................. 16 
6.2.2. 
Safety Variables .................................................................................................................... 16 
7. 
INTERIM AND FINAL ANALYSIS ....................................................................................... 17 
8. 
STATISTICAL METHODS ................................................................................................... 17 
8.1. 
GENERAL CONSIDERATIONS ................................................................................................. 17 
8.2. 
ANALYSIS OF THE CONDUCT OF THE STUDY ......................................................................... 18 
8.2.1. 
Subject Enrollment and Disposition...................................................................................... 18 
8.2.2. 
Protocol Deviations .............................................................................................................. 18 
8.3. 
STUDY PERIODS .................................................................................................................... 18 
8.4. 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ................................................. 19 
8.5. 
CONCOMITANT MEDICATIONS .............................................................................................. 20 
8.6. 
STUDY DRUG EXPOSURE ...................................................................................................... 20 
8.7. 
SUBSEQUENT ANTINEOPLASTIC THERAPY FOR MULTIPLE MYELOMA .................................. 21 
8.8. 
EFFICACY ANALYSES ........................................................................................................... 21 
8.8.1. 
Primary Efficacy Endpoint.................................................................................................... 22 
8.8.2. 
Secondary Efficacy Endpoints .............................................................................................. 23 
8.8.3. 
Exploratory Efficacy Endpoints ............................................................................................ 25 
8.9. 
SAFETY ANALYSES ............................................................................................................... 28 
8.9.1. 
Adverse Events ...................................................................................................................... 31 
8.9.2. 
Other Safety Observations .................................................................................................... 32 
8.9.3. 
Laboratory Evaluation .......................................................................................................... 32 
8.9.4. 
Electrocardiogram ................................................................................................................ 33 
8.9.5. 
Vital Signs and Physical Examination Findings ................................................................... 33 
8.9.6. 
ECOG Performance Status ................................................................................................... 33 
9. 
PATIENT REPORTED OUTCOME ...................................................................................... 33 
9.1. 
NEUROPATHY ASSESSMENT ................................................................................................. 33 
9.2. 
BONE PAIN ASSESSMENT ...................................................................................................... 34 
10. 
MODIFICATIONS TO THE PROTOCOL ............................................................................. 34 
REFRERENCES  ........................................................................................................................... 36 
APPENDIX 1 PREFERRED TERMS FOR CYP3A4 INHIBITORS/INDUCERS ............................ 37 
APPENDIX 2 HAEMORRHAGE SEARCH TERMS ...................................................................... 38 


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REVISION HISTORY 
 
Version  
Date 
Version Description 
1.0 
05SEP2013 
Original version 
2.0 
15APR2015 
SAP was updated to reflect changes in Protocol Amendment 4. 
3.0 
28OCT2015 
SAP was revised to update the definition of progressive disease per 
modified IMWG for efficacy analysis and to reflect changes in 
Protocol Amendment 5. 
4.0 
16JUN2016 
SAP was revised to 1) remove detailed definition of study completion 
as the definition of study completion will be per protocol, and to 2) 
update preferred terms for CYP3A4 inhibitors in Appendix 1 per 
newly revised company standard. 
 


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ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
Btk 
Bruton’s tyrosine kinase 
CBR 
Clinical benefit response 
CI 
Confidence interval 
Clcr 
Creatinine clearance rate 
CR 
Complete response or complete remission 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCB 
Duration of benefit 
DILI 
Drug-Induced Liver Injury 
DOR 
Duration of response 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
FISH 
Fluorescent in situ hybridization 
Hgb 
Hemoglobin 
HI 
Hematologic improvement 
MedDRA 
Medical Dictionary for Regulatory Activities 
IMiD 
Immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IRC 
Independent review committee 
mITT 
Modified intent-to-treat 
MM 
Multiple myeloma 
MR 
Minimal response 
NCI 
National Cancer Institute 
ORR 
Objective response rate 


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OS 
Overall survival 
PD 
Progressive disease/disease progression 
PFS 
Progression-free Survival 
PI  
Proteasome inhibitors 
PK 
Pharmacokinetic(s) 
PR 
Partial response or partial remission 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
sCR 
Stringent complete response 
SD 
Stable disease 
SFLC 
Serum free light chain 
SPEP 
Serum protein eletrophoresis 
TCB 
Time to clinical benefit 
TEAE 
Treatment emergent adverse event 
TSHI 
Time to sustained hematologic improvement  
TTP 
Time to progression 
TTR 
Time to response 
UPEP 
Urine protein eletrophoresis 
VGPR 
Very good partial response 
 
 
 
 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a comprehensive description 
of the final statistical analyses for efficacy and safety data that have been outlined within the 
protocol. 
This plan does not cover the analyses for pharmacokinetic (PK) and biomarker data. The PK 
analysis will be performed separately and included in the clinical study report. The biomarker 
data will be analyzed and reported separately from the clinical study report. 
The SAP is based on protocol Amendment 5, dated 25 August, 2015. Any changes to the 
protocol analysis plan, including additional analyses are documented here. 
1.1. 
Protocol Number and Title 
Study PCYC-1111-CA: A Multicenter Phase 2 Study of the Bruton’s Tyrosine Kinase (Btk) 
Inhibitor, PCI-32765, in Subjects with Relapsed or Relapsed and Refractory Multiple 
Myeloma.  
1.2. 
Study Objectives 
1.2.1. 
Primary Objective 
The primary objective of this study is to determine the efficacy of ibrutinib (PCI-32765), both 
as a single agent and in combination with dexamethasone, in subjects with relapsed or 
relapsed and refractory multiple myeloma (MM) as measured by clinical benefit response 
(CBR) rate, defined as the proportion of subjects who achieved stringent complete response 
(sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or 
minimal response (MR) as assessed by the modified International Myeloma Working Group 
(IMWG) response criteria 1,3,6 (see protocol Appendix 6). 
1.2.2. 
Secondary Objectives 
Secondary objectives are to evaluate the efficacy, safety and pharmacokinetics of ibrutinib in 
this population as assessed by the following: 
 Duration of clinical benefit (DCB; MR or better)  
 Objective response rate (ORR) defined as the proportion of subjects who achieved 
sCR, CR, VGPR, or PR (ORR;  PR or better ) 
 Duration of objective response (DOR) 
 Safety (assessed by reporting of SAEs, AEs, and treatment-related discontinuations) 


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 Pharmacokinetics (assessed by sampling and testing for drug and metabolite levels at 
designated time points) 
1.2.3. 
Exploratory Objectives 
Exploratory objectives are to evaluate the following: 
 Progression-free survival (PFS) 
 Time to progression (TTP) 
 Overall survival (OS) 
1.2.4. 
Exploratory Analyses 
 Prognostic and predictive biomarkers and genetics relative to treatment outcomes 
1.3. 
Study Design 
This is a Phase 2, open-label, nonrandomized, multi-cohort, multicenter Simon 2-stage study 
designed to assess the safety and efficacy of ibrutinib in subjects with relapsed or relapsed and 
refractory multiple myeloma.   
Treatment of ibrutinib 420 mg once daily in the original protocol (hereafter referred to as 
Cohort 1) was designed to detect a meaningful signal of activity while minimizing risk of 
continuing enrollment under null conditions. Amendment 1 was designed to further explore 
the optimal regimen by increasing doses of ibrutinib and/or by routine combination with low 
dose dexamethasone. Cohorts 1 and 3 test activity of ibrutinib monotherapy; Cohorts 2 and 4 
test ibrutinib in combination with dexamethasone.   
Stage 1:   
 Up to eleven (11) subjects were to be enrolled to Cohort 1.  
 Up to eighteen (18) subjects will be enrolled to each Cohort 2, 3 and 4.   
 Stage 1 enrollment to Cohorts 3 and 4 may begin concurrently after Cohort 2 Stage 1 
enrollment is complete.  If there is concurrent enrollment, Sponsor will implement 
centralized assignments into cohorts.  
Stage 2: 
 If ≥ 2 CBRs are observed among the first 11 subjects in Cohort 1, the cohort will be 
expanded for up to a total enrollment of 35 subjects. 


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 If ≥ 3 CBRs are observed within Cohorts 2, 3, or 4 in Stage 1, the cohort(s) may be 
selected for expansion for up to a total enrollment of 43 subjects in each cohort or until 
observing ≥ 8 CBRs, whichever occurs earlier. 
 If there is concurrent Stage 2 enrollment to more than 1 cohort at any given time, 
Sponsor will implement centralized assignments into cohorts. 
Sponsor maintains the prerogative to select regimen, which gives optimal efficacy and safety 
results at interim analysis for further development while suspending other cohorts at any time. 
The expected total enrollment is between 67 (minimal) and 164 subjects.  Dosages and 
regimens by cohort are summarized in Table 1. 
Table 1: 
Treatment Cohorts and Planned Enrollment 
Cohort 
Ibrutinib 
(mg/day) 
Dexamethasone 
Planned 
First Stage 
Enrollment 
CBR 
Criteria for 
First Stage 
Total Enrollment 
(First and 
Second Stages) 
1 
420 
Upon progressive 
disease (PD), 40 mg 
once weekly is 
allowed† 
11* 
≥ 2 
35 
2 
560 
40 mg once weekly#  
18 
≥ 3 
43 
3 
840 
Upon PD, 40 mg once 
weekly is allowed† 
18 
≥ 3 
43 
4 
840 
40 mg once weekly#  
18** 
≥ 3 
43 
 
* n=11 planned for Cohort 1 First Stage, n=13 were enrolled.  The decision for second stage 
expansion will be based on the number of CBR in the first 11 subjects.  
** n=18 planned for Cohort 4 First Stage, n=20 were enrolled.  The decision for second stage 
expansion will be based on the number of CBR in the first 18 subjects. 
# Dexamethasone administration starts on Cycle 1 Day 4 for Cohort 2 and 4.  For Cohort 4 
expansion, dexamethasone will be administered starting on Cycle 1 Day 8. 
 † For Cohorts 1 and 3 subjects who have confirmed PD, and who are clinically stable, without 
significant worsening of symptoms or hematologic status (ie, meet all entry criteria for the study 
in regard to symptoms and hematology), will be eligible to receive dexamethasone 40 mg orally 
once per week in addition to continued treatment with ibrutinib, at the discretion of the 
investigator. 
Subjects are allowed to continue study drug as long as the subject is clinically stable (stable 
disease [SD] or better) and the subject is not experiencing any unacceptable toxicity.  Subjects 
in the monotherapy cohorts (1 and 3) who have PD confirmed as required by definition in the 
protocol, and without significant worsening of symptoms or hematologic status (ie, meet all 
entry criteria for the study in regard to symptoms and hematology), will be eligible to receive 
dexamethasone 40 mg orally once per week in addition to continued treatment with ibrutinib, 


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at the discretion of the investigator.  Otherwise, subjects having PD will be removed from 
study. Note that the decision for second stage expansion of Cohorts 1 and 3 will be based on 
the number of subjects who achieved CBR (MR or better) prior to addition of dexamethasone.   
2. 
STUDY ENDPOINTS 
2.1. 
Primary Endpoint 
CBR rate: defined as the proportion of subjects achieving a MR or better as assessed by 
investigator per the modified IMWG criteria. 
2.2. 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
Safety:  
 Safety parameters including the incidences and types of clinical adverse 
events, laboratory variables, and vital signs measurements 
Efficacy: 
 Duration of clinical benefit (DCB)   
 Objective response rate (ORR) 
 Duration of objective response (DOR) 
Pharmacokinetics: 
 Plasma PK of ibrutinib and metabolite PCI-45227 
2.3. 
Exploratory Endpoints 
 Progression-free survival (PFS) 
 Time to progression (TTP) 
 Overall survival (OS)  
 Time to Clinical Benefit 
 Time to Response 


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3. 
SAMPLE SIZE CONSIDERATIONS 
Cohort 1 was designed to detect a meaningful signal of activity while minimizing risk of 
continuing enrollment under null conditions.  Cohorts 2-4 were designed to further explore 
the optimal regimen.  The sample size was estimated for each cohort without multiplicity 
adjustment. 
3.1. 
Cohort 1   
Full enrollment to Cohort 1 will be contingent upon Simon 2 stage design rules with a target 
sample size of 35 evaluable subjects based on meeting interim efficacy endpoints, i.e., if 
≥ 2 CBRs are observed among the first 11 subjects within Cohort 1.  This study cohort is 
designed to test the null hypothesis that the CBR rate of ibrutinib monotherapy at a dose of 
420 mg/day is ≤ 10% (not clinically compelling) versus the alternative hypothesis that CBR 
rate will be ≥ 30%, at a 1-sided significance level of 5%, with 85% power.  Observation of 
≥ 7 CBRs within an expanded cohort of 35 subjects will be considered consistent with the 
alternative hypothesis of CBR rate ≥ 30%. 
Although the design described above is setup to detect cohort specific CBR rates of 30%, 
CBR rates as low as 20% is still considered clinically meaningful, as the drug may be 
developed in combination therapy and/or in less heavily pre-treated populations.  With this 2-
stage design, the probability to continue enrolling subjects for the second stage is 
approximately 0.68 if the true CBR rate is 20%.  
3.2. 
Cohorts 2-4 
Simon optimal 2-stage study design is utilized in Cohorts 2, 3 and 4. 
Up to eighteen subjects will be enrolled to each subsequent cohort (2-4).  Stage 1 enrollment 
to Cohorts 2, 3, and 4 will not be contingent upon results of preceding cohorts. Full 
enrollment to Cohort 2, 3, and 4 will be contingent upon Simon 2-stage design rules with a 
sample size of  up to 43 evaluable subjects based on meeting interim efficacy endpoints, i.e., 
if ≥ 3 CBRs are observed among the first 18 subjects within the subject cohort.  This design 
has 80% power to reject the null hypothesis of CBR rate ≤ 10%, at a 1-sided significance 
level of 5%. Observation of ≥ 8 CBRs within an expanded cohort of up to 43 subjects will be 
considered consistent with the alternative hypothesis of CBR rate ≥ 25%.  The enrollment of 
that cohort may be closed early for success once 8 CBRs observed. 
Sponsor maintains the prerogative to select regimen that gives optimal efficacy and safety 
results at interim analysis for further development and suspend other cohorts at any time. 


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This study design is not powered or intended to allow direct comparison of percent CBR 
among the cohorts.  Results of this study will inform alternative directions for future 
combination and single agent development in alternative multiple myeloma study populations.   
4. 
STUDY POPULATIONS AND ANALYSIS SETS 
The analysis and summary of data for this study will be performed using the following 
populations: 
All enrolled population:  All subjects who signed the informed consent form and were 
enrolled to one of the treatment cohorts. This population will be used to summarize 
disposition information. 
All treated population:  All enrolled subjects who received at least one dose of study 
drug. This population will be used to summarize subject enrollment, demographics, 
baseline and disease characteristics, prior therapies, and concomitant medications. This 
population is referred to as the “modified intent-to-treat (mITT) population” in the 
protocol. This is the primary analysis population for efficacy endpoints. 
Response evaluable population:  All enrolled subjects who received at least one dose of 
study drug and underwent at least one response assessment after start of treatment. 
Response rates (CBR rate and ORR) will be analyzed based on response evaluable 
population and will be considered as sensitivity analyses.  
Safety population:  All enrolled subjects who received at least one dose of study drug. 
This population will be used for analyzing the safety (including dosing) data. 
Subjects in treated, response evaluable and safety populations will be analyzed according to 
the actual treatment received (i.e. as treated). 
5. 
ANALYTIC DEFINITIONS 
5.1. 
Study Day and Duration of Treatment 
Study day will be calculated in reference to the date of the first dose of study drug.  Study 
Day 1 corresponds to the date the subject received the first dose of study drug.  For 
assessments/events occurred on or after Study Day 1, study day is calculated as 
(assessment/event date – date of the first dose of study drug + 1 day).  For assessments/events 
occurred prior to Study Day 1, study day is calculated as (assessment/event date – date of the 
first dose of study drug).  Study Day −1 is the day before Study Day 1.  There will not be a 
Study Day 0.   


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Treatment duration for ibrutinib will be calculated as the interval from the date of the first 
dose of ibrutinib to the date of the last dose of ibrutinib. Similarly, treatment duration for 
dexamethasone will be calculated. 
Treatment duration (day) = date of the last dose – date of the first dose + 1 day 
5.2. 
Time on Study 
Time on study is defined as the interval between the date of the first dose of study drug and 
the date last known alive. Subjects who died will be censored at death date. 
5.3. 
Baseline 
Unless otherwise specified, the baseline value is defined as the last observation with a non-
missing result prior to the start of study drug.  
5.4. 
Disease Status 
“Relapsed disease” is defined as the occurrence of progression following a response to a prior 
therapy.  “Refractory” is defined as best response of SD or PD to last line of therapy while on 
treatment or within 60 days of last therapy. 
5.5. 
Disease Stage 
The international staging system (see Table 2) for multiple myeloma will be applied for 
patient classification at baseline. 
Table 2: 
International Staging System for Multiple Myeloma 
Stage 
Criteria
I 
Serum β2-micoglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL 
II 
Not Stage I or III (Serum β2-micoglobulin < 3.5 mg/L and serum albumin < 3.5 
g/dL; or Serum β2-micoglobulin 3.5 to <5.5 mg/L irrespective to the serum 
albumin level) 
III 
Serum β2-micoglobulin ≥ 5.5 mg/L 
 
5.6. 
ECOG and Karnofsky Performance Status Scores 
For subjects in Cohort 1, Karnofsky performance status scores are measured and recorded 
according to the original protocol dated November 4, 2011. For those subjects, the ECOG 
performance status will be derived from Karnofsky performance scores (see Table 3). 


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Under protocol amendment 1, the decision was made to collect ECOG performance status 
rather than Karnofsky performance status for all subjects enrolled afterwards.   
Table 3: 
ECOG and Karnofsky Performance Status Scores 
Karnofsky Performance Status (%)
ECOG Performance Status 
90, 100 
0 
70, 80 
1 
50, 60 
2 
30, 40 
3 
10, 20 
4 
0 
5 
 
5.7. 
Treatment-Emergent Period 
The treatment-emergent period is defined as the period of time from the date of the first dose 
of study drug through 30 days after the date of the last dose of study drug (ibrutinib or 
dexamethasone) or the day before initiation of any subsequent anti-myeloma therapy, 
whichever occurs first.  
The treatment-emergent period for monotherapy (Cohorts 1 and 3 only) is defined as the 
period of time from the date of the first dose of ibrutinib through 30 days after the date of the 
last dose of ibrutinib, or the day before the addition of dexamethasone, or the day before 
initiation of any subsequent anti-myeloma therapy, whichever occurs first. 
5.8. 
Average Dose and Relative Dose Intensity 
For ibrutinib:  
Average dose administered (mg/day) = total cumulative dose administered (mg) / treatment 
duration (day) for ibrutinib. 
For dexamethasone:  
Average dose administered (mg/week) = total cumulative dose administered (mg) / 
treatment duration (week) for dexamethasone. 
Total cumulative dose administered is the sum of dose actually taken during the treatment 
period. Relative dose intensity is defined as the percentage of the total expected dose that was 
actually administered.  


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 Relative dose intensity (%) = total cumulative dose administered / total expected dose × 
100%. 
For ibrutinib:  
Total expected dose (mg) = treatment duration (day) for ibrutinib × protocol assigned daily 
dose (e.g. 420 mg/day for Cohort 1). 
For dexamethasone:  
Total expected dose (mg) = treatment duration (week) for dexamethasone × protocol 
assigned weekly dose (40 mg/week). 
5.9. 
Calculation of Laboratory Values 
Absolute neutrophil count (ANC): 
ANC (109/L) = (%neutrophils+%bands) × white blood cell / 100, where neutrophils and 
bands are in percentages and white blood cell is in 109/L. 
Estimated creatinine clearance (Clcr) calculated using Cockcroft-Gault (C-G) formula:  


)
/
(
72
85
.0
)
(
)]
(
140
[
min)
/
(
dL
mg
Creatinine
Serum
Female
if
kg
Weight
years
Age
mL
Clcr





 
In this calculation, if weight is not measured at the same visit as creatinine, the weight 
measured prior and closest to the creatinine collection time will be used. 
5.10. 
Other General Definitions 
Age: 
Age in years will be calculated at the date of informed consent. 
Conversions: 
   1 month = 30.4375 days.   
   1 year = 365.25 days. 


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6. 
Missing Data Handling 
6.1. 
General Approach  
In order to achieve the goal of a well conducted clinical study according to Good Clinical 
Practice, every effort will be made to collect all data. However, despite best efforts, it may be 
inevitable that some data may be missing or incomplete. Missing or partial data will be 
presented in the subject data listing as they are recorded on the case report forms (CRFs).    
6.2. 
Missing and Incomplete Data  
6.2.1. 
Efficacy Variables  
No imputation of missing values will be performed for efficacy data unless otherwise 
specified.  
6.2.2. 
Safety Variables  
No imputation of missing values for safety data will be performed.   
For missing or partial start and end dates for AEs, medical history, prior therapy and 
concomitant medication, no imputation will be performed. However, a conservative approach 
should be taken when performing the related analyses. If the available information is not 
enough to judge whether an event or a therapy duration has overlapped with study treatment 
duration, events reported on AE pages will be taken as treatment emergent AEs, events 
reported on medical history page will be treated as prior medical condition, prior or 
concomitant therapy will be considered as continuing therapy which started prior to first study 
treatment. 
However, an intermediate imputation of partial dates may be taken in order to calculate the 
study day for AEs, medical history, prior therapy and concomitant medications. This is just 
for estimation of the timing of events relative to the study course. All missing or partial dates 
should remain the same values as they were recorded on the CRFs. The intermediate 
imputation rules are: 
If only day is missing, then the 15th of that month will be used. 
If only year is present, then June 30th will be used. 
If such imputed date for prior therapies or initial diagnosis is on or after the date of the first 
dose of study drug, then date of the first dose - 1 will be used. If such imputed date for the 
start or end of subsequent therapies is before date of last dose of study drug, then date of last 


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dose of study drug +1 will be assumed. If an imputed start date of prior or subsequent therapy 
is after the end date, the end date will be used. If an imputed end date of prior or subsequent 
therapy is before the start date, the start date will be used. 
If an imputed AE start date is in the same month and year as the first dose date of study drug 
but on an earlier date, the first dose date will be used. If an imputed AE start date is in the 
same month and year as the date of 30 days post the last dose of study drug but on a later date, 
the date of 30 days post the last dose will be used. If an imputed AE start date is after the AE 
end date, the AE end date will be used. 
If the imputed date is for an AE end date and is after the death date, then the death date will 
be used, or if the imputed AE end date is before the AE start date, then the AE start date will 
be used. 
7. 
INTERIM and FINAL ANALYSIS 
For each cohort, a futility interim analysis will be performed when stage 1 enrollment target 
met (Cohort 1; 11 subjects, Cohorts 2-4; 18 subjects) and either all enrolled subjects have 
evaluable response data (ie, completed 6 treatment cycles and the Cycle 7 Day 1 assessments 
or have discontinued treatment) or the number of clinical benefit responders met stage 2 
enrollment expansion criteria (≥ 2 for Cohort 1, ≥ 3 for Cohorts 2-4), whichever occurs 
earlier.  Further enrollment will be halted until the cohort meet stage 2 enrollment expansion 
criteria.  All enrolled subjects will be followed to further assess their responses.  Enrollment 
may resume earlier while waiting for the confirmation of response of the last clinical benefit 
responder.  If a cohort failed to meet stage 2 enrollment expansion criteria when all first stage 
subjects have evaluable response data, the cohort will be suspended for futility.  
The final analysis will occur upon study completion.   
8. 
STATISTICAL METHODS 
8.1. 
General Considerations 
Unless otherwise stated, continuous variables will be summarized with descriptive statistics 
(mean, standard error or standard deviation, median, interquartile range, minimum, and 
maximum). For categorical variables, number and percentage of subjects in each category will 
be provided.  
Time to event or duration of event endpoints will be based on the event date (or censoring 
date) rather than visit number or visit label.  


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For by-visit analysis, visit windows will be used to associate assessment with a scheduled 
visit and will be created in reference to the date of first dose of study drug to assign visit 
number based on evaluation date. If more than one assessment falls into a given visit window, 
the one closest to the target date will be used.  If two assessments are equally close to the 
target day, the earlier assessment will be used.   
All data collected on the CRFs will be presented in data listings upon request.  All statistical 
analyses will be performed using SAS® version 9.2 or higher. 
8.2. 
Analysis of the Conduct of the Study 
8.2.1. 
Subject Enrollment and Disposition 
Subject enrollment will be summarized by country, study site and treatment cohort.  
The disposition of all enrolled subjects will be summarized by treatment cohort:  
 Number of subjects as enrolled, number of subjects as treated, number (%) of subjects 
in safety and response evaluable populations 
 Number (%) of subjects who are still on study treatment.  
 Number (%) of subjects with dexamethasone added (Cohorts 1 and 3 only).  
 Number (%) of subjects who discontinued the study treatment and  reason for  
discontinuation 
 Number (%) of subjects who  exited the study and reason for study exit 
 Descriptive statistics for time on study; time on study is defined in the same way as 
overall survival with reversed censoring, i.e., subjects who died will be censored at 
death date. The Kaplan-Meier method will be used to estimate the median time on 
study.   
The percentages will be based on the number of subjects treated. 
8.2.2. 
Protocol Deviations 
Subjects with important protocol deviations (IPDs) will be identified and documented by 
clinical team.  
8.3. 
Study Periods 
The whole study period is defined as the period of time from the date of the first dose of study 
drug until the end of the study.  


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The monotherapy period (Cohorts 1 and 3 only) is defined as the period of time from the date 
of the first dose of ibrutinib through the day before the addition of dexamethasone, or the day 
before initiation of any subsequent anti-myeloma therapy, whichever occurs first. 
8.4. 
Demography and Baseline Disease Characteristics 
The following demographic and baseline disease characteristics will be summarized for the all 
treated population by treatment cohort.   
 Demographics: Sex, age (continuous and grouped as <65, ≥65, <70, ≥70, <75, ≥75 
years), race, and ethnicity 
 Baseline and disease characteristics:  
o Weight and height  
o ECOG performance status (0, 1) 
o Creatinine, estimated creatinine clearance rate (continuous and grouped as < 30, 
30-<60, ≥ 60 mL/min)  
o Hematologic abnormalities (hemoglobin [Hgb] < 10  g/dL, platelets < 100×109/L, 
ANC < 1×109/L) 
o Hemoglobin, platelet counts and ANC  
o Time since initial diagnosis (continuous and grouped as <3, ≥3 years) 
o Disease status (relapsed, relapsed and refractory)  
o Serum β2-microglobulin (continuous and grouped as <3.5, ≥3.5 - <5.5, ≥5.5 mg/L) 
o Serum albumin (continuous and grouped as <3.5, ≥3.5 g/dL) 
o Disease stage (I, II, III) at baseline per International Staging System (see Table 2) 
o Immunoglobulin heavy chain class (e.g. A, G, M), immunoglobulin light chain 
class (, ) 
o Measurable disease (SPEP only, UPEP only, SPEP and UPEP, sFLC only)  
o Bone marrow plasma cell percentage 
o Cytogenetic/FISH prognostic markers [e.g. del(17p), del(13q14), t(4;14), t(11;14)] 
 Prior cancer-related therapies:  
o Prior radiotherapy (yes, no), prior surgery (yes, no), prior systemic therapy (yes, 
no)  
o Number of prior systemic therapies (continuous and grouped as 2-3, ≥4) 


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o Type of prior systemic therapies: lenalidomide, thalidomide, pomalidomide, 
bortezomib, carfilzomib, alkylator (melphalan, cyclophosphamide), doxorubicin, 
corticosteroid (dexamethasone, prednisone), fludarabine, vincristine, etc. 
o Type of bone marrow or stem cell transplant: autologous, allogeneic 
o Refractory to last line of therapy  
o Refractory to prior immunomodulatory drugs: lenalidomide, thalidomide, 
pomalidomide   
o Refractory to prior proteasome inhibitors: bortezomib, carfilzomib 
o Refractory to prior immunomodulatory drugs and proteasome inhibitors (i.e. 
refractory to at least one prior immunomodulatory drug and at least one prior 
proteasome inhibitor) 
o Last prior treatment [(no PI/IMiD) vs. (PI or IMiD) vs. (PI and IMiD)] 
o Last prior treatment included PI 
o Last prior treatment included IMiD 
8.5. 
Concomitant Medications  
Concomitant medications are defined as medications taken during the treatment emergent 
period.  
Concomitant medications will be summarized by the World Health Organization Drug 
Dictionary therapeutic class, pharmacological class, and preferred term. Concomitant use of 
CYP3A4 strong, moderate or weak inhibitors will be listed and/or summarized separately. 
The search for usage of CYP3A4 inhibitors will be based on, but not limited to the preferred 
terms in Appendix 1.  
8.6. 
Study Drug Exposure 
Ibrutinib and/or dexamethasone dose for a subject may be held and/or reduced according to 
the protocol specified criteria (see protocol Section 6.5).  
For each subject the following parameters will be calculated when applicable.  
 
Treatment duration for each study drug (ibrutinib or dexamethasone) in month   
 
Time to addition of dexamethasone in month (Cohorts 1 and 3 only) 
 
Total cumulative dose administered for each study drug  
 
Average dose administered for each study drug   


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 
Relative dose intensity for each study drug 
 
Number of dose missed for each study drug 
 
Number of dose reduction for each study drug 
 
Ibrutinib dose interruption ≥ 7 consecutive days (yes or no) 
 
Dexamethasone dose interruption ≥ 14 consecutive days (yes or no) 
 
For each parameter, descriptive statistics (mean, standard deviation, median, and range for 
continuous variables; number and proportion for categorical variables) will be calculated by 
treatment cohort. 
8.7. 
Subsequent Antineoplastic Therapy for Multiple Myeloma 
Anti-myeloma treatments that started after discontinuation of study treatment (i.e. started after 
the last dose of study drug) will be considered as subsequent antineoplastic therapies for 
multiple myeloma. Subsequent antineoplastic therapies will be summarized by type (e.g. 
radiotherapy, systemic therapy, bone marrow or stem cell transplant) and preferred term. 
8.8. 
Efficacy Analyses 
Starting from Cycle 2, subjects will be evaluated by the investigators per the modified IMWG 
response criteria. Confirmation of investigator-assessed responses by an independent review 
committee (IRC) may be done as a supportive assessment. The method of independent review 
will be governed by an IRC charter, if needed. Some or all of the following assessments may 
be required to confirm the response categories: M-protein evaluations (UPEP and SPEP, 
serum and urine IFE, serum FLC), plasmacytoma evaluation, bone radiological assessment, 
bone marrow aspiration and biopsy, and serum chemistries including calcium and albumin. 
The all treated population is the primary population for the efficacy endpoints. Unless 
specified otherwise, the all treated population will be used for all efficacy analyses.   
Response rates (CBR rate and ORR) will also be analyzed based on response evaluable 
population and will be considered as sensitivity analyses.  Only adequate response 
assessments will be included in the analysis.  An adequate response assessment is one for 
which the response assignment is sCR, CR, VGPR, PR, MR, SD or PD (i.e. not 
UE/Unknown). 
IMWG criteria specify that all response categories require confirmation from a second 
consecutive assessment made at any time after the initial assessment with the exception of 
sCR and CR.  The initial sCR or CR will be reported as confirmed response.  However, if a 
subject has only one adequate post baseline assessment for which the response assignment is 
MR, PR or VGPR, then the best response will be summarized as SD.   


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In Cohorts 1 and 3, subjects will be on ibrutinib monotherapy and may convert to ibrutinib 
and dexamethasone combination therapy at the discretion of the investigator after a confirmed 
PD on ibrutinib monotherapy.  Thus the efficacy endpoints (CBR, DCB, ORR, DOR, PFS, 
and TTP) will be presented and distinguished as with and without dexamethasone for subjects 
in Cohorts 1 and 3, when applicable. 
No inferential statistical comparisons among treatment cohorts will be performed in this 
study. 
8.8.1. 
Primary Efficacy Endpoint 
The primary endpoint of the study is the CBR rate, defined as the proportion of subjects 
achieving a MR or better prior to initiation of new antineoplastic therapy as assessed by 
investigator per modified IMWG criteria. 
The number and percent of subjects in each best response category (sCR, CR, VGPR, PR, 
MR, SD, PD) will be summarized by treatment cohort.  
CBR rate and its corresponding 2-sided 90% exact binomial confidence interval (CI) will be 
calculated and presented by treatment cohort.  For subjects in Cohorts 1 and 3, CBR will be 
calculated during ibrutinib monotherapy period (i.e. prior to addition of dexamethasone) as 
primary analysis.  CBR across the whole study course (including ibrutinib and dexamethasone 
combination therapy period) will be calculated and presented as secondary analysis.   
In addition, CBR rate will be analyzed based on response evaluable population and will be 
considered as sensitivity analyses. 
Subgroup Analysis 
Subgroup analyses may be performed for the following selected baseline characteristics and 
potential prognostic variables. 
 Sex (male vs. female) 
 Age (<65 vs. ≥65 years, <75 vs. ≥75 years) 
 Race (Caucasian vs. non-Caucasian) 
 Baseline ECOG score (0 vs. 1) 
 Baseline hematologic abnormality (yes vs. no); hematologic abnormality: Hgb < 10 
g/dL, platelets < 100×109/L or ANC < 1×109/L 
 Disease status (relapsed vs. relapsed and refractory) 


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 Number of prior systemic therapies (2-3 vs. ≥4) 
 Refractory status of last line of prior therapy (yes vs. no)  
 Refractory to prior immunomodulatory drugs (yes vs. no) 
 Refractory to prior proteasome inhibitors (yes vs. no) 
 Refractory to prior immunomodulatory drugs and proteasome inhibitors (yes vs. no) 
 FISH abnormalities  
o Del 17p (present vs. absent) 
o t(14;16) (present vs. absent) 
o t(4;14) (present vs. absent) 
o At least a presence of Del 17p, t (14;16) or t(4;14) vs. none of the three 
 Last prior treatment [(no PI/IMiD) vs. (PI or IMiD) vs. (PI and IMiD)] 
 Last prior treatment included PI (yes vs. no) 
 Last prior treatment included IMiD (yes vs. no) 
CBR rate and its corresponding 2-sided 90% exact binominal CI will be calculated within 
each stratum of every subgroup. Forest plot will be provided for the subgroup analyses.    
8.8.2. 
Secondary Efficacy Endpoints 
8.8.2.1. 
Duration of Clinical Benefit (DCB) 
For all cohorts, DCB will be computed for those subjects with confirmed responses (MR or 
better) prior to initiation of new antineoplastic therapy. DCB will be calculated from the first 
observation of response (before confirmation) to the time of PD (earliest occurrence), with 
death from causes other than progression censored.  
PD based upon changes in monoclonal protein levels requires confirmation. No minimal time 
interval between assessments is stipulated. PD based upon bone marrow, bone lytic lesions, or 
plasmacytoma changes, or upon development of hypercalcemia attributed to multiple 
myeloma do not require confirmation. DCB will be right-censored for subjects who meet one 
or more of the censoring conditions listed in Table 4 below. 
Similarly, for Cohorts 1 and 3 ibrutinib monotherapy, DCB will be computed for those 
subjects with confirmed responses (MR or better) prior to initiation of dexamethasone or new 
antineoplastic therapy, whichever occurs first.  


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Table 4:  Date of Event and Censoring Rules for DCB Analysis 
Row 
Situation 
Date of Event or Censoring 
Outcome 
Events include death due to progression or first documentation of confirmed PD that occurred  on or 
prior to the data analysis cutoff date.  For Cohorts 1 and 3 ibrutinib monotherapy, events need to meet 
one additional criterion:  occurred at or prior to initiation of dexamethasone. 
1.1 
Death due to progression or confirmed 
PD documented at scheduled disease 
assessments or between two scheduled 
disease assessments. 
Earliest date of adequate disease 
assessment documenting confirmed PD 
or date of death due to progression, 
whichever occurs first. 
Progressed
1.2 
Death before first disease assessment  
Date of death 
Progressed
All other cases will be censored as follows: 
2.1 
No baseline assessment  
Date of first study treatment 
Censored 
2.2 
No adequate post-baseline assessment 
(including lost to follow-up since 
enrollment)  
Date of first study treatment 
Censored 
2.3 
Not known to have confirmed PD  or 
died due to progression at the data 
analysis cutoff date (this includes 
subjects who were known to have 
confirmed PD  or died after the data 
analysis cutoff date) 
Date of last adequate disease 
assessment showing no evidence of 
confirmed PD on or before data 
analysis cutoff date 
Censored 
2.4 
Addition of dexamethasone (Cohorts 1 
and 3 ibrutinib monotherapy only) 
The start date of dexamethasone 
Censored 
2.5 
Death from causes other than 
progression 
Date of death 
Censored 
 
For subjects who meet more than one censoring condition, DCB will be censored according to 
the earliest censoring condition. For subjects who meet none of the censoring conditions, 
DCB will be calculated using the earliest event date. 
DCB Event (day) = Date of event – Date of first overall response 
DCB Censor (day) = Date of censoring – Date of first overall response + 1 
Kaplan-Meier curves will be used to estimate the distribution of DCB.  The 50th percentile of 
Kaplan-Meier estimates will be used to estimate the median DCB.  A 2-sided 95% CI will be 
provided for this estimate. For the cases in which the median is not reached as if the study 
closure, the 25th percentile and its 2-sided 95% CI will be provided.    


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8.8.2.2. 
Objective Response Rate (ORR) 
Objective response rate (ORR) is defined as the proportion of subjects achieving confirmed 
responses (PR or better) prior to initiation of new antineoplastic therapy as assessed by 
investigator per the modified IMWG criteria.  ORR and its corresponding 2-sided 90% exact 
binomial confidence interval will be calculated and presented by treatment cohort.   
Subgroup Analysis 
The same subgroup analyses will be performed as those for CBR. 
8.8.2.3. 
Duration of Response (DOR) 
DOR will include only subjects with confirmed responses (PR or better).  DOR will be 
calculated from the first observation of response (before confirmation) to the time of PD 
(earliest occurrence), with death from causes other than progression censored. The calculation 
for the time of PD and censoring rules are the same as those for DCB (see Table 3). 
DOR Event (day) = Date of event – Date of first overall response 
DOR Censor (day) = Date of censoring – Date of first overall response + 1 
The same analyses will be done for DOR as those for DCB described in Section 8.7.2.1.    
8.8.3. 
Exploratory Efficacy Endpoints 
8.8.3.1. 
Progression-free Survival (PFS) 
PFS is defined as the duration from the start of study treatment to PD (earliest occurrence) or 
death (regardless of cause of death), whichever comes first. The calculation for the time of PD 
will be the same as that for DCB (Section 8.7.2.1).  
PFS will be right-censored for subjects who meet one or more of the censoring conditions 
listed in Table 5 below. 
 
 


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Table 5:  Date of Event and Censoring Rules for PFS Analysis 
Row 
Situation 
Date of Event or Censoring 
Outcome 
Events include death or first documentation of confirmed PD that occurred on or prior to the data 
analysis cutoff date.  For Cohorts 1 and 3 ibrutinib monotherapy, events need to meet one additional 
criterion:  occurred at or prior to initiation of dexamethasone. 
1.1 
Death or confirmed PD documented at 
scheduled disease assessments or 
between two scheduled disease 
assessments. 
Earliest date of adequate disease 
assessment documenting confirmed PD 
or date of death due to progression, 
whichever occurs first. 
Progressed
1.2 
Death before first disease assessment  
Date of death 
Progressed
All other cases will be censored as follows: 
2.1 
No baseline assessment  
Date of first study treatment 
Censored 
2.2 
No adequate post-baseline assessment 
(including lost to follow-up since 
enrollment)  
Date of first study treatment 
Censored 
2.3 
Not known to have confirmed PD or 
died at the data analysis cutoff date (this 
includes subjects who were known to 
have confirmed PD or died after the data 
analysis cutoff date) 
Date of last adequate disease 
assessment showing no evidence of 
confirmed PD on or before data 
analysis cutoff date 
Censored 
2.4 
Addition of dexamethasone (Cohorts 1 
and 3 ibrutinib monotherapy only) 
The start date of dexamethasone 
Censored 
 
For subjects who meet more than one censoring condition, PFS will be censored according to 
the earliest censoring condition. For subjects who meet none of the censoring conditions, PFS 
will be calculated using the earliest event date. 
PFS Event (day) = Date of PFS event – Date of first study treatment 
PFS Censor (day) = Date of censoring – Date of first study treatment + 1   
Kaplan-Meier curves will be used to estimate the distribution of PFS.  The 50th percentile of 
Kaplan-Meier estimates will be used to estimate the median PFS.  A 2-sided 95% confidence 
interval (CI) will be provided for this estimate. PFS at landmark time points (e.g. 4, 8, 12, 16 
months from first study treatment) will also be estimated with corresponding 2-sided 95% CI.  
Subgroup Analysis 
Subgroup analyses will be performed for the selected factors (see Section 8.7.1). PFS event 
rate, Kaplan-Meier estimates for the median and PFS at landmark time (decided by data status 


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at final analysis) will be provided for each stratum of the subgroups. Forest plot will be 
provided for PFS at landmark time.  
8.8.3.2. 
Time to Progression (TTP) 
Time to progression (TTP) is defined as the duration from start of treatment to PD (earliest 
occurrence), with deaths from causes other than progression not counted, but censored. The 
calculation for the time of PD and censoring rules are the same as those for DCB (see Table 
4). 
TTP Event (day) = Date of progression – Date of first study treatment 
TTP Censor (day) = Date of censoring – Date of first study treatment + 1 
The same analyses will be done for TTP as those for DCB described in Section 8.7.2.1.    
8.8.3.3. 
Overall Survival (OS) 
Overall survival (OS) will be measured from the date of first study drug administration until 
the date of death from any cause.   
For subjects who have an incomplete death date, the death date will be imputed as the earliest 
possible date that incorporates the available death date information and that does not 
contradict the date last known alive in the database. 
For subjects who were not known to have died prior to the analysis cutoff date, the overall 
survival will be right-censored based on the earliest censoring condition in Table 6. 
OS Event (day) = Date of death – Date of first study treatment 
OS Censor (day) = Date of censoring – Date of first study treatment + 1 
Table 6:  Date of Censoring for OS Analysis 
Situation 
Date of Censoring 
Outcome 
Not known to have died at the 
analysis cutoff date (this includes 
subjects who were known to have 
died after the data analysis cutoff 
date) 
Date last known alive or data analysis cutoff 
date, whichever occurs first (specifically, for 
subjects who were known to have died after 
the data analysis cutoff date, overall survival 
will be censored at the data analysis cutoff 
date) 
Censored 
 
 


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The date the subject was last known to be alive will be derived as follows: 
 For subjects who became lost to follow-up when they were in the treatment phase, 
date last known alive will be derived using date of last assessment/visit, last dose date 
of study drug, or study exit date whichever occurs later;  
 For subjects who became lost to follow-up when they were in the follow-up phase, 
date last known alive will be derived using date last known alive reported on the 
Follow-up CRF page or study exit date, whichever occurs later. 
The same analyses (including subgroup analyses) will be done for OS as those for PFS 
described in Section 8.7.3.1.  
8.8.3.4. 
Time to Clinical Benefit and Time to Response 
Time to clinical benefit (TCB) will be analyzed for subjects achieving CBR (MR or better) 
prior to initiation of new antineoplastic therapy as evaluated by investigators. Time to initial 
response as well as best response will be derived. 
Time to initial clinical benefit response is defined as the interval between the date of first dose 
and the date of initial documentation of a response (MR or better). Time to best response is 
defined as the interval between the date of first dose and the date of initial documentation of 
the best response that a subject achieved prior to initiation of new antineoplastic therapy. 
Similarly, time to response will be analyzed for subjects achieving PR or better prior to 
initiation of new antineoplastic therapy as evaluated by investigators.  
For Cohorts 1 and 3 ibrutinib monotherapy, time to clinical benefit and time to response will 
be analyzed for subjects achieving response prior to initiation of dexamethasone or new 
antineoplastic therapy, whichever occurs first. 
Time to clinical benefit and time to response will be summarized descriptively by treatment 
cohort as a continuous variable.   
8.9. 
Safety Analyses 
All safety analyses will be based on the safety population. 
In Cohorts 1 and 3, subjects will be on ibrutinib monotherapy and may convert to ibrutinib 
and dexamethasone combination therapy at the discretion of the investigator after a confirmed 
PD on ibrutinib monotherapy.  Thus the safety data (e.g. incidence of TEAEs, laboratory 
values) will be presented and distinguished as with and without dexamethasone for subjects in 
Cohorts 1 and 3, when applicable. 


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Table 7: Summary of Safety Analyses to be Performed 
 
Category 
Analysis 
Summarize By 
Listing 
Adverse Events 
General 
Overall summary 
Study Period 
 
 
TEAEs 
SOC+ PT+Study Period;  
PT+ toxicity grade+Study 
Period 
 
 
Grade 3 or worse TEAE 
SOC+ PT+Study Period; 
PT+ toxicity grade+Study 
Period 
 
 
Ibrutinib Related TEAE 
SOC+ PT (Whole Study 
Period only) 
 
 
Dexamethasone Related TEAE 
SOC+ PT (Whole Study 
Period only) 
 
 
Grade 3 or worse Ibrutinib 
Related TEAE 
SOC+ PT (Whole Study 
Period only) 
 
 
Grade 3 or worse 
Dexamethasone Related TEAE 
SOC+ PT (Whole Study 
Period only) 
 
 
TEAEs leading to treatment 
discontinuation  
 
 
 
TEAEs leading to Ibrutinib 
discontinuation  
SOC+ PT (Whole Study 
Period only) 
 
 
TEAEs leading to 
Dexamethasone discontinuation  
SOC+ PT (Whole Study 
Period only) 
 
 
TEAEs leading to dose reduction 
or dose withheld 
 
 
 
TEAEs leading to Ibrutinib dose 
reduction 
SOC+ PT+Study Period  
 
 
TEAEs leading to 
Dexamethasone dose reduction 
SOC+ PT+Study Period 
 
 
TEAEs leading to Ibrutinib dose 
withheld 
SOC+ PT+Study Period  
 
 
TEAEs leading to 
Dexamethasone dose withheld 
SOC+ PT+Study Period  
 
 
Serious TEAEs 
SOC+ PT + Study Period;  
PT + toxicity grade + Study 
Period
 
 
Ibrutinib Related Serious TEAEs SOC+ PT (Whole Study 
Period only) 
 
 
Dexamethasone Related Serious 
TEAEs 
SOC+ PT (Whole Study 
Period only) 
 
 
Treatment emergent bleeding 
events  
PT + toxicity grade+Study 
Period 
 


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Category 
Analysis 
Summarize By 
Listing 
 
Treatment emergent major 
hemorrhage  
PT + toxicity grade+Study 
Period 
 
 
Treatment emergent 
atrial fibrillation and atrial flutter 
events 
 
 
Death 
Death within 30 days of last 
study treatment  
Whole Study Period 
 
 
All Deaths 
 
 
Laboratory Evaluations 
Hematology 
Measured values and change 
from baseline 
Visit+Study Period 
 
 
Treatment emergent worst post-
baseline low abnormalities 
Toxicity grade+Study Period  
 
Shift of toxicity grade in low 
direction 
Toxicity grade+Study Period  
Chemistry 
Measured values and change 
from baseline 
Visit+Study Period 
 
 
Treatment emergent worst post-
baseline abnormalities 
Toxicity grade+Study Period  
 
Shift of toxicity grade in low 
direction 
Toxicity grade+Study Period  
 
Shift of toxicity grade in high 
direction 
Toxicity grade+Study Period  
 
Shift from baseline in Creatinine 
Clearance 
Study Period 
 
 
DILI related lab criteria 
Study Period 
 
 
Liver function abnormalities 
DILI; NCI criteria; Hy’s Law , only if 
any potential 
Hy’s Law 
identified 
 
Treatment emergent abnormal 
uric acid 
Study Period 
 
Vital Signs 
General 
Measured values and change 
from baseline 
Visit+Study Period 
 
 
Shift of ECOG Performance 
Status 
Study Period 
 
Other Safety Observations 
General 
 
Other malignancy 
 
Treatment Emergent Period 
(primary analysis) + Study 
Period  
 
 
PT = preferred term; SOC = system organ class 
Study Periods refer to Whole Study Period and Monotherapy Period 
DILI = drug induced liver injury 


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8.9.1. 
Adverse Events 
Verbatim descriptions of AEs will be mapped to preferred terms using the Medical Dictionary 
for Regulatory Activities (MedDRA). The severity of AEs will be assessed using National 
Cancer Institute (NCI) common toxicity criteria for adverse events (CTCAE) Version 4.0 or 
higher. 
Drug-related AEs are those assessed by investigator as being possible, and definitely related 
to study drug.  
Treatment-emergent adverse events (TEAEs) are defined as those events that 1) occur after 
the first dose of study drug, through the treatment phase, and within 30 days following the last 
dose of study drug or the day prior to initiation of subsequence anti-myeloma therapy, 
whichever occurs earlier; 2) any event with missing onset date and its resolution date is during 
the treatment phase; 3) any event that is considered study drug-related regardless of the start 
date of the event; or 4) any event that is present at baseline but worsens in severity or is 
subsequently considered drug-related by the investigator. 
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms and will be tabulated. Major hemorrhage is a subset of 
hemorrhagic events which are grade ≥ 3 or serious or belong to central nervous system (CNS) 
hemorrhage/hematoma.   
The causal relationship between the occurrence of an AE and study drug will be judged by the 
investigator as unrelated, possibly related, or definitely related. In the event a subject 
experiences repeat episodes of the same AE, then the event with the highest severity grade 
and/or strongest causal relationship to study drug will be used for purposes of incidence 
tabulations. 
The analyses for AEs are summarized in Table 7. AEs will be summarized based on the 
number and percentage of subjects experiencing events by MedDRA system organ class and 
preferred term and by NCI toxicity grade.  
Incidence of all reported deaths and deaths within 30 days after the last dose of study drug 
will be tabulated by cause of death.  


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8.9.1.1. 
Adverse Events of Special Interest 
Major Hemorrhage: The PCYC standard definition of major hemorrhage is listed in 
Appendix 2.  Major hemorrhage will be analyzed and listed. 
8.9.2. 
Other Safety Observations 
8.9.2.1. 
 Other Malignancies 
Other malignancies are defined as new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies and are to be reported by investigators for the 
duration of study treatment and during any protocol-specified follow-up periods including 
post-progression follow-up for overall survival. Malignancy events by preferred term and 
toxicity grade will be summarized for treatment emergent period and whole study period. A 
data listing will also be provided.  
8.9.3. 
Laboratory Evaluation 
Hematology and serum chemistry parameters will be measured at screening, on Days 1, 2, 8 
and 15 of Cycle 1, and at each study visit thereafter. Urinalysis tests will be done at screening.   
All laboratory values will be converted to standard international (SI) units and classified as 
normal, low, or high based on the Pharmacyclics standard reference ranges whenever local 
laboratory reference ranges are not available. The severity of laboratory abnormalities will be 
graded using NCI CTCAE version 4.0 or higher. 
Number and percentage of subjects with treatment emergent laboratory abnormalities will be 
presented by treatment cohort for the following hematology and chemistry parameters: Hgb, 
ANC, platelets, aspartate transaminase (AST/SGOT), alanine transaminase (ALT/SGPT), 
albumin, total bilirubin, creatinine, estimated creatinine clearance (Clcr), lactate 
dehydrogenase (LDH), uric acid and electrolytes (sodium, potassium, calcium). Shift tables 
summarizing baseline CTCAE grade versus the worst post-baseline CTCAE grade will also 
be provided.  The shift of creatinine clearance rate from baseline to the lowest post-baseline 
value will also be summarized by categories (≥ 60, 30 - <60, and < 30 mL/min). 
To conservatively evaluate potential Drug-Induced Liver Injury (DILI), the incidence of any 
ALT or AST > 3 × upper limit of normal range (ULN) and any total bilirubin > 2 × ULN post 
baseline will be reported respectively. Subjects who had both events occurred at any time post 
baseline (not necessary on the same lab evaluation) plus ALP < 2 × ULN at any time post 
baseline will be identified as potential Hy’s law cases. A full listing of ALT, AST, total 
bilirubin and ALP values will be provided for the potential Hy’s law cases.  Frequency of 
abnormal treatment emergent uric acid will also be summarized. 


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Summary statistics for hematology and chemistry parameters will be calculated by treatment 
cohort for the measured values and for their changes from baseline at each scheduled visit of 
assessment.  
Graphs displaying descriptive statistics over time will be provided for selected laboratory 
parameters including, but not limited to, Hgb, ANC, and platelets. 
Laboratory values up to 30 days after the last dose of study drug will be included in the 
tabulations and graphs. Laboratory values after initiation of subsequence anti-myeloma 
therapy will be excluded. 
8.9.4. 
Electrocardiogram 
12-lead ECGs will be done at screening. ECGs will be captured on the CRFs and kept in the 
clinical database. No formal analysis will be performed. 
8.9.5. 
Vital Signs and Physical Examination Findings 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) and weight will 
be recorded at screening and each study visit. Physical examination will be done at screening 
and symptom-directed physical examinations will be performed during the treatment period. 
Summary statistics for vital signs parameters will be calculated by treatment cohort for the 
measured values and for their changes from baseline at each scheduled visit of assessment.  
8.9.6. 
ECOG Performance Status 
ECOG performance status will be recorded at screening and each study visit. 
A shift table will be provided for baseline score versus the maximum post-baseline score 
during the treatment emergent period.  
9. 
Patient Reported Outcome 
9.1. 
Neuropathy Assessment 
The neurotoxicity (Ntx) subscale of FACT/GOG-NTX will be utilized for neuropathy 
assessment. The Ntx subscale scores will be derived per FACT/GOG-Ntx Scoring 
Guidelines4.   
Descriptive analysis (mean, standard deviation, median, and range) will be provided by cohort 
for baseline subscale scores and change from baseline prior to initiation of subsequent anti-
myeloma therapy. Baseline value is defined as the last score collected on or prior to first dose 
of study drug.   


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9.2. 
Bone Pain Assessment 
Brief Pain Inventory by Cleeland2 will be utilized for bone pain assessment.   
Descriptive analysis (mean, standard deviation, median, and range) will be provided by cohort 
for baseline scores and change from baseline prior to initiation of subsequent anti-myeloma 
therapy.  Baseline score is defined as the last score collected on or prior to first dose of study 
drug.   
The following parameters will be summarized:    
 
Pain at its worst in last 24 hrs  
 
Pain at its least in last 24 hrs 
 
Pain on the average 
 
Pain when assessment occurred 
 
Pain relief in last 24 hrs 
 
Activity interference caused by pain in last 24 hrs 
o General activity 
o Mood 
o Walking ability 
o Normal work 
o Sleep 
o Relations with other people 
o Enjoyment of life 
10. 
MODIFICATIONS TO THE PROTOCOL 
The following analysis modifications are made: 
 
Two additional exploratory endpoints, Time to Clinical Benefit and Time to Response, 
and the associated analysis methods are added to the SAP.  
 
The definition for major hemorrhage is updated in alignment with the related post 
marketing commitment on major bleeding and allows consistent analysis for the 
ibrutinib clinical development program. The updated definition is based on searching 
and subtyping grade ≥ 3 or serious or central nervous system (CNS) 
hemorrhage/hematoma by hemorrhage SMQ excluding laboratory terms. The 
following types of events in protocol definition were removed because they are grade 
≥ 3 or serious hemorrhage events according to NCI CTCAE criteria: intraocular 


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bleeding causing loss of vision, the need for a transfusion of two or more units of red 
cells or an equivalent amount of whole blood, hospitalization or prolongation of 
hospitalization. Intracranial hemorrhage in protocol is included in the CNS 
hemorrhage/hematoma as a component of major hemorrhage. 
 


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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. Cleeland CS. Brief Pain Inventory (Short Form), 1991.  
3. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for 
multiple myeloma. Leukemia 2006; 20(9):1467-1473. 
4. FACT/GOG-Ntx Scoring Guidelines, Version 4, www.facit.org, 2003. 
5. FDA Guidance for industry clinical trial endpoints for the approval of cancer drugs and 
biologics, May 2007. 
6. 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. 
 
 
 


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APPENDIX 1. PREFERRED TERMS FOR CYP3A4 INHIBITORS/INDUCERS 
 
Strong inhibitors: 
Moderate inhibitors: 
Indinavir 
Aprepitant 
Nelfinavir 
Amprenavir  
Ritonavir 
Amiodarone  
Clarithromycin 
Atazanavir  
Itraconazole 
Ciprofloxacin  
Ketoconazole 
Crizotinib 
Nefazodone 
Darunavir/ritonavir  
Saquinavir 
Dronedarone  
Suboxone 
Erythromycin  
Telithromycin 
Diltiazem  
Cobicistat  
Fluconazole 
Boceprevir  
Fosamprenavir 
Mibefradil  
Grapefruit juice 
Telaprevir  
Seville orange juice  
Troleandomycin  
Verapamil 
Posaconazole  
Voriconazole  
 
Imatinib  
 
 
 
 
Strong Inducers: 
Avasimibe  
Carbamazepine 
Phenytoin 
Rifampin 
St. John’s Wort 
Moderate Inducers: 
Bosentan 
Efavirenz  
Etravirine 
Modafinil 
Nafcillin 
 
Weak Inducers: 
Amprenavir 
Aprepitant 
Armodafinil 
Clobazam 
Echinacea 
Pioglitazone 
Prednisone 
Rufinamide 
Vemurafenib 
 
Source for inhibitors:  http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
Source for inducers: FDA Guidance for Drug Interaction Studies – Study Design, Data Analysis, Implications 
for Dosing, and Labeling Recommendations February 2012. 
 
 
 


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APPENDIX 2. HAEMORRHAGE SEARCH TERMS 
 
Grade 3 or higher AEs using Hemorrhage Standard MedDRA (Version 17.0) Query (SMQ) 
without labs 
 
Any SAE using Hemorrhage SMQ without labs 
 
All Grades of CNS hemorrhage listed below: 
CNS hemorrhage Preferred Terms:  
 
Acute haemorrhagic leukoencephalitis   
 
Basal ganglia haemorrhage 
 
Brain stem haemorrhage 
 
Brain stem haematoma 
 
Central nervous system haemorrhage 
 
Cerebellar haematoma 
 
Cerebellar haemorrhage 
 
Cerebral arteriovenous malformation haemorrhagic 
 
Cerebral haematoma 
 
Cerebral haemorrhage 
 
Cerebral microhaemorrhage 
 
Encephalitis haemorrhagic 
 
Epidural haemorrhage 
 
Extradural haematoma 
 
Haemorrhagic intracranial 
 
Haemorrhagic cerebral infarction 
 
Haemorrhagic stroke 
 
Haemorrhagic transformation stroke 
 
Intracerebral haematoma evacuation 
 
Intracranial haematoma 
 
Intracranial tumour haemorrhage 
 
Intraventricular haemorrhage 
 
Pituitary haemorrhage 
 
Putamen haemorrhage 
 
Ruptured cerebral aneurysm  
 
Spinal cord haemorrhage 
 
Spinal epidural haematoma 
 
Spinal epidural haemorrhage 
 
Spinal subarachnoid haemorrhage 
 
Spinal haematoma 
 
Spinal subdural haematoma 
 
Spinal subdural haemorrhage 
 
Subarachnoid haemorrhage 
 
Subdural haematoma 


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 
Subdural haemorrhage 
 
Subgaleal haematoma 
 
Thalamus haemorrhage