Conditions: Diffuse Large B Cell Lymphoma Relapsed Diffuse Large B Cell Lymphoma Refractory
Keywords: DLBCL ABC GCB Primary Mediastinal B-cell lymphoma Pharmacyclics Lenalidomide lymphoma Rituximab EPOCH Recommended Phase 2 Dose(RP2D)
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 35
Healthy volunteers: no

Brief summary:
This is a Phase 1b/2, open-label, non-randomized multicenter study to assess the safety and efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects with relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL).

Detailed description:
This is a Phase 1b, open-label, non-randomized multicenter study conducted in 2 parts. Part 1, will determine the MTD of the combination of ibrutinib, lenalidomide and DA-EPOCH-R in subjects with DLBCL.

Ibrutinib will be administered at a fixed dose of 560 mg and lenalidomide will be dose-escalated. DA-EPOCH-R will be given at standard doses.

For Part 2, the MTD determined in Part 1 will be the dose used for all subjects. If no MTD is identified, then subjects in Part 2 will be treated with the maximum administered doses (MAD, treatment doses from dose Level 4).

The primary objective for Part 2 is to determine the ORR of ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects with ABC DLBCL as analyzed by gene expression profiling when treated at recommended phase 2 dose (RP2D).

Arms:
arm 1: Ibrutinib 560 mg PO + DA-EPOCH-R arm 2: Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R arm 3: Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R arm 4: Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R arm 5: Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R

Interventions: intervention 1: Ibrutinib intervention 2: DA-EPOCH-R intervention 3: Lenalidomide
Intervention descriptions: intervention 1: Ibrutinib intervention 2: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim intervention 3: Lenalidomide

Protocol document:
Prot_000.pdf: 
 
 
PROTOCOL 
 
TITLE: 
A Multicenter Study of Ibrutinib and Lenalidomide in 
Combination with DA-EPOCH-R in Subjects with Relapsed or 
Refractory Diffuse Large B-cell Lymphoma 
PROTOCOL NUMBER: PCYC-1124-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
102,688 
SPONSOR MEDICAL 
MONITOR: 
Nora Marie Cavazos, M.D.  
Pharmacyclics, Inc. 
Phone: +1 (408) 215-3489 
Fax: 
+1 (408) 215-3684 
Email:  ncavazos@pcyc.com 
SPONSOR: 
Pharmacyclics, Incorporated  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
16 December 2013 
 
AMENDMENT 1 Date: 
30 September 2014 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics, Inc. 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, Inc. 


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PROTOCOL APPROVAL PAGE 
Study Title: A Multicenter Study of Ibrutinib and Lenalidomide in Combination 
with DA-EPOCH-R in Subjects with Relapsed or Refractory Diffuse 
Large B-cell Lymphoma 
Study Number: PCYC-1124-CA 
Protocol Date: 16 December 2013 
Amendment 1 Date: 30 September 2014 
 
 
I have carefully read Protocol PCYC-1124-CA entitled “A Multicenter Study of Ibrutinib and 
Lenalidomide in Combination with DA-EPOCH-R in Subjects with Relapsed or Refractory 
Diffuse Large B-cell Lymphoma”.  I agree to conduct this study as outlined herein and in 
compliance with Good Clinical Practices (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that the Sponsor, Pharmacyclics, and the Institutional Review 
Board/Research Ethics Board/Independent Ethics Committee (IRB/REB/IEC) must approve any 
changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
of Pharmacyclics.  All data pertaining to this study will be provided to Pharmacyclics.  
The policy of Pharmacyclics, Inc requires that any presentation or publication of study data by 
clinical Investigators be reviewed by Pharmacyclics, before release, as specified in the protocol. 
 
Principal Investigator’s Signature 
Date 
Print Name 
The following Pharmacyclics, Inc. representative is authorized to sign the protocol and any 
amendments: 
 
Medical Monitor’s Signature 
Date 
Nora Marie Cavazos, M.D. 
Medical Director, Clinical Science, Pharmacyclics, Inc. 


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SYNOPSIS 
Title: 
A Multicenter Study of Ibrutinib and Lenalidomide in Combination with 
DA-EPOCH-R in Subjects with Relapsed or Refractory Diffuse Large B-cell 
Lymphoma 
Protocol Number: 
PCYC-1124-CA 
Phase: 
1b/2 
Indication: 
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) 
Part 2 of the study is limited to the non-germinal center B cell-like 
(non-GCB) subtype, which includes activated B-cell (ABC) DLBCL.  
The final Part 2 analysis will be performed in subjects with ABC DLBCL 
profiled by GEP. 
Study Drug and 
Comparator: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
Lenalidomide will be supplied as hard gelatin capsules for PO 
administration. 
The following drugs will be commercially supplied as standard of care by 
the participating sites: 
Rituximab as 100 mg/10 mL or 500 mg/50 mL solution in single-use vials 
for IV administration. 
Cyclophosphamide as 100, 200, 500, 1000 or 2000 mg solution in single-use 
vials for IV administration. 
Doxorubicin as 10, 20, 50, 100, 250, 500 and 750 mg solution in single-use 
vials for IV administration. 
Vincristine in 1, 2 and 5 mg single use vials for IV administration. 
Etoposide as a concentrate for parenteral use in 100 mg vials. 
Prednisone in 20 and 50 mg tablets for oral administration. 
Pegfilgrastim as a 6 mg-prefilled single-use syringe for subcutaneous 
administration. 
No comparator is used in this study. 
Objectives: 
Part 1 
Primary Objectives: 
• 
To determine the maximum tolerated dose (MTD) of the combination 
of ibrutinib, lenalidomide and dose-adjusted (DA)-EPOCH-R in 
relapsed or refractory DLBCL 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide 
in combination with DA-EPOCH-R in relapsed or refractory DLBCL  
Secondary Objective: 
• 
To determine the efficacy of ibrutinib and lenalidomide in 
combination with DA-EPOCH-R in relapsed or refractory DLBCL 
subjects as assessed by overall response rate (ORR) 
 


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Part 2 
Primary Objective: 
• 
To determine the efficacy of ibrutinib and lenalidomide in 
combination with DA-EPOCH-R in relapsed or refractory ABC 
DLBCL subjects as assessed by overall response rate (ORR) 
Secondary Objectives: 
• 
To determine the efficacy of ibrutinib and lenalidomide in 
combination with DA-EPOCH-R in relapsed or refractory ABC 
DLBCL as assessed by progression-free survival (PFS), duration of 
response (DOR) and overall survival (OS) 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide 
in combination with DA-EPOCH-R in subjects with ABC DLBCL 
Exploratory Objectives: 
• 
To determine the pharmacokinetics (PK) of ibrutinib when dosed with 
lenalidomide in combination with DA-EPOCH-R  
• 
To evaluate biomarkers of sensitivity or resistance to ibrutinib and 
lenalidomide in combination with DA-EPOCH-R 
Study Design: 
This is a Phase 1b, open-label, non-randomized multicenter study conducted 
in 2 parts.  In Parts 1 and 2, treatment will be administered in 3-week 
(21-day) cycles.  A standard 3+3 design will be employed in Part 1 to 
determine the MTD, which will then define the dose to be used in Part 2.   
Part 1:  
The dose-escalation part of the study, Part 1, will determine the MTD of the 
combination of ibrutinib, lenalidomide and DA-EPOCH-R in subjects with 
DLBCL.  Ibrutinib will be administered at a fixed dose of 560 mg and 
lenalidomide will be dose-escalated at doses of 0, 15, 20 and 25 mg for 
7 days of each 21-day cycle.  DA-EPOCH-R will be given on Days 1–5 of 
each 21-day cycle at standard doses.   
The dose escalation will follow a 3+3 design with 3 subjects in each cohort.  
Cohort dose escalation will occur if the subject incidence of DLTs during the 
first 22 days of study treatment is <33%.  If one subject within the initial 
cohort of 3 subjects (dose Level 1) experiences a DLT, an additional 
3 subjects may be enrolled at the same dose level.  If the initial dose is safe 
and tolerable with no further DLTs, the next dose level examined will be 
dose level 2.  Dose escalation will continue to dose Level 4.  The MTD will 
be defined as the highest dose level with an observed incidence of DLTs in 
<33% of the subjects enrolled in the cohort.  If in dose Level 4 DLTs occur 
in <33% of subjects, than the MTD will not be identified.  A dose de-
escalation of ibrutinib will be permitted from dose Level 1 to dose Level -1 
if required based on the number of DLTs.   


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Part 1 
Dose Level 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
-1 
420 mg 
0 mg 
Standard doses 
1 
560 mg 
0 mg 
Standard doses 
2 
560 mg 
15 mg 
Standard doses 
3 
560 mg 
20 mg 
Standard doses 
4 
560 mg 
25 mg 
Standard doses 
 
A DLT (Dose-Limiting Toxicity) is defined as an Adverse Event (AE) that 
occurs within the first 22 days (Cycle 1, Cycle 2 Day 1 predose) of dosing 
that meets the DLT definition, is clinically relevant, and considered at least 
possibly related to study drug (ibrutinib and/or lenalidomide) in the opinion 
of the investigator. 
 
Part 2: 
For Part 2, the MTD determined in Part 1 will be the dose used for all 
subjects.  If no MTD is identified, then subjects in Part 2 will be treated with 
the maximum administered doses (MAD, treatment doses from dose 
Level 4).   
The expansion part of the study, Part 2, will only enroll subjects with 
non-GCB DLBCL.  The primary objective is to determine the ORR of 
ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects 
with ABC DLBCL (a subset of non-GCB DLBCL) as analyzed by gene 
expression profiling. 
Approximately 26 subjects will receive ibrutinib at a fixed dose of 560 mg 
and lenalidomide at the established MTD for 7 days.  DA-EPOCH-R will be 
given on Days 1–5 of each 3-week (21-day) cycle at standard doses. 
 
Part 2 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
560 mg 
(or 420 mg if toxicity with 560 mg) 
TBD 
Standard doses 
 


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Subjects in Part 1 and Part 2 will receive therapy until a maximum of six 
cycles or disease progression, whichever occurs first.  Subjects will be 
restaged after Cycle 3 (Cycle 4 Day 1, -4 days [Cycle 3 Day 19 to Cycle 4 
Day 1]) and after Cycle 6 (Cycle 6 Day 21±4 days) of treatment, and then 
every 3, 4, and 6 months (every 12, 16 and 26 weeks) during post-treatment 
years 1, 2, and 3, respectively.   
In this study, immunohistochemisty (IHC) will be performed in Part 1 and 
Part 2; however IHC will be used to assess subject eligibility with respect to 
subtype of DLBCL only for Part 2.  Gene expression profile (GEP) will be 
performed in Part 2 to confirm the ABC subtype for analysis purposes.  
The limitations of IHC allow only a distinction between subjects as either 
non-GCB or GCB phenotype since within the non-GCB group one may 
include subjects with a true unclassified (intermediate) subtype.  With GEP, 
the subjects can be further categorized into the following subtypes:  ABC, 
GCB, unclassified, and unknown due to tissue limitations.  Throughout the 
protocol, description of enrolled subjects as “non-GCB” is based on IHC 
testing used at screening.  The use of the term “ABC subtype” refers to 
subjects who have been subsequently (ie, after starting protocol treatment) 
profiled by GEP and then classified as the true ABC subtype.   
Population 
Subjects with relapsed or refractory DLBCL who have failed at least 1 prior 
line of therapy.  In Part 1, a minimum of 4 and a maximum of 30 DLBCL 
subjects will be enrolled.  In Part 2, 26 relapsed or refractory de novo 
DLBCL subjects with non-GCB subtype will be enrolled.  Enrollment may 
be increased to include 26 subjects with confirmed ABC DLBCL depending 
on data availability.  Subjects with ABC subtype from Part 1 that received 
the MTD or MAD of lenalidomide may be carried over to Part 2. 
Centers: 
Multicenter – US only 
Major Inclusion 
Criteria: 
Note for the complete list of inclusion/exclusion criteria refer to Section 4. 
Major inclusion criteria: 
1. Men and women ≥18 years of age 
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 
3. Pathologically confirmed DLBCL: 
• 
Part 1:  all subtypes are eligible 
• 
Part 2:  only non-GCB subtype is eligible 
4. Relapsed or refractory disease, defined as either: 1) recurrence of 
disease after a complete remission (CR), or 2) partial remission (PR), 
stable disease (SD), or progressive disease (PD) at completion of the 
treatment regimen preceding entry to the study (residual disease): 
a) Subjects must have previously received an appropriate first-line 
treatment regimen. 
b) For subjects in whom a post-treatment residual computed 
tomography (CT) scan abnormality exists, and a definitive 
distinction between residual DLBCL and a non-lymphomatous 
process (eg, fibrosis) is clinically indicated, those subjects must 
have biopsy confirmation of residual DLBCL prior to study entry.  
 
 
 


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5. Subjects must have ≥1 measurable disease site on CT scan (≥ 1.5 cm in 
longest dimension).  Lesions in anatomical locations (such as extremities 
or soft tissue lesions) that are not well visualized by CT may be 
measured by MRI instead. 
6. Subjects must have adequate fresh or paraffin tissue for confirmation of 
diagnosis and molecular evaluation.  Tissue may be from either the 
initial diagnosis or from relapsed or refractory disease. 
7. Meet the following laboratory parameters:  
a) Absolute neutrophil count (ANC) ≥1,000 cells/mm3 (1.0 x 109/L)  
b) Platelets ≥75,000 cells/mm3 (75 x 109/L)   
c) ALT and AST ≤2.5 x ULN unless lymphoma-related 
d) Bilirubin ≤1.5 x ULN, except ≤2 mg/dL (total) in subjects with 
Gilbert’s syndrome (as defined by >80% unconjugated 
hyperbilirubinemia) 
e) Serum Creatinine ≤2.0 mg/dL or creatinine clearance 
≥60 mL/min/1.73 m2 
f) Hemoglobin ≥ 8.0 g/dL  
g) Prothrombin time (PT) and activated partial thromboplastin time 
(aPTT) must be ≤1.5 x the upper limit of the normal range (ULN); 
except if, in the opinion of the Investigator, the aPTT is elevated 
because of a positive Lupus Anticoagulant 
8. Left ventricular ejection fraction (LVEF) >45% as assessed by 
echocardiogram or multigated acquisition scan (MUGA) 
9. Able to provide written informed consent and can understand and 
comply with the requirements of the study 
10. All study participants must be registered into the mandatory Revlimid 
REMS™ program, and be willing and able to comply with the 
requirements of Revlimid REMS™. 
11. Female subjects of childbearing potential (FCBP) † must have a negative 
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 
within 10–14 days and again within 24 hours prior to prescribing 
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as 
required by Revlimid REMS) and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable 
methods of birth control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days before she 
starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  See Appendix F:  Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods. 
12. Male subjects must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  
See Appendix F:  Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods.  
13. Life expectancy of more than 3 months 
 
 
 
† A female of childbearing potential is a sexually mature female who:  1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 


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Major Exclusion 
Criteria 
1. Transformed DLBCL or DLBCL with coexistent histologies 
(eg, follicular or mucosa-associated lymphoid tissue [MALT] 
lymphoma) for enrollment into Part 2 only 
2. Primary mediastinal (thymic) large B-cell lymphoma for enrollment into 
Part 2 only 
3. Known central nervous system lymphoma  
4. Any chemotherapy, external beam radiation therapy, or anti-cancer 
antibodies within 2 weeks prior to the first dose of study drug 
5. Radio- or toxin-immunoconjugates within 10 weeks prior to the first 
dose of study drug 
6. Concurrent enrollment in another therapeutic investigational clinical 
study 
7. Previously taken ibrutinib or lenalidomide 
8. Major surgery within 4 weeks prior to the first dose of study drug 
9. Prior allogenetic stem cell (or other organ) transplant within 6 months or 
any evidence of active graft-versus-host disease or requirement for 
immunosuppressants within 28 days prior to first dose of study drug 
10. History of other malignancies, except: adequately treated non-melanoma 
skin cancer, curatively treated in-situ cancer, or other solid tumors 
curatively treated with no evidence of disease for ≥ 2 years 
11. Currently active, or clinically significant cardiovascular disease such as 
uncontrolled arrhythmia, congestive heart failure, any Class 3 or 
4 cardiac disease as defined by the New York Heart Association 
Functional Classification (Appendix E), or history of myocardial 
infarction within 6 months prior to first dose with study drug 
12. Significant screening electrocardiogram (ECG) abnormalities, including 
left bundle branch block, 2nd degree atrioventricular (AV) block 
Type II, 3rd degree block, or QTc ≥470 msec 
13. Recent infection requiring intravenous anti-infective treatment that was 
completed ≤14 days before the first dose of study drug  
14. Unresolved toxicities from prior anti-cancer therapy, defined as having 
not resolved to Common Terminology Criteria for Adverse Event 
(CTCAE, version 4.03), grade 0 or 1, or to the levels dictated in the 
inclusion/exclusion criteria with the exception of alopecia  
15. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia 
16. Known history of infection with human immunodeficiency virus (HIV) 
or chronic or active infection with Hepatitis C virus (HCV) or 
Hepatitis B virus (HBV).  Viral load by PCR must be confirmed negative 
in equivocal cases for subjects who are Hepatitis B core antibody 
positive, Hepatitis B surface antigen positive, Hepatitis B surface 
antibody positive (unless immunized) or Hepatitis C antibody positive.   
17. Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise the 
subject’s safety or put the study outcomes at undue risk 
18. Unable to swallow capsules or disease significantly affecting 
gastrointestinal function and/or inhibiting small intestine absorption such 
as malabsorption syndrome, resection of the small bowel, or poorly 
controlled inflammatory bowel disease affecting the small intestine 
 
 


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19. Received or receiving anticoagulation with warfarin or equivalent 
vitamin K antagonists (eg, phenprocoumon) within 28 days of first dose 
of study drug 
20. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor 
21. Lactating or pregnant women 
Endpoints: 
Part 1: 
Primary Endpoint: (for all subtypes of DLBCL) 
• 
MTD 
• 
Safety and tolerability of ibrutinib and lenalidomide in combination 
with DA-EPOCH-R in relapsed or refractory DLBCL   
Secondary Endpoint: (for all subtypes of DLBCL) 
• 
ORR 
Part 2: 
Primary Endpoint: 
• 
ORR including CR (complete response) and PR (partial response) in 
ABC DLBCL 
Secondary Endpoints:  
Efficacy: 
• 
Duration of response (DOR) in ABC DLBCL 
• 
Progression-free survival (PFS) in ABC DLBCL 
• 
Overall survival (OS) in ABC DLBCL 
Safety: 
• 
Frequency, severity, and relatedness of AEs  
• 
Frequency of AEs requiring discontinuation of study drug or dose 
reductions 
Pharmacokinetics: 
• 
Plasma pharmacokinetics of ibrutinib  
Exploratory Analyses: 
• 
Identification of signaling pathways or biomarkers that predict 
sensitivity or resistance to ibrutinib  
• 
Frequency of tumor mutations (or other molecular markers) between 
pre- and post-treatment tissue that predict acquired resistance.  
• 
Change in secreted protein levels (ie, chemokines, cytokines) 
• 
Change in peripheral T/B/natural killer (NK) counts and 
immunophenotypical analysis 
Safety plan: 
This study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures.  AEs and serious adverse events 
(SAEs) will be reviewed internally on an ongoing basis to identify safety 
concerns.  A Dose Level Review Committee will evaluate safety data from 
the dose escalation portion of Part 1.  Members of this committee will 
include the Sponsor (at a minimum:  the Medical Monitor or designee, a 
Drug Safety representative and a Biostatistician) as well as participating 
Investigators and Sub-Investigators.    


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Study Treatment: 
Day 1–7 of each cycle:  ibrutinib PO 
Day 1–7 of each cycle:  lenalidomide PO 
Day 1–5 of each cycle:  DA-EPOCH-R  
Day 6 (with a +48 hour window) of each cycle:  Pegfilgrastim 
1 cycle = 21 days; maximum 6 cycles  
Study follow-up will be for 1 year after the last subject received the first 
dose.  
Part 1: 
Part 1 
Dose Level 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
-1 
420 mg 
0 mg 
Standard doses 
1 
560 mg 
0 mg 
Standard doses 
2 
560 mg 
15 mg 
Standard doses 
3 
560 mg 
20 mg 
Standard doses 
4 
560 mg 
25 mg 
Standard doses 
Part 2:  
Part 2 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
560 mg 
TBD 
Standard doses 
 
Study treatment will continue for up to 6 cycles and as long as:  
• 
subject is deriving clinical benefit (complete remission [CR], partial 
remission [PR], or stable disease [SD]) and  
• 
subject is not experiencing any unacceptable toxicity 
Concomitant Therapy 
and Clinical Practice: 
Refer to Section 6 for information on concomitant therapy 
Statistical Methods: 
Subjects meeting the stated eligibility requirements will be enrolled in the 
study.  Part 1 of the study is based on a Phase 1 3+3 design described in the 
Study Design Section.  Part 2 of the study is an expansion of the non-GCB 
subtype of DLBCL population (ABC DLBCL will be subsequently 
confirmed by GEP).  Subjects with the ABC subtype from Part 1 that 
received the MTD or MAD of lenalidomide may be carried over to Part 2.  
The study will expand to N=26 relapsed or refractory de novo DLBCL 
subjects in Part 2, which will provide 81% power when comparing an ORR 
of 60% versus 85% with 1-sided alpha level 5% by exact test.  Enrollment 
may be increased to include 26 subjects with confirmed ABC DLBCL 
depending on data availability.   
The primary endpoint (ORR) will be reported including an exact 1-sided 
95% confidence interval.  The secondary efficacy endpoints (DOR, PFS, 
and OS) will be summarized by Kaplan-Meier analyses with estimated 
means, medians and ranges reported in months.  The secondary safety 
endpoints will be summarized by incidences and types of clinical AEs. 
The final analysis will occur approximately 1 year after the last subject 
received the first dose.  Analyses methods will be detailed in the Statistical 
Analysis Plan. 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .............................................................................................. 2 
SYNOPSIS ..................................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 11 
LIST OF TABLES ...................................................................................................................... 17 
LIST OF FIGURES .................................................................................................................... 17 
LIST OF APPENDICES ............................................................................................................ 17 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................... 18 
1. 
BACKGROUND ................................................................................................................. 21 
1.1. 
Overall Summary ........................................................................................................ 21 
1.2. 
Diffuse Large B-cell Lymphoma (DLBCL) ............................................................... 21 
1.3. 
Ibrutinib Background .................................................................................................. 23 
1.4. 
Lenalidomide Background .......................................................................................... 24 
1.5. 
Combination of Ibrutinib and Lenalidomide in ABC Subtype of DLBCL ................ 26 
1.6. 
Summary of Relevant Nonclinical Data for Ibrutinib ................................................. 27 
1.6.1. 
Nonclinical Pharmacology Studies ............................................................. 27 
1.6.2. 
Toxicology Studies ...................................................................................... 27 
1.7. 
Summary of Clinical Studies for Ibrutinib.................................................................. 28 
1.7.1. 
Summary of Clinical Pharmacokinetics ...................................................... 28 
1.7.2. 
Summary of Clinical Safety for Ibrutinib ................................................... 29 
1.7.2.1.  Monotherapy Studies ....................................................................29 
1.7.2.2.  Combination Therapy Studies .......................................................30 
1.7.3. 
Risks ............................................................................................................ 31 
1.7.3.1.  Bleeding-related Events ................................................................31 
1.7.3.2.  Cardiac ..........................................................................................31 
1.7.3.3.  Cytopenias .....................................................................................31 
1.7.3.4.  Diarrhea .........................................................................................31 
1.7.3.5.  Infections .......................................................................................31 
1.7.3.6.  Other Malignancies .......................................................................31 
1.7.3.7.  Rash ...............................................................................................32 
1.7.3.8.  Treatment-related Lymphocytosis ................................................32 
1.7.3.9.  R-CHOP with Ibrutinib .................................................................32 
1.8. 
Summary of Clinical Safety for Lenalidomide in Lymphoma ................................... 33 
1.8.1. 
Venous Thromboembolism ......................................................................... 33 
1.8.2. 
Second New Cancers ................................................................................... 34 
1.8.3. 
R-CHOP with Lenalidomide ....................................................................... 34 
1.9. 
Summary of Clinical Safety for DA-EPOCH-R Chemotherapy in Lymphoma ......... 34 
1.10.  Justification of Study Design and Dose Rationale ...................................................... 35 
1.10.1.  Dose Selection Rationale for DA-EPOCH-R .............................................. 35 
1.10.2.  Dose Selection Rationale for Ibrutinib ........................................................ 35 
1.10.3.  Dose Selection Rationale for Lenalidomide ................................................ 36 


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2. 
STUDY OBJECTIVES ....................................................................................................... 36 
2.1. 
Primary Objectives ...................................................................................................... 36 
2.1.1. 
Part 1 ........................................................................................................... 36 
2.1.2. 
Part 2 ........................................................................................................... 36 
2.2. 
Secondary Objectives .................................................................................................. 36 
2.2.1. 
Part 1 ........................................................................................................... 36 
2.2.2. 
Part 2 ........................................................................................................... 37 
2.3. 
Exploratory Objectives ............................................................................................... 37 
3. 
STUDY DESIGN ................................................................................................................. 37 
3.1. 
Overview of Study Design: ......................................................................................... 37 
3.2. 
Endpoints .................................................................................................................... 37 
3.2.1. 
Part 1: .......................................................................................................... 37 
3.2.1.1.  Primary Endpoint: (for all subtypes of DLBCL) ..........................37 
3.2.1.2.  Secondary Endpoint (for all subtypes of DLBCL) .......................37 
3.2.2. 
Part 2: .......................................................................................................... 38 
3.2.2.1.  Primary Endpoint ..........................................................................38 
3.2.2.2.  Secondary Endpoints .....................................................................38 
3.3. 
Part 1 – Dose Escalation ............................................................................................. 38 
3.4. 
Part 2 – Expansion ...................................................................................................... 40 
3.5. 
All Subjects in Part 1 and Part 2 ................................................................................. 40 
4. 
SUBJECT SELECTION .................................................................................................... 41 
4.1. 
Inclusion Criteria ........................................................................................................ 41 
4.2. 
Exclusion Criteria ....................................................................................................... 43 
5. 
TREATMENT OF SUBJECTS ......................................................................................... 44 
5.1. 
Treatment Part 1 .......................................................................................................... 44 
5.2. 
Treatment Part 2 .......................................................................................................... 45 
5.3. 
Dosages Overview ...................................................................................................... 46 
5.4. 
Dose Escalation for Part 1 ........................................................................................... 46 
5.5. 
Dose-Limiting Toxicities for Part 1 ............................................................................ 47 
5.5.1. 
DLT Definition ............................................................................................ 47 
5.6. 
Ibrutinib....................................................................................................................... 48 
5.6.1. 
Formulation, Packaging, and Storage of Ibrutinib ...................................... 48 
5.6.2. 
Dosage and Administration of Ibrutinib ...................................................... 48 
5.6.3. 
Dose Reduction and Discontinuation .......................................................... 49 
5.6.4. 
Overdose Instructions .................................................................................. 50 
5.6.5. 
Precautions and Adverse Events ................................................................. 51 
5.7. 
Lenalidomide .............................................................................................................. 51 
5.7.1. 
Formulation, Packaging, and Storage of Lenalidomide .............................. 51 
5.7.2. 
Lenalidomide Prescribing Information (applies to US sites only) .............. 51 
5.7.3. 
Pregnancy Testing while Taking Lenalidomide .......................................... 52 
5.7.4. 
Dosage, Preparation and Administration of Lenalidomide ......................... 52 


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5.7.5. 
Dose Delay, Reduction or Discontinuation of Lenalidomide ..................... 52 
5.7.5.1.  Part 1 Cycle 1 Lenalidomide Dose Modifications ........................52 
5.7.5.2.  Part 1 Cycles 2-6 and Part 2 Lenalidomide Dose Modifications ..53 
5.7.6. 
Safety Profile ............................................................................................... 55 
5.8. 
Rituximab .................................................................................................................... 56 
5.8.1. 
Supply .......................................................................................................... 56 
5.8.2. 
Storage ......................................................................................................... 56 
5.8.3. 
Preparation .................................................................................................. 56 
5.8.4. 
Stability ....................................................................................................... 56 
5.8.5. 
Administration ............................................................................................. 57 
5.8.6. 
Safety Profile ............................................................................................... 57 
5.9. 
Cyclophosphamide ...................................................................................................... 58 
5.9.1. 
Supply .......................................................................................................... 58 
5.9.2. 
Storage and Preparation .............................................................................. 58 
5.9.3. 
Administration ............................................................................................. 58 
5.9.4. 
Toxicities ..................................................................................................... 58 
5.9.5. 
Hydration Guidelines .................................................................................. 58 
5.10.  Vincristine/Doxorubicin/Etoposide ............................................................................ 59 
5.10.1.  Central Venous Access ................................................................................ 59 
5.10.2.  Vincristine ................................................................................................... 59 
5.10.2.1. Supply ...........................................................................................59 
5.10.2.2. Toxicities .......................................................................................60 
5.10.3.  Doxorubicin ................................................................................................. 60 
5.10.3.1. Supply ...........................................................................................60 
5.10.3.2. Toxicities .......................................................................................60 
5.10.4.  Etoposide ..................................................................................................... 60 
5.10.4.1. Supply ...........................................................................................60 
5.10.4.2. Toxicities .......................................................................................60 
5.11.  Prednisone ................................................................................................................... 60 
5.11.1.  Supply .......................................................................................................... 60 
5.11.2.  Doses ........................................................................................................... 61 
5.11.3.  Toxicities ..................................................................................................... 61 
5.12.  Pegfilgrastim (Neulasta) ............................................................................................. 61 
5.12.1.  Supply .......................................................................................................... 61 
5.12.2.  Toxicities ..................................................................................................... 61 
5.13.  Dose Adjustment for EPOCH-R ................................................................................. 62 
5.13.1.  EPOCH-R Dose Adjustment for Part 1 and 2 ............................................. 62 
5.13.2.  Vincristine Dose Reduction for Ileus Toxicity ........................................... 63 
5.13.3.  Vincristine Dose Reduction for Neurological Toxicity .............................. 63 
5.13.4.  Etoposide Dose Reduction for Renal Dysfunction ..................................... 64 
5.13.5.  EPOCH-R Dose for Obese Subjects ........................................................... 64 
5.13.6.  Pretreatment and Dose Modifications for Rituximab ................................. 64 


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5.14.  Criteria for Permanent Treatment Discontinuation  .................................................... 65 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .................................................... 65 
6.1. 
Permitted Concomitant Medications........................................................................... 65 
6.1.1. 
Prophylaxis of Pneumocystis Jirovecii (Previously Pneumocystis 
Carinii) ........................................................................................................ 66 
6.1.2. 
Prophylaxis for Tumor Lysis Syndrome (TLS) .......................................... 66 
6.1.3. 
Recommended Bowel Regimen .................................................................. 66 
6.2. 
Concomitant Medications to be Used with Caution ................................................... 66 
6.2.1. 
Concomitant Use of CYP3A Inhibitors/Inducers ........................................ 66 
6.2.1.1.  Ibrutinib .........................................................................................66 
6.2.1.2.  Lenalidomide .................................................................................67 
6.2.2. 
QT Prolongation .......................................................................................... 67 
6.2.3. 
Antiplatelet Agents and Anticoagulants ...................................................... 67 
6.2.3.1.  Ibrutinib .........................................................................................67 
6.3. 
Prohibited Concomitant Therapy ................................................................................ 68 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ......................... 68 
7. 
STUDY EVALUATIONS ................................................................................................... 68 
7.1. 
Description of Procedures ........................................................................................... 69 
7.1.1. 
Assessments ................................................................................................ 69 
7.1.1.1.  Informed Consent ..........................................................................69 
7.1.1.2.  Confirmation of Eligibility ............................................................69 
7.1.1.3.  Medical History .............................................................................69 
7.1.1.4.  Prior and Concomitant Medications ..............................................69 
7.1.1.5.  Adverse Events ..............................................................................70 
7.1.1.6.  Physical Examination, and Height ................................................70 
7.1.1.7.  Venous Thromboembolism Risk Assessment ...............................70 
7.1.1.8.  Vital Signs .....................................................................................70 
7.1.1.9.  ECOG Performance Status ............................................................71 
7.1.1.10. Electrocardiogram (ECG) .............................................................71 
7.1.1.11. Echocardiogram or MUGA ...........................................................71 
7.1.1.12. Bone Marrow Aspirate and Biopsy ...............................................71 
7.1.1.13. Optional Tumor Biopsy .................................................................72 
7.1.2. 
Laboratory ................................................................................................... 72 
7.1.2.1.  Hematology ...................................................................................72 
7.1.2.2.  Serum Chemisty ............................................................................72 
7.1.2.3.  Hepatitis Serologies ......................................................................73 
7.1.2.4.  Pregnancy Test ..............................................................................73 
7.1.2.5.  Coagulation Studies ......................................................................73 
7.1.2.6.  T/B/NK Cell Count .......................................................................73 
7.1.2.7.  Blood Samples for Biomarkers .....................................................74 
7.1.2.8.  Pharmacokinetics (PK) Sample Collection ...................................74 
7.1.2.9.  Urinalysis ......................................................................................74 
7.1.3. 
Radiological Examinations ......................................................................... 74 
7.1.4. 
Overall Response Assessments ................................................................... 75 


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7.1.5. 
Survival ....................................................................................................... 75 
8. 
STUDY PROCEDURES .................................................................................................... 76 
8.1. 
Screening Phase .......................................................................................................... 76 
8.2. 
Treatment Phase .......................................................................................................... 77 
8.2.1. 
Cycle 1 ......................................................................................................... 77 
8.2.1.1.  Cycle 1 Day 1 ................................................................................77 
8.2.1.2.  Cycle 1 Day 2-6 ............................................................................78 
8.2.1.3.  Cycle 1 Day 8 and 15 ....................................................................78 
8.2.2. 
Cycles 2-6 .................................................................................................... 79 
8.2.2.1.  Day 1 .............................................................................................79 
8.2.2.2.  Day 2-6 ..........................................................................................79 
8.2.2.3.  Day 8  ............................................................................................80 
8.2.3. 
Response Assessments ................................................................................ 80 
8.2.4. 
Suspected CR .............................................................................................. 81 
8.3. 
Follow-up Phase.......................................................................................................... 81 
8.3.1. 
Safety Follow-up Visit ................................................................................ 81 
8.3.2. 
Survival Follow-up Visit ............................................................................. 82 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ........................................................ 82 
9.1. 
Completion .................................................................................................................. 82 
9.2. 
Treatment Discontinuation .......................................................................................... 82 
9.3. 
Study Exit/Withdrawal................................................................................................ 83 
10.  STATISTICAL METHODS AND ANALYSIS ............................................................... 83 
10.1.  General Considerations ............................................................................................... 83 
10.1.1.  Response Assessment .................................................................................. 83 
10.1.2.  Safety Monitoring ....................................................................................... 84 
10.2.  Definition of Analysis Populations ............................................................................. 84 
10.3.  Endpoint Data Analysis .............................................................................................. 84 
10.3.1.  Demographic/Baseline Characteristics and Study Conduct ........................ 84 
10.3.2.  Efficacy Endpoints for Part 1 ...................................................................... 85 
10.3.3.  Primary Efficacy Endpoint for Part 2 .......................................................... 85 
10.3.4.  Secondary Efficacy Endpoints for Part 2 .................................................... 85 
10.3.4.1. Duration of Response ....................................................................85 
10.3.4.2. Progression-free Survival ..............................................................85 
10.3.4.3. Overall Survival ............................................................................86 
10.3.5.  Exploratory/Sensitivity Analysis ................................................................. 86 
10.3.6.  Safety Endpoint ........................................................................................... 86 
10.3.7.  Pharmacokinetics ........................................................................................ 86 
10.3.8.  Biomarkers .................................................................................................. 87 
10.4.  Handling of Missing Data ........................................................................................... 87 
10.5.  Determination of Sample Size .................................................................................... 87 
10.6.  Safety Analysis ........................................................................................................... 88 
10.6.1.  Adverse Events ............................................................................................ 88 


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10.6.2.  Clinical Laboratory Tests ............................................................................ 88 
11.  ADVERSE EVENT REPORTING ................................................................................... 89 
11.1.  Adverse Event Definitions and Classifications ........................................................... 89 
11.1.1.  Adverse Events ............................................................................................ 89 
11.1.2.  Serious Adverse Event ................................................................................ 90 
11.1.3.  Unexpected Adverse Events ........................................................................ 91 
11.1.4.  Severity Criteria (Grade 1-5) ....................................................................... 91 
11.1.5.  Causality (Attribution) ................................................................................ 92 
11.2.  Documenting and Reporting of Adverse Events ........................................................ 92 
11.2.1.  Special Reporting Situations ....................................................................... 92 
11.2.2.  All Adverse Events ...................................................................................... 93 
11.2.2.1. Expedited Reporting Criteria for Serious Adverse Events ...........93 
11.2.3.  Events of Special Interest ............................................................................ 94 
11.2.3.1. Major Hemorrhage ........................................................................94 
11.2.3.2. Intracranial Hemorrhage ...............................................................94 
11.2.4.  Other Malignancies ..................................................................................... 94 
11.2.5.  Pregnancy .................................................................................................... 95 
11.3.  Safety Cohort Review Committee .............................................................................. 95 
12.  STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .................... 95 
12.1.  Regulatory and Ethical Compliance ........................................................................... 95 
12.2.  Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval ......................................................... 95 
12.3.  Informed Consent........................................................................................................ 96 
12.4.  Quality Control and Quality Assurance ...................................................................... 96 
12.5.  Protected Subject Health Information Authorization ................................................. 96 
12.6.  Study Files and Record Retention............................................................................... 97 
12.7.  Case Report Forms and Record Maintenance ............................................................. 98 
12.8.  Investigational Study Drug Accountability ................................................................ 98 
12.9.  Study Monitoring/Audit Requirements ....................................................................... 99 
12.10. Investigator Responsibilities ..................................................................................... 100 
12.11. Sponsor Responsibilities ........................................................................................... 100 
12.12. Financial Disclosure .................................................................................................. 100 
12.13. Liability and Clinical Trial Insurance ....................................................................... 101 
12.14. Protocol Amendments ............................................................................................... 101 
12.15. Publication of Study Results ..................................................................................... 101 
12.16. Study Discontinuation ............................................................................................... 102 
12.17. Study Completion ..................................................................................................... 102 
13.  REFERENCE LIST .......................................................................................................... 103 
14.  APPENDICES ................................................................................................................... 109 


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LIST OF TABLES 
Table 1: 
Part 1 Dose Levels ...................................................................................................40 
Table 2: 
Part 2 Dose Levels ...................................................................................................40 
Table 3: 
Part 1 Dosing Levels ...............................................................................................45 
Table 4: 
Part 2 Dose Levels ...................................................................................................45 
Table 5: 
Dosages ...................................................................................................................46 
Table 6: 
Part 1 Dosing Levels ...............................................................................................47 
Table 7: 
Dose Modification for Ibrutinib Toxicity ................................................................50 
Table 8: 
Dose Modification or Interruption for Lenalidomide Toxicity During 
Administration or for Delay in a Treatment Cycle of Greater Than 1 Week ..........54 
Table 9: 
Lenalidomide Dose Reduction ................................................................................55 
Table 10: 
Hydration Guidelines for Cyclophosphamide .........................................................58 
Table 11: 
Prednisone Doses per BSA .....................................................................................61 
Table 12: 
EPOCH-R Dose Adjustment ...................................................................................62 
Table 13: 
Doses per Dose Levels for Doxorubicin, Etoposide and Cyclophosphamide .........63 
Table 14: 
Sensory Neuropathy Grade and Vincristine Dose Reduction .................................63 
Table 15: 
Motor Neuropathy Grade and Vincristine Dose Reduction ....................................64 
Table 16: 
Dose Modification for Rituximab Toxicity .............................................................64 
Table 17: 
PK Sample Collection Schedule..............................................................................74 
 
LIST OF FIGURES 
Figure 1: 
3+3 Dose Escalation Design ...................................................................................39 
 
LIST OF APPENDICES 
Appendix A:  Schedule of Assessments.......................................................................................110 
Appendix B:  ECOG Status Scores ..............................................................................................113 
Appendix C:  Inhibitors and Inducers of CYP3A ........................................................................114 
Appendix D:  Guidelines for Establishing Response to Treatment .............................................115 
Appendix E:  New York Heart Association Functional Classification .......................................116 
Appendix F:  Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods ....................................................................................................117 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABC 
Activated B-cell  
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AV 
atrioventricular 
BCR 
B-cell receptor 
BR 
bendamustine/rituximab 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD20 
cluster of differentiation 20 
CDC 
complement dependent cytotoxicity 
CEOP 
cyclophosphamide, etoposide, vincristine, prednisone 
CEPP 
cyclophosphamide, etoposide, prednisone, procarbazine 
CFR 
Code of Federal Regulations 
CIV 
continuous intravenous infusion 
CLL 
chronic lymphocytic leukemia 
CNS 
central nervous system 
CR 
complete remission (response) 
CrCl 
creatinine clearance 
CRF 
case report form 
CRi 
CR with incomplete bone marrow recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
DA-EPOCH-R 
Dose Adjusted Cyclophosphamide, Doxorubicin, Etoposide, Vincristine, 
Prednisone +/- Rituximab 
DLBCL 
diffused large B-cell lymphoma 
DLT 
dose-limiting toxicity  
DOR 
duration of response 
DVT 
Deep Venous thromboembolism 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
EDC 
electronic data capture 
EMR 
electronic medical records 


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Abbreviation 
Definition 
EORTC 
European Organisation for Research and Treatment of Cancer 
ESMO 
European Society for Medical Oncology 
FCBP 
Females of childbirthing potential 
FCR 
fludarabine/cyclophosphamide/rituximab 
FFPE 
Formulin-fixed paraffin embedded tissue 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FL 
follicular lymphoma 
GCB 
germinal center B cell-like 
GCP 
Good Clinical Practice 
GDP 
gemcitabine, dexamethasone, cisplatin  
G-CSF 
Granulocyte colony-stimulating factor 
GemOx 
gemcitabine, oxaliplatin 
GEP 
gene expression profile 
HDT/ASCT 
high-dose chemotherapy with autologous stem cell support 
HED 
human equivalent dose 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
immunohistochemisty  
IMiD 
immunomodulatory derivatives 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
IRF 
independent review facility 
ITP 
idiopathic thrombocytopenic purpura 
ITT 
Intent-to-treat 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LN 
lymph node 
LVEF 
left ventricular ejection fraction 
MAD 
maximum administered dose 
MALT 
mucosa-associated lymphoid tissue 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
MTD 
maximum tolerated dose 
MUGA 
Multigated Acquisition Scan 
MM 
multiple myeloma 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
Non-GCB 
Non-Germinal Center B-cell like 
NS 
normal saline 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PE 
pulmonary embolism 
PET 
Positron emission tomography  
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PMBL 
primary mediastinal B-cell lymphoma 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (oral) 
PR 
partial remission (response) 
PRN 
pro re nata, as needed 
PT 
prothrombin time 
QTc 
corrected QT interval 
R-CHOP 
rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone 
REB 
Research Ethics Board 
REMS™ 
Revlimid Risk Evaluation and Mitigation Strategy 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SCRC 
Safety Cohort Review Committee 
SD 
stable disease 
SI 
standard international units 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
SOP 
standard operating procedures 
SPD 
sum of the product of the diameters 
Tmax 
time to maximum drug concentration 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
USP 
United States pharmacopeial convention 
UTI 
urinary tract infection 
WM 
Waldenstrom’s Macroglobulinemia 


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1. BACKGROUND 
1.1. 
Overall Summary 
Treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL) remains 
challenging.  Following initial therapy, re-induction chemotherapy followed by high-dose 
therapy with autologous stem cell support (HDT/ASCT) remains the current standard of care.  
For patients not eligible for stem cell transplant, per NCCN guidelines, a variety of therapies are 
recommended.  However, the overall outcome is relatively poor, with a worse prognosis in the 
non-GCB subtype including patients with ABC DLBCL.  Based on this information, new 
therapies are needed, particularly for non-transplant eligible subjects with the ABC subtype. 
DA-EPOCH-R (dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, 
prednisone +/- rituximab) is one of the recommended therapies for relapsed DLBCL per NCCN 
guidelines.  Preclinical and clinical data for lenalidomide, another recommended therapy in the 
relapsed setting, implies it is equally efficacious or perhaps even more efficacious in patients 
with ABC DLBCL (Yang 2012, Hernandez-Ilizaliturri 2011, Wang 2013).  Similarly, clinical 
data with ibrutinib also implies greater activity in the ABC subtype (de Vos 2013).  Since 
accepted therapy for relapsed DLBCL consists of DA-EPOCH-R, we hypothesize that the 
addition of ibrutinib and lenalidomide may further enhance the response to chemotherapy in 
patients with non-GCB (ABC) DLBCL which will be tested in Part 2 of this study.  Synergistic 
activity may also be seen in other forms of DLBCL (ie, transformed, primary mediastinal, 
germinal center B cell-like [GCB]) which will be tested in a limited number of patients in Part 1. 
1.2. 
Diffuse Large B-cell Lymphoma (DLBCL) 
Diffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive non-Hodgkin 
lymphomas (NHL) in the United States, with an annual incidence that has been rising gradually 
since the 1990s (Fisher 2004).  The estimated 2010 prevalence of NHL in the US was 
approximately 509,000 individuals, with over 200,000 of these cases in individuals over the age 
of 70 years (SEER 2010).  It is estimated that 30-40% of NHL cases are of the DLBCL category 
(Hans 2004).  According to the current SEER data, the median age at diagnosis is 67 years 
(SEER 2010).  While approximately half of the incremental rise in incidence of DLBCL is 
attributable to identifiable factors, such as the increase in the incidence of human 
immunodeficiency virus (HIV)-related DLBCL, the evolution of more specific diagnostic 
techniques, and revisions in lymphoma classification schemes, much of the rising incidence 
remains unexplained (Holford 1992).  A very aggressive malignancy in its untreated natural 
history, DLBCL is a potentially curable disease, with a significant proportion of patients cured 
with modern chemoimmunotherapy.  Nonetheless, for those patients not cured by standard initial 
therapy, the prognosis remains generally poor (Gisselbrecht 2010) and DLBCL still accounts for 
the highest number of deaths per year of all the NHL histologies. 


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Treatment for relapsed and refractory DLBCL remains challenging.  Following initial therapy, 
the approach of re-induction chemotherapy followed by high-dose chemotherapy with 
HDT/ASCT for responding patients remains the current standard of care.  For patients that are 
not eligible for stem cell therapy, per NCCN guidelines, a variety of therapies are recommended 
for second line treatment.  These include DA-EPOCH +/- rituximab (Jermann 2004; 
Wilson 2008), CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) +/- rituximab 
(Chao 1990), CEOP (cyclophosphamide, etoposide, vincristine, prednisone) +/- rituximab 
(Bartlett 2001; Moccia 2009), GDP (gemcitabine, dexamethasone, cisplatin) +/- rituximab 
(Crump 2004), GemOx (gemcitabine, oxaliplatin) +/- rituximab (Lopez 2008; Corazzelli 2009; 
El Gnaoui 2007), Bendamustine +/- rituximab (Ohmachi 2013; Weidmann 2002; Rigacci 2012), 
Lenalidomide +/- rituximab (Wiernik 2008; Witzig 2011) and rituximab single-agent therapy 
(Robach 2002).  Despite a number of therapeutic options, the overall outcome remains poor, 
with a worse prognosis in non-GCB subjects including the ABC subtype.  Therefore new 
treatement regimens are needed.  
DA-EPOCH-R (a recommended therapy per NCCN guidelines) was chosen for this study to be 
used in combination with ibrutinib and lenalidomide.  The activity of DA-EPOCH in previously 
untreated subjects with DLBCL was demonstrated in a study with 50 DLBCL subjects 
(Wilson 2002).  A complete response (CR) was seen in 92% of patients (Wilson 2002).  
The median follow-up time was 62 months, and progression-free survival (PFS) was 70% and 
overall survival (OS) was 73% (Wilson 2002).  The use of DA-EPOCH in subjects with relapsed 
or refractory DLBCL and mantle-cell lymphoma (MCL) was demonstrated in another study with 
50 subjects (Jermann 2004).  The median number of prior chemotherapy regimens was 
1.7 (range one to four).  Twenty-five subjects had primary DLBCL, 18 had transformed DLBCL 
and 7 had MCL.  The overall response rate (ORR) was 68% (28% CR, 40% PR), median OS was 
17.9 months and the projected OS at 1, 2 and 3 years was 66, 42 and 35%, respectively.  Median 
PFS was 11.8 months; projected PFS at 1, 2 and 3 years was 50, 30 and 26%, respectively.   
The efficacy of EPOCH in subjects with relapsed and resistant lymphomas was further 
demonstrated in a study with 131 subjects (Gutierrez 2000).  This study included 86 patients 
(68%) with DLBCL.  One hundred and thirty-one patients were assessable for toxicity and 
125 patients were assessable for response.  Among 125 assessable patients, 93 (74%) achieved 
objective responses, including 30 (24%) complete and 63 (50%) partial responses.  Patients 
generally had a poor prognosis with high-intermediate or high International Prognostic Index 
(IPI) scores in 46%.  All patients were extensively pretreated having received a median (range) 
of 8 (1-17) different drugs and 1 (1-5) or 2 (1-7) regimens, respectively, if they had aggressive or 
indolent histologies.  Of the drugs present in the EPOCH regimen, 57% of patients had received 
all 5 and 88% had received at least 4 of the agents.  All but 4 (6%) patients had previously 
received doxorubicin.  To help assess if the infusional schedule increased efficacy, the response 
to EPOCH in patients who showed no response to their last combination regimen (ie. resistant 
disease) was analyzed.  In this group of 42 patients, 57% responded to EPOCH.  Among patients 
with chemotherapy-sensitive disease, 83% responded with 33% CRs (Gutierrez 2000).  EPOCH 
can also be administered to patients who have received prior anthracyclines because it has low 


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rates of cardiac toxicity due to the infusional schedule of doxorubicin (Gutierrez 2000).  
Adding rituximab to DA-EPOCH also showed promising clinical outcome in 72 patients with 
untreated de novo DLBCL (Wilson 2008).  Taken together, DA-EPOCH-R provides an excellent 
salvage regimen to assess targeted agents and can be administered to previously untreated as well 
as relapsed and refractory lymphoma patients.  
DLBCL gene expression profiling reveals 3 molecular subtypes: activated B cell-like (ABC), 
germinal center-like (GCB) and primary mediastinal (PMBL).  The ABC subtype accounts for 
~30% of cases of DLBCL and has an inferior prognosis.  Chronic active BCR signaling is a 
pathogenic mechanism in ABC DLBCL and this chronic activation engages the classic NF-κB 
pathway.  In contrast, GCB DLBCL pathogenesis is independent of the NF-κB pathway 
(Lenz 2010).  This difference in the molecular mechanism of pathogenesis may explain why the 
ABC subtype is less sensitive to chemotherapy and remains less curable than the GCB subtype.  
Thus, new strategies for the ABC subtype are needed.  Importantly, pre-clinical studies imply 
synergy when ibrutinib and lenalidomide are combined predominantly but not exclusively in 
lymphoma cell lines of the ABC subtype.   
Previous clinical studies with ibrutinib have shown benefit in the ABC subtype (de Vos 2013), 
as have trials with lenalidomide (Hernandez-Ilizaliturri 2011).  The clinical outcome of the 
combination of ibrutinib and lenalidomide in DLBCL currently remains unknown.  Since 
patients with DLBCL can be salvaged with DA-EPOCH-R, we hypothesize that the addition of 
ibrutinib and lenalidomide may further enhance response, and warrants testing in both GCB and 
non-GCB subtypes of DLBCL.   
1.3. 
Ibrutinib Background 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling 
pathways and thus prevents B-cell proliferation.  In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases.  
Ibrutinib (IMBRUVICA®) is approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of: 1) mantle cell lymphoma (MCL) in patients who have received at least one prior 
therapy based on overall response rate, 2) chronic lymphocytic leukemia (CLL) in patients who 
have received at least one prior therapy, and 3) CLL in patients with 17p deletion. Ibrutinib is 
currently under investigation in various indications. 
B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the BCR, which is activated by binding to antigen.  Antigen 
binding induces receptor aggregation and the clustering and activation of multiple tyrosine 
kinases, which in turn activate further downstream signaling pathways (Bishop 2003).  
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 


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mutations and translocations acquired during normal B-cell development (Shaffer 2002).  
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 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells (Satterthwaite 2000). 
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from 
the plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain 
maximal pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg.  
In Study PCYC-04753, the BTK occupancies in PBMCs 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.  In addition, because of an expected 
tissue-to-plasma concentration ratio of 50% in more distant compartments, such as 
blood-forming organs (bone marrow, spleen, and lymph node) and lymphoid tumor tissue 
(based on ratio data in the range of 0.44 to 0.67 observed in rats), it is reasonable to expect full 
BTK occupancy in these tissues at doses of 5 mg/kg and above. 
Ibrutinib has demonstrated single agent activity in the treatment of relapsed or refractory de novo 
DLBCL in Study PCYC-1106-CA.  Study PCYC-1106-CA is an ongoing Phase 2, open-label, 
nonrandomized, multicenter study in patients with relapsed or refractory de novo DLBCL 
receiving 560 mg/day of ibrutinib.  Data are currently available on 70 patients from this trial who 
have relapsed or refractory disease with 29 ABC subtype, 20 GCB subtype, 16 Type 3 subtype 
and 5 subjects subtype unknown.  The ORR in these 70 patients was 25% (17/70) with 9% of 
patients achieving a complete response (CR) and 16% of patients achieving a partial response 
(PR).  Of the patients with ABC subtype, the ORR was 41% (12/29) with 17% CR and 24% PR.  
Of the patients with GCB subtype the ORR was 5% (1/20) with the one responder achieving a 
PR.  The median OS was 9.76 months for those with ABC subtype and 3.35 months for those 
with GCB subtype (de Vos 2013). 
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib IB. 
1.4. 
Lenalidomide Background 
The immunomodulating drug lenalidomide (IMiD compound, CC-5013, Celgene) is a structural 
and functional analogue of thalidomide.  The second generation of IMiD compounds were 
designed to enhance immunologic and anti-cancer properties while potentially decreasing the 


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neurotoxic and teratogenic adverse effects of the parent compound thalidomide (Barlett 2004).  
These drugs have been extensively used and have shown clear benefit in other diseases, 
particularly multiple myeloma and myelodysplastic syndromes.  Lenalidomide has been reported 
to down-regulate key prosurvival cytokines such as tumor necrosis factor-α (TNF-α), 
interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) 
(Corral 1999).  Other immunomodulatory activities of IMiDs include inhibition of T-regulatory 
cell function (Galustian 2009) and potent T-cell co-stimulatory activity, leading to increased 
secretion of the T-cell lymphokines interferon (IFN)-γ, and IL-2.  This enhances Th1-type 
cellular immunity and natural killer (NK) T-cell cytotoxicity (Corral 1999, LeBlanc 2004, 
Chang 2006, Davies 2001).  IMiDs have also demonstrated direct antiproliferative effects by 
inhibiting the Akt pathway and increasing the expression of the p21 tumor suppressor protein, 
leading to G1 cell cycle arrest (Dredge 2005, Gandhi 2006), as well as its inhibition of 
angiogenesis (Lentzsch 2003).  As described above, lenalidomide has specific activity against 
ABC DLBCL that appears related to its effect on Type I interferon and the NF-kB pathway.  
A Phase 2 study (NCI study NHL-002) of 50 patients with relapsed or refractory aggressive 
NHL showed moderate single-agent activity with lenalidomide.  The study included patients 
with DLBCL, follicular lymphoma (FL), MCL, and transformed NHL.  Lenalidomide (25 mg/d) 
was administered on Days 1 to 21, every 28 days for 52 weeks as tolerated or until disease 
progression.  The ORR was 35% for all patients, 19% for DLBCL patients and 53% in MCL.  
Clinical responses were also observed in all lymphoma subtypes.  The main adverse event (AE) 
was hematologic, severe neutropenia being the most common reason for dose reduction.  
The results from this study suggest that lenalidomide has potentially important activity in 
aggressive lymphoma (Wiernik 2008).  Based on these results, an international Phase 2 trial 
(NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory 
aggressive NHL.  The preliminary results from the 39 MCL and 73 DLBCL patients enrolled in 
this study were recently reported.  The ORR in patients with MCL was 41%, with five patients 
(13%) achieving CR/CRu and eleven (28%) reaching PR.  The response rate was slightly lower 
in patients with DLBCL, with an ORR of 29%, with 3 patients (4%) achieving CR and 
18 patients (25%) achieving PR. Eleven patients (15%) had stable disease.  The drug was well 
tolerated with a manageable toxicity profile, similar to that observed in NHL-002.  
These preliminary results further validate the role of lenalidomide in the treatment of patients 
with relapsed or refractory DLBCL and MCL (Zinzani 2008, Czuczman 2008). 
A retrospective analysis was performed on 3 different studies evaluating the use of lenalidomide 
alone or in combination with rituximab or dexamethasone for the treatment of NHL.  The final 
reported analysis was on 40 patients that received lenalidomide monotherapy for treatment of 
DLBCL, with an ORR of 27.5%.  The outcomes were also reported based upon DLBCL subtype.  
Of the patients with ABC subtype (n=17), the ORR was 53% with 29.4% CR and 23.5% PR, and 
a median PFS of 6.2 months.  For those patients with the GCB subtype (n=23), the ORR was 9% 
with 1 CR and 1 PR and a median PFS of 1.7 months.  The OS for both groups was similar at 
14 months and 13.5 months respectively (Hernandez-Ilizaliturri 2011).  Another Phase 2 study 


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(N=45) evaluated the safety and efficacy of lenalidomide in combination with rituximab in 
relapsed or refractory NHL (Wang 2013).  For the included DLBCL patients (n=32), the ORR 
was 28% with a CR rate of 22% and a median PFS of 2.8 months and OS of 10.2 months.  
There were no significant differences in clinical responses by DLBCL subtype (Wang 2013).   
1.5. 
Combination of Ibrutinib and Lenalidomide in ABC Subtype of DLBCL 
The ABC subtype of DLBCL has constitutive NF-kB activation.  The NF-kB pathway is 
activated by chronic active BCR signaling and can be additionally activated by certain mutations. 
Combined use of functional and structural genomics has revealed the molecular basis for 
constitutive NF-kB activation in ABC DLBCL.  In response to BCR engagement by antigen, 
the signaling adapter CARD11 coordinates the activation of IkB kinase (IKK), the key regulatory 
kinase of the NF-kB pathway (Thome 2010).  CARD11 is more highly expressed in ABC 
DLBCL than in other lymphoma subtypes and is continuously required for NF-kB activity and 
viability of ABC DLBCL cell lines (Ngo 2006).  In approximately 10% of ABC DLBCLs, 
CARD11 acquires activating mutations in its coiled-coil domain, leading to spontaneous 
aggregation of the mutant isoform, thereby activating IKK and the NF-kB pathway (Lenz 2008).  
In other DLBCLs, upstream signaling from the BCR engages wild type CARD11 to activate the 
pathway, a phenomenon termed chronic active BCR signaling (Davis 2010).  More than 20% of 
ABC DLBCL tumors have mutations in the CD79A and CD79B subunits of the BCR that 
augment BCR signaling to NF-kB, establishing the pathogenetic importance of this pathway for 
ABC DLBCL (Davis 2010). 
MYD88 is the key signaling adapter in toll-like receptor signaling (Ngo 2011).  During innate 
immune responses to microorganisms, toll-like receptors bind to pathogen-associated molecular 
patterns, leading to the recruitment of a signaling complex composed of MYD88 and the kinases 
IRAK1 and IRAK4, ultimately engaging the NF-kB, MAP kinase and type I interferon pathways.  
In ABC DLBCL cell lines, knockdown of MYD88 is lethal due to inhibition of NF-kB and the 
loss of autocrine IL-6/IL-10 signaling through JAK kinase and STAT3 (Ngo 2011, Lam 2008).   
Based on the NF-kB signaling pathway, as exploratory analyses in ABC DLBCL, this study aims 
to analyze the mutations of CARD11, CD79A, CD79B, and MYD88 and perform correlations 
with clinical outcome.  By affecting different targets involving the B-cell receptor and the NF-kB 
activation pathway, ibrutinib and lenalidomide are expected to have a synergistic effect in 
chronically activated ABC subtype tumor cells.  
In summary, adding ibrutinib and lenalidomide to a regimen of DA-EPOCH-R is expected to 
improve the overall clinical outcome in subjects with relapsed and refractory DLBCL, especially 
in the ABC subtype.  Based upon the safety profile of ibrutinib monotherapy and the lack of 
significant myelosuppression, the combination of lenalidomide and ibrutinib may be well 
tolerated with the potential to exploit synergistic effects for improvement in outcomes in a frail 
population with minimal therapeutic options and a poor prognosis. 


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1.6. 
Summary of Relevant Nonclinical Data for Ibrutinib 
1.6.1. 
Nonclinical Pharmacology Studies 
Ibrutinib was designed as a selective covalent inhibitor of BTK (Pan 2007) and in vitro is a 
potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of ibrutinib to 
cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic activity 
and enhanced selectivity over other kinases that do not contain a cysteine at this position.  When 
added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011).  Ibrutinib arrested cell growth and induced 
apoptosis in human B-cell lymphoma cell lines in vitro and inhibited tumor growth in vivo in 
xenograft models (Herman 2011).  Ibrutinib also inhibited adhesion and migration of MCL cells 
in co-culture and reduced tumor burden in lymph node and bone marrow in a murine model of 
MCL dissemination and progression (Chang 2013a, Chang 2013b).  Therefore, ibrutinib may 
also disrupt key interactions with the tumor microenvironment. 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB. 
1.6.2. 
Toxicology Studies 
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system or respiratory system in rats at any dose tested.  Further, no treatment-related 
corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs.   
Based on data from the rat and dog including general toxicity studies up to 13 weeks duration, 
the greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and in the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).  Relative to a human 
dose of 560 mg/day and the no-observed-adverse-effect-level (NOAEL) in 13-week studies in 
animals, the maximum concentration (Cmax)-based safety margins were 3.7 to 8.4 for male and 
female rats, respectively and 0.9 to 2.7 for female and male dogs, respectively.  The area under 
the curve (AUC)-based safety margin ratios for the 560 mg/day human dose and the NOAEL in 
animals were 2.6 to 20.3 for male and female rats, respectively and 0.4 to 1.7 for female and 
male dogs, respectively.  
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study, ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity).  The NOAEL for effects on embryo/fetal development was 
10 mg/kg/day (human equivalent dose [HED] = 1.6 mg/kg/day).    


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For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the IB.  
1.7. 
Summary of Clinical Studies for Ibrutinib 
Ibrutinib is under late-stage development as an orally administered anticancer agent with lead 
indications in the relapsed/refractory setting and in treatment-naïve patients with B-cell 
malignancies as a single agent.  Combination studies with chemoimmunotherapy and 
immunotherapy have been initiated.  There are 20 ongoing and 4 completed company-sponsored 
clinical studies of ibrutinib.  Across all studies, malignancies under investigation include CLL, 
SLL, MCL, DLBCL, FL, MM, and Waldenstrom’s Macroglobulinemia (WM).  As of the data 
cutoff of 06 April 2013, safety data are available for 736 subjects treated with ibrutinib: 
506 subjects receiving ibrutinib monotherapy; 100 healthy subjects in the pharmacokinetic 
(PK)/clinical pharmacology studies; and 130 subjects receiving ibrutinib in combination with 
1 or more marketed chemo/immunotherapeutic agents.  In addition, approximately 537 subjects 
have been treated with ibrutinib or placebo in 5 randomized, controlled trials.  In Study PCYC-
1103-CA, a rollover extension study, 196 subjects continue to be treated with ibrutinib. 
1.7.1. 
Summary of Clinical Pharmacokinetics 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased with substantial intersubject variability.  The mean half-life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 10 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours.  Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
overnight fasting with median time to Tmax delayed from 2 to 4 hours.  Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with 
approximately 15 times lower inhibitory potency compared to ibrutinib.  The metabolite-to-
parent AUC ratio ranged from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was 
less than 2-fold of first dose exposure. 
Ibrutinib is minimally cleared renally.  The results of a human mass balance study of 
[14C]-ibrutinib conducted in six healthy male subjects demonstrated that less than 10% of the 
total dose of [14C]-ibrutinib is renally excreted, whereas approximately 80% is recovered in 
feces.  No specific clinical studies have been conducted in subjects with renal impairment.  
In Study PCYC-1102-CA, subjects with mild and moderate renal insufficiency (creatinine 
clearance >30 mL/min) were enrolled.  No dose adjustment is needed for subjects with mild or 
moderate renal impairment (greater than 30 mL/min creatinine clearance) in this study.  There is 
no data in patients with severe renal impairment or subjects on dialysis.  The study of ibrutinib in 
hepatic impaired subjects is currently in progress. 


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Ibrutinib is primarily metabolized by cytochrome P450 (CYP) 3A.  Concomitant use of ibrutinib 
and drugs that inhibit CYP3A can increase ibrutinib exposure.  Co-administration of 
ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects, increased dose normalized 
exposure (Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, respectively.  However, 
in 38 cancer subjects treated with mild and/or moderate CYP3A inhibitors, the ibrutinib exposure 
(AUC) was ≤2-fold the upper limit of the range of 76 patients not treated concomitantly with 
CYP3A inhibitors.  Clinical safety data in patients treated with weak, moderate or strong CYP3A 
inhibitors did not reveal meaningful increases in toxicities.   
Administration of ibrutinib with strong inducers of CYP3A can decrease ibrutinib plasma 
concentrations.  Physiologically based PK modeling and simulation indicates that rifampin, 
a strong inducer, can cause a 10-fold decrease in ibrutinib exposure. 
The risks associated with ibrutinib and the dihydrodiol metabolite PCI-45227 as potentially 
affecting the clearance of R-CHOP were assessed in subjects with CD20-Positive B-Cell NHL in 
Study PCI-32765DBL1002.  Vincristine pharmacokinetics were evaluated since CYP3A has 
been shown to be relevant for vincristine’s systemic clearance.  No indications for an effect of 
ibrutinib dosed at 560 mg on vincristine pharmacokinetics were apparent.  For the other CHOP 
compounds, which are not substrates of CYP3A, clinical drug-drug interaction with ibrutinib is 
much less likely to occur.  Regarding the effect of concomitant medication on ibrutinib 
pharmacokinetic behavior, preliminary pharmacokinetic data for ibrutinib and metabolite 
PCI-45227 from Study PCI-32765DBL1002 were compared with exposure data derived from 
PCYC-1104-CA, an ibrutinib monotherapy study in subjects with MCL.  Co-administration of 
R-CHOP and ibrutinib did not affect ibrutinib exposures in a clinically meaningful way.  
These data are relevant since several of the agents used in the CHOP regimen are similar to that 
of DA-EPOCH.   
1.7.2. 
Summary of Clinical Safety for Ibrutinib 
1.7.2.1. 
Monotherapy Studies 
Pooled safety data for subjects treated with ibrutinib monotherapy in 11 nonrandomized studies 
(PCYC -1102-CA, PCYC-1117-CA, PCYC-1112-CA [crossover only], PCYC-1104-CA, 
PCI-32765MCL2001, PCI-32765MCL4001, PCYC-1106-CA, PCYC-1111-CA, 
PCI-32765FLR2002, PCYC-04753, and PCI-32765-JPN-101) has been evaluated 
(ibrutinib Investigator’s Brochure [IB], version 8.0).  
The most frequently reported treatment-emergent adverse events (AEs) in more than 10% of 
subjects receiving ibrutinib as monotherapy in nonrandomized studies (N=1061) were diarrhea 
(35.9%), fatigue (28.6%), nausea (20.2%), cough (17.5%), and anemia (15.2%).  The most 
commonly reported Grade 3 or 4 AEs that were hematologic in nature were neutropenia (10.7%), 
thrombocytopenia (6.2%), and anemia (5.5%).  Pneumonia (5.7%), fatigue (2.9%), hypertension 
(2.7%), and atrial fibrillation (2.6%) were the most frequently reported nonhematologic Grade 3 
or 4 adverse events.   


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The incidence of treatment emergent SAEs reported was 41.3% (N=1061); pneumonia (7.0%), 
atrial fibrillation (2.8%), and febrile neutropenia (2.3%) were the most commonly reported 
treatment-emergent SAEs.  
In a randomized Phase 3 study in subjects with CLL/SLL (PCYC-1112-CA), the most frequently 
reported treatment-emergent adverse events in the ibrutinib arm were diarrhea (47.7%), fatigue 
(27.7%), nausea (26.2%), pyrexia (23.6%), anemia (22.6%), and neutropenia (21.5%).  Adverse 
events reported at a higher incidence (>10% difference) in the ibrutinib arm than in the 
ofatumumab arm included diarrhea (ibrutinib:  47.7%, ofatumumab:  17.8%), arthralgia (17.4%, 
6.8%), and petechiae (13.8%, 1.0%).  
The most commonly reported Grade 3 or 4 adverse events in more than 2% of ibrutinib treated 
subjects that were hematologic in nature were neutropenia (16.4%), thrombocytopenia (5.6%), 
and anemia (4.6%).  Pneumonia (6.7%) was the most frequently reported nonhematologic event. 
The most frequently reported SAEs in ibrutinib subjects were pneumonia (8.7%), atrial 
fibrillation (3.1%), pyrexia (3.1%), lung infection (2.6%), lower respiratory tract infection 
(2.1%) and urinary tract infection (2.1%). For more detailed information please refer to the 
current version of the IB. 
1.7.2.2. 
Combination Therapy Studies 
Pooled safety data for subjects (N=136) treated with ibrutinib as combination therapy in 
3 non-randomized studies (ibrutinib + BR or FCR (n=33); ibrutinib + ofatumumab (n=71), 
and ibrutinib + R-CHOP (n=32) are summarized below. The median duration of treatment was 
11.1 months (range: 0.0 to 19.5). 
The most frequently reported treatment-emergent adverse events reported in more than 10% 
of subjects were diarrhea (62.5%), nausea (45.6%), neutropenia (37.5%), fatigue (32.4%), 
peripheral sensory neuropathy (30.9%), upper respiratory tract infection (26.5%), vomiting 
(26.5%), anemia (21.3%), and thrombocytopenia (21.3%).  The most commonly reported 
Grade 3 or 4 adverse events were: neutropenia (36.0%), pneumonia (8.1%), febrile neutropenia 
(7.4%), thrombocytopenia (7.4%), diarrhea (5.1%), anemia (4.4%), cellulitis (4.4%) and urinary 
tract infection (4.4%).  
Treatment-emergent SAEs in subjects receiving ibrutinib as combination therapy (N=136) were 
reported in 39.0% of subjects.  The most frequently reported serious adverse events were 
pneumonia (8.8%), febrile neutropenia (7.4%), cellulitis (4.4%), and atrial fibrillation (2.9%).  
For more detailed information please refer to the current version of the IB. 


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1.7.3. 
Risks 
1.7.3.1. 
Bleeding-related Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and 
without thrombocytopenia.  These include primarily minor hemorrhagic events such as 
contusion, epistaxis and petechiae; and major hemorrhagic events including gastrointestinal 
bleeding, intracranial hemorrhage and hematuria.   
1.7.3.2. 
Cardiac 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly 
in subjects with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.  
In particular subjects with a history of cardiac arrhythmias should be monitored closely. 
1.7.3.3. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 
1.7.3.4. 
Diarrhea 
Approximately one-third of subjects treated with ibrutinib monotherapy and two-thirds treated with 
combination therapy reported diarrhea.  Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation.  These events are rarely severe, with only a small number of 
Grade 3 events, and no Grade 4 events reported to date. 
1.7.3.5. 
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.  Isolated cases of JC virus 
reactivation resulting in progressive multifocal leukoencephalopathy (PML) have been observed 
and resulted in death.  Two cases in relapsed CLL subjects have been reported.  One case 
occurred after multiple prior rituximab regimens and less than one year after the last dose of 
rituximab and high dose steroid administration.  The second case occurred during concomitant 
administration of rituximab, bendamustine and ibrutinib. 
1.7.3.6. 
Other Malignancies 
Other malignancies, most frequently skin cancers, have occurred in subjects treated with 
ibrutinib.  Across the MCL (PCYC-1104-CA) and CLL/SLL studies (PCYC-1112-CA and 
PCYC-1102-CA), skin cancers and non-skin cancers were reported in 5.0% (18/357) and 2.5% 
(9/357) of subjects who received ibrutinib, respectively. 


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1.7.3.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agend ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-112-CA), rash occurred 
at a higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to moderate 
in severity.  One case of Stevens-Johnson Syndrome (SJS), with a fatal outcome, was reported in 
a subject with CLL.  The subject received ibrutinib (420 mg/day) and was also receiving various 
antibiotics and antigout medication (allopurinol) known to be associated with SJS. 
1.7.3.8. 
Treatment-related Lymphocytosis 
Similar to other agents targeting BCR signaling, transient lymphocytosis is a pharmacodynamic 
effect of ibrutinib, in which the inhibition of BTK-mediated cellular homing and adhesion results 
in a mobilization of tumor cells to the peripheral blood (Stevenson 2011). 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts (ie, ≥50% 
increase from baseline and above absolute count 5000/µL), often associated with reduction of 
lymphadenopathy, has been observed in most subjects (75%) with relapsed/refractory CLL/SLL 
treated with ibrutinib.  This effect has also been observed in some subjects (33%) with 
relapsed/refractory MCL treated with ibrutinib.  This observed transient lymphocytosis is usually 
not associated with an AE and should not be considered progressive disease (PD) in the absence 
of other clinical findings.  In both disease types, lymphocytosis typically occurs during the first 
few weeks of ibrutinib therapy (median time 1.1 weeks) and resolves within a median of 
7.1 weeks in the MCL and 18.7 weeks in the CLL subjects. 
A substantial increase in the number of circulating lymphocytes (eg, >400,000/µL) has been 
observed in a subset of subjects.  There have been isolated cases of leukostasis reported in 
subjects treated with ibrutinib. 
1.7.3.9. 
R-CHOP with Ibrutinib 
Many of the chemotherapeutic agents used in the R-CHOP regimen are also used in 
DA-EPOCH-R.  Relevant to this, ibrutinib has been evaluated in a Phase 1b study combining 
ibrutinib with R-CHOP in patients with CD20-positive B-Cell NHL (Younes 2013).  Patients 
received an oral daily dose of ibrutinib (280, 420, or 560 mg) in combination with standard doses 
of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and vincristine on Day 1, and 
prednisone on Days 1 through 5 of each 21-day cycle for up to 6 cycles).  The primary objective 
was to determine the recommended Phase 2 dose of ibrutinib in combination with standard 
R-CHOP.  The secondary objectives were to assess safety, ORR, pharmacokinetics, 
and pharmacodynamic biomarkers. 
Seventeen patients (7, 4, and 6 receiving increasing ibrutinib doses) were enrolled: 59% male, 
median age 65 (Range 46–81) years, 47% DLBCL, 29% MCL and 24% FL.  In the 280 mg 
cohort, 2 patients had dose-limiting toxicity (DLT): 1 with transient syncope and 1 with 


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periorbital cellulitis; at 560 mg, 1 patient had gastritis (Grade 2).  The recommended Phase 2 
dose was established at 560 mg ibrutinib.   
The most common (≥ 20% of patients) AEs were neutropenia (77%), thrombocytopenia (65%), 
vomiting (59%), anemia (53%), nausea (47%), fatigue (35%), headache (29%), constipation 
(24%), diarrhea (24%), and dizziness (24%).  To date, 6 patients completed 6 cycles of 
treatment, and 2 patients discontinued treatment (1 due to noncompliance with the study drug 
and 1 due to non-DLT AE).  Preliminary efficacy assessments showed a favorable response 
(Younes 2013). 
Based on these studies, ibrutinib can be safely combined with systemic chemotherapy and a 
similar regimen to DA-EPOCH-R produced promising results in patients with newly diagnosed 
DLBCL. 
1.8. 
Summary of Clinical Safety for Lenalidomide in Lymphoma 
Lenalidomide is currently approved for the treatment of relapsed or refractory mantle cell 
lymphoma at a recommended starting dose of 25 mg orally once daily for 21 days every 28 days.  
The safety data for 134 patients receiving monotherapy for MCL has been evaluated.  The most 
common treatment-emergent adverse events (>15%) were neutropenia (49%), thrombocytopenia 
(36%), fatigue (34%), diarrhea (31%), anemia (31%), nausea (30%), cough (28%), pyrexia 
(23%), rash (22%), dyspnea (18%), pruritis (17%), constipation (16%), and peripheral edema 
(16%).  The most common Grade 3 or 4 adverse events were hematologic in nature: neutropenia 
(43%), thrombocytopenia (28%), and anemia (11%).  Pneumonia (9%) was the most frequent 
non-hematologic Grade 3/4 adverse event.   
The median duration of treatment in this patient population was 95 days (1–1002 days).  
Seventy-six patients (57%) required at least one dose interruption for an adverse event, 
while 51 patients (38%) had at least one dose reduction due to toxicity.  Twenty-six patients 
(19%) discontinued treatment due to adverse events. 
Lenalidomide has a black box warning for embryo-fetal toxicity, hematologic toxicity and 
venous thromboembolism. 
1.8.1. 
Venous Thromboembolism 
Venous thromboembolism including deep vein thromobis (DVT) and pulmonary embolism (PE) 
has been reported in patients during treatment for NHL generally, occurring at incidences from 
~7% up to 20% (Zhou 2010; Park 2012; Lyman 2013).  In lenalidomide clinical trials, DVT and 
PE were reported in 7 (2.6%) and 6 (2.2%) of 266 subjects with relapsed or refractory NHL 
receiving lenalidomide in clinical studies NHL-002 and NHL-003 (Wiernik 2008; Witzig 2011).  
Anti-thrombotic prophylaxis was not suggested in NHL-002 but was required for subjects 
considered to be at high risk of developing DVT in NHL-003.  In a study evaluating 
lenalidomide plus rituximab versus lenalidomide alone in relapsed follicular lymphoma subjects, 


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thrombosis was reported in 2 (4%) of the combination arm versus 7 (16%) in the single agent 
arm (Leonard 2012).  In an additional study evaluating lenalidomide plus rituximab in MCL 
patients 2 (5%) Grade 3 and 1 (5%) Grade 4 thromboembolic events were reported (Wang 2013). 
1.8.2. 
Second New Cancers 
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer.  In clinical studies of newly diagnosed multiple 
myeloma, a higher number of second cancers were reported in patients treated with induction 
therapy (treatment as first step to reducing number of cancer cells) and/or bone marrow 
transplant then lenalidomide for a long period of time compared to patients treated with 
induction therapy and/or bone marrow transplant then placebo (a capsule containing no 
lenalidomide).  Patients should make their doctors aware of their medical history and any 
concerns they may have regarding their own increased risk of other cancers.  
For more complete safety information, please refer to the prescribing information 
(REVLIMID™ Prescribing Information 2013).   
1.8.3. 
R-CHOP with Lenalidomide 
Lenalidomide has been evaluated in a Phase 1 study with R-CHOP (Nowakowski 2011).  
Patients with newly diagnosed, untreated DLBCL or Grade III FL were treated with standard 
doses of R-CHOP and escalating doses of lenalidomide.  Doses were tested at 15 mg, 20 mg, and 
25 mg on Days 1–10 and no DLT was found.  The ORR rate was 100% with a CR rate of 77%.  
Lenalidomide 25 mg was then used in a Phase 2 study with R-CHOP in newly diagnosed 
DLBCL or FL Grade III (Nowakowski 2012).  Ninety-two % (47 patients) of these patients had 
DLBCL and 60% (31 patients) had stage IV disease.  The most common toxicities were 
hematological toxicities with Grade 3 and 4 thrombocytopenia (20% for both groups) and 
Grade 3 and 4 neutropenia (18% and 71%, respectively).  Non-hematological toxicities in 
Grade 3 or higher were seen in 27% of patients and included febrile neutropenia (10%), 
nausea (4%), urinary tract infection (4%), vascular access complication (4%) and dehydration 
(4%).  One patient developed thrombosis and one patient died secondary to bowel perforation.  
The ORR was 98% and the CR rate was 83%, with PFS at 12 months being 73%.  
Based on these studies, lenalidomide can be safely combined with systemic chemotherapy and a 
similar regimen to DA-EPOCH-R produced promising results in patients with newly diagnosed 
DLBCL. 
1.9. 
Summary of Clinical Safety for DA-EPOCH-R Chemotherapy in Lymphoma 
A long-term follow-up study evaluated relapsed and refractory lymphoma patients, including 
86 patients (68%) with DLBCL (Gutierrez 2000).  The toxicity of EPOCH was evaluated over 
535 cycles in 131 patients (Gutierrez 2000).  A common pattern of toxicity consisted of a brief 
neutropenia, usually less than 4 days and occurring around day 10 to 14 of treatment, and 


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minimal gastrointestinal toxicity.  Thrombocytopenia below 50,000/µL occurred during 24% of 
cycles, and neutropenia occurred during 48% of cycles with hospitalization for neutropenia with 
fever during 18% of cycles.  There were 3 infection-related deaths.  Gastrointestinal toxicity was 
mild.  Neurological toxicity necessitating vincristine reduction occurred in 10% of cycles, 
despite prior vincristine exposure in most patients.  Cardiac toxicity, a major limitation of 
doxorubicin, was rarely seen despite unspecified maximum allowable doxorubicin exposure 
(in 3% of patients).  A modest and clinically insignificant decline in the median ejection fraction 
(EF) over multiple cycles of EPOCH was observed; a paired t-test (p2) analysis comparing 
Cycle 0-1 vs. Cycle 2-3, Cycle 4-5 and Cycle 6 revealed a difference of -2.58%, (0.13); 
-5.5%, (0.0038) and -6.32%, (0.020), respectively.  Although patients were heavily pretreated, 
the toxicity profile of EPOCH allowed delivery of 71%, 92%, 92% and 93% of planned 
cyclophosphamide, doxorubicin, vincristine and etoposide, respectively. 
1.10. Justification of Study Design and Dose Rationale  
This non-randomized, multicenter, open-label, study is designed to evaluate whether a 
combination of DA-EPOCH-R, ibrutinib and lenalidomide has clinical benefit in subjects with 
relapsed or refractory DLBCL.  In Part 1 of the study, the MTD of the combination of 
DA-EPOCH-R, ibrutinib and lenalidomide will be assessed in relapsed or refractory DLBCL.  
In part 2 of the study, the efficacy in the ABC subtype of DLBCL will be explored.  
DA-EPOCH-R is one of the recommended therapies per NCCN guidelines for relapsed or 
refractory DLBCL not eligible for stem cell therapy.  The treatment combination of ibrutinib and 
lenalidomide may prove to be beneficial in both the GCB and non-GCB subtypes. 
1.10.1. 
Dose Selection Rationale for DA-EPOCH-R 
The rationale for the current dose and schedule of each agent is based not only upon the 
approved dose for these treatments, but also based upon the safety data known regarding the use 
of these therapies for the treatment of NHL in the relapsed and refractory setting.   
The doses of DA-EPOCH-R are standard doses; doses will be adjusted per ANC as previously 
described (Wilson 2002).   
1.10.2. 
Dose Selection Rationale for Ibrutinib 
The proposed dose for ibrutinib is 560 mg PO once per day (4 x 140-mg capsules) administered 
from Day 1–7 in each cycle.  In the Phase 1 study PCYC-04753 in subjects with NHL, 
the 560 mg dose administered once daily appeared safe and favorable responses were observed.   
Study PCYC-04753 was a first-in-human, Phase 1, dose-escalating study of ibrutinib in 
66 subjects with recurrent B-cell lymphoma including NHL, CLL, FL, MCL, and WM. 
Five sequential cohorts of subjects received ibrutinib from 1.25 to 12.5 mg/kg/day for 28 days of 
a 35-day cycle and 2 additional cohorts received either a continuous ibrutinib dose of 
8.3 mg/kg/day or a 560-mg fixed dose. 


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Ibrutinib was well tolerated across a broad range of doses (1.25 through 12.5 mg/kg/day) 
both when given intermittently and continuously on a 35-day cycle.  The most common AEs 
(>20% of subjects) in this population were diarrhea, fatigue, cough, nausea, headache, and 
pyrexia.  AEs were generally mild to moderate (Grade 1 or 2) and readily managed or reversible. 
There was no apparent relationship between the incidences or severity of AEs and dose or 
schedule of ibrutinib.  In addition, the maximum tolerated dose of ibrutinib was not reached. 
Pharmacodynamic studies revealed complete BTK active-site occupancy in PBMCs at doses of 
2.5 mg/kg and above, including the 560 mg continuous dosing cohort.  The 560 mg dose was 
chosen for this study since it was found to be active in NHL not only in this Phase 1 trial, but 
also in several Phase 2 studies in patients with NHL.    
1.10.3. 
Dose Selection Rationale for Lenalidomide 
The established dose in monotherapy studies of lenalidomide is 25 mg administered orally once 
daily for 21 days on a 28-day cycle (Witzig 2009).  Escalating doses of lenalidomide used in this 
study are 0, 15, 20 and 25 mg.  Thus, the top dose of lenalidomide tested in combination with 
DA-EPOCH-R and ibrutinib in this study is the established dose of 25 mg. 
2. STUDY OBJECTIVES  
2.1. 
Primary Objectives  
2.1.1. 
Part 1 
• 
To determine the maximum tolerated dose (MTD) of the combination of ibrutinib, 
lenalidomide and dose-adjusted (DA)-EPOCH-R in relapsed or refractory DLBCL 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide in combination with 
DA-EPOCH-R in relapsed or refractory DLBCL 
2.1.2. 
Part 2 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R 
in relapsed or refractory ABC DLBCL subjects as assessed by overall response rate (ORR) 
2.2. 
Secondary Objectives 
2.2.1. 
Part 1 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R 
in relapsed or refractory DLBCL subjects as assessed by overall response rate (ORR) 


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2.2.2. 
Part 2 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R 
in relapsed or refractory ABC DLBCL as assessed by progression-free survival (PFS), 
duration of response (DOR) and overall survival (OS) 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide in combination with 
DA-EPOCH-R in subjects with ABC DLBCL 
2.3. 
Exploratory Objectives 
• 
To determine the pharmacokinetics (PK) of ibrutinib when dosed with lenalidomide in 
combination with DA-EPOCH-R 
• 
To evaluate biomarkers of sensitivity or resistance to ibrutinib and lenalidomide in 
combination with DA-EPOCH-R 
3. STUDY DESIGN 
3.1. 
Overview of Study Design: 
This is an open-label, non-randomized multicenter study conducted in 2 parts.  In Parts 1 and 2, 
treatment will be administered in 3-week cycles (21 days each).  In Part 1, a minimum of 4 and a 
maximum of 30 subjects with DLBCL will be enrolled into a standard 3+3 design to determine 
the MTD which will then be used in Part 2.  Approximately 26 subjects with relapsed or 
refractory de novo DLBCL non-GCB subtype will be enrolled in Part 2 and will receive 
ibrutinib at a fixed dose of 560 mg and lenalidomide at the established MTD together with 
DA-EPOCH-R.  If no MTD is identified, then subjects in Part 2 will be treated with the 
maximum administered doses (MAD), which is the treatment dose from Part 1 dose Level 4.   
3.2. 
Endpoints 
3.2.1. 
Part 1: 
3.2.1.1. 
Primary Endpoint: (for all subtypes of DLBCL) 
• 
MTD 
• 
Safety and tolerability of ibrutinib and lenalidomide in combination with DA-EPOCH-R in 
relapsed or refractory DLBCL   
3.2.1.2. 
Secondary Endpoint (for all subtypes of DLBCL) 
• 
ORR 


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3.2.2. 
Part 2: 
3.2.2.1. 
Primary Endpoint  
• 
ORR including CR (complete response) and PR (partial response) in ABC DLBCL 
3.2.2.2. 
Secondary Endpoints 
Efficacy: 
• 
Duration of response (DOR) in ABC DLBCL 
• 
Progression-free survival (PFS) in ABC DLBCL 
• 
Overall survival (OS) in ABC DLBCL 
Safety: 
• 
Frequency, severity, and relatedness of AEs  
• 
Frequency of AEs requiring discontinuation of study drug or dose reductions 
Pharmacokinetics: 
• 
Plasma pharmacokinetics of ibrutinib  
Exploratory Analyses: 
• 
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib  
• 
Frequency of tumor mutations (or other molecular markers) between pre- and post-treatment 
tissue that predict acquired resistance.  
• 
Change in secreted protein levels (ie, chemokines, cytokines) 
• 
Change in peripheral T/B/natural killer (NK) counts and immunophenotypical analysis 
3.3. 
Part 1 – Dose Escalation 
The dose-escalation part of the study, Part 1, will determine the MTD of the combination of 
ibrutinib, lenalidomide and DA-EPOCH-R in subjects with DLBCL.  Subjects will receive 
ibrutinib at a fixed dose of 560 mg (or 420 mg if there is toxicity associated with 560 mg) and 
lenalidomide at an escalating dose of 0, 15, 20 and 25 mg on Days 1–7 of each 21-day cycle.  
DA-EPOCH-R will be given at standard doses on Days 1-5 of each 21-day cycle.   
The dose escalation will follow a 3+3 design with 3 subjects in each cohort.  Cohort dose 
escalation will occur if the subject incidence of DLTs during the first 22 days of study treatment 
is <33%.  If one subject within the initial cohort of 3 subjects experiences a DLT, an additional 
3 subjects may be enrolled at the same dose level.  If the initial dose is safe and tolerable with no 
further DLTs, the next dose level examined will be dose Level 2.  Dose escalation will continue 


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to dose Level 4.  The MTD will be defined as the highest dose level with an observed incidence 
of DLTs in <33% of the subjects enrolled in the cohort.  If in dose Level 4 DLTs occur in <33% 
of subjects, then the MTD will not be identified and the dose Level 4 dose will be the maximum 
administered doses (MAD).   
In the event of toxicity associated with 560 mg of ibrutinib (DLTs during the first 22 days of 
study treatment is >33% in dose Level 1), 420 mg of ibrutinib (dose Level -1) may be used for 
the dose escalation cohorts if it is deemed safe in combination with DA-EPOCH-R.  In this case, 
a maximum of 30 subjects may be enrolled in Part 1 (up to 6 subjects at the -1 level and 
4 x 6 = 24 subjects at levels 1, 2, 3 and 4). 
At the MTD or MAD, at least 6 subjects will be treated at this level prior to start of Part 2 of the 
study. 
Figure 1: 
3+3 Dose Escalation Design 
 
 


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Table 1: 
Part 1 Dose Levels 
Part 1 
Dose Level 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
-1 
420 mg 
0 mg 
Standard doses 
1 
560 mg 
0 mg 
Standard doses 
2 
560 mg 
15 mg 
Standard doses 
3 
560 mg 
20 mg 
Standard doses 
4 
560 mg 
25 mg 
Standard doses 
 
Subjects will be monitored through all cycles of treatment for related toxicities.  Dose-limiting 
toxicities are defined in Section 5.5. 
3.4. 
Part 2 – Expansion 
The expansion part of the study, Part 2, will only enroll subjects with non-GCB DLBCL as 
identified by IHC.  The primary objective is to determine the ORR of ibrutinib and lenalidomide 
in combination with DA-EPOCH-R in subjects with ABC DLBCL as analyzed by gene 
expression profiling (GEP). 
The MTD determined in Part 1 will be the dose used for all subjects.  If no MTD is identified, 
then subjects in Part 2 will be treated with the MAD which is the treatment dose from dose 
Level 4.  Approximately 26 subjects will receive ibrutinib at a fixed dose of 560 mg (or 420 mg 
if there is toxicity associated with 560 mg, see dose escalation schema above) on Days 1–7 and 
lenalidomide at the established MTD on Days 1–7.  DA-EPOCH-R will be given on Days 1–5 of 
each 3-week (21-day) cycle at standard doses.  
Depending on the number of subjects enrolled at the MTD in Part 1 and depending on the 
number of subjects with the ABC subtype that will be identified, additional subjects may be 
enrolled (please see sample size calculation). 
Table 2: 
Part 2 Dose Levels 
Part 2 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
560 mg 
(or 420 mg if toxicity with 560 mg) 
TBD 
Standard doses 
3.5. 
All Subjects in Part 1 and Part 2 
Subjects in Part 1 and Part 2 will receive therapy until a maximum of six cycles or disease 
progression, whichever occurs first.  Subjects will be restaged after cycle 3 (Cycle 4 Day 1, 
-4 days [Cycle 3 Day 19 to Cycle 4 Day 1]) and after Cycle 6 (Cycle 6 Day 21 ±4 days) 
of treatment, and then every 3, 4, and 6 months (every 12, 16 and 26 weeks) during 
post-treatment years 1, 2, and 3 respectively. 


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In this study, immunohistochemisty (IHC) using Hans method (Hans 2004) will be used to assess 
subject eligibility with respect to subtype of DLBCL for Part 2.  GEP will be performed to 
confirm the ABC subtype for analysis purposes.  The limitations of IHC allow only a distinction 
between subjects as either non-GCB or GCB phenotype since within the non-GCB group one 
may include subjects with a true unclassified (intermediate) subtype.  With GEP, the subjects can 
be further categorized into the following subtypes: ABC, GCB, unclassified, and unknown due to 
tissue limitations.  Throughout the protocol, description of enrolled subjects as “non-GCB” is 
based on IHC testing used at screening.  The use of the term “ABC subtype” refers to subjects 
who have been subsequently profiled by GEP and then classified as the ABC subtype by GEP.  
Subjects with primary mediastinal B cell lymphoma (PMBL) are excluded in Part 2 as they can 
be erroneously identified by IHC as ABC DLBCL. 
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 28 days prior to first dose of study drug, during which the 
subject’s eligibility and baseline characteristics will be determined. 
The Treatment Phase will extend from enrollment until study drug discontinuation.  Subjects will 
receive treatment for up to 6 (21-day) cycles as long as the subject is deriving clinical benefit 
(complete remission [CR], partial remission [PR], or stable disease [SD]) or until the subject 
experiences any unacceptable toxicity, whichever occurs first.  Further information on dosing is 
provided in Section 5.  Regularly scheduled disease assessments are required throughout the 
Treatment Phase (Section 8.2). 
The Post-treatment Phase will extend from the discontinuation of treatment up until the subject 
has progressive disease or other criteria listed in Section 9.  Response evaluations will be 
continued every 3, 4 and 6 months during post-treatment years 1, 2 and 3 respectively.   
Response assessments will be completed by the investigator using the Revised Response Criteria 
for Malignant Lymphoma (Cheson 2007).   
The Investigator will evaluate sites of disease by radiological imaging (primary), physical 
examination or other procedures as necessary, review of hematology and serum chemistry 
results, and disease-related symptoms.  The same methods of assessment used to assess disease 
at baseline should be used throughout the study.  Local laboratories will perform all hematology 
and serum chemistry testing for the primary endpoint analysis.   
4. SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
Subjects will be considered for inclusion in this study if they meet all of the following criteria: 
1. Men and women ≥ 18 years of age 


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2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
3. Pathologically confirmed DLBCL: 
• Part 1:  all subtypes are eligible 
• Part 2:  only non-GCB subtype is eligible 
4. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a complete 
remission (CR), or 2) partial remission (PR), stable disease (SD), or progressive disease (PD) 
at completion of the treatment regimen preceding entry to the study (residual disease): 
a) Subjects must have previously received an appropriate first-line treatment regimen. 
b) For subjects in whom a post-treatment residual computed tomography (CT) scan 
abnormality exists, and a definitive distinction between residual DLBCL and a 
non-lymphomatous process (eg, fibrosis) is clinically indicated, those subjects must have 
biopsy confirmation of residual DLBCL prior to study entry.  
5. Subjects must have ≥ 1 measurable disease site on CT scan (≥ 1.5 cm in longest dimension).  
Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well 
visualized by CT may be measured by MRI instead. 
6. Subjects must have adequate fresh or paraffin tissue for confirmation of diagnosis and 
molecular evaluation.  Tissue may be from either the initial diagnosis or from relapsed or 
refractory disease. 
7. Meet the following laboratory parameters:  
c) Absolute neutrophil count (ANC) ≥1,000 cells/mm3 (1.0 x 109/L)  
d) Platelets ≥75,000 cells/mm3 (75 x 109/L)   
e) ALT and AST ≤2.5 x the upper limit of the normal range (ULN) unless lymphoma-
related 
f) Bilirubin ≤1.5 x ULN, except ≤2 mg/dL (total) in subjects with Gilbert’s syndrome 
(as defined by >80% unconjugated hyperbilirubinemia) 
g) Serum Creatinine ≤2.0 mg/dL or creatinine clearance ≥60 mL/min/1.73 m2 
h) Hemoglobin ≥8.0 g/dL  
i) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be  
≤1.5 x ULN; except if, in the opinion of the Investigator, the aPTT is elevated because of 
a positive Lupus Anticoagulant 
8. Left ventricular ejection fraction (LVEF) >45% as assessed by echocardiogram or multigated 
acquisition scan (MUGA) 
9. Able to provide written informed consent and can understand and comply with the 
requirements of the study 
10. All study participants must be registered into the mandatory Revlimid REMS™ program, 
and be willing and able to comply with the requirements of Revlimid REMS™. 


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11. Female subjects of childbearing potential (FCBP)1 must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10–14 days and again within 
24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 
7 days as required by Revlimid REMS) and must either commit to continued abstinence from 
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method AT THE SAME TIME, at least 
28 days before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  See Appendix F: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
12. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  See Appendix F: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods.   
13. Life expectancy of more than 3 months 
4.2. 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Transformed DLBCL or DLBCL with coexistent histologies (eg, follicular or 
mucosa-associated lymphoid tissue [MALT] lymphoma) for enrollment into Part 2 only 
2. Primary mediastinal (thymic) large B-cell lymphoma for enrollment into Part 2 only 
3. Known central nervous system lymphoma  
4. Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 
2 weeks prior to the first dose of study drug 
5. Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug 
6. Concurrent enrollment in another therapeutic investigational clinical study 
7. Previously taken ibrutinib or lenalidomide 
8. Major surgery within 4 weeks prior to the first dose of study drug 
9. Prior allogenetic stem cell (or other organ) transplant within 6 months or any evidence of 
active graft-versus-host disease or requirement for immunosuppressants within 28 days prior 
to first dose of study drug 
10. History of other malignancies, except: adequately treated non-melanoma skin cancer, 
curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of 
disease for ≥2 years 
11. Currently active, or clinically significant cardiovascular disease such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification (Appendix E), or history of myocardial 
infarction within 6 months prior to first dose with study drug 
 
1 A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 


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12. Significant screening electrocardiogram (ECG) abnormalities, including left bundle branch 
block, 2nd degree atrioventricular (AV) block Type II, 3rd degree block, or QTc ≥ 470 msec 
13. Recent infection requiring intravenous anti-infective treatment that was completed ≤ 14 days 
before the first dose of study drug  
14. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade 0 or 1, or to 
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia  
15. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia 
16. Known history of infection with human immunodeficiency virus (HIV) or chronic or active 
infection with Hepatitis C virus (HCV) or Hepatitis B virus (HBV).  Viral load by PCR must 
be confirmed negative in equivocal cases for subjects who are Hepatitis B core antibody 
positive, Hepatitis B surface antigen positive, Hepatitis B surface antibody positive (unless 
immunized) or Hepatitis C antibody positive. 
17. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk 
18. Unable to swallow capsules or disease significantly affecting gastrointestinal function and/or 
inhibiting small intestine absorption such as malabsorption syndrome, resection of the small 
bowel, or poorly controlled inflammatory bowel disease affecting the small intestine 
19. Received or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon) within 28 days of first dose of study drug 
20. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor 
21. Lactating or pregnant women 
5. TREATMENT OF SUBJECTS 
This is an open-label single-arm study conducted in 2 parts.  Subjects will not be blinded to the 
study treatment nor will they be randomized.  Enrolled subjects will receive open-labeled 
ibrutinib capsules in combination with lenalidomide and DA-EPOCH-R. 
All subjects will receive the following treatment regimen:  Ibrutinib and lenalidomide will be 
given on Days 1–7 and DA-EPOCH-R will be given on Days 1–5, repeating each cycle every 
3 weeks (=21 days) until disease progression or for a maximum of 6 cycles. 
Study follow-up will be for 1 year after the last subject received the first dose.  
5.1. 
Treatment Part 1 
Ibrutinib and lenalidomide (lenalidomide dose-escalated in cohorts, Table 3) and DA-EPOCH-R 
Day 1–7 of each cycle:  ibrutinib PO 
Day 1–7 of each cycle:  lenalidomide PO 


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Day 1–5 of each cycle:  DA-EPOCH-R  
Day 6 (with a +48 hour window) of each cycle:  Pegfilgrastim 
Table 3: 
Part 1 Dosing Levels 
Part 1 
Dose Level 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
-1 
420 mg 
0 mg 
Standard doses 
1 
560 mg 
0 mg 
Standard doses 
2 
560 mg 
15 mg 
Standard doses 
3 
560 mg 
20 mg 
Standard doses 
4 
560 mg 
25 mg 
Standard doses 
 
Part 1 Cycle 1 and predose Cycle 2 Day 1 (=22 days) is the DLT assessment window.  
Blood draws on Cycle 2 Day 1 on study Day 22 occur predose.  The DLT period ends after the 
blood draws on Cycle 2 Day 1, before Cycle 2 Day 1 treatment begins.  Laboratory samples 
drawn pre-dose Cycle 2 Day 1 need to be reviewed prior to dosing on Day 22.  
5.2. 
Treatment Part 2 
Ibrutinib and lenalidomide (lenalidomide dose as determined in Part 1) and DA-EPOCH-R 
Day 1–7 of each cycle:  ibrutinib PO 
Day 1–7 of each cycle:  lenalidomide PO 
Day 1–5 of each cycle:  DA-EPOCH-R 
Day 6 (with a +48 hour window) of each cycle:  Pegfilgrastim 
 
Table 4: 
Part 2 Dose Levels 
Part 2 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
560 mg 
(or 420 mg if there is toxicity 
associated with 560 mg) 
TBD 
Standard doses 
 


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5.3. 
Dosages Overview 
Table 5: 
Dosages 
Drugs 
Dosages & Administration/Schedule 
Ibrutinib 
560 mg/day taken by mouth Days 1–7 
Lenalidomide 
Dose escalated as described in Section 5.7.4 and taken by mouth Days 1–7 
Prednisone 
60 mg/m2 PO* BID Days 1–5 (first dose should be given 1–12 hours before 
starting rituximab) 
Rituximab 
375 mg/m2 day 1 (before etoposide+doxorubicin+vincristine infusion begins; see 
Section 5.8.5 for administration instructions) 
Etoposide 
50 mg/m2/day CIV Days 1–4 (96-hour infusion) 
Doxorubicin 
10 mg/m2/day CIV Days 1–4 (96-hour infusion) 
Vincristine 
0.4 mg/m2/day CIV Days 1–4 (96-hour infusion) 
Cyclophosphamide 
750 mg/m2 IV Day 5 over 30–60 mins 
Pegfilgrastim 
6 mg SC on Day 6 (with a +48 hour window) 
Cycle Length 
Repeat cycle every 21 days, CBCs are checked twice a week every cycle to 
identify ANC nadir  
BID =twice daily; CIV=continuous intravenous infusion; IV=intravenous infusion; PO = oral; SC=subcutaneous 
* For subjects who cannot tolerate prednisone PO, please contact the Hospital Pharmacist for guidance on dosing 
equivalents of other corticosteroid preparations. 
 
Dose adjustment for EPOCH-R:  Please see instructions in Section 5.13.  
5.4. 
Dose Escalation for Part 1 
The dose-escalation part of the study, Part 1, will determine the MTD of the combination of 
ibrutinib, lenalidomide and DA-EPOCH-R in subjects with DLBCL.  DA-EPOCH-R will be 
given at standard doses on Days 1–5 of each 21-day cycle.  The dose level of lenalidomide will 
be escalated.  Subjects will receive ibrutinib at a fixed dose of 560 mg PO on Days 1–7 and 
lenalidomide PO at an escalated dose of 0, 15, 20 and 25 mg for 7 days of each 21-day cycle.  
The dose escalation will follow a 3+3 design with 3 subjects in each cohort.   
• 
The first cohort of 3 subjects will begin at Part 1 dose Level 1; if 0 of 3 subjects experience 
a DLT within the first 22 days, then the next dose level cohort (Part 1 Level 2) with 3 new 
subjects will be enrolled.   
• 
If 1 of 3 subjects experiences a DLT, 3 additional subjects will be enrolled at the same dose 
level for a total of 6 subjects.   
• 
If no additional subjects experience a DLT at that dose level, meaning that no more than 1 of 
6 subjects at the same dose level experience a DLT, then the next dose level cohort will be 
enrolled with 3 new subjects.    


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• 
If >1 of the 6 subjects experiences DLT, then the MTD is one dose level below.   
• 
Part 1 cohort 1–4 dose levels are given in the table below.   
• 
Dose Level 4 defines the maximum administered dose (MAD) in this study. 
The MTD will be defined as the highest dose level with an observed incidence of DLTs in < 33% 
of the subjects enrolled in the cohort.  If in dose Level 4 DLTs occur in < 33% of the subjects, 
then the MTD will not be identified.  In this case, the MAD of 25 mg lenalidomide from dose 
Level 4 will be the lenalidomide dose used in Part 2. 
Table 6: 
Part 1 Dosing Levels 
Part 1 
Dose Level 
Ibrutinib 
Lenalidomide 
DA-EPOCH-R 
-1 
420 mg 
0 mg 
Standard doses 
1 
560 mg 
0 mg 
Standard doses 
2 
560 mg 
15 mg 
Standard doses 
3 
560 mg 
20 mg 
Standard doses 
4 
560 mg 
25 mg 
Standard doses 
 
If 2 or more DLTs are seen in dose Level 1, ibrutinib may be reduced to a dose of 420 mg 
(dose Level -1).  If the 420 mg dose of ibrutinib is the MTD that can be combined with 
DA-EPOCH-R, then dose escalation of lenalidomide will proceed with dose escalation Levels 2, 
3, and 4 as outlined above. 
In Part 1, during the first 21-day cycle, lenalidomide will NOT be reduced due to toxicity. 
Lenalidomide toxicity will be considered a Dose-Limiting Toxicity (DLT) during this period 
(see Section 5.5). 
After Cycle 1, EPOCH-R will be dose-adjusted as described below and as previously described 
(Wilson 2002). 
5.5. 
Dose-Limiting Toxicities for Part 1 
A DLT is defined as an Adverse Event (AE) that occurs within the first 22 days (Cycle 1, 
Cycle 2 Day 1 predose) of dosing that meets the DLT definition below, is clinically relevant, and 
is considered at least possibly related to study drug (ibrutinib and/or lenalidomide) in the opinion 
of the investigator. 
5.5.1. 
DLT Definition 
DLT assessments will only be conducted during the dose-escalation part during the first 22 days 
(Cycle 1, Cycle 2 Day 1 predose). 


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A DLT is defined as any Grade 3 or higher adverse event at least possibly related to study drug 
(ibrutinib and/or lenalidomide) and occurring during the DLT window with the following 
clarifications for the toxicities below:  
Non-Hematologic: 
• 
Grade 3 or 4 nausea, vomiting or diarrhea despite maximum medical supportive care and 
persisting ≥ 7 days 
• 
Grade 3 fatigue persisting ≥ 7 days  
• 
Grade 3 infection is not a DLT, however an infection with life-threatening consequences or 
requiring urgent intervention (grade 4) will be considered a DLT 
• 
Treatment delay of Cycle 2 ≥ 7 days for toxicity 
Hematologic: 
• 
Grade 4 neutropenia (ANC <500/mm3) lasting for ≥ 7 days  
• 
Grade 4 thrombocytopenia (<25,000/mm3) that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia associated with grade 2 or greater bleeding  
• 
Grade 3 anemia lasting for ≥ 7 days or Grade 4 anemia  
• 
Treatment delay of Cycle 2 ≥ 7 days for hematologic toxicity 
5.6. 
Ibrutinib 
5.6.1. 
Formulation, Packaging, and Storage of Ibrutinib 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  
All formulation excipients are compendial and are commonly used in oral formulations.  
Please refer to the ibrutinib IB for a list of excipients.  
Ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drug will be dispensed in child-resistant packaging.   
Please refer to the pharmacy manual for additional guidance on study drug preparation, 
handling and storage. 
5.6.2. 
Dosage and Administration of Ibrutinib 
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily on Days 1–7 with 
8 ounces (approximately 240 mL) of water.  Grapefruit or Seville orange juice should be avoided 
due to CYP3A inhibition.  The capsules should be swallowed intact and subjects should not 
attempt to open capsules or dissolve them in water.  Each dose of ibrutinib should be taken at 
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each day.  Ibrutinib and lenalidomide which are given PO can be administered together.  
On Day 1, ibrutinib and lenalidomide will be administered first and infusions will be started 
within 30 min of the PO doses. 
If a dose of ibrutinib is missed, it can be taken as soon as possible on the same day with a return 
to the normal schedule the following day.  No extra capsules to make up missed doses of 
ibrutinib should be taken. 
Ibrutinib will be dispensed to subjects in bottles.  All doses of ibrutinib taken in the clinic should 
be taken from the bottle dispensed to the subject.  Unused ibrutinib capsules dispensed during 
previous visits must be returned to the site and drug accountability records (Section 12.8) must 
be updated.  Returned capsules must not be re-dispensed to anyone.  Subjects should return all 
used bottles to the site when they receive new study drug.  For the purpose of drug 
accountability, empty bottles and returned capsules should be kept at the site until after the 
review of the site monitor if allowed by local institution policy. 
Investigators are prohibited from supplying ibrutinib capsules to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on Food and Drug Administration (FDA) Form 1572.  The investigator must 
ensure that subjects receive ibrutinib capsules only from personnel who fully understand the 
procedures for administering the drug. 
Treatment will continue for up to 6 cycles of treatment until disease progression or other reason 
for treatment discontinuation as outlined in Section 9.  
Dose modifications for toxicity are outlined in Section 5.6.3. 
5.6.3. 
Dose Reduction and Discontinuation 
Outside of the DLT window in Part 1 and in Part 2 of the study, the ibrutinib dose should be held 
for any unmanageable, potentially ibrutinib-related toxicity. 
Note:  During Part 1, ibrutinib may be reduced from 560 mg to a dose of 420 mg (dose Level -1).  
If this is the case, apply the table below using recommendations for 1 dose level lower than that 
used for 560 mg. 
Please see Section 11.2.3 for event of special interest reporting of major hemorrhage 
(Section 11.2.3.1) and intracranial hemorrhage (Section 11.2.3.2). 
The action in Table 7 should be taken for the following ibrutinib-related toxicities: 
• 
Grade 4 ANC (<500/µL) for more than 7 days.  The use of neutrophil growth factors is 
permitted per American Society of Clinical Oncology (ASCO) guidelines (Smith 2006) 
and must be recorded in the electronic case report form (eCRF). 


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• 
Grade 3 thrombocytopenia (<50,000/µL) for subjects with normal platelet count at baseline; 
or for subjects with baseline thrombocytopenia, a platelet decrease of 50% to 74% from 
baseline in the presence of >Grade 2 bleeding 
• 
Grade 4 thrombocytopenia (<25,000/µL) for subjects with normal platelet count at baseline; 
or for subjects with baseline thrombocytopenia, a platelet decrease of ≥75% from baseline or 
<20,000/µL, whichever is higher 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic and/or 
anti-diarrheal therapy 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 6.2.3.1). 
Table 7: 
Dose Modification for Ibrutinib Toxicity 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose level 
Second 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
(420 mg per day) 
Third 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
(280 mg per day) 
Fourth 
Discontinue ibrutinib 
 
An ibrutinib-related toxicity that results in a dose delay of greater than 1 week should result in a 
dose reduction as per the table above. 
At the investigator’s discretion, the dose of ibrutinib may be re-escalated after a dose reduction 
in the absence of a recurrence of the toxicity that led to the reduction. 
Please see Section 6.2.1 for guidelines for management of ibrutinib in subjects who require 
treatment with a strong CYP3A inhibitor.  
Dose modifications of ibrutinib must be recorded in the eCRF. 
5.6.4. 
Overdose Instructions 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any SAE criterion must be reported as 
an SAE in the appropriate time frame and documented as clinical sequelae to an overdose. 
There is no specific antidote for ibrutinib.  In the event of an overdose, subjects should be closely 
monitored and given appropriate supportive treatment. 


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5.6.5. 
Precautions and Adverse Events 
The most common AEs reported for subjects across studies with ibrutinib have included 
diarrhea, nausea, and fatigue.  Additional common AEs such as cough, muscle spasm, urinary 
tract infection, headache, vomiting, pyrexia, arthralgia, constipation, and rash have been reported 
in 15−25% of subjects.  The remaining more common AEs reported for 10−15% of subjects 
include peripheral edema, anemia, contusion, dyspepsia, insomnia, abdominal pain, dyspnea, 
myalgia, dizziness, pain in extremity, and thrombocytopenia.  In addition, Events of Special 
Interest are outlined in Section 11.2.3.  For complete information on precautions, please refer to 
the IB. 
5.7. 
Lenalidomide 
All subjects in both parts of this study will receive lenalidomide and will follow guidelines for 
lenalidomide dosing and toxicity management. 
5.7.1. 
Formulation, Packaging, and Storage of Lenalidomide   
Lenalidomide (Revlimid®) will be supplied as capsules for oral administration by Celgene 
Corporation.   
Lenalidomide will be shipped to the pharmacy at the study site in individual bottles or blister 
packs.  Bottles or blister packs will contain a sufficient number of capsules to last for 1 cycle of 
dosing.  Lenalidomide must be dispensed in the original packaging with the label clearly visible.  
Only lenalidomide for 1 cycle of therapy may be provided to the subject each cycle. 
The Investigator or designee is responsible for taking an inventory of each shipment of 
lenalidomide received on the drug accountability form.   
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
5.7.2. 
Lenalidomide Prescribing Information (applies to US sites only) 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this study at no charge to them or their insurance providers.  Lenalidomide will 
be provided in accordance with the Revlimid REMS™ program of Celgene Corporation.  
Per standard Revlimid REMS™ requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this study, and all research subjects enrolled into this study, 
must be registered in and must comply with all requirements of the Revlimid REMS™ program.  
Prescriptions must be filled within 7 days for females of childbearing potential and within 
14 days for all other risk categories.  Drug will be shipped on a per patient basis by the contract 
pharmacy to the clinic site for IND studies.  Only enough lenalidomide for one cycle of therapy 
will be supplied to the patient each cycle.  


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5.7.3. 
Pregnancy Testing while Taking Lenalidomide 
Please refer to Appendix F:  Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
5.7.4. 
Dosage, Preparation and Administration of Lenalidomide 
The first dose of lenalidomide will be administered PO on Cycle 1 Day 1 of the Treatment Phase, 
after which lenalidomide will be self-administered daily by the subjects on Days 1-7 of each 
cycle. 
Lenalidomide and ibrutinib which are given PO can be administered together.  On Day 1, 
ibrutinib and lenalidomide will be administered first and infusions will be started within 30 min 
of the PO doses. 
Lenalidomide should be administered with water.  The capsule should be swallowed intact and 
subjects should not attempt to chew capsules, open capsules or dissolve them in water.  
Results from human in vitro studies show that lenalidomide is neither metabolized by nor 
inhibits or induces the CYP450 pathway.  
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  
If a dose is missed for the entire day, it should not be made up. 
Lenalidomide dosing during the Treatment Phase occurs on Days 1–7 of each cycle.  If a Day 1 
(of any cycle) is delayed due to scheduling, instruct the subject that lenalidomide dosing should 
not be initiated until Day 1 assessments can occur. 
Treatment will continue for up to 6 cycles of treatment until disease progression or other reason 
for treatment discontinuation as outlined in Section 9.  
Dose modifications for toxicity are outlined in Section 5.7.5, Table 8, and Table 9. 
For instructions regarding drug accountability and disposal/return of unused lenalidomide please 
refer to the Pharmacy Manual. 
5.7.5. 
Dose Delay, Reduction or Discontinuation of Lenalidomide 
5.7.5.1. 
Part 1 Cycle 1 Lenalidomide Dose Modifications 
During the first cycle in Part 1 which is the DLT period, the lenalidomide dose will not be 
reduced. 


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5.7.5.2. 
Part 1 Cycles 2–6 and Part 2 Lenalidomide Dose Modifications 
A new course with 7-day lenalidomide treatment may begin on Day 1 of a new cycle if  
o ANC ≥ 1,000/µL and  
o Platelet count ≥ 50,000/µL and  
o No lenalidomide-related ≥ Grade 3 toxicity  
If the criteria are not met, per investigator’s discretion, assessments may be repeated.    
The initiation of lenalidomide should be delayed until subject meets criteria to receive drug as 
planned.  Once a 7-day cycle has initiated, if lenalidomide must be held for toxicity during 
dosing (Day 1–7), lenalidomide will not resume until Day 1 of the next cycle, provided the 
subject meets criteria above, with dose adjustments as per Table 8.   
If a lenalidomide-related toxicity occurs after dosing between Day 8 and 21, lenalidomide may 
resume at Day 1 of the next cycle, provided the subject meets criteria above.  No dose 
adjustment is required if the next cycle resumes on schedule or is delayed less than 1 week.  
If the next treatment cycle is delayed more than 1 week due to a lenalidomide-related toxicity, 
then dose adjustments should be undertaken as per Table 9. 
Dose adjustments are to be made according to the system showing the greatest toxicity.  
If a patient experiences several toxicities and there are conflicting recommendations, 
the recommended dose adjustment that reduces the dose to the lowest level will be used.  
The major toxic effects which limit dose are: vomiting, diarrhea, neuropathy, thrombocytopenia, 
neutropenia and anemia.  In the event a patient is diagnosed with a thyroid condition or 
experiences a drop in creatinine clearance to <60 mL/min please refer to Table 8 for further 
instructions.   


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Table 8: 
Dose Modification or Interruption for Lenalidomide Toxicity During 
Administration or for Delay in a Treatment Cycle of Greater Than 1 Week 
Toxicity 
Intervention 
Thrombocytopenia: 
• 
Grade 3 (decrease to <50,000/ µL) 
associated with ≥ Grade 2 
bleeding, OR 
• 
Grade 4 (decrease to <25,000/ µL) 
 
• 
Interrupt lenalidomide for remainder of cycle  
• 
Reduce lenalidomide by 1 dose level (5 mg) at Day 1 next cycle if 
patient meets cycle initiation criteria (see Section 5.7.5.2).   
• 
Minimum dose 5 mg daily 
Neutropenia: 
• 
ANC <1,000/µL for at least 7 days, 
OR 
• 
ANC <1,000/µL with an associated 
temperature ≥38.5°C, OR 
• 
ANC <500/µL 
 
• 
Interrupt lenalidomide for remainder of cycle 
• 
Reduce lenalidomide by 1 dose level (5 mg) at Day 1 next cycle if 
patient meets cycle initiation criteria (see Section 5.7.5.2).   
• 
Minimum dose 5 mg daily 
Rash: 
• 
Any Grade desquamating 
(blistering)  
• 
Grade 4 non-blistering 
 
• 
Discontinue lenalidomide 
 
Venous thromboembolism ≥ Grade 3 
• 
Interrupt lenalidomide for remainder of cycle 
• 
Initiate therapeutic anticoagulation as clinically indicated, please 
evaluate interactions with other study drugs 
• 
Resume lenalidomide without dose modification at Day 1of next 
cycle if benefit of therapy outweighs bleeding risk 
Hyperthyroidism or hypothyroidism 
• 
Interrupt lenalidomide treatment for remainder of cycle 
• 
Evaluate etiology & initiate appropriate therapy 
• 
Reduce lenalidomide by 1 dose level (5 mg) at Day 1 next cycle.  
Start new cycle when patient meets cycle initiation criteria 
(see Section 5.7.5.2).  
• 
Minimum dose 5 mg daily 
Creatinine Clearance <60 mL/min (CrCl, 
Cockcroft-Gault) 
• 
Interrupt lenalidomide for remainder of cycle 
• 
Reduce lenalidomide according to recommendations below based 
upon CrCl at Day 1 of next cycle if patient meets cycle initiation 
criteria (see Section 5.7.5.2).   
• 
Minimum dose 5 mg daily 
o 
CrCl 30–60 mL/min: 10 mg every 24 hours 
o 
CrCl <30 mL/min (not requiring dialysis):  15 mg every 
48 hours  
• 
If CrCl becomes >60mL/min for a minimum of 2 cycles one may 
re-escalate to the prior dose at investigator’s discretion 
Any other Grade 3/4 non-hematologic 
toxicities attributed to lenalidomide 
• 
Interrupt lenalidomide for remainder of cycle 
• 
Reduce lenalidomide by 1 dose level (5 mg) at Day 1of next cycle 
if patient meets cycle initiation criteria (see Section 5.7.5.2).   
• 
Minimum dose 5 mg daily 
 


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Table 9: 
Lenalidomide Dose Reduction 
Current Dose Level 
15 mg 
20 mg 
25 mg 
Dose Reduction 1 
10 mg 
15 mg 
20 mg 
Dose Reduction 2 
5 mg 
10 mg 
15 mg 
Dose Reduction 3 
Discontinue 
5 mg 
10 mg 
Dose Reduction 4 
NA 
Discontinue 
5 mg 
Dose Reduction 5 
NA 
NA 
Discontinue 
 
5.7.6. 
Safety Profile 
Please see prescribing information for lenalidomide/REVLIMID®. 
There are boxed warnings for lenalidomide, embryo-fetal toxicity (please see Appendix F), 
hematologic toxicity and venous thromboembolism.  Lenalidomide can cause significant 
neutropenia and thrombocytopenia; for venous thromboembolism please see background section 
(clinical safety).  
In addition, there are warnings regarding allergic reactions, tumor lysis syndrome, tumor flare 
reaction and second primary malignancies.   
Allergic reactions 
Hypersensitivity, angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis have 
been reported. 
Tumor lysis syndrome 
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. 
The subjects at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. 
These subjects should be monitored closely and appropriate precautions taken. 
Tumor flare reactions 
Serious tumor flare reactions have occurred during investigational use of lenalidomide for 
chronic lymphocytic leukemia and lymphoma. 
Adverse Events 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 


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Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
Second new cancers 
Please see Section 1.8.2 Summary of Clinical Safety.  
Complete and updated adverse events are available in the IB and the IND Safety Letters. 
5.8. 
Rituximab 
All subjects in both parts of this study will receive rituximab and will follow guidelines for 
rituximab dosing and toxicity management.  Please refer to the FDA approved package insert for 
complete product information. 
5.8.1. 
Supply 
Rituximab is available in either 100 mg/10 mL single-use vials or 500 mg/50 mL single-use 
vials.  The active ingredient is rituximab and the inactive ingredients are sodium chloride, 
sodium citrate dihydrate, polysorbate 80, and water for injection. 
5.8.2. 
Storage 
Rituximab vials are stable at 2°C to 8°C (36°F to 46°F) and should not be used beyond 
expiration date stamped on carton.  Rituximab vials should be protected from direct sunlight.  
Do not freeze or shake.   
For more information regarding stability and storage refer to the Pharmacy Manual. 
5.8.3. 
Preparation 
Rituximab will be diluted to a final volume of 0.9% Sodium Chloride or 5% Dextrose Injection 
to prepare a standard product with concentration of 2 mg/mL.  Caution should be taken during 
the preparation of the drug, as shaking can cause aggregation and precipitation of the antibody. 
5.8.4. 
Stability 
After dilution, rituximab is stable at 2ºC to 8ºC (36ºF to 46ºF) for 24 hours and at room 
temperature for an additional 24 hours. 


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5.8.5. 
Administration 
Per prescribing information: 
First Infusion:  The rituximab solution for infusion should be administered intravenously at an 
initial rate of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs. 
If hypersensitivity or infusion reactions do not occur, the infusion rate may be escalated in 
50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.  If a hypersensitivity 
(non-IgE-mediated) or an infusion reaction develops, the infusion should be temporarily slowed 
or interrupted.  The infusion can continue at one-half the previous rate upon improvement of 
subject symptoms. 
Subsequent Infusions:  If the subject tolerated the first infusion well, subsequent rituximab 
infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr 
increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.  If the subject did 
not tolerate the first infusion well, follow the guidelines for the first infusion. 
Some individual subjects may require close monitoring during the first and all subsequent 
infusions, eg subjects who have pre-existing cardiac or pulmonary conditions, prior clinically 
significant cardiopulmonary AEs or high numbers of circulating malignant cells (≥25,000/mm3) 
with or without evidence of high tumor burden. 
5.8.6. 
Safety Profile 
The information below is based on the information given in the package insert for rituximab. 
Please see the package insert for more information. 
Rituximab is contraindicated in patients with known anaphylaxis or IgE-mediated 
hypersensitivity to murine proteins or to any component of the drug product.  
In addition, there are boxed warnings for rituximab.  These include severe infusion reactions, 
tumor lysis syndrome and severe mucocutaneous reactions.  
Other severe reactions to rituximab include allergic reactions, cardiac arrhythmias, renal toxicity 
and progressive multifocal leukoencephalopathy (PML). 
The most common side effects of rituximab (in more than 30% of 356 subjects with B-cell 
lymphoma included in clinical studies) were fever and chills, infection and lymphopenia. 
Serious infections including reactivation of viral infections have been seen.  
Other side effects of rituximab (in more than 10% of 356 subjects with B-cell lymphoma included 
in clinical studies) were general weakness, headache, abdominal pain, general pain, back pain, 
low blood pressure, nausea diarrhea, vomiting, low white blood cells, low platelets, cough, runny 
nose, throat irritation, general swelling, joint pain, dizziness, night sweats, rash and itching. 


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5.9. 
Cyclophosphamide 
Refer to the FDA approved package insert for complete product information. 
5.9.1. 
Supply 
Commercially available in white crystalline formulation for intravenous injection, in vials 
containing 100 mg, 200 mg, 500 mg, 1 gm, and 2 gm.  
5.9.2. 
Storage and Preparation 
Intact vials are stable at room temperature (not to exceed 30oC).  Reconstitute with appropriate 
amounts of 0.9% NaCl to produce a final concentration of 20 mg/mL.  Discard solution after 
24 hours at room temperature.  Stable up to 6 days if refrigerated (2ºC to 8oC).  
5.9.3. 
Administration 
Cyclophosphamide will be diluted in 100 mL of D5W or 0.9% NaCl and infused over 
30 minutes or according to institutional standard.  Subjects will be instructed to drink an 
adequate amount of fluids and empty their bladders frequently during cyclophosphamide 
administration.  
5.9.4. 
Toxicities  
Myelosuppression, nausea and vomiting, hemorrhagic cystitis, and alopecia.  Cystitis can be 
largely prevented by maintaining a good state of hydration and good urine flow during and after 
drug administration using the following.  Please refer to the package insert for a complete listing 
of all toxicities.   
5.9.5. 
Hydration Guidelines 
All subjects should receive 0.9%NS at the following volumes (based on cyclophosphamide dose 
levels) and rates with half the specified volume given before starting cyclophosphamide 
administration and half the volume given after completion of the cyclophosphamide 
administration.   
Table 10: 
Hydration Guidelines for Cyclophosphamide  
Cyclophosphamide 
Dosage Levels (please refer to Table 13 with dosage levels 
for Doxorubicin, Etoposide and Cyclophosphamide) 
Fluid Volume and Administration Rate 
Levels 1 & 2 
1000 mL 0.9%NS @ 300–500 mL/h 
Levels 3, 4, & 5 
2000 mL 0.9%NS @ 300–500 mL/h 
Levels ≥6 
2500 mL 0.9%NS @ 300–500 mL/h 


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5.10. Vincristine/Doxorubicin/Etoposide 
Stability studies conducted by the Pharmaceutical Development Service, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP at concentrations, respectively, of 1, 25 and 
125 mcg/mL; 1.4, 35 and 175 mcg/mL; 2, 50 and 250 mcg/mL; and 2.8, 70 and 350 mcg/mL are 
stable for at least 36 hours at room temperature when protected from light.  Also admixtures 
containing vincristine, doxorubicin and etoposide concentrations of 1.6, 40 and 200 mcg/mL are 
stable for at least 30 hours at 32ºC.   
For this study, vincristine, doxorubicin, and etoposide comprising a daily dose (a 24-hour 
supply) will be diluted in 0.9%NS.  Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment.  Product volumes will be determined by 
the amount of etoposide present in a 24-hour supply of medication.  For daily etoposide doses 
≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS.  For daily etoposide 
doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS. 
Vincristine + doxorubicin + etoposide admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access device. 
5.10.1. 
Central Venous Access 
Central Venous Access is required for EPOCH administration.  Possible lines include:  
• 
Temporary internal jugular line (preferred);  
• 
PICC lines via the brachial vein;  
• 
semi-permanent HICKMAN; 
• 
GROSHONG catheters; or 
• 
medi-port implanted devices.   
All devices will have nursing supervision to include subject self-care and cleaning/flushing of 
the devices. 
5.10.2. 
Vincristine 
Refer to the FDA approved package insert for complete product information. 
5.10.2.1. Supply 
Commercially available in 1 mg, 2 mg, and 5 mg vial sizes.  Each ml contains 1 mg of 
vincristine, 100 mg mannitol, 1.3 mg methylparaben, and 0.2 mg propylparaben.  Drug should be 
stored at 2ºC to 8oC and should be protected from light.  


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5.10.2.2. Toxicities 
Peripheral neuropathy, autonomic neuropathy, and alopecia.  Local necrosis if injected 
subcutaneously.  Please refer to the package insert for a complete listing of all toxicities. 
5.10.3. 
Doxorubicin 
Refer to the FDA approved package insert for complete product information. 
5.10.3.1. Supply 
Commercially available in 10, 20, 50, 100, and 150 mg vials with 50, 100, 250, 500, and 750 mg, 
of lactose, respectively. 
5.10.3.2. Toxicities 
Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and chronic cardiac 
toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the latter uncommon at total 
cumulative doses less than 500 mg/m2.  The drug causes local necrosis if infiltrated into 
subcutaneous tissue.  Please refer to the package insert for a complete listing of all toxicities.   
5.10.4. 
Etoposide 
Refer to the FDA approved package insert for complete product information. 
5.10.4.1. Supply 
Commercially available as a concentrate for parenteral use in 100 mg vials; each ml contains 
20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of 
polyethylene glycol 300, and 30.5% alcohol.  
5.10.4.2. Toxicities 
Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if 
infusion is too rapid.  Please refer to the package insert for a complete listing of all toxicities. 
5.11. Prednisone 
Refer to the FDA approved package insert for complete product information. 
5.11.1. 
Supply 
Commercially available in a large number of oral dosage strengths including pills and liquid 
formulations.  Tablets should be stored in well-closed containers at temperatures between  
15–30oC.  


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5.11.2. 
Doses 
Prednisone utilization will be simplified by using only 20- and 50-mg tablets to produce individual 
doses and by stratifying prednisone doses by a subject’s body surface area (BSA), as follows: 
Table 11: 
Prednisone Doses per BSA 
BSA (m2) 
Each Dose 
1.25–1.49 
80 mg 
1.5–1.83 
100 mg 
1.84–2.16 
120 mg 
2.17–2.41 
140 mg 
2.42–2.6 
150 mg 
2.7–3 
170 mg 
5.11.3. 
Toxicities 
Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, 
Cushingoid facies, immunosuppression, and propensity to gastrointestinal ulceration.  
Please refer to the package insert for a complete listing of all toxicities.  
5.12. Pegfilgrastim (Neulasta) 
Refer to the FDA approved package insert for complete product information. 
5.12.1. 
Supply 
Commercially available in a prefilled single use syringe containing 6 mg pegfilgrastim, supplied 
with a 27-gauge, 1/2-inch needle with an UltraSafe® Needle Guard.  The needle cover of the 
prefilled syringe contains dry natural rubber (a derivative of latex).  Neulasta is provided in a 
dispensing pack containing one syringe (NDC 55513-190-01).  
Store refrigerated between 2°C to 8°C (36°F to 46°F) in the carton to protect from light.  Do not 
shake.  Discard syringes stored at room temperature for more than 48 hours.  Avoid freezing; 
if frozen, thaw in the refrigerator before administration.  Discard syringe if frozen more than 
once.  Pegfilgrastim will be given by subcutaneous injection; subject or other caregiver will be 
instructed on proper injection technique. 
5.12.2. 
Toxicities 
Rare anaphylactic reactions with the first dose; bone pain at sites of active marrow with 
continued administration.  Local reactions at injection sites.  Constitutional symptoms, increased 
alkaline phosphatase, LDH, uric acid; worsening of pre-existing inflammatory conditions. 
Splenic rupture and acute respiratory distress syndrome (ARDS) can occur in subjects receiving 
Neulasta, including fatal cases.  Please refer to the package insert for a complete listing of all 
toxicities. 


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5.13. Dose Adjustment for EPOCH-R 
5.13.1. 
EPOCH-R Dose Adjustment for Part 1 and Part 2 
• 
Dose adjustments for DA-EPOCH-R are based on twice weekly CBC obtained between 
cycles.  Nadir ANC and platelets are usually observed between Day 10–14 and Day 11–16, 
respectively.  
• 
Dose adjustments above starting dose level (Level 1) apply to etoposide, doxorubicin and 
cyclophosphamide. 
• 
Dose adjustments below starting dose level (Level 1) apply to cyclophosphamide only.   
• 
Drug doses based on previous cycle ANC nadir: 
 
Table 12: 
EPOCH-R Dose Adjustment 
• 
If Nadir ANC ≥ 500/µL on all measurements: 
↑ One dose level above last cycle 
• 
If Nadir ANC < 500/µL on 1 or 2 measurements: 
   Same dose level as last cycle 
• 
If Nadir ANC < 500/µL ≥ 3 measurements: 
↓ One dose level below last cycle 
Or 
 
• 
If nadir platelet < 25,000/µL on ≥ 1 measurement: 
↓ One dose level below last cycle 
 
• If ANC ≥1000/μL and platelets ≥75,000/μl on Day 22, begin treatment (even if ibrutinib 
and/or lenalidomide are withheld due to ibrutinib- or lenalidomide-related toxicity). 
• If ANC <1000/μL or platelets <75,000/μl on Day 22, delay up to 1 week. If EPOCH-R 
cannot be administered then ibrutinib and lenalidomide will also be delayed.  Filgrastim 
may be started for ANC <1000/μL and stopped 24 hours before treatment.  If counts still 
low after 1 week delay, ↓ 1 dose level below last cycle.  
• Important:  Measurement of ANC nadir based on twice weekly CBC only (3 days apart, 
e.g. on Monday & Thursday or Tuesday & Friday to assure that counts are checked every 
3 to 4 days).  Only use results from twice weekly CBCs for dose adjustment, even if 
additional (daily) CBC’s are obtained.  Note:  Not all the CBC blood draws for the dose 
adjustment are included in the schedule of assessments; please draw twice weekly for the 
dose adjustment of EPOCH and as clinically indicated. 
• The Investigator or his designee must be consulted on all dose adjustments. 
• Note:  The Investigator may use discretion in adjusting doses in subjects with 
compromised bone marrow function due to involvement by lymphoma.  Subjects with 
severe cytopenias due to compromised marrow function from lymphoma will have repeat 
bone marrow biopsies and will only be retreated if there is evidence of tumor response.  
This judgment may be made by the investigator in consultation with the local 
hematopathologists. 


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Table 13: 
Doses per Dose Levels for Doxorubicin, Etoposide and Cyclophosphamide 
Drugs 
Doxorubicin, Etoposide & Cyclophosphamide Doses per Dose Levels 
-2 
-1 
1 
2 
3 
4 
5 
6 
Doxorubicin (mg/m2/day) 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
Etoposide (mg/m2/day) 
50 
50 
50 
60 
72 
86.4 
103.7 
124.4 
Cyclophosphamide (mg/m2/day) 
480 
600 
750 
900 
1080 
1296 
1555 
1866 
5.13.2. 
Vincristine Dose Reduction for Ileus Toxicity 
Symptomatic ileus/constipation may occur.  Because the severity of constipation is dose related, 
it is usually unnecessary to stop the vincristine altogether.  Every effort should be made to not 
unnecessarily reduce vincristine doses.  Ileus/constipation is usually worse during the first cycle, 
so prophylactic bowel care is essential.  If vincristine dose is reduced for this toxicity, it can 
often be increased to full dose on subsequent cycles without recurrence of severe 
ileus/constipation.  The following guidelines for symptomatic ileus on a previous cycle should be 
followed. 
1. Clinical ileus <8 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting >2 days:  Reduce vincristine dose 25%. 
2. Clinical ileus 8–12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting >2 days:  Reduce vincristine dose 50%.  
3. Clinical ileus >12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting >2 days:  Hold vincristine on next cycle.  May restart at 50% reduction on 
subsequent cycle. 
5.13.3. 
Vincristine Dose Reduction for Neurological Toxicity 
Table 14: 
Sensory Neuropathy Grade and Vincristine Dose Reduction 
Grade  
% Dose of Vincristine 
2 
100 
3 
50 
4 
0 
 


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Table 15: 
Motor Neuropathy Grade and Vincristine Dose Reduction 
Grade  
% Dose of Vincristine 
1 
100 
2 
75 
3 
25 
4 
0 
5.13.4. 
Etoposide Dose Reduction for Renal Dysfunction 
Etoposide should be reduced 25% for creatinine clearance 15- 50 mL/min/1.73 m2.  
Etoposide should be returned to full dose (or escalated if indicated) once creatinine clearance 
> 50 mL/min/1.73 m2.  Data are not available in patients with creatinine clearance 
< 15 mL/min/1.73 m2.  Note:  Entry criteria for this study require creatinine clearance 
≥ 60 mL/min/1.73 m2 so this situation pertains to renal dysfunction on treatment. 
5.13.5. 
EPOCH-R Dose for Obese Subjects 
All dosing is based on the patient’s BSA as calculated from actual weight without capping.  
There is no clearly documented adverse impact of treatment of obese subjects when dosing is 
performed according to actual body weight. 
5.13.6. 
Pretreatment and Dose Modifications for Rituximab  
Pretreatment for rituximab with diphenhydramine and acetaminophen using standard medical 
practice may be used.  Side effects of rituximab may be infusion-rate related and may be reduced 
by slower administration or premedication.  At the investigator’s discretion, rituximab may be 
discontinued for the duration of the cycles in subjects with allergic reactions and may be 
administered on the following cycles using slower infusion rates. 
At the investigator’s discretion, the rituximab dose should be held for any unmanageable, 
potentially rituximab-related toxicity.  The dose of rituximab should be modified according to 
the dose modification guidelines in Table 16 if any Grade 4 or unmanageable Grade 3 
non-hematologic toxicity attributed to rituximab occurs. 
Table 16: 
Dose Modification for Rituximab Toxicity 
Occurrence 
Action to be Taken 
First, Second, Third 
Withhold rituximab until recovery to Grade ≤1 or baseline; 
may restart at original dose level 
Fourth 
Discontinue rituximab 
 


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5.14. Criteria for Permanent Treatment Discontinuation  
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk.  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 study drug administration. 
• 
Subject decides to withdraw from study. 
• 
Subject requires a prohibited concomitant medication. 
• 
Investigator decision (such as chronic noncompliance, significant protocol deviation, or best 
interest of the subject) 
• 
Study termination by Sponsor 
• 
Subject becomes pregnant. 
Subjects who withdraw for any reason other than those specified in Section 9 will not be 
replaced.  A Safety Follow-up visit (Section 8.3.1) is required for all subjects except for those 
subjects who have withdrawn full consent (see Section 9.3). 
6. CONCOMITANT MEDICATIONS/PROCEDURES  
6.1. 
Permitted Concomitant Medications 
Blood and platelet transfusions and supportive medications (such as for emesis, diarrhea, etc.) in 
accordance with standard practice are permitted.  
In Part 1, erythropoietic and hematopoietic growth factors (filgrastim and pegfilgrastim except 
for what is included in the EPOCH regimen) should only be given during the DLT period 
(ie, Cycle Day 1 through Cycle 2 Day 1 pre-dose [22 days total]) for Grade 3 or greater events, 
or if the patient fits the criteria for a DLT. During subsequent cycles in Part 1 and in Part 2, 
erythropoietic growth factors (eg, erythropoietin) and hematopoietic growth factors filgrastim 
and pegfilgrastim are allowed per institutional policy and in accordance with the ASCO 
guidelines (Smith 2006).   
Short courses of corticosteroids (< 14 days) for non-cancer-related medical reasons 
(eg, treatment for rash, arthritis, asthma) at doses that do not exceed 100 mg per day of 
prednisone or equivalent are permitted. 


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6.1.1. 
Prophylaxis of Pneumocystis Jirovecii (Previously Pneumocystis Carinii) 
Adult subjects will receive prophylaxis for Pneumocystis Jiroveci during EPOCH chemotherapy. 
Trimethoprim/sulfamethoxazole 1 DS PO QD on Monday, Wednesday, Friday is the preferred 
schedule.  
Subjects allergic to either component may receive inhaled pentamidine 300 mg once a month or 
other standard treatments. 
6.1.2. 
Prophylaxis for Tumor Lysis Syndrome (TLS) 
At the discretion of the principal investigator, subjects with high tumor burden may be treated 
with allopurinol 600 mg PO x 1 dose following by 300 mg PO daily for up to 7 days. 
Hospitalization with aggressive IV hydration and urinary alkalization may be used. 
6.1.3. 
Recommended Bowel Regimen  
The goal is to have at least 1 soft bowel motion every 24 hours while receiving treatment.  
Adult Subjects: Sodium Docusate 100 mg capsule; take 1 to 2 capsules once a day on Day 1–7 of 
each cycle.  If needed can double the frequency to 2 capsules every 12 hours.  If needed add oral 
lactulose 15–30 mL prn / q 6-hourly. 
6.2. 
Concomitant Medications to be Used with Caution 
For subjects taking digoxin, periodic monitoring of digoxin plasma levels is recommended due to 
increased Cmax and AUC with concomitant lenalidomide therapy (please see prescribing 
information). 
Subjects taking concomitant therapies such as erythropoietin stimulating agents or estrogen 
containing therapies, may have an increased risk of venous thromboembolism (please see 
prescribing information and lenalidomide background section). 
6.2.1. 
Concomitant Use of CYP3A Inhibitors/Inducers 
6.2.1.1. 
Ibrutinib 
Ibrutinib is metabolized primarily by CYP3A.  Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
Co-administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased 
dose normalized exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively.  
The maximal observed ibrutinib exposure (AUC) was ≤ 2-fold in 37 subjects treated with mild 
and/or moderate CYP3A inhibitors when compared with the ibrutinib exposure in 76 subjects not 
treated concomitantly with CYP3A inhibitors.  Clinical safety data in 66 subjects treated with 
moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in 
toxicities. Co-administration of strong CYP3A inhibitors (eg, ketoconazole, indinavir, nelfinavir, 


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ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, and nefazadone) should be 
avoided.  If a strong CYP3A inhibitor must be used, consider reducing the ibrutinib dose to 
140 mg or withhold treatment temporarily.  Subjects should be monitored for signs of ibrutinib 
toxicity.  
If the benefit outweighs the risk and a moderate CYP3A inhibitor must be used, monitor subject 
for toxicity and follow dose modification guidance as needed (Section 5.6.3).  Subjects should 
avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate 
inhibitors of CYP3A. 
Co-administration of ibrutinib with strong CYP3A inducers, rifampin, in healthy subjects 
decrease ibrutinib plasma concentrations by approximately 10-fold.  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 or inducers is provided in Appendix C; a comprehensive list 
of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  This website is continually revised and 
should be checked frequently for updates. 
6.2.1.2. 
Lenalidomide 
Results from human in vitro studies show that lenalidomide is neither metabolized by nor 
inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to 
cause or be subject to P450-based metabolic drug interactions (please see lenalidomide 
prescribing information). 
6.2.2. 
QT Prolongation 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered. 
6.2.3. 
Antiplatelet Agents and Anticoagulants 
6.2.3.1. 
Ibrutinib 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil and vitamin E preparations should be avoided.  Ibrutinib should be 
used with caution in subjects requiring other anticoagulants or medications that inhibit platelet 
function.  Subjects with congenital bleeding diathesis have not been studied.  For guidance on 
ibrutinib and the use of anticoagulants during procedures/surgeries see Section 6.4.   
For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and not be restarted until the subject 


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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 ibrutinib is restarted. 
6.3. 
Prohibited Concomitant Therapy 
Chemotherapy, anticancer immunotherapy, corticosteroids for cancer-related reasons (except for 
the corticosteroids included in the DA-EPOCH-R regimen), experimental therapy, or 
radiotherapy are prohibited while the subject is receiving ibrutinib.   
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   
• 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure and restarted at the discretion of the investigator when the surgical site is 
reasonably healed without serosanguinous drainage or the need for drainage tubes.   
• 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should 
not be restarted for at least 3 days after the procedure.  For bone marrow biopsies that are 
performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures.   
• 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site 
is reasonably healed, for at least 7 days after the urgent surgical procedure. 
7. STUDY EVALUATIONS 
The Schedule of Assessments is provided in Appendix A.  Descriptions of the scheduled 
evaluations are outlined below. 
Before study entry, throughout the study, and at the follow-up evaluations, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and efficacy assessments.  Clinical evaluations and 
laboratory assessments may be repeated more frequently if clinically indicated. 


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7.1. 
Description of Procedures 
7.1.1. 
Assessments 
7.1.1.1. 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC)-approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed.  Subjects must also grant permission to use protected health 
information per Health Insurance Portability and Accountability Act (HIPAA).  In addition, 
subjects must sign all approved ICF amendments per the site IRB/REC/IEC’s guidelines during 
the course of the study. 
7.1.1.2. 
Confirmation of Eligibility 
Perform all necessary procedures and evaluations to document that the subject meets each 
eligibility criterion (Section 4).  De-identified copies of the pathology report confirming 
diagnosis of DLBCL (tumor biopsy and bone marrow biopsy), a list of prior anticancer therapies 
and best responses, and the radiology report from screening CT scan (or MRI if indicated) and 
positron emission tomography (PET) will need to be submitted to the sponsor as part of the 
enrollment process.  In addition, DLBCL subtype should be provided (IHC testing at local 
laboratory) at the time of eligibility verification.   
To be eligible, all subjects must also have archival tissue for central IHC and GEP.  Formulin-
fixed paraffin embedded tissue (FFPE), a minimum of 10 slides, however 15–30 slides or a 
paraffin block is preferred, must be provided for central confirmation of DLBCL subtype (results 
not required for enrollment).  Tumor samples can be archival tissue from original diagnosis or 
from relapsed or refractory disease, or a fresh (recent) biopsy.  Refer to the laboratory manual for 
a more detailed description of the archival tissue preparation and handling.   
7.1.1.3. 
Medical History 
The subject’s complete history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis and list of 
all prior anti-cancer treatments, dates administered, and responses and duration of response to 
these treatments, also will be recorded. 
7.1.1.4. 
Prior and Concomitant Medications 
All medications from 14 days before the start of study drug administration through 30 days after 
the last dose of study drug will be documented. 


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7.1.1.5. 
Adverse Events 
All AEs whether serious or non-serious, will be documented in the source documents from the 
time signed and dated ICF is obtained until 30 days following the last dose of study drug. 
Only SAEs will be reported to the Sponsor prior to the first dose of study drug.  From the first 
dose of study drug, AEs/SAEs will be recorded in the eCRFs and will continue until 30 days 
after the last dose of study drug.  
Laboratory abnormalities which result in signs and symptoms, require intervention or follow-up 
and are considered clinically significant should be recorded as AEs.  AEs will be recorded at 
each visit or as reported during the treatment period. 
7.1.1.6. 
Physical Examination, and Height  
The physical examination will include, at a minimum, the general appearance of the subject, 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities and lymphatic 
system.  The musculoskeletal system and nervous system may be included in the examination if 
clinically indicated.  A complete physical examination will be performed at Screening, Response 
Assessment Visits, Day 1 of each Cycle and at the Safety Follow-Up Visit.  Symptom-directed 
physical examinations may be performed at all other visits.  Only physicians, physician assistant, or 
oncology nurse practitioners should perform the lymphatic system examination.  As much as 
possible, the same person should perform all the lymphatic examinations for a given subject. 
Height will be collected at Screening only. 
7.1.1.7. 
Venous Thromboembolism Risk Assessment 
The subject’s risk for development of venous thromboembolism (VTE) will be assessed.  General 
risk factors for subjects with cancer include, but are not limited to:  underlying disease, family 
history, age, obesity, immobilization, hormonal therapy, central venous catheter, recent DVT, gender, 
renal dysfunction and certain chemotherapy based regimens.  It is not known whether prophylactic 
anticoagulation or anti-platelet therapy prescribed in conjunction with lenalidomide may lessen the 
potential for venous thromboembolism.  It is up to the discretion of the Investigator after 
consideration of the subject’s individual risk/benefit profile whether to institute VTE prophylaxis 
using a permitted concomitant medication (see Section 6.2.3).  It is recommended that protocol 
appropriate VTE prophylaxis be used in subject’s considered at high-risk for thrombosis.  
This assessment must be performed at the Screening Visit and may be performed anytime thereafter 
as appropriate.  Refer to Table 8 for dose modification in the event a VTE occurs while on treatment. 
7.1.1.8. 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be assessed 
after the subject has rested in the sitting position for approximately 3 minutes.   
Weight will also be collected. 


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7.1.1.9. 
ECOG Performance Status 
The ECOG performance index is provided in Appendix B. 
7.1.1.10. Electrocardiogram (ECG) 
Subjects should be in supine position and resting for at least 10 minutes before study-related 
ECGs.  During visits in which both ECGs and blood draws are performed, ECGs should be 
performed first. 
12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTc average of the 
3 ECGs must be <470 msec for eligibility.  
Abnormalities noted at Screening should be included in the medical history.  
Unscheduled ECGs should be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea. 
7.1.1.11. Echocardiogram or MUGA 
An echocardiogram (ECHO) or MUGA will be performed at Screening on all subjects to assess 
cardiac function and measure ejection fraction.  Abnormalities noted at screening should be 
included in the medical history, as appropriate.   
Additional ECHO or MUGA examinations may be performed at any time during the study, 
as determined by the investigator. 
7.1.1.12. Bone Marrow Aspirate and Biopsy 
For Eligibility 
A unilateral bone marrow aspirate and biopsy must be obtained at Screening or up to 28 days 
prior to the first administration of study drug.  Subjects who have a bone marrow aspirate and 
biopsy result since completion of their last therapy for DLBCL may use those bone marrow 
results, provided the biopsy/aspirate was done <28 days prior to first dose of study drug. 
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the investigator’s form FDA 1572.  De-identified copies of all bone marrow biopsy/aspirate 
results must be provided to the Sponsor. 
For Response Confirmation 
If the subject’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved in all response parameters, and the screening 
bone marrow evaluation was positive for lymphoma, a repeat bone marrow aspirate and biopsy 
must be obtained to confirm the CR and to evaluate minimal residual disease (MRD).  In cases 


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where cytopenic progression is suspected, a bone marrow aspirate or biopsy should be performed 
to distinguish autoimmune and drug-related cytopenias. 
7.1.1.13. Optional Tumor Biopsy 
Patients with accessible tumor tissue who agree to have an optional biopsy performed will be 
biopsied prior to treatment.  Patients who have a partial or complete response and later develop 
recurrent disease will be encouraged to have an additional biopsy at the time of recurrence.  
Molecular characterization of this sample may identify altered signaling patterns or mutations 
that associate with response or resistance to ibrutinib treatment.   
For a subject who consents to participate in the optional tumor tissue sample assessment, fresh, 
frozen and/or formalin-fixed, paraffin-embedded (FFPE) tissue will be collected at least 3 days 
prior to the start of ibrutinib/lenalidomide for pre-treatment biopsies, and within 30 (±7) days 
after the last dose of ibrutinib or prior to the start of a new anti-cancer treatment for post 
treatment biopsies.  Please refer to the laboratory binder for additional instructions on collecting 
and processing this sample. 
Material from the biopsy may be used for exploratory analysis including gene expression 
profiling, sequencing to look for mutations in BTK, related kinases or other critical genes.   
7.1.2. 
Laboratory 
7.1.2.1. 
Hematology 
During scheduled visits, hematology parameters will include a complete blood count: white 
blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, bands (if reported), and atypical lymphocytes (if reported).   
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the investigator’s form FDA 1572. 
During Cycles 1-6, standard of care, hematology blood draws for dose adjustments to EPOCH 
regimen should include at a minimum, white blood cells, neutrophils, bands if present, and 
platelets, and should be checked twice weekly on days 4 or 5, 11 or 12, 15 and 18 or 19 (e.g. on 
Monday (Day 1) & Thursday or Friday (Day 4 or 5), or Tuesday (Day 1) & Friday or Saturday 
(Day 4 or 5) to assure that counts are checked every 3 to 4 days). 
7.1.2.2. 
Serum Chemisty 
Chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 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. 


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7.1.2.3. 
Hepatitis Serologies 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
surface antibody, and Hepatitis B core antibody.  Viral load by PCR must be confirmed negative 
in equivocal cases for subjects who are Hepatitis B core antibody positive, Hepatitis B surface 
antigen positive, Hepatitis B surface antibody positive (unless immunized) or Hepatitis C 
antibody positive.   
7.1.2.4. 
Pregnancy Test 
A pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be done in accordance 
with Celgene Revlimid REMS™ guidelines for females of childbearing potential (FCBP) only.  
If the pregnancy test is positive at Screening, the subject is not eligible.   
A FCBP is a sexually mature female who:  1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).   
Pregnancy tests must occur within 10–14 days and again within 24 hours prior to prescribing 
Cycle 1 of lenalidomide.  A FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including 
breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of 
lenalidomide.  A FCBP with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), 
at discontinuation of lenalidomide and at Day 14 and Day 28 following lenalidomide 
discontinuation.  
In order to allow for drug delivery in the US, pregnancy testing can be performed on Days 15–21 
of each cycle.  A pregnancy test may be performed more frequently if required by local and 
national requirements. 
7.1.2.5. 
Coagulation Studies 
Coagulation includes PT, PTT and INR.  Testing will be performed at the study center’s local 
laboratory or other clinical laboratory listed on the investigator’s form FDA 1572. 
7.1.2.6. 
T/B/NK Cell Count 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
taken predosePercentages and absolute counts of CD3+, CD4+, CD8+, CD19+, and CD16/56+ 
cells will be collected.  Testing will be performed at the central laboratory. 


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7.1.2.7. 
Blood Samples for Biomarkers 
Samples collected may be used for pharmacodynamic and biomarker assessments including 
BTK and other kinase activity and signaling, determination of BTK active-site occupancy, 
gene expression profiling (GEP), sequencing, circulating tumor DNA, flow cytometry and 
secreted protein analyses.  Cytokines, chemokines and exploratory investigations of predictive 
biomarkers and mechanisms of resistance may also be performed.  Testing will be performed at 
the central laboratory or by the sponsor. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the CRF or laboratory requisition form.  Please refer to the Schedule of 
Assessments (Appendix A) for the timing and frequency of all sample collections. 
Instructions for the collection, handling and shipment of samples are found in the laboratory 
manual that will be provided for sample collection and handling.  
7.1.2.8. 
Pharmacokinetics (PK) Sample Collection 
PK samples will be collected in all patients in Part 2.  Please refer to Table 17 for the 
pharmacokinetic sample schedule.   
Table 17: 
PK Sample Collection Schedule 
Cycle 
Day 
Predose 
Time After Dosing* 
1 h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
6 h ± 30 min 
1 
5 
x 
x 
x 
x 
x 
*  Time after dosing of ibrutinib 
 
On the day of the sampling visit, the subject will not take lenalidomide or ibrutinib dose before 
arrival at the clinic.  Study drug intake will be observed by clinic staff.  The time of the PK 
sample and the time of the study drug dose will be recorded in the CRF. 
7.1.2.9. 
Urinalysis 
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. 
7.1.3. 
Radiological Examinations 
Pretreatment tumor assessment will be performed within 21 days before the first dose of study 
drug.  Lesions that have been irradiated cannot be included in the tumor assessment unless 
unequivocal tumor progression has been documented in these lesions after radiation therapy.  


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A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any 
other disease sites (eg, extremity) and a positron emission tomography (PET) scan are required 
for the pretreatment tumor assessment.  Information on extranodal involvement (eg, gastric or 
ocular disease) will also be obtained.  Lesions in anatomical locations that are not well visualized 
by CT may be measured at baseline by MRI instead and should continue to be measured by MRI 
until disease progression.   
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the chest and neck without contrast.  In this case, neck nodes 
cannot be used as target lesions. 
There must be radiographically measurable disease at Screening (at least one lymph node 
≥ 1.5 cm in the longest diameter).  Up to 6 measurable lymph nodes (target lesions ≥1.5 cm in 
the longest diameter), clearly measurable in 2 perpendicular dimensions, will be followed as 
target lesions for each subject.  Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease.  In addition, selection of target lesions should be from as 
disparate regions of the body as possible when these areas are significantly involved.  
If additional lesions are present but are not included in the target lesion assessment, they can be 
added as non-target lesions and followed throughout the study. 
NOTE:  PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
parameters, and includes the use of intravenous (IV) contrast.    
If using a hybrid machine to acquire both PET and CT, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results.  
If independent CT and PET scanners are used, and the subject is receiving both scans on the 
same day, the PET must be performed prior to the CT with IV contrast. 
7.1.4. 
Overall Response Assessments 
Overall response assessments will include evaluation of physical examinations, recording of 
symptoms, hematological evaluations, and radiographic evaluations as per the schedule of 
assessments (see Appendix A).  Subjects will be restaged after Cycle 3 (Cycle 4 Day 1, -4 days 
[Cycle 3 Day 19 to Cycle 4 Day 1]) and after Cycle 6 (Cycle 6 Day 21 ± 4 days) of treatment, 
then every 3, 4, and 6 months during post-treatment years 1, 2 and 3 respectively.  Response 
assessments will be performed according to the revised International Working Group Response 
Criteria for NHL (Cheson 2007), as assessed by investigators (see Appendix D).   
7.1.5. 
Survival 
After progression, survival status will be assessed approximately every 12 weeks until death, 
withdrawal by subject, lost to follow-up, or study terminated by Sponsor, whichever comes first.  


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At the time of the interim analysis and at study closure, a survival sweep will be conducted.  
All subjects who are on study and not known to have died prior to the survival sweep will be 
contacted at that time. 
8. STUDY PROCEDURES 
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase.  
The Schedule of Assessments Table (Appendix A) summarizes the frequency and timing of 
efficacy, PK, biomarker, and safety measurements applicable to this study.  The PK assessments 
are detailed in the PK Sample Collection Schedule (Table 17). 
8.1. 
Screening Phase 
Screening procedures will be performed up to 28 days before Cycle 1, Day 1, unless otherwise 
specified.  All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF 
before any study-specific screening procedures are performed.  After signing the ICF, screening, 
and being deemed eligible for entry, subjects will be enrolled in the study.  
Screening Procedures 
• 
Informed consent 
• 
Review of eligibility criteria 
• 
Tumor sample for eligibility 
• 
Medical history  
• 
Adverse events 
• 
Prior and concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins and herbs)  
• 
Complete physical examination 
• 
Venous Thromboembolism Risk Assessment 
• 
Vital signs  
• 
ECOG performance status 
• 
12-lead ECG (in triplicate) 
• 
Echocardiogram 
• 
Bone marrow biopsy and aspirate (within 28 days of randomization) 
• 
Laboratory Tests 
o Hematology  
o Serum chemistry 
o Hepatitis Serologies 


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o Pregnancy test (for women of childbearing potential only) 
o Coagulation parameters 
o Urinalysis 
• 
Radiologic examination by CT/PET  
• 
Optional Tumor Biopsy:  Where possible, tumor biopsies will be obtained by core needle 
biopsy or surgery at least 3 days prior to first dose of ibrutinib and lenalidomide.   
8.2. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed by PCYC, 
subjects must begin the Treatment Phase of the study within 7 days of enrollment.  If laboratory 
tests are required to be collected pre-dose of Day 1 of Cycle 1, subject must continue to meet all 
eligibility criteria to begin treatment.  After Cycle 1, pre-dose assessments may be performed up 
to 2 days prior to Day 1 of a cycle expect where otherwise noted. 
In the Treatment Phase, subjects will receive therapy until disease progression or a maximum of 
six cycles of 21 days each whichever occurs first.    
Study drug treatment should be continued until disease progression, unacceptable 
treatment-related toxicity, or other reasons outlined in Section 9.2.  Local laboratory results will 
be used to guide all dosing-related decisions.  Hematology results during the first cycle to assess 
dose adjustments for EPOCH-R will be performed as previously described (Wilson 2008). 
Refer to the Schedule of Assessments (Appendix A) for a complete list of procedures to be 
performed at each scheduled study visit. 
8.2.1. 
Cycle 1 
8.2.1.1. 
Cycle 1 Day 1 
Pre-Dose 
The following procedures will be performed prior to dosing Cycle 1, Day 1 visit unless otherwise 
noted.  Screening tests may be used at baseline if done within 28 days of Cycle 1 Day 1 where 
indicated.  
• 
Confirmation of eligibility 
• 
Update medical history 
• 
Adverse events 
• 
Prior and concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins and herbs) 
• 
Complete physical examination 


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• 
Vital signs 
• 
ECOG performance status 
• 
Laboratory Tests 
o Hematology 
o Serum chemistry 
o Pregnancy test (for women of childbearing potential only) 
o T/B/NK cell count 
o Biomarker blood sample 
Dosing and Post-Dose 
• 
Administration of ibrutinib, lenalidomide, rituximab and EPOCH 
• 
Dispense ibrutinib and lenalidomide 
• 
Review of AEs 
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs) 
8.2.1.2. 
Cycle 1 Day 2–6 
Pre-dose 
• 
Review of AEs (Days 2–5) 
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs)  
• 
Vital Signs (Days 2–5) 
Dosing and Post Dose 
• 
Administration of ibrutinib and lenalidomide  
• 
Administration of EPOCH (Days 2–4), Cyclophosphamide (Day 5) and Pegfilgrastim 
(Day 6 with a +48 hour window) as standard of care (Table 5) 
• 
Review of AEs (Days 2–5) 
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs, Days 2–5)  
• 
Pharmacokinetics (Part 2 only) 
o PK pre- and post-dose Cycle 1, Day 5 
8.2.1.3. 
Cycle 1 Day 8 and 15 
• 
Review of AEs 
• 
Concomitant medications (including over the counter drugs, vitamins and herbs) 
• 
Vital Signs 
• 
Laboratory Tests 


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o Hematology 
o Serum chemistry 
o Pregnancy test (for women of childbearing potential only, Day 15 only) 
o Biomarker blood sample 
8.2.2. 
Cycles 2–6 
8.2.2.1. 
Day 1 
• 
Review of Adverse events 
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs) 
• 
Complete physical examination 
• 
Vital signs 
• 
ECOG performance status 
• 
Laboratory Tests 
o Hematology 
o Serum chemistry 
o Pregnancy test (for women of childbearing potential only; pregnancy testing can be 
collected on Day 15–21 of previous cycle to ensure delivery by Day 1 of new cycle) 
o T/B/NK cell count (Day 1 of Cycles 2, 3, and 6) 
o Biomarker blood sample (Day 1 of Cycles 2, 3, and 6) 
• 
Administration of ibrutinib, lenalidomide, rituximab and EPOCH 
8.2.2.2. 
Day 2–6 
Predose 
• 
Review of AEs (Days 2–5) 
• 
Concomitant medications (including over the counter drugs, vitamins and herbs, Days 2–5)  
• 
Vital Signs (Days 2–5) 
Dosing and Post-Dose 
• 
Administration of ibrutinib and lenalidomide  
• 
Administration of EPOCH (Days 2–4), Cyclophosphamide (Day 5) and Pegfilgrastim 
(Day 6 with a +48 hour window) as standard of care (Table 5) 
• 
Review of AEs (Days 2–5) 
• 
Concomitant medications (including over the counter drugs, vitamins and herbs, Days 2–5)  
 


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8.2.2.3. 
Day 8  
• 
Review of Adverse events 
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs) 
• 
Vital signs 
• 
Laboratory Tests 
o Hematology 
o Serum chemistry 
o Biomarker blood sample (Cycle 2 only) 
8.2.3. 
Response Assessments 
Subjects will be restaged at the following timepoints (per Cheson 2007): 
• 
After Cycle 3 (Cycle 4 Day 1, minus up to 4 days [Cycle 3 Day 19 to Cycle 4 Day 1])  
• 
After Cycle 6 (Cycle 6 Day 21 ±4 days)  
• 
Every 12 weeks during post treatment year 1 (±7 days) 
• 
Every 16 weeks post-treatment year 2 (±7 days) 
• 
Every 26 weeks post-treatment year 3 (±7 days) 
Response Assessment procedures will be performed in conjunction with standard visits as 
described below: 
• 
Review of AEs 
• 
Concomitant medications (including over the counter drugs, vitamins and herbs) 
• 
Complete physical examination 
• 
Vital Signs 
• 
ECOG Status 
• 
Laboratory Tests 
o Hematology 
o Serum chemistry 
o T/B/NK cell count 
o Biomarker blood sample 
• 
Radiologic examination by CT or MRI scan 
• 
PET (repeat to confirm CR if positive at screening) 
• 
Bone marrow biopsy and/or aspirate for MRD analysis (repeat to confirm CR if positive at 
screening) and possibly for other biomarkers  


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• 
Overall response assessment 
8.2.4. 
Suspected CR  
The Suspected CR visit should be performed at any time during the study, if the investigator 
suspects CR based on clinical, radiographic and/or laboratory evaluation.  The following 
procedures are required to confirm CR: 
• 
Imaging by CT or MRI; and PET if applicable 
• 
Bone marrow aspirate/biopsy (only if biopsy at Screening was positive) 
The following assessments should also be performed after CR is confirmed: 
• 
Review of AEs  
• 
Concomitant medications (including over-the-counter drugs, vitamins and herbs) 
• 
T/B/NK cell count 
• 
Biomarker blood sample 
8.3. 
Follow-up Phase 
8.3.1. 
Safety Follow-up Visit 
The Safety Follow-Up Visit should occur 30 days (±7 days) after the last dose of study drug.  
The following procedures will be performed at the Safety Follow-Up visit: 
• 
Review of AEs 
• 
Concomitant medications (including over the counter drugs, vitamins and herbs) 
• 
Complete physical examination including weight 
• 
Vital Signs 
• 
ECOG Performance Status 
• 
12-lead ECG (in triplicate) 
• 
Laboratory tests: 
o Hematology 
o Serum chemistry 
o Pregnancy test for FCBP 
o Coagulation studies 
o T/B/NK cell count  
o Biomarker blood sample  


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o Urinalysis 
8.3.2. 
Survival Follow-up Visit 
Once subjects progress or start use of alternative antineoplastic therapy (for subjects who have 
not withdrawn consent), they will be contacted approximately every 12 weeks (±7 days) from 
last dose by clinic visit or telephone to assess survival and the use of alternative antineoplastic 
therapy and stem cell transplant, up to 1 year after the first dose of the last subject enrolled. 
Subjects will be contacted until death, subject withdrawal, lost to follow-up, or study termination 
by the Sponsor, whichever occurs first. 
9. SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study. 
9.2. 
Treatment Discontinuation 
Study treatment will be discontinued in the event of any of the following events: 
• 
Subject has confirmed progressive disease. 
• 
Subject has an intercurrent illness or AE that prevents further study drug administration. 
• 
Subject decides to withdraw from study.  
• 
Subject requires a prohibited concomitant medication. 
• 
Investigator decision (such as chronic noncompliance, significant protocol deviation, or best 
interest of the subject) 
• 
Study termination by Sponsor 
• 
Subject becomes pregnant. 
All subjects, regardless of reason for discontinuation of study treatment (with the exception of 
withdrawal of consent) will undergo a Safety Follow-Up visit and be followed for progression 
and survival.  
The Investigator should notify the Sponsor within 24 hours if a subject discontinues study 
treatment due to disease progression and should provide documentation of disease progression 
for review by the Sponsor’s Medical Monitor.  If a subject shows signs of disease progression on 
physical examination or laboratory assessment, the subject may continue study treatment until 
disease progression is confirmed.  These subjects should stay in the study to be followed for 
survival.  


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9.3. 
Study Exit/Withdrawal 
Exit from study (including all follow-up) will occur under the following circumstances: 
• 
Withdrawal of consent for follow-up observation by the subject 
• 
Lost to follow-up 
• 
Study termination by Sponsor 
• 
Death 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject.  The measures taken to follow up should be documented. 
When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
• 
Reason for withdrawal; 
• 
Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits) 
10. STATISTICAL METHODS AND ANALYSIS  
Statistical analysis will be performed by the sponsor or under the authority of the sponsor.  
A general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below.  Specific details will be provided in the Statistical Analysis Plan (SAP). 
10.1. General Considerations 
Part 1 of this study is a dose-escalation study.  All safety and efficacy assessments will be 
summarized by dose group. 
Part 2 of this single-arm study is designed to assess the efficacy and safety of ibrutinib in 
combination with multiple anti-tumor agents (defined in Section 5) in subjects with relapsed or 
refractory de novo non-GCB DLBCL.  Non-GCB subtype subjects will be enrolled by IHC but 
the primary analysis will be in ABC subjects only as classified by GEP. 
10.1.1. 
Response Assessment 
Response assessments will be made by investigators.  Tumor response will be assessed by the 
investigator using the revised International Working Group Response Criteria for NHL 
(Cheson 2007). 


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Confirmation of investigator-assessed responses by an independent review facility (IRF) may be 
done as a supportive assessment.  The method of independent review will be governed by an IRF 
charter. 
10.1.2. 
Safety Monitoring 
This study will be monitored in accordance with the Sponsor’s Pharmacovigilance Committee 
procedures.  AEs and serious adverse events (SAEs) will be reviewed internally on an ongoing 
basis to identify safety concerns.  A Dose Level Review Committee will evaluate safety data 
from the dose escalation portion of Part 1.  Members of this committee will include the Sponsor 
(at a minimum: the Medical Monitor or designee, a Drug Safety representative and a 
Biostatistician) as well as participating Investigators and Sub-Investigators. 
10.2. Definition of Analysis Populations 
The following definitions will be used for the efficacy and safety analysis sets.  Analyses in 
Part 1 will be performed across subtypes of DLBCL (eg, GCB, non-GCB, PMBL, ABC).  
Part 2 analyses will be performed on the ABC subtype of DLBCL, with sensitivity analyses for 
the efficacy endpoints performed using the non-GCB subtype of DLBCL as determined by IHC. 
• 
All-treated analysis population:  All-treated analysis population will include subjects who 
have enrolled in the study and received at least 1 dose of any of the study treatments.  This is 
the primary analysis population for efficacy endpoints for Part 1. 
• 
Safety analysis population:  All enrolled subjects who have received at least 1 dose of any 
of the study treatments.  Safety analysis will be performed using the safety population.  
• 
Response evaluable population:  All enrolled subjects who have received at least 1 dose of 
any of the study treatments and have measurable disease at baseline and have at least one 
adequate post treatment disease assessment by investigator before the start of subsequent 
anti-cancer therapy.  This is the analysis population for sensitivity analyses for the efficacy 
endpoints. 
• 
Combined efficacy population:  All enrolled analysis population includes subjects who 
have received at least 1 dose of any of the study treatments and were enrolled in the 
MTD/MAD Part 1 or Part 2.  This population is the subset of the all treated analysis 
population that will be used to analyze all efficacy endpoints for Part 2. 
10.3. Endpoint Data Analysis 
10.3.1. 
Demographic/Baseline Characteristics and Study Conduct 
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease 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. 


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Further, compliance parameters (including number of doses taken compared with number of 
doses that should have been taken), the reason for discontinuation, and concurrent treatments 
will also be similarly summarized. 
10.3.2. 
Efficacy Endpoints for Part 1 
The efficacy endpoints for Part 1 of this trial are overall response (ORR) defined as the 
proportion of subjects who achieve either a CR or a PR according to the International Working 
Group Response Criteria for NHL as assessed by the investigators (Cheson 2007).  The ORR of 
Part 1 and its 95% 2-sided exact confidence interval (CI) will be calculated for the All Treated 
Population of Part 1b.  
10.3.3. 
Primary Efficacy Endpoint for Part 2 
The primary efficacy endpoint for Part 2 is the ORR (CR+PR) as assessed by investigators. 
The ORR will be calculated for the combined efficacy population of Part 2 for each subtype of 
DLBCL as determined by GEP.  The corresponding 95% 1-sided exact CI will be derived for 
each subtype.  If the lower bound of the CI around the ORR is greater than or equal to 60% for 
the ABC subtype of DLBCL, then the hypothesis that the ORR of ibrutinib combination 
treatment in the ABC subtype of DLBCL is equal to or lower than 60% will be rejected at the 
α = 5% level. 
10.3.4. 
Secondary Efficacy Endpoints for Part 2 
The secondary efficacy endpoints of Part 2 of this trial are DOR, PFS and OS. 
10.3.4.1. 
Duration of Response 
For subjects achieving objective response as assessed by investigators, their DOR as assessed by 
investigators will be calculated to determine durability.  Duration of response will be measured 
from the time by which the measurement criteria are met for CR or PR, whichever is recorded 
first, until the first date by which recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).   
The distribution (median, its 95% CI and Kaplan-Meier curves) of DOR will be provided using 
Kaplan-Meier estimates for responders in the combined efficacy population. 
10.3.4.2. 
Progression-free Survival 
Progression-free survival will be measured as time from first study drug administration to 
disease progression or death from any cause.  Data for subjects without disease progression or 
death will be censored at the date of the last tumor assessment and before the initiation of 
alternative anticancer therapy.  


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Progression-free survival will be calculated using assessments by investigators.  Kaplan-Meier 
methodology will be used to estimate event-free curves and corresponding quartiles 
(including the median) using the combined efficacy population. 
10.3.4.3. 
Overall Survival 
The duration of overall survival (OS) will be measured from the time of first study drug 
administration until the date of death.  Kaplan-Meier methodology will be used to estimate 
overall survival curves and corresponding quartiles (including the median).  Data for subjects 
who have not died will be censored at the date of the last known to be alive.  
The distribution (median, its 95% CI and Kaplan-Meier curves) of OS will be provided using 
Kaplan-Meier estimates using the combined efficacy population. 
10.3.5. 
Exploratory/Sensitivity Analysis 
Exploratory subgroup analyses and sensitivity analyses using the non-GCB subtype of DLBCL 
as determined by IHC from the combined efficacy population will be conducted focusing on key 
efficacy parameters such as ORR, DOR, PFS and OS. 
10.3.6. 
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 (ibrutinib, lenalidomide, and DA-EPOCH-R). 
AEs requiring discontinuation of study drug will be summarized separately, both overall and by 
AE severity and by relationship to study drug. 
Clinically significant abnormal laboratory values will be summarized.  Laboratory shift tables 
containing counts and percentages will be prepared by laboratory parameter and time.  Summary 
tables will be prepared for each laboratory parameter.  Figures of changes in laboratory 
parameters over time will be generated. 
Safety: Missing or partial start and end dates for AEs and concomitant medications will be 
imputed according to pre-specified, conservative imputation rules.  No other imputation of 
values for missing data will be performed. 
10.3.7. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and a major metabolite (PCI-45227) will be determined using 
a validated analytical method.  Other potential metabolites of ibrutinib may be explored. 


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Bioanalytical data from this study will be used in noncompartmental PK analysis.  Ibrutinib and 
PCI-45227 data will be listed for all subjects with available plasma concentrations.  Subjects will 
be excluded from the PK analysis if their data do not allow for accurate assessment of the PK 
(eg, incomplete administration of the study agent; concentration data not sufficient for PK 
parameter calculation due to missing PK draws at multiple visits; or early discontinuation from 
the study). 
Derived PK parameters may be subjected to further explore PK/pharmacodynamic correlation 
between exposure and relevant clinical or biomarker information. 
Bioanalytical data from this study may also be combined with data from other studies performed 
with ibrutinib in subjects with hematologic malignancies as part of a population PK analysis 
using nonlinear mixed effects models using NONMEM.  Available subject characteristics 
(demographics, laboratory variables, genotypes, etc) will be tested as potential covariates 
affecting PK parameters.  The results of the population PK analyses (if performed) will be 
presented in a separate report. 
10.3.8. 
Biomarkers 
• 
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib.  
• 
Frequency of tumor mutations (or other molecular markers) between pre- and post-treatment 
tissue that predict acquired resistance. 
Additional analysis details will be provided in the SAP.  
10.4. Handling of Missing Data 
General Considerations: Subjects lost to follow-up (or who dropped out) will be included in 
statistical analyses up to the point of their last evaluation. 
10.5. Determination of Sample Size  
The planned sample size for Part 2 is approximately 26 subjects.  The main analysis will be the 
comparison of the response rate within the ABC subtype of DLBCL to the ORR of a historical 
control of 60%.  In subjects with relapsed and refractory DLBCL, EPOCH was observed to have 
a response rate of between 68–75% (Gutierrez 2000, Jermann 2004), and since the response rate 
is expected to be lower in the more aggressive ABC subtype, an ORR of 60% has been selected 
for the historic control value.  A Part 2 sample size of 26 subjects will have 81% power to test 
the null hypothesis that ORR will be ≤60% versus the alternative hypothesis that ORR will be 
≥85% at the 1-sided significance level α=5% when the exact test method is used. 


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10.6. Safety Analysis 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who receive at least 1 dose of any of the study treatments.  The baseline value for safety 
assessments will be defined as the last value on or before the day of the first dose of study drugs 
if not specified.  Further details for selecting the baseline value of safety parameters will be 
described in the SAP.  The safety analyses will be based on the monitoring of adverse events, 
survival status, ECOG performance status, vital sign measurements, and clinical laboratory 
results. 
The safety variables to be analyzed include AEs, clinical laboratory test results (hematology and 
chemistry), physical examination findings, and vital sign measurements.  Exposure to ibrutinib 
and other study drugs and reasons for discontinuation from study treatment will be tabulated.  
In general, continuous variables will be summarized using descriptive statistics (n, mean, 
median, standard deviation, standard error and range).  Categorical variables will be summarized 
using frequencies and percentages.  No formal statistical testing is planned.  
10.6.1. 
Adverse Events 
AE parameters to be evaluated are the type, incidence, and intensity of AEs; the relationship of 
AEs to ibrutinib; and the action taken with respect to ibrutinib treatment due to AEs. 
The verbatim terms used in the eCRF by Investigators to identify non-hematological adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs are those AEs occurring after the first dose of study drugs and within 
30 days following the last dose of study drug; any AE that is considered study drug-related 
regardless of the start date of the event; or any AE that is present at baseline but worsens after 
the first administration of study drug in severity or is subsequently considered drug-related by 
the Investigator.  All treatment-emergent AEs will be included in the analysis.  For each AE, 
the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized.  The number and percent of subjects with treatment-emergent adverse events will 
be summarized according to intensity (NCI CTCAE, Version 4.03) and drug relationship as well 
as categorized by system organ class and preferred term.  Summaries, listings, datasets, 
or subject narratives may be provided, as appropriate, for those subjects who die, 
who discontinue treatment due to an AE, or who experience a severe or a serious AE. 
10.6.2. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry.  
Local laboratory results will be converted based on the normal ranges and standardized using the 
SI unit.  Selected hematologic and chemistry laboratory parameters are detailed in Section 7.1.2. 
Descriptive statistics will be provided for the values of selected clinical laboratory tests at each 
scheduled on-treatment evaluation including the final value.  Percent change from baseline to 
each scheduled on-treatment evaluation and to the final value will also be summarized. 


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For selected variables, the mean value and mean percent change over time will be presented 
graphically. 
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided.  The worst toxicity grade 
during the study will be tabulated. 
All laboratory values will be converted to standard international units and will be graded using 
the NCI CTCAE Version 4.03.  Standard methods for summarizing laboratory variables will be 
used, including the use of summary statistics and shift tables. 
11. ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide.  The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
11.1. Adverse Event Definitions and Classifications 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including 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 (ICH-E2A 1995).  
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions.  
Disease progression is not an AE; rather it may be the cause of an AE.  AEs that occur 
due to disease progression must be reported as all other treatment-emergent AEs.  
“Disease progression” should never be an AE term. 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the subject and/or observed by 
the investigator or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the subject after the ICF is signed and for 30 days following the 
last dose of study drug. 


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• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with DLBCL that were not present 
before the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered an AE: 
• 
Pre-existing condition:  A pre-existing condition (documented on the medical history 
eCRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
• 
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, which prolongs the hospitalization or meets any 
other SAE criteria, the event will be considered an SAE.  Surgeries or interventions that 
were under consideration, but not performed before enrollment in the study will not be 
considered serious if they are performed after enrollment in the study for a condition that has 
not changed from its baseline level.  Elective hospitalizations for social reasons, solely for 
the administration of chemotherapy, or due to long travel distances are also not SAEs. 
• 
Diagnostic testing and procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
• 
Asymptomatic treatment related lymphocytosis:  This event should also not be 
considered an AE.  Subjects with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures. 
• 
DA-EPOCH induced neutropenia or thrombocytopenia:  The dose-adjustment paradigm 
was designed to produce a period of shallow neutropenia resulting in ANC nadirs of 
between 0.499 and 0.1 × 109/L in 34% of cycles, with more severe neutropenia (ANC 
< 0.1 × 109/L) in 15% of cycles (Wilson, 2002).  Therefore, EPOCH-induced neutropenia or 
thrombocytopenia should not be recorded as an AE, unless neutropenia is accompanied by 
fever (febrile neutropenia) or infection, or if thrombocytopenia is accompanied by bleeding, 
or the event meets criteria for serious.   
11.1.2. 
Serious Adverse Event 
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
• 
results in death (ie, the AE actually causes or leads to death) 
• 
is life-threatening. “life-threatening” is defined as an AE in which the 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 


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• 
results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event that may not result in death, be immediately life-threatening or 
require hospitalization, but may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject, or subject may require intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such events are 
intensive treatment in an emergency department or at home for allergic bronchospasm, 
blood dyscrasias, or convulsion that does not result in hospitalization; or development of 
drug dependency or drug abuse. 
Given that the investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the investigator believes that 
the event is serious, the event will be considered serious. 
11.1.3. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation. 
11.1.4. 
Severity Criteria (Grade 1–5) 
Definitions found in the CTCAE (version 4.03) will be used for grading the severity (intensity) 
of AEs.  The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE.  Should a subject experience any AE not listed in the CTCAE 
v4.03, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences that are usually transient, requiring no special treatment, 
and do not interfere 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. 


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• 
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. 
11.1.5. 
Causality (Attribution) 
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered biologically 
implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other drugs or 
procedures.  Possibly related should be used when the investigational 
product is one of several biologically plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
11.2. Documenting and Reporting of Adverse Events  
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the eCRF.  All SAEs also must 
be reported on an SAE Worksheet and submitted to the Sponsor (see Section 11.2.2.1)  
11.2.1. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• 
Overdose of a study drug 
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to a study drug 
• 
Medication error involving a product (with or without subject/patient exposure to the study 
drug, eg, name confusion) 
Special reporting situations should be recorded in the eCRF.  Any special reporting situation that 
meets the criteria of a serious AE should be recorded on the serious AE page of the eCRF. 


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11.2.2. 
All Adverse Events 
All subjects who receive at least 1 dose of study drug(s) will be considered evaluable for 
toxicity.  All AEs (with the exception of disease progression) and special reporting situations, 
whether serious or non-serious, will be recorded in the source documents from the time a signed 
and dated ICF is obtained until 30 days following the last dose of study drug.  Starting from the 
time of first dose of study drug, all AEs and SAEs will be entered in the eCRF until 30 days after 
the date of last dose of study drug.  Serious Adverse Events that occur during study conduct 
including the screening period must be reported to the Sponsor Serious adverse events occurring 
more than 30 days following the last dose of study drug should also be reported if considered 
related to any of the study drugs.  Resolution information after 30 days should be provided.  
All Grade 3 or Grade 4 adverse events considered related to study drug must be followed until 
recovery to baseline or Grade ≤1.  The unresolved aforementioned events will be followed for a 
maximum of 6 months.   
Progressive disease should NOT be reported as an AE, but instead symptoms/clinical signs of 
disease progression may be reported.  Otherwise, all events that meet the definition of a SAE will 
be reported as SAEs, regardless of whether they are protocol-specific assessments. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document.  All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, investigator’s evaluation of its relationship to the study drug, and the event outcome.  
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection").  Investigators must record in the eCRF their opinion concerning 
the relationship of the AE to study therapy.  All measures required for AE management must be 
recorded in the source document and reported according to sponsor instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations. 
11.2.2.1. 
Expedited Reporting Criteria for Serious Adverse Events 
All SAEs occurring during the study must be reported to the Sponsor contact person within 
24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the Sponsor using the SAE Form/MedWatch 
or Council for International Organizations of Medical Sciences (CIOMS), which must be 
completed by a physician from the study site, and submitted to the Sponsor within 24 hours of 
when the investigator becomes aware of the event.  


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts) 
11.2.3. 
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 will be reported to the sponsor within 24 hours of awareness 
irrespective of seriousness (ie, serious and nonserious AEs) following the procedure described 
above for SAEs and will require enhanced data collection.   
11.2.3.1. 
Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in severity or 
that results in one of the following: intraocular bleeding causing loss of vision, any hemorrhagic 
event which results in the need for a transfusion of 2 or more units of red cells or an equivalent 
amount of whole blood, hospitalization, or prolongation of hospitalization.  
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.2.3 above. 
11.2.3.2. 
Intracranial Hemorrhage 
Any intracranial hemorrhage AE, including subdural hematoma/hemorrhage, epidural 
hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be captured as 
an AESI according to Section 11.2.3 above. 
11.2.4. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for overall survival. 


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11.2.5. 
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form.  Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered SAEs and must be reported in a timely fashion.  Any subject who 
becomes pregnant during the study must discontinue further study treatment.  Because the effect 
of the study drug on sperm is unknown, pregnancies in partners of male subjects included in the 
study will be reported by the study-site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy notification form.  Follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant will be required. 
11.3. Safety Cohort Review Committee 
A Safety Cohort Review Committee (SCRC) will review safety data in Part 1 after at least 
3 subjects are enrolled and complete one cycle of therapy.  Members of this committee will 
include the Sponsor (at a minimum: the Medical Monitor or designee, a Drug Safety 
representative and a Biostatistician) as well as participating Investigators and Sub-Investigators. 
All investigators who enrolled subjects in the safety cohort must agree on the course of action 
based on the safety findings.  At least 2/3 of these investigators who enrolled subjects in the trial 
must attend the committee meeting, the rest can provide their vote by e-mail or other 
correspondence.  Based on the safety findings and recommendations of the SCRC, enrollment 
may continue at the current dose level, commence with the next dosing level of lenalidomide, 
be halted, or undergo modifications in dose until the MTD is established.  
12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
12.1. Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. 
12.2. Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 


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The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) 
as well as country-specific national regulations and/or local laws. 
The following documents must be provided to the Sponsor or its authorized representative before 
entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal approval; 
and (2) a copy of the IRB/REB/IEC-approved ICF. 
12.3. Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.   
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail.  This process must be documented in the subject’s source record.  
Each subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed.  The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time.  A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
12.4. Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements.  This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, 
Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on GCP 
(ICH E6).   
12.5. Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 12.3), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific HIPAA consent may be used).  The Investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 


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protected health information obtained during the study may be shared with the Sponsor and its 
designees, regulatory agencies, and IRBs/REBs/IECs.  The Sponsor will not use the subject’s 
protected health information or disclose it to a third party without applicable subject 
authorization.  It is the Investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each subject.  If a subject withdraws permission to use 
protected health information, it is the Investigator’s responsibility to obtain the withdrawal 
request in writing from the subject and to ensure that no further data will be collected from the 
subject.  Any data collected on the subject before withdrawal will be used in the analysis of 
study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. Study Files and Record Retention 
The Investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study.  For those subjects subsequently excluded 
from enrollment, the reason(s) for exclusion is to be recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 
transmitted to the Sponsor, or designee, and notification of SAEs and related reports, source 
documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
The Investigator must notify the Sponsor and obtain written approval from the Sponsor before 
destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at any 
time.  Should an Investigator wish to assign the study records to another party or move them to 
another location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 


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The Sponsor must be notified in advance of, and the Sponsor 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 the Sponsor to store such documents in sealed containers away from the study 
site so that they can be returned sealed to the Investigator for audit purposes. 
12.7. Case Report Forms and Record Maintenance 
CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents).  Authorized study site personnel (ie, listed on the Delegation 
of Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided.  The Investigator will ensure that the CRFs are accurate, 
complete, legible, and completed as soon as reasonably possible, after completion of each 
subject’s visit.  At all times, the Investigator has final responsibility for the accuracy and 
authenticity of all clinical data. 
The CRFs exists within an electronic data capture (EDC) system with controlled access managed 
by the Sponsor or its authorized representative for this study.  Study staff will be appropriately 
trained in the use of CRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system.  Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail.  The Investigator attests that the information contained in the CRFs is true 
by providing electronic signature within the EDC system.  After database lock, the Investigator 
will receive a copy of the subject data (eg, paper, CD, or other appropriate media) for archiving 
at the study site. 
12.8. Investigational Study Drug Accountability 
Ibrutinib and any comparator used must be kept in a locked limited access room.  The study drug 
must not be used outside the context of the protocol.  Under no circumstances should the 
Investigator or other site personnel supply ibrutinib or comparator to other Investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from the Sponsor. 
Accountability records for ibrutinib and any comparator must be maintained and readily 
available for inspection by representatives of the Sponsor and are open to inspections by 
regulatory authorities at any time.  


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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-1124-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib or comparator dispensed for that subject 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with the Sponsors’ requirements.  If the 
site cannot meet the Sponsors’ requirements for disposal/destruction, arrangements will be made 
between the site and the Sponsor or its representative, for return of unused investigational 
product.  Before disposal/destruction, final drug accountability and reconciliation must be 
performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
12.9. Study Monitoring/Audit Requirements 
Representatives of the Sponsor or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone.  
The purpose of monitoring is to ensure that the study is conducted in compliance with the 
protocol, standard operating procedures (SOPs), and other written instructions and regulatory 
guidelines, and to ensure the quality and integrity of the data.  This study is also subject to 
reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice.  During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/REB/IEC, representatives of the Sponsor, its designated agents and 
authorized employees of the appropriate regulatory authority to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects enrolled into this study.  A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. 


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The Sponsor 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, the Sponsor will be available to assist in the preparation.  
All pertinent study data should be made available as requested to the regulatory authority for 
verification, audit, or inspection purposes. 
12.10. Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the 
Investigator before commencement of the study.  In summary, the Investigator will conduct the 
study according to the current protocol; will read and understand the IB; will obtain 
IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study 
participant; will maintain and supply to the Sponsor or designee, auditors and regulatory 
agencies adequate and accurate records of study activity and drug accountability for 
study-related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report 
SAEs to the Sponsor or designee and IRB/REB/IEC according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments. 
12.11. Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted.  In summary, 
the Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug. 
12.12. Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and the 
Sponsor or its authorized representative before the study drug is delivered. 
For this study, each Investigator and Subinvestigator (as designated on the Form FDA1572) will 
provide a signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each Investigator 
will notify the Sponsor or its authorized representative of any relevant changes during the 
conduct of the study and for 1 year after the study has been completed. 


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12.13. Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, the Sponsor will 
reimburse for reasonable physician fees and medical expenses necessary for treatment of only 
the bodily injury which is not covered by the subject’s medical or hospital insurance, provided 
that the injury is not due to a negligent or wrongful act or omission by the Investigator/ study 
staff.  The ICF will include a description of this reimbursement policy, incorporating country-
specific national regulations and/or local laws.  Financial compensation for lost wages, disability 
or discomfort due to the study is not available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
12.14. Protocol Amendments 
The Sponsor will initiate any change to the protocol in a protocol amendment document.  
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF.  Written documentation of IRB/REB/IEC and required site approval must be 
received by the Sponsor before the amendment may take effect at each site.  Additionally under 
this circumstance, information on the increased risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand and sign any 
revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and the 
Sponsor. 
12.15. Publication of Study Results 
The Sponsor may use the results of this clinical study in registration documents for regulatory 
authorities in the US or abroad.  The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an Investigator.  In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, the Sponsor reserves the right to preview all 
manuscripts and abstracts related to this study, allowing the Sponsor sufficient time to make 
appropriate comments before submission for publication. 


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In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  The Medical Monitor, study 
director and/or lead statistician may also be included in the list of authors.  This custom can be 
adjusted upon mutual agreement of the authors and the Sponsor. 
12.16. Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, 
both the Sponsor and the Investigator(s) will arrange discontinuation procedures.  In terminating 
the study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
12.17. Study Completion 
The study is expected to be completed approximately 1 year after the last subject is enrolled and 
receives the first dose.   
 
 


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Jermann M, Jost LM, Taverna Ch, et al. Rituximab-EPOCH, an effective salvage therapy for 
relapsed, refractory or transformed B-cell lymphomas: results of a Phase II study. Annals of 
Oncology 2004;15:511-516. 
Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and 
activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large 
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LeBlanc R, Hideshima T, Catley LP, et al. Immunomodulatory drug costimulates T cells via the 
B7-CD28 pathway. Blood 2004;103:1787-90. 
Lentzsch S, LeBlanc R, Podar K, et al. Immunomodulatory analogs of thalidomide inhibit 
growth of Hs Sultan cells and angiogenesis in vivo. Leukemia 2003;17:41-4. 
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2010;362:1417-29. 
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14. APPENDICES 
 


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Appendix A: Schedule of Assessments 
Study Drug Administration 
 
Study Cycles (21 days each) 
1–6 
Study Cycle Week 
1 
Study Cycle Days  
1 
2 
3 
4 
5 
6 
7 
Study Drug Administration 
 
 
 
 
 
 
 
Ibrutinib PO (Days 1–7 of each cycle) 
X 
X 
X 
X 
X 
X 
X 
Lenalidomide (Days 1–7 of each cycle) a 
X 
X 
X 
X 
X 
X 
X 
Rituximab (Day 1 of each cycle) 
X 
 
 
 
 
 
 
Etoposide, Doxorubicin, Vincristine Days 1–4 of each cycle 
X 
X 
X 
X 
 
 
 
Prednisone (Days 1–5 of each cycle) 
X 
X 
X 
X 
X 
 
 
Cyclophosphamide (Day 5 of each cycle) 
 
 
 
 
X 
 
 
Pegfilgrastimb 
 
 
 
 
 
X 
 
 
Footnote:  
a. 
Lenalidomide is not dosed for patients in Dose Level -1 or 1. 
b. 
Pegfilgrastim is administered on Day 6 of each cycle with a +48 hour window and can be self-administrated. 
 
 


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Schedule of Assessments 
Footnotes: 
a. Response Assessments occur at the end of Cycle 3 (-4 days of Cycle 4 Day 1) and after Cycle 6 (±4 days) during treatment; post treatment Q12 weeks in year 1, Q16 weeks in 
year 2, and Q26 weeks in year 3 (±7 days) until PD or study end. 
Study Cycles (21 days each) 
Screening 
1 
2–6 
Response Assessmenta 
Safety Follow-up
Study Cycle Week 
1 
2 
3 
1 
2 
Study Cycle Days  
 
1 
2 
3 
4 
5 
8 
15 
1 
2 
3 
4 
5 
8 
Cycles 3, 6, q12w Yr 1, 
q16w Yr 2, q26w Yr 3 until PD
30 days after last 
dose of study 
drug 
Visit Window 
-28 days 
±7 days 
Procedures 
Informed Consent 
x 
Tumor Sample for Eligibilityb 
x 
Medical History 
x 
x 
Adverse Event Assessment c 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medicationsd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x 
x 
x 
x 
Physical Exame 
x 
x 
x 
x 
x 
Venous Thromboembolism Risk Assessmentt 
x 
Vital Signsf 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x 
x 
x 
x 
ECOG Status 
x 
x 
x 
x 
x 
12-lead ECGg 
x 
x 
Echocardiogram 
x 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
Bone Marrow Aspiration/Biopsyh 
x 
only required to confirm complete response 
Optional Tumor Biopsy i 
x 
Laboratory Assessments 
Hematologyj 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Chemistryk  
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis Serologiesl 
x 
Pregnancy Test m 
x 
x 
x 
x 
x 
x 
Coagulation Parameters (PT, PTT, INR) 
x 
x 
T/B/NK Cell Countn 
x 
x 
x 
x 
Biomarker Blood Sampleo 
x 
x 
x 
x 
x 
x 
x 
PK p 
x 
Urinalysisq 
x 
x 
Radiological Exams 
CT Neck, Chest, Abdomen, Pelvisr 
x 
x 
PET or PET/CTr 
x 
x 
Survival Statuss 
Abbreviations:  CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; INR= International Normalized Ratio; PD=progressive 
disease; PET=positron emission tomography; PO=oral; PT=prothrombin time; PTT=partial thromboplastin time; Yr=year; DLT=dose-limiting toxicities 


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b. Tumor Tissue: Either unstained slides (minimum of 10 slides, preferably 15-30 or a paraffin block) must be sent to the central laboratory for determination of DLBCL subtype 
within 3 weeks of enrollment. The tumor sample(s) can be archival tissue from original diagnosis, from relapsed or refractory disease, or a fresh (recent) biopsy, if done to 
confirm eligibility for this study.   
c. Adverse Events:  Adverse events are collected from consent through 30 days after the last dose of study drug. DLT assessment window is Part 1 starting from Cycle 1 Day 1 to 
predose Cycle 2 Day 1 (=22 days).  Laboratory samples drawn pre-dose on Cycle 2 Day 1 need to be reviewed prior to dosing. 
d. Concomitant medications are collected from within 14 days before the first dose through 30 days after the last dose of study drug. 
e. Physical Exam: A complete physical examination performed at Screening, Day 1 of each Cycle, Response Assessments, and Safety Follow-up will include, at a minimum, 
the general appearance of the subject, height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, lymphatic 
system. The musculoskeletal and nervous systems may be included if clinically indicated.  A symptom-directed physical exam may be perfomed at all other visits. 
f. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.  
g. ECG:  12-lead ECG will be done in triplicate (≥1 minute apart).  The calculated QTc average of the 3 ECGs must be <470 msec for eligibility.  Subjects should be in a supine 
position and resting for at least 10 minutes before ECGs.  Unscheduled ECG’s may be performed at the investigator’s discretion, particularly in subject with arrhythmic 
symptoms (eg, palpitations, lightheadedness) or new dyspnea.  
h. Bone Marrow Biopsy:  A unilateral bone marrow aspirate and biopsy  must be obtained at screening or up to 28 days before the first administration of study drug. Subjects who 
have a bone marrow aspirate and biopsy result since completion of their last therapy for DLBCL may use those bone marrow results in lieu of the baseline bone marrow 
aspirate/biopsy required for this study, provided the biopsy/aspirate was done < 28 days of first dose of study drug. Thereafter, bone marrow aspirate and biopsy will only be 
required to confirm any complete remission if result was positive at screening. 
i. Optional Tumor Biopsy: Where possible, tumor biopsies will be obtained by core needle biopsy or surgery prior to treatment in Cycle 1 only.  Subjects with partial or complete 
response who later develop recurrent disease are encouraged to have an additional biopsy at time of recurrence. Snap freeze and store tissue biopsies at -80°C. 
j. During Cycles 1-6, modified hematology blood draws should include at a minimum, white blood cells, neutrophils, bands if present, and platelets, and should be checked twice 
weekly on days 4 or 5, 11 or 12, 15, and 18 or 19 (e.g. on Monday (day 1) & Thursday or Friday (Day 4 or 5), or Tuesday (Day 1) & Friday or Saturday (Day 4 or 5) to assure 
that counts are checked every 3 to 4 days). 
k. Serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, 
lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate 
l. Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B surface antibody and Hepatitis B core antibodyViral load by PCR must be confirmed 
negative in equivocal cases for subjects who are Hepatitis B core antibody positive, Hepatitis B surface antigen positive, Hepatitis B surface antibody positive (unless 
immunized) or Hepatitis C antibody positive. 
m. Pregnancy Test: Must be done in accordance with Celgene Revlimid REMS™ program guidelines and protocol Section 7.1.2.4 for women of childbearing potential only.   
n. T/B/NK cell count (ie, CD3+, CD4+, CD8+, CD16/56+, CD19+) done at predose on Day 1 of Cycle 1 and then on Day 1 of Cycles 2, 3, and 6; at Response Assessments post 
treatment period and at Safety Follow-up visit. 
o. Biomarker Blood Sample: done at predose Cycle 1 Day 1, Day 8 and Day 15; Cycle 2 Day 1 and Day 8, Cycle 3 Day 1, Cycle 6 Day 1, at each posttreatment response assesment 
and at Safety Follow-up visit. 
p. Phamacokinetic samples will be drawn for all subjects in Part 2 of protocol according to the schedule in Table 17.   
q. Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose 
r. CT and PET or PET/CT:  A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any other disease sites (eg, extremity) and a PET or 
PET/CT scan are required for the pretreatment tumor assessment within 21 days of the first dose.  During treatment, CT scans will be done for tumor assessments within 4 days 
of the end of Cycles 3, (-4 days of Cycle 4 Day 1) and ±4 days of the end of Cycle 6 and then at each response assessment time point thereafter, until PD or use of alternative 
antineoplastic therapy.  PET or PET/CT is mandatory to confirm a CR.  In the event that CT contrast is contraindicated, MRI of the abdomen and pelvis and CT of the chest and 
neck without contrast may be performed as an alternative.  Lesions in anatomical locations that are not well visualized by CT may be measured at baseline from MRI instead and 
should continue to be measured from MRI until disease progression. 
s. Survival status is to assess survival and the use of alternative antineoplastic therapy and stem cell transplant up to 1 year after the first dose of the last subject enrolled.  
Survival status will be assessed approximately every 12 weeks (±7 days) from last dose. 
t. Refer to Section 7.1.1.7 for a description of the venous thromboembolism assessment 


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


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Appendix C: Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below. Refer to 
Section 6.2.1.1 on instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. 
 
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 
TELITHROMYCIN 
Pioglitazone 
Moderate inhibitors: 
Rifabutin 
aprepitant 
Rifampin 
erythromycin 
St. John’s Wort 
diltiazem 
Troglitazone 
fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
Weak inhibitors: 
 
cimetidine 
 
All other inhibitors: 
 
amiodarone 
 
NOT azithromycin 
 
chloramphenicol 
 
boceprevir 
 
ciprofloxacin 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
fluvoxamine 
 
gestodene 
 
imatinib 
 
mibefradil 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
telaprevir 
 
troleandomycin 
 
voriconazole 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx 


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Appendix D: Guidelines for Establishing Response to Treatment 
Response 
Definition 
Nodal Masses* 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted 
if PET negative 
(b) Variably FDG-avid or 
PET negative; regression 
to normal size on CT 
Not palpable, 
nodules disappeared 
If infiltrate present at 
screening, infiltrate 
cleared on repeat 
biopsy; if 
indeterminate by 
morphology, 
immune-histochemistry 
should be negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes 
(a) FDG-avid or PET 
positive prior to therapy; 
≥1 PET positive at 
previously involved site 
(b) Variably FDG-avid or 
PET negative; regression 
on CT 
≥50% decrease in 
SPD of nodules 
(for single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to attain 
CR/PR or 
progressive disease 
(a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior sites 
of disease, and no new 
sites on CT or PET 
(b) Variably FDG avid or 
PET negative; no change 
in size of previous lesions 
on CT 
 
 
Abbreviations: CR = complete remission, CT = computed tomography, FDG = [18F]fluorodeoxyglucose,  
PET = positron emission tomography, PR = partial remission, SD = stable disease,  
SPD = sum of the product of the diameters 
*Change in target lesion measurement by CT, unless MRI used as the assessment modality for lesions in anatomical 
locations not amenable to CT 
Progressive disease for Non-Hodgkin’s lymphoma is characterized by any new lesion or 
increase by ≥ 50% of previously involved sites from nadir for example: 
• 
Appearance of a new lesion(s) >1.5 cm in any axis, ≥50% increase in SPD of >1 node, 
or ≥50% increase in longest diameter of a previously identified node >1 cm in short axis 
• 
Lesions PET positive if FDG-avid lymphoma or PET positive before therapy 
• 
>50% increase from nadir in the SPD of any previous lesions in the liver or spleen 
• 
New or recurrent involvement in the bone marrow 
• 
An increase of ≥50% in blood lymphocytes with ≥5 x 109/L B-cells only in setting of 
enlarging lymph node, liver, or spleen (note: an isolated elevation of white blood cell count 
by itself will not be considered progressive disease unless subject becomes symptomatic 
from this). 


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Appendix E: New York Heart Association Functional Classification 
Class 
Functional Capacity:  How a patient with cardiac disease feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are comfortable 
at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort increases. 
Class 
Objective Assessment 
A 
No objective evidence of cardiovascular disease.  No symptoms and no limitation in ordinary 
physical activity. 
B 
Objective evidence of minimal cardiovascular disease.  Mild symptoms and slight limitation during 
ordinary activity. Comfortable at rest. 
C 
Objective evidence of moderately severe cardiovascular disease.  Marked limitation in activity due to 
symptoms, even during less-than-ordinary activity.  Comfortable only at rest. 
D 
Objective evidence of severe cardiovascular disease.  Severe limitations.  Experiences symptoms 
even while at rest. 
 
 
 


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Appendix F: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of lenalidomide on human eggs and sperm.  Lenalidomide is structurally related to 
thalidomide.  Thalidomide is a known human teratogenic active substance that causes severe 
life-threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug 
during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMS® program, and be 
willing and able to comply with the requirements of Revlimid REMS®. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the 
preceding 24 consecutive months). 
The investigator must ensure that 
• 
Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding 
• 
Females NOT of childbearing potential acknowledge that she understands the hazards and 
necessary precautions associated with the use of lenalidomide 
• 
Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential teratogenic risk if 
engaged in sexual activity with a female of childbearing potential or pregnant female, 
and that he understands the need for the use of a condom even if he has had a vasectomy, 
if engaged in sexual activity with a female of childbearing potential or pregnant female.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study:  1) for at least 28 days before 
starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation.  


Ibrutinib (PCI-32765) 
 
Protocol PCYC-1124-CA - Amendment 1 
IND 102,688 
 
30 September 2014 
Pharmacyclics, Inc. 
Proprietary and Confidential 
118 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method.  FCBP must be referred to a qualified provider of 
contraceptive methods if needed.  The following are examples of highly effective and additional 
effective methods of contraception:   
• 
Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
• 
Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia. 
Pregnancy Testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10–14 days prior to 
prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior 
to prescribing lenalidomide.  The patient may not receive lenalidomide until the Investigator has 
verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 3 months following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   


Ibrutinib (PCI-32765) 
 
Protocol PCYC-1124-CA - Amendment 1 
IND 102,688 
 
30 September 2014 
Pharmacyclics, Inc. 
Proprietary and Confidential 
119 
During study participation and for 28 days following lenalidomide discontinuation  
Female Patients: 
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the 
first 28 days of lenalidomide treatment, including dose interruptions and then every 28 days 
throughout the remaining duration of lenalidomide treatment, including dose interruptions, 
at lenalidomide discontinuation, and at Day 28 following lenalidomide discontinuation.  
If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 
28 days of lenalidomide treatment, including dose interruptions, and then every 14 days 
throughout the remaining duration of lenalidomide treatment, including dose interruptions, 
at lenalidomide discontinuation, and at Day 14 and Day 28 following lenalidomide 
discontinuation.   
• 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use two 
reliable methods of birth control at each visit during the time that birth control is required.   
• 
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be 
immediately discontinued. 
• 
Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must be 
temporarily discontinued during this evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 
28 days after lenalidomide discontinuation. 
Male Patients: 
• 
Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of lenalidomide 
treatment, during dose interruptions and for at least 3 months following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy.   
• 
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient 
during study participation, the investigator must be notified immediately. 
• 
Male patients should not donate semen or sperm during therapy or for at least 3 months 
following discontinuation of lenalidomide. 
Additional Precautions: 
• 
Patients should be instructed never to give lenalidomide to another person. 
• 
Patients should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• 
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy.  
• 
Any unused lenalidomide must be returned as instructed through the Revlimid REMS 
program. 

SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan 
 
 
TITLE:  
A Multicenter Study of Ibrutinib and Lenalidomide in 
Combination with DA-EPOCH-R in Subjects with 
Relapsed or Refractory Diffuse Large B-cell 
Lymphoma  
 
PROTOCOL:  
 
PCYC-1124-CA  
 
 
DATE:  
 
 
29 September 2017  
 
 
 
 
 
 
 
 
 
Confidential Information 
The information in this document is considered privileged and confidential by Pharmacyclics 
LLC, and may not be disclosed to others except to the extent necessary to obtain Institutional 
Review Board approval and informed consent, or as required by Federal and State Laws.  
Persons to whom this information is disclosed must be informed that this information is 
privileged and confidential and that it should not be further disclosed. 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
2 
Table of Contents  
1 
Introduction ......................................................................................................... 5 
2 
Study Objectives and Endpoints ................................................................................ 5 
2.1 
Study Objectives ............................................................................................ 5 
2.1.1 
Part 1 .................................................................................................... 5 
2.1.2 
Part 2 .................................................................................................... 5 
2.2 
Endpoints ..................................................................................................... 6 
2.2.1 
Part 1 .................................................................................................... 6 
2.2.2 
Part 2 .................................................................................................... 6 
3 
Study Methods ..................................................................................................... 6 
3.1 
General Study Design and Plan .......................................................................... 6 
3.2 
Part 1 – Dose Escalation ................................................................................... 7 
3.3 
Part 2 – Expansion .......................................................................................... 7 
4 
Sample Size ......................................................................................................... 8 
5 
General Considerations ........................................................................................... 8 
5.1 
Analysis Populations ....................................................................................... 8 
5.2 
Changes from the Protocol ................................................................................ 8 
6 
Subject Information ............................................................................................... 9 
6.1 
Subject Disposition ......................................................................................... 9 
6.2 
Demographic and Baseline Variables ................................................................... 9 
6.3 
Prior and Concurrent Medications ....................................................................... 9 
6.4 
Exposure to Study Drug ................................................................................... 9 
7 
Efficacy Analyses ............................................................................................... 10 
7.1 
Primary Efficacy Endpoint .............................................................................. 10 
7.2 
Secondary Efficacy Endpoint ........................................................................... 10 
7.3 
Sensitivity Analysis ....................................................................................... 11 
8 
Safety Analyses .................................................................................................. 11 
8.1 
DLT Assessment .......................................................................................... 11 
8.2 
Adverse Events ............................................................................................ 11 
8.2.1 
Treatment-emergent Adverse Events ........................................................... 11 
8.2.2 
Adverse Events of Special Interest .............................................................. 12 
8.2.3 
Other Safety Observations in AE Reporting ................................................... 12 
8.2.4 
Other Malignancies ................................................................................. 12 
8.2.5 
Deaths ................................................................................................. 12 
8.3 
Clinical Laboratory Tests ................................................................................ 12 
9 
References ........................................................................................................ 12 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
3 
SUMMARY OF PLANNED ANALYSES 
Endpoint 
Definition 
Analysis Method 
Part 1: 
 
 
Primary Endpoints (for all subtypes of DLBCL): 
 
MTD 
MTD and DLTs 
Descriptive summaries and/or listings. 
Safety and tolerability 
TEAEs, SAEs, and other safety parameters 
Descriptive summaries and/or listings. 
Secondary Endpoint (for all subtypes of DLBCL): 
 
ORR  
Proportion of subjects achieving the best overall 
responses of CR or PR prior to initiation of the next line 
of antineoplastic therapy as assessed by investigator per 
the Cheson (2007) criteria. 
ORR and its corresponding exact binomial 2-sided 90% CI, based on the all-
treated population enrolled in Part 1. Analysis will be also conducted for ABC 
DLBCL subtype and for ABC and other non-GCB subtype, determined by GEP. 
Part 2: 
 
 
Primary Endpoint: 
 
ORR  
The same as above 
Primary 
ORR and its 2-sided 90% CI will be calculated using the exact binomial 
distribution, based on the all-treated population at the RP2D with the ABC subtype 
of DLBCL, determined by GEP. 
Sensitivity 
• 
Based on the response-evaluable population at the RP2D with the ABC 
subtype of DLBCL, determined by GEP.  
• 
Based on the all-treated population at the RP2D with ABC and other non-
GCB subtype, determined by GEP. 
Secondary Endpoints: 
 
Efficacy:  
 
 
PFS 
Time from the date of the first dose of study drug to 
confirmed PD or death from any cause, whichever 
occurred first. 
 
Primary 
Kaplan-Meier method, based on the all-treated population at the RP2D with the 
ABC subtype of DLBCL, determined by GEP. 
Sensitivity 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
4 
Endpoint 
Definition 
Analysis Method 
Based on the all-treated population at the RP2D with ABC and other non-GCB 
subtype, determined by GEP. 
DOR 
Time from the date of the first documented response 
(CR or PR) to the first documented evidence of PD or 
death from any cause.  
For subjects who have achieved an overall response but 
did not die or progress at the time of analysis, DOR will 
be censored on the date of the last adequate post-
baseline disease assessment, or on the date of the first 
occurrence of response (CR or PR) if there is no disease 
assessment afterwards. 
Primary 
Analysis of DOR will be based on the subjects who have achieved a response (CR 
or PR) prior to initiation of the next line of anticancer therapy in the all-treated 
population at the RP2D with the ABC subtype of DLBCL, determined by GEP. 
The median DOR and its 2-sided 95% CI will be obtained using the same method 
described for PFS. 
Sensitivity 
Based on the all-treated population at the RP2D with ABC and other non-GCB 
subtype, determined by GEP. 
OS 
Overall survival (OS) is defined as the time from the 
date of the first dose of study drug to the date of death 
due to any cause.  
For subjects who are not known to have died at or prior 
to the database lock date, OS data will be censored at 
the date last known alive.  Subjects who withdraw 
consent prior to study closure will be censored on the 
date of the consent withdrawal. 
Primary 
Based on the all-treated population at the RP2D with the ABC subtype of DLBCL, 
determined by GEP, KM curves will be used to estimate the distribution of OS.  
Sensitivity 
Based on the all-treated population at the RP2D with ABC and other non-GCB 
subtype, determined by GEP. 
Safety: 
 
 
Safety and tolerability 
TEAEs, SAEs, and other safety parameters 
Descriptive summaries and/or listings. 
ABC: Activated B-cell; CI: confidence interval; CR: complete response; DLBCL: diffused large B-cell lymphoma; ECOG PS: Easter Cooperative Oncology Group 
Performance Status; GCB: germinal center B cell-like; GEP: gene expression profile; KM: Kaplan-Meier; ORR: overall response rate; OS: overall survival; PD: progressive 
disease; PFS: progression-free survival; PR: partial response; RP2D: recommended phase 2 dose. 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
5 
1 
Introduction 
This Phase 1/2b open-label, non-randomized U.S. multicenter study is designed to evaluate 
the safety and efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R in 
the treatment of subjects with relapsed or refractory diffuse large B-cell Lymphoma. 
This statistical analysis plan (SAP) describes the statistical methodology of efficacy and 
safety analyses for this study. This plan does not cover the pharmacokinetic (PK) or 
biomarker analyses, which will be performed and reported by the DMPK Department and 
Biomarker group of Pharmacyclics, respectively.   
2 
Study Objectives and Endpoints 
2.1 
Study Objectives 
2.1.1 
Part 1 
Primary Objectives: 
• 
To determine the maximum tolerated dose (MTD) of the combination of ibrutinib, 
lenalidomide and dose-adjusted (DA)-EPOCH-R in relapsed or refractory DLBCL. 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide in combination 
with DA-EPOCH-R in relapsed or refractory DLBCL. 
Secondary Objectives: 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-
EPOCH-R in relapsed or refractory DLBCL subjects as assessed by the ORR. 
2.1.2 
Part 2 
Primary Objectives: 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-
EPOCH-R in relapsed or refractory ABC DLBCL subjects as assessed by overall 
response rate (ORR). 
Secondary Objectives: 
• 
To determine the efficacy of ibrutinib and lenalidomide in combination with DA-
EPOCH-R in relapsed or refractory ABC DLBCL as assessed by progression-free 
survival (PFS), duration of response (DOR) and overall survival (OS). 
• 
To determine the safety and tolerability of ibrutinib and lenalidomide in combination 
with DA-EPOCH-R in subjects with ABC DLBCL. 
Exploratory Objectives: 
• To determine the pharmacokinetics (PK) of ibrutinib when dosed with lenalidomide in 
combination with DA-EPOCH-R  
• To evaluate biomarkers of sensitivity or resistance to ibrutinib and lenalidomide in 
combination with DA-EPOCH-R 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
6 
2.2 
Endpoints 
2.2.1 
Part 1 
Primary Endpoint: (for all subtypes of DLBCL) 
• MTD 
• Safety and tolerability of ibrutinib and lenalidomide in combination with DA-EPOCH-
R in relapsed or refractory DLBCL   
Secondary Endpoint: (for all subtypes of DLBCL) 
• ORR 
2.2.2 
Part 2 
Primary Endpoint: 
• ORR including CR (complete response) and PR (partial response) in ABC DLBCL 
Secondary Endpoints: 
Efficacy: 
• Duration of response (DOR) in ABC DLBCL 
• Progression-free survival (PFS) in ABC DLBCL 
• Overall survival (OS) in ABC DLBCL 
Safety: 
• Frequency, severity, and relatedness of AEs  
• Frequency of AEs requiring discontinuation of study drug or dose reductions 
Exploratory Endpoints: 
• Plasma pharmacokinetics of ibrutinib  
• Identification of signaling pathways or biomarkers that predict sensitivity or resistance 
to ibrutinib  
• Frequency of tumor mutations (or other molecular markers) between pre- and post-
treatment tissue that predict acquired resistance.  
• Change in secreted protein levels (ie, chemokines, cytokines) 
• Change in peripheral T/B/natural killer (NK) counts and immunophenotypical analysis 
3 
Study Methods 
3.1 
General Study Design and Plan 
This is an open-label, non-randomized multicenter study conducted in 2 parts.  In Parts 1 and 
2, treatment will be administered in 3-week cycles (21 days each).  In Part 1, a minimum of 3 
and a maximum of 24 subjects with DLBCL will be enrolled into a standard 3+3 design to 
determine the MTD which will be used in Part 2.  Approximately 26 subjects with relapsed or 
refractory de novo DLBCL non-GCB subtype will be enrolled in Part 2 and will receive 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
7 
ibrutinib at a fixed dose of 560 mg and lenalidomide at the established MTD together with 
DA-EPOCH-R.  If no MTD is identified, then subjects in Part 2 will be treated with the 
maximum administered doses (MAD), which is the treatment dose from Part 1 dose level 4.   
3.2 
Part 1 – Dose Escalation 
The dose-escalation part of the study, Part 1, will determine the MTD of the combination of 
ibrutinib, lenalidomide and DA-EPOCH-R in subjects with DLBCL.  Subjects will receive 
ibrutinib at a fixed dose of 560 mg (or 420 mg if there is toxicity associated with 560 mg) and 
lenalidomide at an escalating dose of 0, 15, 20 and 25 mg on Days 1-7 of each 21-day cycle.  
DA-EPOCH-R will be given at standard doses on Days 1-5 of each 21-day cycle.   
The dose escalation will follow a 3+3 design with 3 subjects in each cohort.  Cohort dose 
escalation will occur if the subject incidence of Dose-limiting toxicities (DLTs) during the 
first 22 days of study treatment is <33%.  If one subject within the initial cohort of 3 subjects 
experiences a DLT, an additional 3 subjects may be enrolled at the same dose level.  If the 
initial dose is safe and tolerable with no further DLTs, the next dose level examined will be 
dose level 2.  Dose escalation will continue to dose level 4.  The MTD will be defined as the 
highest dose level with an observed incidence of DLTs in <33% of the subjects enrolled in 
the cohort.  If DLTs occur in <33% of subjects in dose level 4, then the MTD will not be 
identified and the dose level 4 dose will be the maximum administered doses (MAD).   
In the event of toxicity associated with 560 mg of ibrutinib (DLTs during the first 22 days of 
study treatment is >33% in dose level 1), 420 mg of ibrutinib (dose level -1) may be used for 
the dose escalation cohorts if it is deemed safe in combination with DA-EPOCH-R.  In this 
case, a maximum of 30 subjects may be enrolled in Part 1 (up to 6 subjects at the -1 level and 
4 x 6 = 24 subjects at levels 1, 2, 3 and 4). 
At the RP2D, at least 6 subjects will be treated at this level prior to start of Part 2. 
A DLT is defined as an Adverse Event (AE) that occurs within the first 22 days (Cycle 1, 
Cycle 2 Day 1 predose) of dosing that meets the DLT definition (refer to the protocol Section 
5.5.1), is clinically relevant, and is considered at least possibly related to ibrutinib and/or 
lenalidomide in the opinion of the investigator. 
3.3 
Part 2 – Expansion 
Part 2 will enroll subjects with non-GCB DLBCL as identified by IHC.  The primary 
objective is to determine the ORR of ibrutinib and lenalidomide in combination with DA-
EPOCH-R in subjects with ABC DLBCL as analyzed by gene expression profiling (GEP). 
The RP2D determined in Part 1 will be the dose for lenalidomide used for all subjects in Part 
2.  Subjects from Part 1 that received the RP2D of lenalidomide will be carried over to Part 2. 
Depending on the number of subjects enrolled at the RP2D in Part 1 and the number of 
subjects with the ABC subtype that will be identified by GEP in Part 2, additional subjects 
will be enrolled to ensure 26 subjects with confirmed ABC DLBCL.   


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
8 
4 
Sample Size 
The planned sample size for Part 2 is at least 26 subjects with ABC subtype of DLBCL as 
determined by GEP.  The primary efficacy analysis will be the comparison of the ORR within 
the ABC subtype to a historical control ORR of 60%.  In subjects with relapsed and 
refractory DLBCL, EPOCH/EPOCH-R was observed to have a response rate of between 68-
75% (Gutierrez 2000, Jermann 2004).  Since the response rate is expected to be lower in the 
more aggressive ABC subtype, an ORR of 60% has been selected for the historic control 
value.  A Part 2 sample size of 26 subjects will have 81% power to test the null hypothesis 
that ORR will be ≤60% versus the alternative hypothesis that ORR will be ≥85% at the 1-
sided significance level  of 5% when the exact binomial test method is used. 
5 
General Considerations 
5.1 
Analysis Populations 
The Part 1 analyses will be performed by dose cohort pooling all subtypes of DLBCL (e.g., 
GCB, ABC, PMBL, and unclassified).  Part 2 analyses will be performed on the ABC 
subtype of DLBCL as determined by GEP, with sensitivity analyses for the efficacy 
endpoints performed using the non-GCB subtype of DLBCL as determined by IHC. 
• 
All treated population will include subjects who have enrolled and received at least 1 
dose of any of the study treatments.  Efficacy and safety analyses will be performed for 
the all-treated population enrolled in Part 1, and separately for subjects dosed at the 
RP2D (MTD or MAD) from Part 1 and all subjects from Part 2.  
• 
Response-evaluable population will include subjects who have enrolled, received at 
least 1 dose of any of the study treatments, and have measurable disease at baseline and 
have at least one adequate post treatment disease assessment by investigator before the 
start of subsequent anti-cancer therapy.  This is the sensitivity analysis population for 
ORR at the RP2D. 
5.2 
Changes from the Protocol 
Changes from the statistical section in the protocol are as follows: 
1. To be consistent with the biometrics standard method of PFS analysis, the censoring 
rule for PFS has been modified where the censor date for subjects without disease 
progression or death is based on the date of the last disease assessment, regardless of 
whether the given subject received alternative anticancer therapy. In the protocol, the 
censor date is based on the last disease assessment prior to the subsequent anti-cancer 
therapy. For those subjects who were dosed and had received a subsequent anti-cancer 
therapy, the reason for the new therapies and how the new therapy could impact the 
PFS outcome will be described. 
2. Regarding the exploratory analyses for ORR, DOR, PFS and OS in the non-GCB 
subtype of DLBCL, the non-GCB subtype will be determined by GEP by combining 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
9 
the ABC and unclassified categories. Only when the GEP subtype is missing, the 
subjects will be summarized into the category based on the IHC data. In case that 
there is any meaningful difference observed between the non-GCB subgroup 
determined by IHC and that by GEP, an exploratory analysis of ORR will be 
performed in the non-GCB subtype determined by IHC. 
3. The protocol specified combined efficacy population is essentially the all-treated 
analysis population at the RP2D. The safety analysis population and the all-treated 
analysis population have the same definition. Consequently, the combined efficacy 
population and safety analysis population are removed and consolidated into the all-
treated population for simplicity and clarity. 
4. Response-evaluable population will be used for sensitivity analysis of only ORR at 
the RP2D. 
5. PK is noted as an exploratory objective but a secondary endpoint in the protocol. PK 
will be considered an exploratory endpoint for the analysis to align with the protocol 
objectives. 
6 
Subject Information 
6.1 
Subject Disposition 
Subject enrollment will be summarized by dose cohort in Phase 1b or by ABC/non-ABC 
subtype in Phase 2 for subjects treated at the RP2D.  The disposition of all enrolled subjects 
will be summarized by study phase.  
6.2 
Demographic and Baseline Variables 
Summary tables will present demographic information and baseline characteristics for 
subjects in the all-treated population. 
Concordance is summarized for the all-treated population at the RP2D between the DLBCL 
subtypes determined by GEP test in the central lab and that by the IHC test in the local lab.   
6.3 
Prior and Concurrent Medications 
All reported medications will be provided in listings for all subjects in the all-treated 
population.  Prior medications and concomitant medications will be summarized separately. 
Concomitant use of CYP3A inhibitors will be listed and summarized separately.   
Subsequent anticancer therapies are anti-DLBCL treatments that started after discontinuation 
of study treatment (i.e. started after the last dose of study drug) and will be summarized by 
type (e.g. radiotherapy, systemic therapy, bone marrow or stem cell transplant). 
6.4 
Exposure to Study Drug 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
10 
The treatment cycles each subject received will be summarized. Subjects with any dose 
interruption/reduction due to AE will be summarized.  Also the cycle delay and its reasons 
will be summarized for all-treated population at the RP2D. 
Summary tables for ibrutinib and lenalidomide will present the cumulative dose received, the 
number of doses received, the total amount of study drug received, relative dose intensity, 
subjects with at least 1 dose interruption/reduction due to adverse event.   
7 
Efficacy Analyses 
7.1 
Primary Efficacy Endpoint 
There is no primary efficacy endpoint in Part 1. 
The primary endpoint at the RP2D is ORR (CR + PR) based on the Cheson (2007) criteria as 
assessed by the investigator. The primary analysis will be based on subjects in the all-treated 
population at the RP2D (see Section 5.1) with the ABC subtype of DLBCL.  The ORR will 
be estimated according to the crude proportion of confirmed responders based on the best 
overall response.  Subjects without any baseline or post-baseline measurements are 
considered non-responders.  The 90% 2-sided exact confidence interval (CI) will be 
calculated for the ORR. 
If the lower bound of the 2-sided 90% CI for ORR is greater than 60%, then the hypothesis 
that the ORR of ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects 
with relapsed or refractory DLBCL is equal to or lower than 60% will be rejected at the 1-
sided  of 5% significance level. 
7.2 
Secondary Efficacy Endpoints 
The Part 1 secondary efficacy endpoint is ORR (CR + PR) based on the Cheson (2007) 
criteria as assessed by the investigator. The ORR and its 2-sided 90% exact CI will be 
calculated by dose cohort and by DLBCL subtype, respectively, in the all-treated population.  
The all-treated population of each dose cohort will include all subtypes of DLBCL. 
The secondary efficacy endpoints at the RP2D are duration of response (DOR), progression-
free survival (PFS), and overall survival (OS), based on subjects in the all-treated population 
with the ABC subtype of DLBCL. 
Progression free survival (PFS) is defined as the time from the date of the first study drug 
dose to confirmed disease progression or death from any cause, whichever occurs first. The 
median PFS will be obtained using the Kaplan-Meier method and its 95% CI will be 
calculated.  PFS at landmark time points (e.g., 3, 6, 9, 12 months from the first study drug 
dose date) will also be obtained by Kaplan-Meier method.  95% CI for the landmark PFS 
rates will be calculated. 
The DOR is defined as the interval between the date of the first documented response (CR, 
PR) and the date of the first documented evidence of progressive disease (PD) or death.  
DOR will be analyzed for the subjects who achieve an overall response prior to initiation of 


Statistical Analysis Plan 
 
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11 
the next line of anticancer therapy (i.e., responders).  Subjects who have achieved an overall 
response but did not die or experience PD at the time of analysis will be censored at the date 
of the last response assessment.  The median DOR and its 95% CI will be obtained using the 
same method described for PFS. 
OS is defined as the time from the date of the first study drug dose until the date of death due 
to any cause.  Subjects who are not known to have died at or prior to the database lock date 
will be censored at the date last known alive.  The last known alive date will be derived from 
any visit/assessment dates including dosing, laboratory, AE, vital signs, etc.  Subjects who 
are completely lost to follow-up for survival since receiving the first dose will be censored on 
the date of the first dose.  Subjects who withdraw consent prior to study closure will be 
censored on the date of the consent withdrawal.  A similar statistical analysis and estimation 
will be performed for OS as described for PFS. 
7.3 
Sensitivity Analysis 
A sensitivity analysis of ORR for subjects dosed at the RP2D will be performed as assessed 
by investigators for subjects defined by the response-evaluable population. 
A sensitivity analysis of the efficacy endpoints (i.e., ORR, PFS, DOR, and OS) will be 
performed for subjects dosed at the RP2D with the non-GCB subtype of DLBCL as 
determined by GEP. If the subtype cannot be determined by GEP, it will be determined by 
IHC. 
8 
Safety Analyses 
Adverse events, changes in clinical laboratory results from baseline, a summary of vital signs 
and ECG values will be provided. All safety analyses will be based on the all-treated 
population (except for the DLT evaluation which will be based on the DLT population). 
8.1 
DLT Assessment 
At the safety review meeting, DLTs will be assessed for the first 6 to 9 subjects in the DLT 
population. A listing of subjects for the DLT assessment will be provided. 
8.2 
Adverse Events  
Adverse events collected in the CRF (verbatim terms) by investigators will be coded to a 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The 
severity of adverse events is assessed in the National Cancer Institute (NCI) common toxicity 
criteria for adverse events (CTCAE) Version 4.03. 
8.2.1 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events will be summarized by system organ class and preferred 
terms and by NCI toxicity grade. The same summary will be provided for treatment-related 
AEs, AEs leading to treatment discontinuation, AEs leading to treatment discontinuation for 


Statistical Analysis Plan 
 
PCYC-1124-CA 
 
Proprietary and Confidential 
12 
subjects who discontinued treatment due to AE, AEs leading to dose reduction and serious 
TEAEs. An adverse event overview on the incidences of all the above will be presented. 
8.2.2 
Adverse Events of Special Interest 
8.2.2.1 Major Hemorrhage and All Hemorrhagic Events 
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms and 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.  
8.2.3 
Other Safety Observations in AE Reporting  
Summary of treatment-emergent leukostasis, infections, TLS, cytopenia, hypersensitivity, 
hepatic disorders, and atrial fibrillation will be based on the TEAE summary by SOC and 
preferred term. 
Treatment emergent interstitial lung disease, rash, severe cutaneous adverse reactions, and 
cardiac arrhythmia (excluding atrial fibrillation) will be summarized by preferred terms based 
on SMQ term search and/or medical monitor and safety scientist review. 
8.2.4 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies, and hematologic 
malignancies are to be reported for the duration of study treatment and during any protocol-
specified follow-up periods including long-term post-progression follow-up for OS.  Other 
malignancies will be summarized similar to standard AE tables or listed. 
8.2.5 
Deaths 
Treatment-emergent adverse events leading to death with be summarized. 
8.3 
Clinical Laboratory Tests 
A summary of worst post-baseline toxicity grade will be provided. The events with Grade 3 
and 4 as the worst post-baseline toxicity grade will be also provided. 
9 
References 
Cheson B.D, Pfistner B, Juweid ME, et al.  Revised Response Criteria for Malignant 
Lymphoma, Journal of Clinical Oncology 2007; 25: 579-586.Efficacy Analyses