A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (≥ 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
Phase: PHASE3
Conditions: Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia
Sponsor: National Cancer Institute (NCI)

 
 
1 
Update #08 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO A041202 
_________________________________________ 
 
A RANDOMIZED PHASE III STUDY OF BENDAMUSTINE PLUS RITUXIMAB VERSUS IBRUTINIB PLUS 
RITUXIMAB VERSUS IBRUTINIB ALONE IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
Clinicaltrials.gov identifier: NCT01886872 
NCI-supplied agent: Ibrutinib (NSC #748645, IND #117241); 
Commercial agent(s): Rituximab and Bendamustine 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other : 
 
 
 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days.  
Please follow your IRB of record guidelines. 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page (Page 1) 
• 
Cancer in the Elderly has been renamed as Cancer in the Older Adult. 
• 
Dr. Jennifer Le-Rademacher has replaced Dr. Arti Hurria as Cancer in the Older Adult Co-Chair 
(formerly Cancer in the Elderly). All contact information has been updated.  
• 
All contact information for Amy S. Stark (formerly Amy S Ruppert) has been updated.  
• 
Diane Feldman has replaced Samantha Sublett as the Protocol Coordinator. All contact information 
has been updated. 

 
 
2 
• 
Brandon Bright has replaced Luke Wilson as the Data Manager. All contact information has been 
updated. 
• 
NCIC-CTG/NCIC Clinical Trials Group has been renamed CCTG/Canadian Cancer Trials Group 
under Participating Organizations. 
 
Study Resources (Page 2) 
• 
Page 2 has been titled Study Resources to reflect current CTSU boilerplate language.  
• 
Participating Groups has been renamed to Study Champions to reflect current CTSU boilerplate 
language.  
• 
NCIC has been renamed CCTG. 
• 
Carolyn Owen has replaced Stephen Couban as the CCTG (formerly NCIC) Study Champion. All 
contact information has been updated. 
• 
The contact information for the participating groups’ operations offices for ECOG-ACRIN, 
CCTG (formerly NCIC), and SWOG has been removed as this information is out of date and all 
protocol-related questions should be directed to the lead protocol organization (Alliance). 
 
CTSU Contact Information (Page 3) 
The CTSU Contact Information table has been updated with current CTSU boilerplate language.  
 
Section 5.3 (Registration Procedures) 
• 
Section 5.3.1 (CTEP Investigator Registration Procedures) and Section 5.3.2 (CTEP Associate 
Registration Procedures / CTEP-IAM Account) have been removed and replaced with a new 
Section 5.3.1 entitled “CTEP Registration Procedures” which includes updated CTSU boilerplate 
language. Subsequent sections have been renumbered accordingly. 
• 
All text in Section 5.3.2 (CTSU Registration Procedures) (formerly Section 5.3.3) has been 
completely revised to include updated CTSU boilerplate language. 
 
Section 7.0 (Required Data) 
• 
In the Day 1 of Every Third Cycle During Treatment, Arm 1 Observation & Clinical Follow-up 
column, the following laboratory studies have changed from “X” to “A.”  
o Serum creatinine, CrCl (est.), BUN, Serum electrolytes, AST, ALT, PT INR, alk. phos., 
bilirubin, LDH, and albumin 
• 
Footnote A language has been updated from “Ongoing solicited adverse event forms are only 
necessary...” to “Ongoing solicited adverse even forms and indicated laboratory studies are only 
necessary…” in order to reflect the changes made in the required data table.  
• 
Footnote ** language has been updated to reflect that patients continuing to receive ibrutinib with 
“Arms 2 and 3” replacing “Arms 1 and 2.” 
 
Section 11.2 (Ibrutinib [PCI-32765, NSC # 748645, IND #117241]) 
Subheading “Agent Ordering” had been renamed as “Agent Ordering and Agent Accountability.” All text 
in subheading “Agent Ordering and Agent Accountability” (formerly Agent Ordering) has been 
completely revised to include updated CTSU boilerplate language.  
 
Appendix III (Registration Fatigue/Uniscale Assessments) 
In the third paragraph, NCIC has been revised with CCTG to reflect NCIC has been renamed. 
 
_____________________________________________________________________________________ 
UPDATES TO THE MODEL CONSENT: 

 
 
3 
What will happen if I take part in this research study?  
In the second paragraph under “When you are finished taking the study drugs, and/or when you are 
continuing on ibrutinib…” the timing of the Cycle 9 Day 1 blood tests and bone marrow biopsy have 
been corrected from “Nine months after you start treatment” to “Eight months…” for consistency. 
 
What side effects or risks can I expect from being in the study? 
Under “Risks and side effects related to ibrutinib include those which are,” incorrectly presented the 
patient ratio for “Occasional, some may be serious” in the condensed risk profile table. The correct patient 
ratio for “Occasional, some may be serious” is “from 4 to 20” has replaced “more than 20 and up to 100.” 
 
 
 
A replacement protocol document and model consent have been issued. 
This study remains closed to new patient accrual. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
1 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A041202 
 
A RANDOMIZED PHASE III STUDY OF BENDAMUSTINE PLUS RITUXIMAB VERSUS IBRUTINIB PLUS 
RITUXIMAB VERSUS IBRUTINIB ALONE IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
Clinicaltrials.gov identifier: NCT01886872 
NCI-supplied agent: Ibrutinib (NSC #748645, IND #117241);  
Commercial agent(s): Rituximab and Bendamustine 
 
Required Embedded Correlative Science Companion Study: Alliance A041202-LC1 
Optional Companion Studies: CALGB 9665(temporarily suspended on February 28, 2014), Alliance 
A041202-PP1, and Alliance A041202-EL1 
Study Chair 
Jennifer Woyach, MD 
455 A Wiseman Hall 
410 W 12th Ave 
Columbus, OH  43210 
Tel: 614-685-5667  Fax: 614-293-7526 
jennifer.woyach@osumc.edu 
 
Leukemia Correlative Study Co-Chair and Leukemia 
Correlative Science Committee Chair 
Population Pharmacology and Pharmacogenetics Co-
Chair  
John C. Byrd, MD 
Kristy Richards, MD  
The Ohio State University 
University of North Carolina 
Tel: 614-293-7509 
Tel: 919-966-0374 
john.byrd@osumc.edu 
kristy_richards@med.unc.edu 
 
Cancer in the Older Adult Co-Chair 
Jennifer Le-Rademacher, MD 
Alliance for Clinical Trials in Oncology 
Tel: 507-284-44002 
Le-Rademacher.Jennifer@mayo.edu 
 
Leukemia Committee Chair 
Richard M. Stone, MD 
Dana Farber Cancer Institute 
Tel: 617-632-2214 
mstone@partners.org 
 
Community Oncology Co-Chair 
Sreenivasa Nattam, MD 
Fort Wayne Medical Oncology & 
Hematology 
Tel: 260-484-8830 
snattam@me.com 
 
Primary Statistician 
Secondary Statistician 
Sumithra Mandrekar, PhD 
Amy S. Stark, PhD 
Tel: 507-266-6724 
Tel: 614-293-9209 
mandrekar.sumithra@mayo.edu 
amy.stark@osumc.edu 
 
 
 
Protocol Coordinator 
Data Manager 
Diane Feldman 
Brandon Bright 
Tel: 773-702-4236 Fax: 312-345-0117 
Tel: 507-538-1484 Fax: 507-284-1902 
Dfeldman3@bsd.uchicago.edu 
Bright.Brandon@mayo.edu 
 
Participating Organizations:  ALLIANCE/Alliance for Clinical Trials in Oncology, ECOG-ACRIN/ECOG-
ACRIN Cancer Research Group, NRG/NRG Oncology, SWOG/SWOG and CCTG/Canadian Cancer Trials Group 

ALLIANCE A041202 
 
 
Version Date 03/20/2019
 
Update #08 
 
2 
 
Study Resources: 
Alliance Central Protocol Operations Office 
125 South Wacker Drive, Suite 1600 
Chicago, IL  60606 
Tel:  773-702-9171  Fax: 312-345-0117 
www.allianceforclinicaltrialsinoncology.org  
Alliance Statistical Data Center 
Mayo Clinic 
200 First St. SW 
Rochester MN 55905 
 
Expedited Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers/ 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 
Protocol Resources: 
 
A041202 Nursing Contact 
Ilene Galinsky, MSN, ANP-C 
Dana Farber Cancer Institute 
Tel: 617-632-3902 
igalinsky@partners.org 
 
 
 
 
 
A041202 Pharmacy Contacts 
Ryan Daley, PharmD 
University of Vermont 
Tel: 802-847-5577 
ryan.daley@uvmhealth.org 
Caroline Harvey, RPh 
Dana Farber Cancer Inst. 
Tel: 617-632-3786 
caroline.harvey@ 
dfci.harvard.edu 
Alliance Biorepository at Ohio State University 
Department of Pathology 
Polaris Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research 
Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754  Fax: 614-688-4755 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, and 
dose modification: 
Study Chair, Nursing Contact, Protocol Coordinator 
Questions related to data submission, RAVE or patient 
follow-up: 
Data Manager  
Questions regarding the protocol document: 
Protocol Coordinator 
Questions related to IRB issues and model consent 
revisions: 
Regulatory Affairs Manager:  
regulatory@allianceNCTN.org 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
pharmacovigilance@alliancenctn.org 
Study Champions: 
 
ECOG-ACRIN 
SWOG 
CCTG 
Wei Ding, MBBS, PhD 
Steven Coutre, MD 
Carolyn Owen, MD 
Tel: 507-266-0792 
Tel: 650-823-0828 
Tel: 902403-521-3621 
ding.wei@mayo.edu 
coutre@stanford.edu 
carolyn.owen@albertahealthservic
es.ca 

ALLIANCE A041202 
 
 
Version Date 03/20/2019
 
Update #08 
 
3 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments:  
Submit study data:  
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-
tab under the Regulatory 
tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2878 for regulatory 
assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave.  Please see the data submission 
section of the protocol for further 
instructions.  
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Alliance Study Chair. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at https://www.ctsu.org. 
 
 
 
 
 
 
 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
4 
 
 
 
 
A RANDOMIZED PHASE III STUDY OF BENDAMUSTINE PLUS RITUXIMAB VERSUS IBRUTINIB PLUS 
RITUXIMAB VERSUS IBRUTINIB ALONE IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
Schema 
 
Patient Eligibility (see Section 4.0 for complete details) 
Required Initial Laboratory Values
- Diagnosis with CLL in accordance with IWCLL 2008 Criteria 
ANC 
≥ 1,000/µL * 
- Intermediate or high risk Rai Stage CLL 
AST and ALT 
≤2.5 x ULN ** 
-  Criteria met for treatment as defined by IWCLL 2008 guidelines 
Total bilirubin 
≤1.5 x ULN *** 
- No prior therapy for CLL (except palliative steroids or treatment of 
autoimmune complications of CLL with steroids or rituximab) 
Creatinine Clearance 
Platelet count 
≥ 40 mL/min § 
≥ 30,000/µL 
- Age ≥ 65 
- ECOG performance status 0-2 
*     Unless due to bone marrow involvement 
**   Except if due to disease infiltration of the  
- No active hepatitis B 
- No active systemic anticoagulation with heparin or warfarin 
       liver 
*** Unless due to liver involvement, 
- No active intercurrent disease (see Section 4.2.8) 
- No history of Richter’s transformation or prolymphocytic leukemia 
- No prednisone over 20 mg daily or equivalent corticosteroid 
- No uncontrolled active system infection requiring intravenous antibiotics 
- No strong CYP3A4/5 inhibitors or inducers 
- No allergy to mannitol 
- No significant hypersensitivity to rituximab 
- No major surgery within 10 days or minor surgery within 7 days 
       hemolysis or Gilbert’s disease  
§   To be calculated by modified Cockcroft- 
Gault formula (see Section 4.2.16). 
Schema 
1 cycle = 28 days 
 
 
* At the treating investigator’s discretion, the first cycle of bendamustine may be given at 70 mg/m2. 
** Patients randomized to bendamustine plus rituximab will be eligible to cross over to single-agent ibrutinib upon 
documentation of disease progression. Please note that patients who opt to cross over must be re-registered to the 
study. In addition, please make sure to reassess eligibility (Section 4.0) at re-registration. 
† 
After completion or discontinuation  of treatment on Arm 1, 28-day cycles should continue to be counted as patients 
will be followed every third cycle.  
PRE-REGISTRATION 
Arm 1 † 
Bendamustine 90 mg/m2 IV, cycles 1 – 6, days 1 and 2 * 
Rituximab 375 mg/m2 IV, cycle 1, day 0 (day before day 1 of 
cycle 1)  
500 mg/m2 IV, cycles 2 – 6, day 1 
Arm 2 
Ibrutinib 420 mg PO daily until disease progression 
Arm 3 
Ibrutinib 420 mg PO daily until disease progression 
Rituximab 375 mg/m2 IV cycle 2, days 1, 8, 15, 22  
375 mg/m2 IV cycles 3 – 6, day 1  
PD**
P
 
 
Zap 70 
methylation 
(performed 
centrally) 
 
 
FISH 
(performed 
locally) 
 
REGISTRATION/RANDOMIZATION 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
5 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................................... 5 
1.0 
INTRODUCTION ............................................................................................................................. 7 
1.1 
Initial Therapy for CLL in Older Patients ............................................................................... 7 
1.2 
The B Cell Receptor and Bruton’s Tyrosine Kinase in CLL ................................................... 7 
1.3 
Targeting BTK with Ibrutinib and Phase I Evaluation ............................................................ 8 
1.4 
Phase II Study of Ibrutinib in CLL .......................................................................................... 8 
1.5 
Combination Therapy .............................................................................................................. 9 
1.6 
Clinical Safety Update 2015 .................................................................................................... 9 
1.7 
Risks ...................................................................................................................................... 10 
1.8 
Justification ............................................................................................................................ 12 
1.9 
Registration Quality of Life (QOL) Measurements ............................................................... 13 
2.0 
OBJECTIVES ................................................................................................................................. 13 
2.1 
Primary Objective .................................................................................................................. 13 
2.2 
Secondary Objectives ............................................................................................................ 13 
3.0 
ON-STUDY GUIDELINES ............................................................................................................ 14 
4.0 
ELIGIBILITY CRITERIA ............................................................................................................ 15 
4.1 Pre-Registration Eligibility Criteria (Step 0)............................................................................... 15 
4.2 
Registration Eligibility Criteria (Step 1) ................................................................................ 15 
5.0 
REGISTRATION/RANDOMIZATION, STRATIFICATION .................................................. 18 
5.1 
Pre-registration Requirements (Step 0) .................................................................................. 18 
5.2 
Registration Requirements (Step 1) ....................................................................................... 18 
5.3 
Registration Procedures ......................................................................................................... 18 
5.4 
Registration to Correlative Science Studies and Companion Protocols ................................ 22 
5.5 
Stratification .......................................................................................................................... 23 
5.6  
Re-Registration at the Time of Progression ........................................................................... 23 
6.0 
DATA AND SAMPLE SUBMISSION .......................................................................................... 23 
6.1 
Data Submission .................................................................................................................... 23 
6.2 
Specimen Collection & Submission ...................................................................................... 25 
6.3 
Geriatric Assessment (Alliance A041202-EL1) .................................................................... 30 
7.0 
REQUIRED DATA ......................................................................................................................... 32 
8.0 
TREATMENT PLAN ..................................................................................................................... 34 
8.1 
Arm 1: Bendamustine/Rituximab .......................................................................................... 34 
8.2 
Arm 2 Ibrutinib ...................................................................................................................... 34 
8.3 
Arm 3 Ibrutinib/Rituximab .................................................................................................... 35 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ......................................... 36 
9.1 
Dose Modifications for Hematologic Toxicity ...................................................................... 36 
9.2 
Dose Adjustments for Non-Hematologic Toxicity ................................................................ 38 
9.3 
Dose Modifications for Obese Patients ................................................................................. 39 
10.0 EMBEDDED CORRELATIVE SCIENCE COMPANION STUDIES ...................................... 39 
10.1 
Leukemia Correlative Science in Alliance 041202 (Alliance A041202-LC1) ...................... 39 
10.2 
Geriatric Assessment in Alliance A041202 (Alliance A041202-EL1) .................................. 41 
10.3 
Evaluation of Candidate Pharmacogenetic Determinants of Ibrutinib or Ibrutinib/Rituximab 
Response (Alliance A041202-PP1) ....................................................................................... 44 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
6 
11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION ....................................... 45 
11.1 
Rituximab (IDEC-C2B8) ....................................................................................................... 46 
11.2 
Ibrutinib (PCI-32765, NSC # 748645, IND #117241) .......................................................... 47 
11.3 
Bendamustine ........................................................................................................................ 49 
12.0 ANCILLARY THERAPY .............................................................................................................. 50 
12.1 
Alliance Policy Concerning the Use of Growth Factors ........................................................ 50 
12.2 
CYP Inhibiting Drugs ............................................................................................................ 50 
12.3 
Surgery ................................................................................................................................... 51 
12.4 
Permitted Concomitant Medications ..................................................................................... 51 
12.5 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ........................... 51 
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE .......................................... 52 
13.1 
Response Criteria ................................................................................................................... 52 
13.2 Treatment-Related Lymphocytosis ........................................................................................... 53 
14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ................................................. 54 
14.1 
Duration of Treatment ........................................................................................................... 54 
14.2 
Extraordinary Medical Circumstances ................................................................................... 55 
15.0 STATISTICAL CONSIDERATIONS........................................................................................... 55 
15.1 
Overview and Study Design .................................................................................................. 55 
15.2 
Accrual time and study duration ............................................................................................ 57 
15.3 
Analysis Plan ......................................................................................................................... 57 
15.4 
Secondary Endpoint Analysis Plan ........................................................................................ 58 
15.5 
Correlative Science Statistical Considerations ...................................................................... 60 
15.6 
Inclusion of Women and Minorities ...................................................................................... 63 
15.7 
CDUS Reporting .................................................................................................................... 63 
16.0 EXPEDITED ADVERSE EVENT REPORTING AND COMPREHENSIVE ADVERSE 
EVENTS AND POTENTIAL RISKS LISTS ......................................................................................... 64 
16.1 
Expedited Adverse Event Reporting ...................................................................................... 64 
16.2 
Comprehensive Adverse Events and Potential Risks (CAEPR) ............................................ 66 
16.3 
Adverse Event List for Commercial Agents .......................................................................... 70 
16.4 
Events of Special Interest ...................................................................................................... 71 
17.0 REFERENCES ................................................................................................................................ 72 
APPENDIX I 
PATIENT MEDICATION DIARY ............................................................................ 75 
APPENDIX II 
INDUCERS AND INHIBITORS CYP3A4/5 ............................................................. 77 
APPENDIX III REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ................................. 78 
APPENDIX IV COLLABORATIVE AGREEMENTS PROVISIONS ............................................ 80 
APPENDIX V 
GERIATRIC ASSESSMENT (A041202-EL1) MEASURES ................................... 82 
APPENDIX VI CHILD-PUGH SCORE ............................................................................................ 104 

ALLIANCE A041202 
 
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7 
1.0 
INTRODUCTION 
1.1 Initial Therapy for CLL in Older Patients 
CLL is the most prevalent form of adult leukemia and is currently incurable. While fludarabine-
based chemoimmunotherapy (CIT) is standard initial therapy for younger patients with CLL, 
optimal initial therapy for older adults with CLL not as well established. Phase III trials have 
shown that fludarabine is superior to chlorambucil[1] and that fludarabine plus 
cyclophosphamide is superior to fludarabine[2, 3] or chlorambucil[2] alone. In addition, large 
phase II and III trials have demonstrated the superiority of chemoimmunotherapy to 
chemotherapy in this disease.[4, 5] However, all of these studies were heavily skewed toward a 
younger patient population. A randomized phase III trial[6] has demonstrated that in patients 
over the age of 65, fludarabine is not superior to chlorambucil. Similarly, a recent analysis of 
front-line CALGB trials in CLL showed that for patients above the age of 69, fludarabine was 
not superior to chlorambucil in regards to both PFS and OS. In contrast, the addition of the CD20 
monoclonal antibody rituximab to fludarabine improved both PFS and OS over fludarabine 
alone in both younger patients, and those over the age of 69.[7] Presently, most elderly patients 
are treated with chlorambucil often in combination with rituximab based on the results of two 
phase II trials[8, 9] or with the combination of bendamustine plus rituximab (BR). Although BR 
has not been compared directly with chlorambucil + rituximab, results of a recent phase II trial 
show an ORR of 88% with a median event free survival of 33.9 months and 90.5% OS at 27 
months.[10] These results held for patients ≥ 70 years old, and compare favorably with results 
published for chlorambucil + rituximab.[10]  Toxicity with this regimen is usually manageable 
but can be significant, with a reported 64% of patients experiencing a grade 3 or grade 4 toxicity, 
and 19.7% of patients experiencing grade 3 or grade 4 myelosuppression. In older patients 
especially, these toxicities can delay or preclude further therapy, thus, these results underscore 
the need for new therapies in the older population who may be particularly at risk for significant 
toxicity. 
1.2 The B Cell Receptor and Bruton’s Tyrosine Kinase in CLL 
The B cell receptor (BCR) consists of surface immunoglobulin non-covalently bound to the 
heterodimer CD79a/CD79b. In normal B cells, ligation of the BCR results in a signaling cascade 
that can lead to proliferation, apoptosis, or anergy depending on the stage of development and 
antigen ligated.[11] In CLL cells, however, the BCR is dysregulated and activation through 
antigen ligation or auto-stimulation results in the propagation of proliferative and pro-survival 
signals.[12, 13] Thus, the BCR represents a therapeutic target in CLL. There are currently two 
agents clinically available that target different aspects of the BCR in phase III studies:  GS-1101 
(formerly CAL-101), which is an inhibitor of PI3-kinase p110 delta, and ibrutinib, which inhibits 
Bruton’s Tyrosine Kinase (BTK). BTK is a member of the Tec family of kinases, and is an 
integral kinase involved in B cell signaling and B lymphocyte development and differentiation. 
Mutation of the gene encoding BTK, located at Xq21.33-q22 is responsible for X-linked 
agammaglobulinemia (XLA),[14, 15] a disorder characterized by developmental arrest at the 
pre-B stage and profound humoral immune deficiency in humans, and the milder X-linked 
immunodeficiency (XID) phenotype in the mouse.[16] BTK is a crucial mediator of BCR 
signaling in normal B cells and CLL cells, and is genetically upregulated in CLL as compared 
to normal B cells.[17] Activation of BTK results in cell survival and proliferation through the 
MAP kinase pathway, PI3K/Akt pathway, and NF-κB. Because of the key role of BTK in CLL 
signaling, this is an attractive drug target.   

ALLIANCE A041202 
 
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8 
1.3 Targeting BTK with Ibrutinib and Phase I Evaluation 
Ibrutinib (PCI-32765) is an orally-bioavailable irreversible inhibitor of BTK. Pharmacologic 
inhibition of BTK with ibrutinib has been shown to cause modest apoptosis in vitro, and 
significantly inhibits B cell proliferation and signaling both in vitro and in vivo[17], (and our 
unpublished data). The initial phase I study with this agent examined dose escalation in various 
B cell malignancies. In this study, 15 patients with CLL were enrolled with objective response 
observed in 9/15 patients.[18] A fluorescent-labeled probe was used to ensure that the doses 
brought forward occupied >90% of BTK.[19] Based on this study, an oral dose of 420 mg daily 
was established as a tolerable and effective dose. The drug was well tolerated at all dose levels 
examined, with only 5 out of 47 patients discontinuing therapy for toxicity.[18] 
1.4 Phase II Study of Ibrutinib in CLL 
In an ongoing phase Ib/II study, ibrutinib has shown extraordinary activity in patients with 
relapsed or refractory CLL. In patients with relapsed or refractory CLL and measurable 
lymphadenopathy, the rate of lymph node shrinkage >50% is 89%. With a median follow-up of 
4 months, ORR was 48% due to transient asymptomatic lymphocytosis[20], and with longer 
follow-up of 17.3 months in patients receiving the 420 mg dose, has improved to 67%.[21] This 
lymphocytosis has been observed in clinical trials with the PI3kinase delta inhibitor GS-1101 as 
well and is likely related to B cell release from lymph node, spleen and marrow 
microenvironment due to disruption of homing signals or chemoattractants that are relevant to 
usual lymphocyte circulation dynamics. Lymphocytosis with ibrutinib is seen within 1-2 weeks 
of starting therapy, reaches plateau within the first 2-3 cycles, and has resolved over time in 
virtually all patients. While this is currently under investigation, the magnitude and duration of 
lymphocytosis does not appear to be related to the depth of eventual response nor to response 
duration or toxicity. Response to ibrutinib occurs independently of high-risk genomic features 
including IgVH mutational status and del(17p13.1). Responses to this drug have been durable 
as well, with an estimated 22 month PFS of 76% for these relapsed and refractory patients.[21] 
This study also included a cohort of 31 previously untreated patients. With 16.6 months of 
follow-up, ORR is 71%, with an additional 10% of patients having persistent lymphocytosis; 
estimated 22 month PFS is 96%.[21] Thus far only 7 out of 116 patients across treatment cohorts 
have been removed from study for disease progression. This oral agent is well tolerated, with a 
very low rate of hematologic toxicity. The most common toxicities with ibrutinib have been 
diarrhea, rash, bruising, and dyspepsia. There has been no change in the levels of IgG and IgM, 
and an increase in serum IgA has been seen over time.[21]   
Infections, including opportunistic infections have been observed, however, infections are 
common in this refractory patient population. Serious infectious AEs have been experienced by 
20 patients in this relapsed/refractory group, but in general have not led to discontinuation of 
therapy. The efficacy observed thus far in conjunction with the tolerability to continuous 
administration make it an ideal agent for further study, especially in elderly patients. 
In line with all other trials currently including ibrutinib, patients on this trial will adhere to a 
continuous dosing regimen of this agent until disease progression. This model of continuous 
therapy is based on kinase inhibition in chronic myelogenous leukemia (CML) with imatinib, 
and at this point appears reasonable given the relatively large number of patients who achieve 
only partial response and continue to have improving response with longer duration of ibrutinib 
administration.  If, within the duration of this trial, evidence arises suggesting that all or some 
patients would do well with therapy discontinuation or interruption, this protocol will be 
amended to reflect this change.  Until this time, however, patients treated on this protocol are 
expected to receive continuous dosing of ibrutinib until disease progression. 

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1.5 Combination Therapy  
Combination Therapy with CD20 Monoclonal Antibody Therapy and Ibrutinib 
The combination of ibrutinib with a CD20 monoclonal antibody is appealing because the rapid 
clearing of peripheral lymphocytosis that is seen with rituximab and other antibodies is expected 
to increase the rapidity of response with ibrutinib. Additionally, in the laboratory  ibrutinib 
antagonizes the tumor microenvironment,[17] which may increase the bone marrow clearance 
which is limited with rituximab. The combination of ibrutinib and the CD20 monoclonal 
antibodies ofatumumab or rituximab are currently being evaluated in relapsed CLL on two 
separate trials.  One, a phase II study of ibrutinib (420 mg) administered continuously until time 
of relapse and ofatumumab has enrolled three time-sequential cohorts. In the first cohort of 27 
patients, ibrutinib begins day 1 and continues until disease progression, while ofatumumab 
begins month 2 with 300 mg week 5, 2000 mg weeks 6-12 and then monthly for four months. 
All 27 patients completed the first month of therapy without a DLT. Of the twenty-four patients 
with CLL, all attained a partial response (100%) with 23 remaining on treatment and 1 
proceeding to a non-myeloablative stem cell transplant. Infusion toxicities with ofatumumab 
were more modest than expected. Cohorts administering ofatumumab either concurrently or 
prior to ibrutinib have also been completed where feasibility was confirmed, but either early 
toxicity (concurrent schedule) or early progression (ofatumumab first arm) has resulted in 
choosing the run in arm with ibrutinib for 1 month followed by addition of ofatumumab for 
future study. In the other trial performed at MD Anderson which enrolled only patients with 
high-risk disease, rituximab and ibrutinib were administered concurrently beginning in cycle 1, 
with 4 doses of weekly rituximab and then monthly administration for a total of 6 cycles. In this 
trial, toxicities were modest, and responses were again seen at an earlier time point than expected 
from single agent therapy.[22] Overall, experience with different administration sequences 
suggests that a run in with ibrutinib for the first month followed by initiation of antibody 
beginning month two may be better tolerated, and in vivo pharmacodynamic studies support 
target modulation that would enhance tumor apoptosis. This schedule of administration with 
ibrutinib preceding CD20 antibody therapy will be pursued in this phase III trial.  
1.6 Clinical Safety Update 2015 
Pooled safety data are available for a total of 1071 patients treated with ibrutinib monotherapy 
across 9 studies in B-cell malignancies, including patients from 2 randomized-control studies 
who crossed over from comparator treatment or placebo to receive ibrutinib monotherapy 
(Investigator’s Brochure, 2015).  The most frequent treatment-emergent AEs (TEAEs) are 
summarized below. 
Ibrutinib Monotherapy Studies (N=1071) 
Most frequently reported 
TEAEs (>15%)   
Most frequently reported 
Grade 3 or 4 TEAEs (>2%)  
Most frequently reported 
Serious TEAEs (>2%)  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
Diarrhea 
 
 
Febrile neutropenia 
 
 
Hyponatremia 
 
TEAE = treatment-emergent adverse event 
 

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For more detailed information, refer to the current version of the Investigator’s Brochure. 
Pooled safety data are available for a total of 423 patients treated with various therapies in 
combination with ibrutinib across 4 studies conducted in B-cell malignancies, including 1 
randomized-control study (Investigator’s Brochure, 2015). Therapies used in combination with 
ibrutinib in these studies included BR (bendamustine and rituximab), FCR (fludarabine, 
cyclophosphamide, and rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone).  The most frequent TEAEs occurring in these patients 
are summarized below. 
Ibrutinib Combination Therapy Studies (N=423) 
Most frequently reported 
TEAEs >20%   
Most frequently reported 
Grade 3 or 4 TEAEs (>3%)  
Most frequently reported 
Serious TEAEs (>2%)  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
TEAE = treatment-emergent adverse event 
For more detailed information, refer to the current version of the IB. 
1.7 Risks 
Bleeding-related events 
There have been reports of hemorrhagic events in patients treated with ibrutinib, both 
with and without thrombocytopenia.  These include minor hemorrhagic events such as 
contusion, epistaxis, and petechiae; and major hemorrhagic events, some fatal, including 
gastrointestinal bleeding, intracranial hemorrhage, and hematuria.  Use of ibrutinib in 
patients requiring other anticoagulants or medications that inhibit platelet function may 
increase the risk of bleeding.  Patients with congenital bleeding diathesis have not been 
studied. 
Leukostasis  
There were isolated cases of leukostasis reported in patients treated with ibrutinib. A high 
number of circulating lymphocytes (>400000/µL) may confer increased risk.  
Lymphocytosis  
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% 
increase from baseline and an absolute count >5000/µL), often associated with reduction 
of lymphadenopathy, has been observed in most patients with CLL/SLL treated with 
ibrutinib. This effect has also been observed in some patients with MCL treated with 
ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not be 
considered progressive disease in the absence of other clinical findings. In both disease 
types, lymphocytosis typically occurs during the first few weeks of ibrutinib therapy 
(median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in patients 
with MCL and 18.7 weeks in patients with CLL/SLL. 
A large increase in the number of circulating lymphocytes (e.g., >400000/mcL) has been 
observed in some patients.  Lymphocytosis was not observed in patients with WM treated 
with ibrutinib.  Lymphocytosis appeared to occur in lower incidence and at lesser 
magnitude in patients with CLL/SLL receiving ibrutinib in combination with 
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Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in patients treated with ibrutinib, 
particularly in patients with cardiac risk factors, acute infections, and a previous history 
of atrial fibrillation (Investigator’s Brochure, 2015). For atrial fibrillation which persists, 
consider the risks and benefits of ibrutinib treatment and follow the protocol dose 
modification guidelines. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and 
anemia) were reported in patients treated with ibrutinib (Investigator’s Brochure, 2015). 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy 
and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe.  
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy.  At least 25% of 
patients with MCL and 35% of patients with CLL had Grade 3 or greater infections per 
NCI Common Terminology Criteria for Adverse Events (CTCAE) (Investigator’s 
Brochure, 2015).  The most commonly reported infections include pneumonia, cellulitis, 
urinary tract infection and sepsis.  Although causality has not been established, cases of 
progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with 
ibrutinib.  
Second Primary Malignancies  
Other malignancies, most frequently skin cancers, have occurred in patients treated with 
ibrutinib. 
Rash 
Rash has been commonly reported in patients treated with either single agent ibrutinib or 
in combination with chemotherapy.  In a randomized phase 3 study (PCYC-1112-CA), 
rash occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes 
were mild to moderate in severity.  
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in patients treated with 
single-agent ibrutinib or in combination with chemotherapy.  Patients at risk of tumor 
lysis syndrome are those with comorbidities and/or risk factors such as high tumor 
burden prior to treatment, increased uric acid (hyperuricemia), elevated LDH, bulky 
disease at baseline, and pre‐existing kidney abnormalities. 
Overdose 
Any dose of study drug administered in excess of that specified in this protocol is considered 
to be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as a SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose.  
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day).  Healthy subjects were exposed up to single dose of 1680 mg.  
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg.  Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 

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1.8 Justification 
Justification for a Phase III Trial of Ibrutinib and Ibrutinib plus Rituximab versus BR in 
CLL 
The excellent response rates and durable remissions seen thus far with ibrutinib, especially in 
comparison to modest outcomes and significant toxicity with standard therapy in this age group, 
justify the movement to phase III study as initial therapy for older patients with CLL. We 
therefore will perform a phase III trial of bendamustine plus rituximab versus ibrutinib versus 
ibrutinib plus rituximab to determine whether ibrutinib containing regimens are superior to 
standard therapy and also to determine whether combination therapy with ibrutinib plus 
rituximab is superior to ibrutinib alone. Rituximab is chosen as the CD20 antibody as it is 
currently being approved for CLL in combination with fludarabine and cyclophosphamide for 
CLL and also because of its common use with bendamustine in both previously treated and 
recently untreated CLL. This study will include patients aged 65 and older with untreated CLL 
in need of therapy. The primary endpoint will be PFS, which is an appropriate endpoint in an 
indolent disease with multiple options for second-line therapy, especially in an older population 
with competing risk factors for death. We expect that this trial will show that regimens 
containing ibrutinib are superior to standard therapy and thus will be practice changing and will 
transform initial therapy in this disease. Additionally, correlative laboratory samples obtained 
through this trial will allow detailed mechanistic studies into the biology associated with this 
agent. 
Justification for correlative studies  
The high response rates and durable remissions that have been seen with ibrutinib alone and in 
combination in early phase trials have limited the ability to draw conclusions regarding 
prognostic factors with this agent. Similarly, no data is available on resistance to or relapse after 
ibrutinib, both factors that predict resistance/relapse or relapse phenotypes. Therefore, a large 
phase III trial has the opportunity to impact the field both with novel therapies and detailed 
correlative analyses that may be applicable to both this drug and other kinase inhibitors. Since 
the cytogenetic abnormalities of del(17p13.1) and del(11q22.3) have been shown to be such 
strong biomarkers with other CLL therapies, and because there is a suggestion from ongoing 
trials that response may be improved in patients without Zap-70 methylation at CpG3, 
randomization will be stratified based on these factors as well as disease stage. Correlative 
biomarker studies will be required for all trial participants, as they are factors in randomization 
and interpretation of results. In addition, we will evaluate traditional biomarkers that predict 
response and response duration with chemoimmunotherapy, including stimulated cytogenetics 
(or equivalent), FISH, IgVH mutational status, Zap-70 methylation, baseline miR and gene 
expression profiling. Furthermore, novel recurrent DNA mutations have been identified in a 
significant subset of CLL patients and have been shown to be potential biomarkers of disease 
natural history; we will evaluate these in patients treated with standard therapy as well as 
ibrutinib containing regimens. Finally, studies derived from relapsed samples in each arm will 
be assessed for mutations and other biochemical features associated with resistance to ibrutinib  
Identification of patient groups that respond to ibrutinib monotherapy without the need for 
additional therapy is of great interest.  In this regard, it has been identified that serial changes in 
miRs demonstrated 10 that were variably modulated at day 29 of ibrutinib.  Of prime importance 
was down-regulation of miR-155, which has been associated with poor prognosis in CLL.[23] 
The expression of miR-155 is positively regulated by NF-κB,[24] which is inhibited by ibrutinib. 
Similarly, miR-29c has been identified as having reduced expression in progressive CLL[23] 
and in del(17p13.1) disease[25] and ibrutinib treatment increases this miR. Additionally, low 

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miR-155 and high miR-29c was associated with ZAP-70 methylated disease and also favorable 
outcome in two CALGB chemoimmunotherapy studies. These miRs and other plasma or cellular 
markers as potential early biomarkers of response will be pursued as part of this study in the two 
ibrutinib arms.  It is hoped that these early biomarkers will assist in identifying CLL patients 
who gain extended benefit to ibrutinib monotherapy. 
The eradication of minimal residual disease has been shown with chemoimmunotherapy to 
identify a subset of patients with prolonged remission duration and potentially improved 
survival.  Previous studies with kinase inhibitors have not addressed the impact of MRD or MRD 
eradication on response duration, so this will be evaluated in the context of this trial at 9 months 
and 24 months. This will be done centrally as part of bone marrow assessment of disease using 
4-color high sensitivity flow cytometry.  
1.9 Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 NCCTG and 
Mayo Clinic Cancer Center oncology clinical trials, the second involving 43 clinical trials. 
Routine inclusion of these measures should be considered similar to that of including 
performance status, either as stratification or prognostic covariates.[26, 27] 
2.0 
OBJECTIVES  
2.1 Primary Objective 
To determine whether progression free survival (PFS) is superior after therapy with 
bendamustine in combination with rituximab, ibrutinib alone, or ibrutinib in combination with 
rituximab in patients age 65 or older with previously untreated CLL 
2.2 Secondary Objectives 
2.2.1 To determine 2-year PFS in each of the three treatment arms 
2.2.2 To determine which treatment arm produces superior overall survival (OS)  
2.2.3 To determine the complete response (CR) rate, complete and nodular partial response 
(CR/nPR) rate, and overall response (PR+nPR+CR) rate (ORR) among the three treatment 
arms and compare these arms 
2.2.4 To determine the impact of MRD-negative disease at time of CR documentation and at 2 
years on PFS and OS in each of the treatment arms  
2.2.5 To determine duration of response after each of the three treatments and compare these 
treatment arms 
2.2.6 To determine toxicity and tolerability of the three treatment regimens 
2.2.7 To determine response and PFS of patients initially on the bendamustine in combination 
with rituximab arm who cross over to ibrutinib 
2.2.8 To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH mutational 
status, or select DNA mutations predict outcomes or time to response in these three arms 

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2.2.9 To determine whether local FISH results for del(11q22.3) and del(17p13.1) are consistent 
with central analysis. 
2.2.10 To determine whether baseline microRNA and gene expression markers are correlated with 
clinical outcomes of interest (e.g. progression-free and alive at 2 years versus not), as well 
as to explore changes in microRNA expression from baseline to post-treatment time points, 
with a focus on those with persistent lymphocytosis and relapse 
2.2.11 To determine whether eradication of MRD predicts longer duration of response with 
standard therapy and ibrutinib-based regimens 
2.2.12 To describe the baseline functional status, comorbid medical conditions, and number of 
medications of older CLL patients who meet criteria for therapy 
2.2.13 To determine how functional status changes with therapy using baseline to 3-month 
evaluation and end-of-study/2-year evaluation; to determine whether this change is different 
among the treatment groups 
2.2.14 To determine whether geriatric assessment variables known to be associated with 
chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity 
in the CLL population 
2.2.15 To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of 
response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints 
CR rate, rapidity of response, and progression-free survival (PFS) 
2.2.16 To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate, 
rapidity of response, and PFS 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although they 
will not be considered formal eligibility (exclusion) criteria, physicians should recognize that the 
following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness, which would prevent the patient from giving informed consent 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus 
or cardiac disease which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient 
• 
Women and men of reproductive potential should agree to use an appropriate method of birth 
control throughout their participation in this study and for 90 days after the last dose of study 
drug due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of 
birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or 
double barrier method (diaphragm plus condom). 
• 
Patients who are unable to swallow solid oral dosage forms will not be able to take the study 
treatment drugs. 
• 
Patients may not have an active intercurrent disease or concurrent malignancy that is expected to 
limit survival to < 5 years. 

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• 
Patients requiring other anticoagulants or medications that inhibit platelet function should use 
ibrutinib with caution. Ibrutinib use in patients with congenital bleeding diathesis has not been 
studied. Please see Section 11.2 for the specific anticoagulation therapies that must be avoided. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Alliance Study Chair. Please note 
that the Study Chair cannot grant waivers to eligibility requirements.  
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later would be considered 
Day 28. 
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 12 
consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 
4.1 Pre-Registration Eligibility Criteria (Step 0) 
4.1.1 Central Zap-70 submission 
All patients are REQUIRED to be pre-registered to A041202 in order to submit peripheral 
blood to the Alliance Hematologic Malignancy Biorepository (HEME) for central Zap-70 
methylation (See Section 6.2.1). This specimen submission is mandatory prior to 
registration as results will be used for stratification. See Section 6.2 for details on specimen 
submission.  
4.2 Registration Eligibility Criteria (Step 1) 
4.2.1 Documentation of Disease:  
Patients must be diagnosed with CLL in accordance with IWCLL 2008 criteria[28] that 
includes all of the following: 
• 
≥5x109 B lymphocytes (5000/μL) in the peripheral blood 
• 
On morphologic review, the leukemic cells must be small mature lymphocytes, and 
prolymphocytes must not exceed 55% of the blood lymphocytes. 
• 
CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell 
population, which express the B cell surface markers of CD19 and CD20, as well 
as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression 
or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by 
interphase cytogenetics.  
4.2.2 Staging and Indication for Therapy 
• 
Patients must be intermediate or high-risk Rai stage CLL. 
• 
Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus 
enlarged lymph nodes at any site, with or without hepatomegaly or 
splenomegaly 
• 
High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or 
without enlarged nodes and spleen plus disease-related anemia 
(hemoglobin <11 g/dL) or thrombocytopenia (platelet count <100 x 109/L) 
that 
is 
not 
attributable 
to 
autoimmune 
hemolytic 
anemia 
or 
thrombocytopenia 

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• 
Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines[28] 
which includes at least one of the following criteria: 
• 
Evidence of marrow failure as manifested by the development or worsening 
of anemia or thrombocytopenia (not attributable to autoimmune hemolytic 
anemia or thrombocytopenia) 
• 
Massive (≥6 cm below the costal margin), progressive or symptomatic 
splenomegaly 
• 
Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy 
• 
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy 
• 
Constitutional symptoms, which include any of the following: 
▪ 
Unintentional weight loss of 10% or more within 6 months 
▪ 
Significant fatigue 
▪ 
Fevers >100.5 degrees F for 2 weeks or more without evidence of 
infection 
▪ 
Night sweats >1 month without evidence of infection 
4.2.3 Prior Treatment 
• 
Patients must not have had prior therapy for CLL (except palliative steroids or treatment of 
autoimmune complications of CLL with rituximab or steroids). 
• 
Treatment with rituximab and/or high dose corticosteroids for autoimmune complications 
of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at 
a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of 
registration.  
4.2.4 Age ≥ 65 years  
4.2.5 ECOG Performance Status 0-2 
4.2.6 Active Hepatitis B  
Patients with active hepatitis B defined by hepatitis B surface antigen positivity or core 
antibody positivity in the presence of hepatitis B DNA are not eligible for this study. Patients 
with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, 
but must have hepatitis serologies and hepatitis B DNA monitored periodically by the 
treating physician. 
IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have 
core antibody or surface antigen positivity without evidence of active viremia (negative 
hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies 
and hepatitis B DNA monitored periodically by the treating physician. 
4.2.7 Active systemic anticoagulation 
Patients must not be receiving active systemic anticoagulation with heparin or warfarin. 
Patients must be off warfarin therapy for at least 30 days prior to enrollment. 
4.2.8 Active intercurrent disease 
Patients with Class III or Class IV heart failure by New York Heart Association, those with 
unstable angina, and those with uncontrolled arrhythmia are not eligible.   

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Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 
6 months are not eligible.   
Patients with known HIV are eligible if their CD4 count is ≥ 350 cells/mm3 and if they are 
not taking prohibited CYP-interacting medications (See Section 4.2.12).   
4.2.9 Richter’s transformation or prolymphocytic leukemia 
Patients must not have any history of Richter’s transformation or prolymphocytic leukemia 
(prolymphocytes in blood > 55%). 
4.2.10 Prednisone or equivalent corticosteroid 
Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily. 
4.2.11 Intravenous antibiotics 
Patients must not have uncontrolled active systemic infection requiring intravenous 
antibiotics. 
4.2.12 CYP3A4/5 inhibitor or inducer 
Patients must not have continued requirement for therapy with a strong CYP3A4/5 inhibitor 
or inducer (See Appendix II). 
4.2.13 Allergy to mannitol 
Patients must not have a known allergy to mannitol.  
4.2.14 Significant hypersensitivity to rituximab 
Patients must not have prior significant hypersensitivity to rituximab (not including infusion 
reactions). 
4.2.15 Prior Surgery 
Patients may not have had major surgery within 10 days of enrollment, or minor surgery 
within 7 days of enrollment. Examples of minor surgery include dental surgery, insertion of 
a venous access device, skin biopsy, or aspiration of a joint. The decision about whether a 
surgery is major or minor can be made at the discretion of the treating physician.  
4.2.16 Initial laboratory values 
Patients must meet the following required initial laboratory values: 
ANC 
≥ 1,000/µL unless due to bone marrow involvement 
AST or ALT 
≤ 2.5 x upper limits of normal except if due to disease 
infiltration of the liver 
Bilirubin 
≤ 1.5 x upper limits of normal (unless due to liver 
involvement, hemolysis, or Gilbert’s disease) 
Creatinine Clearance 
≥ 40 mL/min* 
Platelet count (untransfused) 
≥ 30,000/µL 
 
 
* To be calculated by modified Cockcroft-Gault formula as follows: 

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CrCl (ml/min) =  (140 – age in years) x actual wt (in kg) 
 
 
 
  72 x serum creatinine (mg/dl) 
5.0 
REGISTRATION/RANDOMIZATION, STRATIFICATION 
5.1 Pre-registration Requirements (Step 0) 
5.1.1 Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. Human subject 
protection committee approval of this protocol and a consent form is required. 
5.1.2 Zap-70 Methylation 
All patients are REQUIRED to be pre-registered to A041202 in order to submit peripheral 
blood to the Alliance Hematologic Malignancy Biorepository (HEME) for central Zap-70 
methylation prior to registration (see Section 6.2.1). Within 10 days of receipt of the 
specimen, the treating physician/institutional contact will be notified of the results, which 
must be documented on the patient enrollment form. Results of Zap-70 are needed for 
patient registration, and patients must register to A041202 within 14 days of notification of 
Zap-70 results. Zap-70 results are only used for stratification purposes and DO NOT 
determine patient eligibility. 
5.2 Registration Requirements (Step 1) 
5.2.1 FISH must be performed locally within 30 days prior to registration (see Section 6.2.1). 
Registration must occur within 14 days of notification of Zap-70 results and prior to the 
initiation of therapy. Rai stage at screening by Zap-70, as well as status of del(11q22.3) and 
del(17p13.1) by FISH, must be documented on registration form. After patient registration, 
the institutional contact will receive a registration confirmation and treatment confirmation, 
which includes the randomization arm. 
5.2.2 Registration to the required laboratory correlative science (A041202-LC1), optional 
pharmacogenetic (A041202-PP1), and optional geriatric functional status assessment 
(A041202-EL1) correlative studies will be performed at the time registration occurs to the 
treatment study. Patients should not be enrolled on the A041202-EL1 correlative study until 
institutional staff have been trained (see Section 5.4.2). See Section 5.4 for correlative 
science registration procedures.  
5.3 Registration Procedures 
5.3.1 CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
x .85 (for female patients) 

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Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact 
the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
5.3.2 CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 

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In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. For 
sites using the CIRB, IRB approval information is received from the CIRB and applied to 
the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent 
to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the A041202 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol #A041202 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
Requirements for A041202 Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
• 
For applicable NCTN studies with a radiation and/or imaging (RTI) component, the 
enrolling site must be aligned to a RTI provider.  To manage provider associations 
access 
the 
Provider 
Association 
tab 
on 
the 
CTSU 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for 
ensuring that the appropriate agreements are in place with their RTI provider, and 
that appropriate IRB approvals are in place. 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 

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→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
      1818 Market Street, Suite 3000 
      Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab  
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
5.3.3 OPEN Access Requirements and Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of pre-
registration, registration and treatment information.   Please print this confirmation for your 
records.  
To receive site reimbursement for patient participation in A041202-PP1 or A041202-EL1, 
completion dates must be entered in the OPEN Funding screen post registration. Please refer 
to the protocol specific funding page on the CTSU members’ website for additional 
information. Timely entry of completion dates is recommended as this will trigger site 
reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 

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5.4 Registration to Correlative Science Studies and Companion Protocols 
5.4.1 Registration to Correlative Studies Described in Section 10.0 
There are three embedded correlative science companion studies within Alliance A041202. 
A041202-LC1 pertaining to correlative studies is essential for interpretation of the trial 
results and is therefore mandatory. A041202-PP1 and A041202-EL1 must be offered to 
all patients enrolled on Alliance A041202 (although patients may opt to not participate). 
These correlative science companion studies do not require separate IRB approval. The 
correlative science companion studies included within Alliance A041202 are: 
• 
Leukemia Correlative Science in Alliance A041202 (A041202-LC1, Section 10.1) 
• 
Geriatric Assessment in Alliance A041202 (A041202-EL1 Section 10.2) 
Geriatric Assessment questionnaire booklets for A041202-EL1 are to be ordered prior 
to the registration of any patients. For booklet ordering instructions see Section 6.3. 
• 
Evaluation 
of 
Candidate 
Pharmacogenetic 
Determinants 
of 
Ibrutinib 
or 
Ibrutinib/Rituximab Response (A041202-PP1, Section 10.3) 
5.4.2 Site Credentialing for Companion Study A041202-EL1 
At least one member of the research team at each participating institution must complete a 
brief training on the geriatric assessment procedures before enrolling any patients to this 
companion study. If multiple individuals are responsible for administering the Geriatric 
Assessment, each of these individuals must complete the training. The training module may 
be 
accessed 
on 
the 
member 
side 
of 
the 
Alliance 
website 
(www.allianceforclinicaltrialsinoncology.org). In order to gain access to the member side 
of the Alliance website, the user must have an active CTEP-IAM account that is linked to 
at least one of the NCTN group rosters.  To login, select “Member Login” on the Alliance 
homepage and enter the CTEP-IAM account username and password.  After logging in, the 
training module can be found under education and training > online training and under “For 
Site Staff.” Once the training is complete, print a copy of the completion certificate to keep 
in study records.  
If you have difficulties accessing or completing the online training, contact that the A041202 
Protocol Coordinator, so that a training may be coordinated via telephone. Retain email 
documentation from the study team that states that the training was completed. 
5.4.3 Registration to Companion Protocol (Temporarily Suspended as of February 28, 2014) 
There is one optional separate companion protocol associated with Alliance A041202, 
CALGB 9665: The CALGB Leukemia Tissue Bank. However, CALGB 9665 was 
temporarily suspended on February 28, 2014. Therefore, after February 28, 2014, Alliance 
institutions may not consent or enroll patients on CALGB 9665. Patients already enrolled 
on CALGB 9665 should continue to submit specimens as required. 
Refer to the CALGB 9665 protocol document for specimen procurement and submission 
instructions. The time points for specimen submission, outlined within CALGB 9665 (as 
well as Section 6.2.1), are: 
• At time of diagnosis/registration: Bone marrow aspirate, peripheral blood, buccal cell 
sample (saliva). Buccal cell sample is collected at diagnosis/registration for 
A041202-LC1, and on day 1 of cycle 1 for CALGB 9665. 
• Relapse/Progression: Bone marrow aspirate, peripheral blood 
• During remission: Bone marrow aspirate, peripheral blood 

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5.5 Stratification 
Stratification on A041202 will be according to Rai stage (intermediate versus high), presence or 
absence of del(11q22.3) or del(17p13.1) on FISH (performed by individual institutions), and < 
versus ≥ 20% methylation of CpG 3 on Zap-70 (performed centrally). In the event that a sample 
does not yield a Zap-70 methylation status, data will be input based on IgVH mutational status 
as follows: >20 if IgVH mutated or <20 for unmutated. 
5.6  Re-Registration at the Time of Progression 
Patients randomized to bendamustine plus rituximab (Arm 1) will be eligible to cross over to 
single-agent ibrutinib upon documentation of disease progression. Please note that patients who 
opt to cross over must be re-registered to the study within 12 months of progression 
documentation. The delay is only to allow for patients who do not immediately require additional 
therapy at the time of progression. Intervening treatment for CLL prior to crossover is not 
permitted. In addition, please make sure to reassess eligibility (Section 4.0) at re-registration. 
Patients do NOT need to meet eligibility requirement of 5x109 B lymphocytes in the peripheral 
blood.  See Section 7.0 for required tests and observations to be completed prior to re-
registration. Please note that even though patients are crossing over to Arm 2, the registration 
system will refer to the re-registration arm assignment as “Arm 4.” Patients who crossover to 
single agent ibrutinib should restart the study calendar after re-registration (i.e. the first day of 
ibrutinib would be considered Day 1 of Cycle 1). Follow the study calendar (Section 7.0) and 
specimen submission schedule (Section 6.2.1) as required for patients assigned to Arm 2 (unless 
specifically stated otherwise). 
Re-registration procedures: 
OPEN may be accessed at https://open.ctsu.org, from the OPEN tab on the CTSU website at 
https://www.ctsu.org, or from the OPEN Registration tab on the CALGB website. 
To enroll a patient within OPEN, institution staff must have: 
1. 
A valid and active CTEP-IAM account. This is the same user ID and password 
used 
for 
CTSU’s 
website 
(for 
more 
information 
see 
https://www.ctsu.org/public/CTEP-IAM_Factsheet.pdf). 
2. 
Enrollment of patients on CALGB coordinated protocols requires a “Registrar” 
role in the CALGB roster. Assignment of the “Registrar” role is managed 
through the CALGB Central Office via submission of a roster update form 
signed by the Principal Investigator of the member network. 
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information is 
provided on the CTSU members’ website OPEN tab, or within the OPEN URL. For any 
additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923, 
or 
ctsucontact@westat.com. 
6.0 
DATA AND SAMPLE SUBMISSION  
6.1 Data Submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS).  To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < 
https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the enrolling 
site. 

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Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 
1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
6.1.1 Data Submission Schedule and Requirements 
A Data Submission Schedule is available on the Alliance study webpage, within the Case 
Report Forms section. The Schedule of Forms is also available on the CTSU site within the 
study-specific Education and Promotion folder, and is named Time & Events.  
Please note that cycles are 28 days (this applies to both treatment and follow-up). Beginning 
with Day 1 of Cycle 6, patients are only required to be seen every 3 cycles. Sites may choose 
to enter data into Rave in either 28 or 84 day cycles. The visit number in Rave will not match 
the treatment cycle # unless 28 day cycles are chosen in Rave after Day 1 of Cycle 6.  
Please contact the Data Manager listed on the protocol cover page for data submission 
questions. 
6.1.2 Adverse Event Data Submission  
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for routine toxicity and adverse event (AE) reporting. Please note that AE 
reporting stops at discontinuation of protocol therapy. Note: CTCAE version 5.0 must be 
used for serious AE reporting through CTEP-AERS as of April 1, 2018 (see Section 16.1). 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. Section 16.0 provides information about expedited reporting. 
Solicited Adverse Events: The following abnormalities/adverse events are considered 
"expected" and their presence/absence should be solicited, and severity graded, at baseline 
and for each cycle of treatment for the first six months on study. After six cycles of 
treatment, patients who continue to receive ibrutinib on Arms 2 and 3 should submit 
solicited AEs every 3 months. 
• 
Neutrophil count decreased (see Investigations in CTCAE v.4) 
• 
Platelet count decreased (see Investigations in CTCAE v.4) 
• 
Infusion related reaction (see General disorders and administration site conditions 
in CTCAE v.4) 

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• 
Anaphylaxis (see Immune system disorders in CTCAE v.4) 
• 
Allergic reaction (see Immune system disorders in CTCAE v.4) 
• 
Tumor lysis syndrome (see Metabolism and nutrition disorders in CTCAE v.4) 
• 
Rash maculo-papular 
• 
Fatigue 
• 
Cough 
• 
Diarrhea 
• 
Edema limbs (see General disorders and administration site conditions in CTCAE 
v.4) 
• 
Dizziness 
• 
Dyspepsia 
• 
Anemia 
• 
Hypertension 
• 
Bruising 
6.2 Specimen Collection & Submission 
Specimens for patients registered on Alliance A041202 and its substudies must be logged and 
shipped using the online Alliance Biospecimen Management System (BioMS).  
All submitted specimens must be labeled with the protocol number (A041202), patient ID 
number, patient’s initials, and date and type of specimen collected (e.g., serum, whole blood). 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. 
Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL: 
http://bioms.wustl.edu/bioms, using most standard web browsers (Safari, Firefox, Internet 
Explorer).  For information on using the BioMS system, please refer to the ‘Help’ links on the 
BioMS web page to access the on-line user manual, FAQs, and training videos.  To report 
technical problems, such as login issues or application errors, please contact: 1-855-55-BIOMS.  
For assistance in using the application or questions or problems related to specific specimen 
logging, please contact: 1-855-55-BIOMS. 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 

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6.2.1 Specimen Submission Overview 
Specimen 
Baseline* 
Day 1, 
Cycle 1 
Day 1, 
Cycle 
2** 
Day 1, 
Cycle 9 
Day 1, 
Cycle 27 
*** 
Remission Progression Ship to: 
For ALL patients registered to A041202, submit the following: 
Central 
morphology 
review 
6 bone marrow smears, 
6 blood smears, 2 
biopsy sections; and if 
dry tap, 2 marrow 
touch preps (see 6.2.2) 
 
 
 
 
 
 
OSU 
Bone 
marrow 
aspirate 
1 x 10 mL EDTA tube 
 
 
1 x 10 mL 
EDTA 
tube 
1x10 mL 
EDTA 
tube 
 
1 x 10 mL 
EDTA tube 
HEME 
Peripheral 
whole blood 
4x10 mL acid citrate 
dextrose (ACD)  tubes, 
1x 5 mL heparin tube,  
1 x 5 mL EDTA tube§ 
 
4x10 mL 
ACD  
tubes 
4x10 mL 
ACD  
tubes 
4x10 mL 
ACD  
tubes 
 
4x10 mL 
ACD   tubes, 
1x10 mL 
heparin tube  
 
 
HEME 
Buccal cell 
sample 
50 mL 
sterile tube 
 
 
 
 
 
 
HEME 
For patients registered to CALGB 9665A, submit the following: 
Bone 
marrow 
aspirate 
5 mL in 1 or 2 
lavender top tubes 
 
 
 
 
5 mL in 1 
or 2 
lavender 
top tubes 
5 mL in 1 or 
2 lavender 
top tubes 
HEME 
Peripheral 
whole blood 
10 mL in 2 – 3 
lavender top tubes 
 
 
 
 
10 mL in 2 
– 3 
lavender 
top tubes 
10 mL in 2 – 
3 lavender 
top tubes 
HEME 
Buccal cell 
sample 
 
50 mL 
sterile 
tube 
 
 
 
 
 
HEME 
For patients registered to A041202-PP1B, submit the following: 
Peripheral 
whole blood  
2 x 5 mL EDTA tubes 
 
 
 
 
 
 
HEME 
Bone 
marrow 
aspirate 
1 mL in 1 EDTA tube 
 
 
 
 
 
 
HEME 
* 
Baseline samples (except the EDTA tube that must be submitted for Zap-70 methylation) may be sent at any point 
from the date of pre-registration, but must be sent prior to the initiation of therapy.  
** 
Arm 2 and arm 3 only  
*** Required for all patients except those on Arm 1 who have crossed over to receive ibrutinib. Patients who have 
crossed over to ibrutinib should restart specimen collection beginning on Day 1 of Cycle 2 of ibrutinib. 
§ 
EDTA tube must be submitted at pre-registration (for Zap-70 Methylation). 
A 
Collect and submit only from patients who enrolled on CALGB 9665 prior to the temporary suspension on February 
28, 2014. 
B 
Collect and submit only from patients who consent to model consent question #2. 
 

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All patients must have FISH for del(17p13.1) and del(11q22.3) performed locally within 30 
days of registration, which will be used for stratification.  FISH results must be documented 
on the OPEN enrollment form at registration. Additionally, a copy of the original forms of 
the FISH results must be submitted via Medidata Rave. 
All patients will undergo Zap-70 methylation centrally prior to randomization. Collect and 
submit the 1 x 5 mL EDTA tube at pre-registration for Zap-70 methylation (see Section 
6.2.4.2). Within 10 days of receipt of the specimens, the treating physician/institutional 
contact will be notified of the results, which must be documented on the OPEN enrollment 
form at registration. Upon patient registration, the institution will be sent a registration 
confirmation, as well as the randomization arm. 
For patients who have undergone a bone marrow procedure prior to patient consent/pre-
registration, enrollment may be permitted provided Study Chair approval is obtained via e-
mail and documented in the patient’s charts. In this case, baseline bone marrow LC1 
specimens are not required, but material will need to be submitted for central morphology 
review. 
6.2.2 Central Morphology Review 
6.2.2.1 
Prior to initiation of therapy, obtain (6) air-dried, unstained bone marrow smears 
(films) and six (6) unstained blood smears (films) for confirmatory cytologic and 
cytochemical studies. These should be sent to the Alliance Biorepository at Ohio State 
University (OSU) immediately at the address below, following instructions in Section 
6.2.2.4. 
6.2.2.2 
Also submit: 1) two unstained bone marrow biopsy sections; and 2) two unstained 
marrow biopsy touch preparations if the aspirate was a dry tap.  
6.2.2.3 
All specimens required for participation on A041202 should take priority over other 
specimens collected, regardless of site or group affiliation. Send the bone marrow 
biopsy smears and films plus core and touch prep unstained slides to the Alliance 
Biorepository at OSU. Send via overnight traceable courier service, no Saturday 
shipments should be included.  
6.2.2.4 
Label each slide with the patient’s Alliance ID number obtained through pre-
registration and protocol number (A041202). Pack carefully in protective slide cartons 
(not cardboard folders). Samples must be logged and shipped via the BioMS see 
Section 6.2 for instructions. A copy of the shipping manifest produced by the BioMS 
must be printed and placed in the shipment with the specimens. Promptly mail (slides 
must arrive within one week of sampling) to:  
Alliance Biorepository at Ohio State University (OSU) 
Department of Pathology 
Polaris Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 
path.calgb@osumc.edu 
Send a copy of your institutional bone marrow aspiration and biopsy report, CBC 
report, and immunophenotyping report as soon as complete to the Biorepository at 
OSU. These reports must include differential cell counts and cytochemistry results.  

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Shipment on Monday through Friday by overnight service to assure receipt is 
encouraged. If shipping on Friday, FedEx or UPS must be used and the air bill must be 
marked “For Saturday delivery” and “Priority Overnight Service”. Do not ship 
specimens on Saturdays. Please be sure to use a method of shipping that is secure and 
traceable.  
6.2.3 Specimen Submission for Correlative Protocol: CALGB 9665 
CALGB 9665 was temporarily suspended on February 28, 2014. Therefore, after February 
28, 2014, Alliance institutions may not consent or enroll patients on CALGB 9665. Patients 
already enrolled on CALGB 9665 should continue to submit specimens. Refer to the 
CALGB 9665 protocol document for specimen submission. The specimens to be submitted 
for CALGB 9665 are also included in the specimen submission table below. CALGB 9665 
is open to Alliance institutions only. 
6.2.4 Specimen Submission for Correlative Studies Alliance A041202-LC1 and Alliance 
A041202-PP1 
6.2.4.1 
Bone Marrow Submission (Alliance A041202-LC1) (For all patients) 
From all patients, collect 10 mL of bone marrow aspirate at baseline, day 1 of cycle 9, 
at month 24, and at time of disease progression in an EDTA tube.  
Specimens for patients registered on this study must be logged and shipped using the 
online Alliance BioMS, as described in Section 6.2. 
The specimens should be labeled with the study number (A041202), Alliance patient 
ID, patient’s initials, institution, and date and time of specimen procurement, and 
sample type. A copy of the shipping manifest produced by the BioMS must be printed 
and placed in the shipment with the specimens. Specimens should be sent at ambient 
temperature on the same day as collection to the Alliance Hematologic Malignancy 
Biorepository (HEME): 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754  Fax: 614-688-4755 
Ship specimens by overnight courier to the Alliance Hematologic Malignancy 
Biorepository the same day they are collected. Shipment on Monday through Friday 
by overnight service to assure receipt is encouraged. If shipping on Friday, FedEx or 
UPS must be used and the air bill must be marked “For Saturday delivery.” Do not ship 
specimens on Saturdays or Sundays. Please be sure to use a method of shipping that is 
secure and traceable.  
6.2.4.2 
Peripheral Blood Submission (Alliance A041202-LC1) (For all patients) 
From all patients, collect peripheral blood samples at baseline, day 1 of cycle 2 (for 
patients on arm 2 and arm 3 only), day 1 of cycle 9, at month 24, and at progression. 
The amounts collected and appropriate tubes for each time point are outlined above in 
the table in Section 6.2.1. 
Specimens for patients registered on this study must be logged and shipped using the 
online Alliance BioMS, as described in Section 6.2.. 

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The specimens should be labeled with the study number (A041202), Alliance patient 
ID, patient’s initials, institution, and date and time of specimen procurement, and 
sample type. A copy of the shipping manifest produced by the BioMS must be printed 
and placed in the shipment with the specimens and sent to the Alliance Hematologic 
Malignancy Biorepository. Specimens should be sent at ambient temperature on the 
same day as collection to the Alliance Hematologic Malignancy Biorepository 
(HEME): 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754  Fax: 614-688-4755 
Ship specimens by overnight courier to the Alliance Hematologic Malignancy 
Biorepository the same day they are collected. Shipment on Monday through Friday 
by overnight service to assure receipt is encouraged. If shipping on Friday, FedEx or 
UPS must be used and the air bill must be marked “For Saturday delivery.” Do not ship 
specimens on Saturdays. Please be sure to use a method of shipping that is secure and 
traceable.  
6.2.4.3 
Buccal Cell Sample Submission (Alliance A041202-LC1) (For all patients) 
One buccal cell sample should be obtained from each patient at baseline.  As noted in 
Section 6.2.1, patients who enrolled on CALGB 9665 prior to February 28, 2014 will 
have an additional sample collected on cycle 1 day 1. Buccal collection kits may be 
obtained by contacting the Alliance HEME Biorepository at 614-688-4754. In the 
event that you need to collect a sample but don't have a kit, have patient rinse mouth 
with 10mL of mouth wash (e.g. Scope) for 30 to 60 seconds, and then spit the 
mouthwash back into a 50 mL sterile tube. Securely tighten the cap on the tube and 
label the tube with the patient ID and date of specimen collection. Place the tube in a 
biohazard bag and seal the bag. Keep any samples refrigerated until you are ready to 
ship. The buccal cell sample must be collected before brushing teeth or at least 2 hours 
after brushing teeth, eating or drinking. This specimen may be collected at any time 
before starting protocol therapy. Buccal cell samples for A041202-LC1 and CALGB 
9665 should not be collected on the same day. The buccal cell specimen should be 
submitted the same day as collected. 
Specimens for patients registered on this study must be logged and shipped using the 
online Alliance BioMS, as described in Section 6.2. 
The specimens should be labeled with the study number (A041202), Alliance patient 
ID, patient’s initials, institution, and date and time of specimen procurement, and 
sample type. A copy of the shipping manifest produced by the BioMS must be printed 
and placed in the shipment with the specimens and sent to the Alliance Hematologic 
Malignancy Biorepository. Specimens should be sent at ambient temperature on the 
same day as collection to the Alliance Hematologic Malignancy Biorepository 
(HEME): 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754  Fax: 614-688-4755 

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Ship specimens by overnight courier to the Alliance Hematologic Malignancy 
Biorepository the same day they are collected. Shipment on Monday through Friday 
by overnight service to assure receipt is encouraged. If shipping on Friday, FedEx or 
UPS must be used and the air bill must be marked “For Saturday delivery.” Do not ship 
specimens on Saturdays. Please be sure to use a method of shipping that is secure and 
traceable.  
6.2.4.4 
Bone Marrow Aspirate and Whole Blood Submission (Alliance A041202-PP1) 
One mL of the initial bone marrow aspirate and the whole blood specimen are collected 
for the correlative study A041202-PP1, described in Section 10.3. From patients who 
consent to model consent question #2, collect 1 mL of bone marrow aspirate and 10 
mL (2 x 5 mL tubes) of whole blood in an EDTA tube at baseline.  
Specimens for patients registered on this study must be logged and shipped using the 
online Alliance BioMS, as described in Section 6.2. 
The specimens should be labeled with the study number (A041202), Alliance patient 
ID, patient’s initials, institution, and date and time of specimen procurement, and 
sample type. A copy of the shipping manifest produced by the BioMS must be printed 
and placed in the shipment with the specimens and sent to the Alliance Hematologic 
Malignancy Biorepository (HEME): 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital and Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754  Fax: 614-688-4755 
Ship specimens on a cold pack by overnight courier to the Alliance Hematologic 
Malignancy Biorepository (HEME) the same day they are collected. Shipment on 
Monday through Friday by overnight service to assure receipt is encouraged. If 
shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For 
Saturday delivery” and “Priority Overnight Service”. Do not ship specimens on 
Saturdays. Please be sure to use a method of shipping that is secure and traceable.  
6.3 Geriatric Assessment (Alliance A041202-EL1)  
Correlative study A041202-EL1 is described in Section 10.2. For patients who consent to 
model consent question #1, the following questionnaires are to be submitted via Medidata 
Rave: 
Questionnaire/Survey To be completed by 
Submission Time Points (+/-30 days) 
Prior to 
treatment* 
Day 1 of 
Cycle 6 
Progression or 2 
Years 
Self Geriatric 
Assessment Measure - 
Patient Questionnaire  
Patient 
X 
X 
X 
Health Care Professional 
Questionnaire 
Nurse, CRA or 
Physician 
X 
X 
X 
* Between pre-registration and start of cycle 1. 
A member of the research team at each participating institution must complete a brief 
training on the geriatric assessment procedures (see Section 5.4.2).  

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Geriatric Assessment questionnaire booklets for A041202-EL1 are to be ordered prior 
to the registration of any patients. The healthcare professional questionnaire and patient 
completed questionnaire booklets can be ordered by downloading and completing the CTSU 
supply request form (located under the site registration documents section of the CTSU 
A041202 Webpage) and faxing the form to the CTSU Data Center. Samples of 
questionnaires found in Appendix V of the protocol document are for reference and IRB 
submission only. They are not to be used for patient completion.  
See Section 6.1 for data submission and Section 10.2 for instructions regarding the Alliance 
A041202-EL1 correlative science companion study. 
 

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7.0 
REQUIRED DATA 
Laboratory and clinical parameters during the treatment courses are to be followed using individual 
institutional guidelines and the best clinical judgment of the responsible physician. It is expected that 
patients on this protocol will be cared for by physicians experienced in the treatment and supportive 
care of patients with leukemia. Sections 11.0 & 16.0 describe possible toxicities that may occur with 
protocol treatment. 
Pre-Study Testing Intervals  
To be completed within 30 DAYS before registration: 
- 
FISH for del(11q22.3) and del(17p13.1) 
- 
Peripheral blood flow cytometry 
- Bone marrow biopsy 
- CT scans 
- HBsAg, HBsAb, Hep C, HB core antibody 
- Serum immunoglobulins 
- Beta 2 microglobulin 
To be completed within 14 DAYS before registration: 
- All blood work (except FISH analysis, peripheral blood flow cytometry, central Zap-70 
hepatitis antibodies, immunoglobulins, and beta 2 microglobulin) 
- History and physical 
 
Tests & Observations1 
Prior 
To 
Study 
Cycle 1 
Day 1 
Day 1 of 
Cycles 2, 
3, 4, 5, 6 
Day 1 of Every Third 
Cycle During Treatment, 
Arm 1 Observation & 
Clinical Follow-up*, ** 
Relapse/ 
Disease 
progression
*** 
Prior to Re-
registration
**** 
History & progress notes 3 
X 
 
X 
X 
X 
 
X 
Physical examination and node measurements3 
X 
 
X 
X 
X 
X 
Height 3 
X 
 
 
 
 
X 
Weight / body surface area 3, 4 
X 
 
X 
X 
 
X 
Performance status 
X 
 
X 
X 
X 
X 
Solicited baseline abnormalities/AEs 
X 
 
X 
A 
 
X 
Registration fatigue/uniscale assessment 
B 
 
 
 
 
 
Laboratory Studies1 
FISH for del(11q22.3) and del(17p13.1) (performed 
locally) 2, 3 
X 
 
 
 
 
 
Zap-70 methylation (central analysis) 3, 5 
X 
 
 
 
 
 
Complete blood count (CBC) 
X 
X 
X 
X 
X 
X 
Serum creatinine, CrCl (est.), BUN 
X 
X 
X 
A 
 
X 
Serum electrolytes 
X 
X 
X 
A 
 
X 
Uric acid / glucose / phosphate / Ca++ 
X 
 
 
 
 
X 
AST, ALT, PT INR, alk. phos., bilirubin 
X 
 
X 
A 
 
X 
LDH, albumin 
X 
 
X 
A 
 
X 
Beta-2-microglobulin 
X 
 
 
 
 
X 
Direct antiglobulin test (Coomb’s test) 
X 
 
 
 
 
X 
Serum or urine HCG9 
X 
 
 
 
 
X 
HBsAg, HBsAb, Hep C, HB core antibody 6 
X 
 
 
 
 
X 
Peripheral blood flow cytometry 3 
X 
 
G 
H 
X 
I 
Serum immunoglobulins (IgG, IgA, IgM) 
X 
 
G 
C 
 
 
Staging 

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CT scan (chest, neck, abdomen, & pelvis) 1, 3 
X 
 
G 
H 
X 
I 
Bone marrow asp. & biopsy 1, 3, 7 
D 
 
 
F 
F 
I 
Additional Required Correlative Samples8 
Peripheral whole blood 
X 
 
E 
H 
X 
 
Buccal cell sample 
X 
 
 
 
 
 
 
* 
For patients in clinical follow up (see definition in Section 14.1.3), Cycle 9 and Cycle 27 visits may be performed 
+/- 1 follow-up cycle (i.e. Day 1 of Cycles 8 or 10, or Cycles 26 or 28). 
** These studies are required for all patients in Arm 1 observation, those continuing to receive ibrutinib on Arms 2 
and 3, and those in clinical follow-up. These studies are required every third cycle until progression or 10 years 
from study registration (step 1), (see Section 14.1.3 for complete definitions). 
*** Required for all patients at time of progression/relapse. For patients who have already crossed over, these studies 
are also required for second progression/relapse.   
****Patients on Arm 1 who progress and crossover to single agent ibrutinib should restart the study calendar after re-
registration (i.e. the first day of ibrutinib would be considered Day 1 of Cycle 1). Crossover patients should follow 
the calendar as if they are assigned to Arm 2, unless stated otherwise in the following footnotes. See Section 6.2.1 
for other specimen submission instructions.  
1 
Tests & observations and laboratory studies can be performed up to 48 hours prior to Day 1 of the specified cycle.  
CT scans and bone marrow biopsy may be completed up to 7 days prior to specified cycle. 
2 
FISH can be performed on peripheral blood (preferred) or bone marrow. 
3 
Reports and clinic notes must be submitted in PDF form via Medidata Rave. Bilateral measurements of largest 
nodes on CT are required. 
4 
The dose of chemotherapy need not be changed unless the calculated dose changes by ≥ 10%. 
5 
All patients will undergo Zap-70 methylation centrally prior to randomization. Within 10 days of receipt of the 
specimens, the treating physician/institutional contact will be notified of the results. See Section 6.2.1.. 
6 
All patients should be screened for hepatitis B prior to registration. Patients who test positive for hepatitis B 
should be monitored closely if randomized to receive rituximab, and should be considered for prophylactic 
antiviral therapy. 
7 
Bone marrow analysis should include flow cytometry.  
8 
Included here are only the specimens to be submitted for the required correlative study A041202-LC1 (please see 
Sections 5.4, 6.2.1, and 10.1). Additional correlative specimens and data are to be collected from patients who 
consent to the optional correlative studies A041202-EL1 and A041202-PP1 (model consent questions # 1 and 2), 
as well as those who enrolled on CALGB 9665 prior to the temporary suspension on February 28, 2014. Please 
see Sections 5.4, 6.2.1, 6.3, 10.2 and 10.3, as well as the companion protocol for CALGB 9665 for further 
information on the additional optional correlative and companion studies. 
9 
Only required for women of childbearing potential. 
A 
Ongoing solicited adverse event forms and indicated laboratory studies are only necessary for patients still on 
ibrutinib (Arms 2 and 3).  
B 
To be completed after registration and ≤ 21 days prior to treatment, see Section 1.7 and Appendix III. 
C 
Serum immunoglobulin should be on Day 1 of Cycle 9 for all patients. For patients on continuous ibrutinib (Arms 
2 and 3), perform serum immunoglobulins on C9D1, C12D1. C27D1, and then, perform yearly. 
D 
In addition to institutional marrow, submit specimens for central morphology review (see Section 6.2.2) and 
A041202-LC1 correlative (see Sections 6.2.1 and 6.2.4.1). 
E 
Submit only on Day 1 of Cycle 2 for patients on continuous ibrutinib (Arms 2 and 3). See Section 6.2.1. 
F 
For all patients, perform Day 1 of Cycle 9, Day 1 of Cycle 27, and at relapse or disease progression. In addition 
to institutional marrow, submit bone marrow aspirate for A041202-LC1 as required in Sections 6.2.1 and 6.2.4.1.  
G 
Day 1 of Cycle 4 only (not required for Day 1 of Cycles 2, 3, 5 and 6). 
H 
Perform Day 1 of Cycle 9 and Day 1 of Cycle 27 only.  
I 
CT scan, peripheral blood flow cytometry, and bone marrow aspirate, biopsy and flow cytometry results can be 
used from progression visit and do not need to be repeated, nor do they need to fall within 14-day window prior 
to re-registration.  
 
 

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8.0 
TREATMENT PLAN 
Questions regarding treatment should be directed to the Alliance Study Chair. All patients will 
undergo FISH (institutionally) for del(17p13.1) and del(11q22.3) as well as Zap-70 methylation 
(centrally) prior to randomization. FISH and Zap-70 methylation results must be documented on 
enrollment form. After registration, the institutional contact will receive a registration confirmation 
and treatment registration that includes the randomization arm. Protocol treatment is to begin within 
7 days of patient registration. 
All patients should be screened for hepatitis B prior to registration. Patients with a positive hepatitis 
B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis 
serologies and hepatitis B DNA monitored periodically by the treating physician. 
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) window 
before and after the protocol-defined date for Day 1 of a new cycle. For example, if the treatment due 
date is a Friday, the window for treatment includes the preceding Thursday through the following 
Monday. In addition, patients are permitted to have a new cycle of chemotherapy delayed up to 7 
days for major life events (e.g., serious illness in a family member, major holiday, vacation that 
cannot be rescheduled) without this being considered a protocol violation. New cycles of ibrutinib 
can be started up to 7 days before the protocol-defined date for major life events. Documentation to 
justify a delay or advance of a cycle should be provided. 
8.1 Arm 1: Bendamustine/Rituximab 
Treatment on Arm 1 consists of six 28-day cycles. The day before day 1 of cycle 1 (day 0), 
rituximab is given at 375 mg/m2 IV, then at 500 mg/m2 IV on day 1 of cycles 2-6. Bendamustine 
is given at 90 mg/m2 IV on days 1 and 2 of each cycle. During cycle 1, at the discretion of the 
treating investigator, the bendamustine may be given at a dose of 70 mg/m2 rather than 90. 
Subsequent cycles should be administered at 90 mg/m2. 
• 
Recommended/prohibited ancillary therapy is outlined in Section 12.0  
• 
Premedication: Premedication per institutional guidelines is permitted, however, 
recommended premedication is the following: 
• 
Bendamustine: ondansetron 16 mg IV prior to each dose 
• 
Rituximab: acetaminophen 650 mg PO and diphenhydramine (or equivalent 
antihistamine) 50 mg PO/IV 30 minutes prior to each dose; other premedications may 
be given per institutional guidelines. 
• 
Drug administration 
Full administration guidelines are outlined in Section 11.0 Bendamustine and rituximab are 
both administered intravenously. Bendamustine should be administered prior to rituximab on 
days that they are both given, but the order of administration may be altered per institutional 
guidelines. 
• 
Dose modifications/dose delays after cycle 1 are outlined in Section 9.0. 
• 
Patients enrolled on Arm 1 bendamustine plus rituximab will be eligible to cross over to 
single-agent ibrutinib upon documentation of disease progression. These patients will remain 
on ibrutinib until they experience a second disease progression. The follow-up schedule for 
those patients who remain on ibrutinib should match those of Arm 2. 
8.2 Arm 2 Ibrutinib 
Treatment on this arm consists of ibrutinib 420 mg PO daily, on days 1-28 of each 28-day cycle, 
until disease progression as defined by IWCLL guidelines.[28] Because of the well-documented 

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lymphocytosis that occurs early with this agent and is not associated with disease progression, 
progressive lymphocytosis in the absence of other signs of disease progression (e.g. 
splenomegaly, enlarging lymph nodes, disease-related constitutional symptoms) will not be 
considered disease progression. 
• 
Recommended/prohibited ancillary therapy is outlined in Section 12.0. 
• 
Premedication is not required. 
• 
Drug administration 
Full administration guidelines are outlined in Section 11.0. Ibrutinib is administered by 
mouth as three capsules daily. 
• 
Patients on ibrutinib should keep a daily drug administration record with dates and times 
taken (see Appendix I, Patient Medication Diary).  
• 
If a dose of ibrutinib is missed, it can be taken as soon as possible on the same day with a 
return to normal schedule the following day. The patient should not take extra capsules to 
make up the missed dose, and any remaining study drug must be returned at the next 
scheduled visit. 
• 
Dose modifications/dose delays after cycle 1 are outlined in Section 9.0. 
8.3 Arm 3 Ibrutinib/Rituximab 
Treatment on this arm consists of ibrutinib 420 mg PO daily, on days 1-28 of each 28-day cycle, 
plus rituximab 375 mg/m2 IV weekly for four weeks starting on cycle 2 day 1 (days 1, 8, 15, and 
22), then day 1 of cycles 3 through 6. Ibrutinib will be continued past cycle 6 until disease 
progression. Because of the well-documented lymphocytosis that occurs early with this agent 
and is not associated with disease progression, progressive lymphocytosis in the absence of other 
signs of disease progression (e.g. splenomegaly, enlarging lymph nodes, disease-related 
constitutional symptoms) will not be considered disease progression. 
• 
Recommended/prohibited ancillary therapy is outlined in Section 12.0.  
• 
Premedication  
No premedication is required for ibrutinib. Rituximab premedication per institutional 
guidelines is permitted. Recommended premedication is acetaminophen 650 mg PO and 
diphenhydramine 50 mg PO/IV (or equivalent antihistamine) 30 minutes prior to each dose 
• 
Drug administration  
Full administration guidelines are outlined in Section 11.0. Ibrutinib is administered orally 
as three capsules daily, and rituximab is administered intravenously. Ibrutinib should be 
administered prior to rituximab on days when both agents are given.  
• 
Patients on ibrutinib should keep a daily drug administration record with dates and times 
taken. 
• 
If a dose of ibrutinib is missed, it can be taken as soon as possible on the same day with a 
return to normal schedule the following day. The patient should not take extra capsules to 
make up the missed dose, and any remaining study drug must be returned at the next 
scheduled visit. 
• 
Dose modifications/dose delays after cycle 1 are outlined in Section 9.0. 

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9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
9.1 Dose Modifications for Hematologic Toxicity 
G-CSF and GM-CSF may not be used prophylactically to avoid dose reductions, but may be 
used in cases of prolonged or recurrent neutropenia or in a patient who has had neutropenia with 
previous cycles.  Dose modifications should be made based on day 1 values for each cycle, or 
the presence of significant bleeding or febrile neutropenia. Hematologic toxicity will be graded 
according to IWCLL 2008 criteria[28], which account for pretreatment cytopenias. These are 
graded as follows: 
 
Grade 
Decrease in Platelets* or Hgb** from 
pretreatment value 
Absolute Neutrophil Count (ANC) (uL)*** 
1 
11%-24% 
≥1500 and <2000 
2 
25%-49% 
≥1000 and <1500 
3 
50%-75% 
≥500 and <1000 
4 
≥75% 
<500 
*Platelet counts must be below normal levels for any grade toxicity to be recorded.  If platelet count is <20x1012/L, this will be 
considered grade 4 toxicity. 
**Hgb levels must be below normal levels for any grade toxicity to be recorded. 
***If ANC is <1000 prior to study, the patient is not evaluable for toxicity assessment based on ANC. 
9.1.1 Arm 1 
Dose Level 
Bendamustine 
Rituximab 
1 (starting dose) 
90 mg/m2 
500 mg/m2 
-1 
50 mg/m2 
500 mg/m2 
-2 
30 mg/m2 
500 mg/m2 
• 
For grade 3 or 4 hematologic toxicity (or significant bleeding), hold therapy until 
toxicity returns to ≤ grade 1, and then dose reduce by 1 level. If patient experiences 
grade 3 or 4 toxicity at dose level -2, protocol therapy should be discontinued.  
• 
For febrile neutropenia, hold therapy until fever resolves and ANC is >1000, and then 
dose reduce by 1 level. If patient experiences febrile neutropenia at dose level -2, 
protocol therapy should be discontinued. 
• 
Once reduced, dose levels may not be escalated 
9.1.2 Arm 2 
Dose Level 
Ibrutinib 
1 (starting dose) 
420 mg 
-1 
280 mg 
-2 
140 mg 
• 
For grade 3 or 4 hematologic toxicity, significant bleeding, or febrile neutropenia, hold 
therapy until toxicity returns to ≤ grade 1. For the first occurrence, drug may be 
restarted at the original dose.  For the second occurrence and beyond, dose reduce by 
1 level.  
• 
Ibrutinib may be held for up to 28 consecutive days for drug-related toxicity.  If drug-
related toxicity persists, ibrutinib must be discontinued permanently. 
• 
Patients who are dose-reduced and are stable for 3 months may have dose escalated 1 
level. 

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• 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts 
(i.e., ≥50% increase from baseline and above absolute count 5000/mcL), often 
associated with reduction of lymphadenopathy, has been observed in most 
patients (75%) with relapsed/refractory CLL/SLL treated with ibrutinib. A 
substantial increase in the number of circulating lymphocytes (e.g., > 400,000/mcL) 
has been observed in a subset of patients. There have been isolated cases of leukostasis 
reported in patients treated with ibrutinib.  
A high number of circulating malignant cells (>400000/mcL) may confer increased 
risk; these patients should be closely monitored. Administer supportive care such as 
hydration and/or leukapheresis as indicated. Ibrutinib should be held if evidence of 
leukostasis until resolution of toxicity. 
9.1.3 Arm 3 
First 6 months 
Dose Level 
Ibrutinib 
Rituximab 
1 (starting dose) 
420 mg 
375 mg/m2 
-1 
420 mg 
No rituximab 
-2 
280 mg 
No rituximab 
-3 
140 mg 
No rituximab 
Subsequent months 
Dose Level 
Ibrutinib 
1 (starting dose) 
420 mg 
-1 
280 mg 
-2 
140 mg 
• 
For grade 3 or 4 hematologic toxicity, significant bleeding, or febrile neutropenia, hold 
therapy until toxicity returns to ≤ grade 1. For the first occurrence, drug may be 
restarted at the original dose.  For the second occurrence and beyond, dose reduce by 
1 level. 
• 
Ibrutinib may be held for up to 28 consecutive days for drug-related toxicity. If drug-
related toxicity persists, ibrutinib must be discontinued permanently. 
• 
Patients who are dose-reduced and are stable for 3 months may have dose escalated 1 
level. 
• 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts 
(i.e., ≥50% increase from baseline and above absolute count 5000/mcL), often 
associated with reduction of lymphadenopathy, has been observed in most 
patients (75%) with relapsed/refractory CLL/SLL treated with ibrutinib. A 
substantial increase in the number of circulating lymphocytes (e.g., > 400,000/mcL) 
has been observed in a subset of patients. There have been isolated cases of leukostasis 
reported in patients treated with ibrutinib.  
A high number of circulating malignant cells (>400000/mcL) may confer increased 
risk; these patients should be closely monitored. Administer supportive care such as 
hydration and/or leukapheresis as indicated. Ibrutinib should be held if evidence of 
leukostasis until resolution of toxicity. 

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9.2 Dose Adjustments for Non-Hematologic Toxicity  
Dose Level 
Bendamustine 
Ibrutinib 
1 (starting dose) 
90 mg/m2 
420 mg 
-1 
50 mg/m2 
280 mg 
-2 
30 mg/m2 
140 mg 
• 
For grade 3 or 4 non-hematologic toxicity at possibly, probably, or definitely related to 
bendamustine, hold bendamustine and rituximab until toxicity returns to ≤ grade 1, and then 
dose reduce by 1 level. If patient experiences grade 3 or 4 toxicity at dose level -2, 
bendamustine should be discontinued, but rituximab can continue for total course or can be 
discontinued at the discretion of the treating physician.  
• 
For grade 3 or 4 non-hematologic toxicity at least possibly, probably, or definitely attributable 
to ibrutinib, hold ibrutinib until toxicity returns to ≤ grade 1.  For a first occurrence, ibrutinib 
may then be restarted at the same dose.  For a second occurrence, once toxicity resolves, dose 
reduce by 1 dose level.  Prior to dose reduction for diarrhea, aggressive supportive care should 
be instituted.  Recommended agents for ibrutinib-induced diarrhea include cholestyramine and 
diphenoxylate/atropine. 
• 
For infusion reactions attributable to rituximab, supportive care should be provided per 
institutional protocols.  Rituximab can be continued without dose reduction. At the discretion 
of the treating physician and with study chair approval, rituximab and/or bendamustine can be 
discontinued for severe infusion reactions. 
• 
Rituximab should be discontinued in the following circumstances:  progressive multifocal 
leukoencephalopathy (PML), significant vesicular or bullous dermatitis, Stevens-Johnsons 
syndrome, or development of hepatitis B reactivation. 
• 
Patients who require the initiation of systemic anticoagulation should have ibrutinib held and 
be placed on low molecular weight heparin (concomitant warfarin therapy is prohibited). 
Treatment with ibrutinib should be held and not be restarted until the patient is clinically stable 
and has no signs of bleeding.  Patients should be observed closely for signs and symptoms of 
bleeding.  No dose reduction is required when study drug is restarted. 
• 
For Grade 3 or 4 skin reactions or infusion reaction/anaphylaxis at least possibly, probably or 
definitely attributable to bendamustine, bendamustine should be permanently discontinued and 
rituximab may be discontinued as well at the discretion of the treating physician. 
• 
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.  
• 
Ibrutinib is metabolized in the liver.  Please see the Child-Pugh scoring system outlined in 
Appendix VI to determine whether dose modifications are warranted according to the following 
instructions.  For patients who develop mild liver impairment while on study (Child-Pugh class 
A), the recommended dose is 280 mg daily (two capsules).  For patients who develop moderate 
liver impairment while on study (Child-Pugh class B), the recommended dose is 140 mg daily 
(one capsule).  Patients who develop severe hepatic impairment (Child-Pugh class C) must hold 
study drug until resolved to moderate impairment (Child-Pugh class B) or better and may be 
re-treated according to resolved hepatic conditions (i.e., 140 mg or 280 mg for moderate or 
mild impairment, respectively).  Monitor patients for signs of toxicity and follow dose 
modification guidance as needed. 

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• 
Investigators should be vigilant about detecting cases of suspected pulmonary and/or CNS 
fungal infections and, specifically, aspergillosis. If a case of aspergillosis is suspected or 
observed in this trial, ibrutinib should be discontinued. All suspected and confirmed cases of 
fungal infections should be reported to CTEP within 24 hours as outlined in Section 16.1. 
• 
For Grade 2 toxicity that is causing significant discomfort or functional impairment, dose 
interruption and modifications may be made using the same guidelines as for Grades 3 and 4 
at the discretion of the treating physician and after discussion with the study chair. 
9.3 Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely by 
actual weight without any modification unless explicitly described in the protocol. This will 
eliminate the risk of calculation error and the possible introduction of variability in dose 
administration. Failure to use actual body weight in the calculation of drug dosages will be 
considered a major protocol deviation. Physicians who are uncomfortable with calculating doses 
based on actual body weight should recognize that doing otherwise would be a protocol violation 
10.0 EMBEDDED CORRELATIVE SCIENCE COMPANION STUDIES  
There are three embedded correlative science companion studies.  Patients are required to participate 
in A041202-LC1, and encouraged to participate in A041202-EL1 and A041202-PP1.  
10.1 Leukemia Correlative Science in Alliance 041202 (Alliance A041202-LC1) 
10.1.1 Background 
Previous CLL research identified specific markers including cytogenetic abnormalities, 
Zap-70 methylation, and IgVH mutational status that predict both the natural history of this 
disease and response with specific therapies. With the studies performed in relapsed disease, 
it appears that the traditional genetic markers that predict poor response, including 
del(17p13.1), del(11q22.3) and complex karyotype are unrelated to outcome with ibrutinib. 
In patients with del(17p13.1), ORR in relapsed disease is 67%.[21] Further, the traditionally 
poor markers of IgVH unmutated disease and lack of Zap-70 methylation, which are 
associated with active BCR signaling are associated with improved responses to ibrutinib. 
We hypothesize that CLL cells with active BCR signaling pathways are dependent on this 
pathway for survival, and thus are more sensitive to BTK inhibition.  These data require 
confirmation in a larger data set, but suggest that novel markers in this disease may be 
important to response and response duration with ibrutinib.  Gene and miR expression 
profiling at baseline will be studied for signatures of extended PFS to treatment arms 
proposed.  Recently, whole genome sequencing has identified recurrent DNA mutations in 
CLL in SF3B1, NOTCH1, CRM1, MyD88, KLHL6, ERK1, and B-RAF with potential 
correlates to disease behavior and response to therapy.[29-31] NOTCH1 mutations are the 
most common in this series, with an overall prevalence of 12.2%, with 20.4% prevalence in 
unmutated CLL, and a relationship with poorer overall survival.  Additionally, mutational 
frequency is higher in those patients with refractory disease or Richter’s transformation.[32] 
SF3B1 mutations as well have been identified in up to 15% of patients with CLL,[31] with 
initial studies suggesting an association between mutations in this RNA splicing factor and 
poor-risk or fludarabine-refractory disease.[30, 33]   
All specimens included in these baseline correlative studies will be shipped to Ohio State 
University. For stimulated cytogenetics, samples will be stimulated using CpG 
oligonucleotides, and at least 20 metaphases will be examined for each patient.  For FISH 
analysis, the following probes will be used: 17p13.1(TP53), 13q14.3(DS13S319), 

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11q22.3(ATM), 6q21(SEC63), 3q27(BCL6), 8q24(CMYC), 14q32.3-11q13(IgH-CCND1), 
and centromere 12.  FISH will be performed per manufacturer’s guidelines, and at least 200 
cells will be analyzed for each probe.  To determine whether local FISH analysis is feasible 
for future studies, for this trial FISH analysis for del(11q22.3) and del(17p13.1) will be 
performed locally and centrally at baseline and results compared for each patient. Dr. Nyla 
Heerema at Ohio State University will perform FISH and cytogenetic studies.  
Zap-70 methylation will be performed by pyrosequencing at Ohio State University.  If, by 
the time this protocol is in place, a clinical Zap-70 test is not available, Zap-70 will be 
performed on a research basis and IgVH will be used for patient stratification. In the event 
that a sample does not yield a result after re-analysis, data will be input based on IgVH 
mutational status as follows: >20 if IgVH mutated or <20 for unmutated. 
DNA mutational analysis will be performed at Ohio State University in the laboratory of 
Dr. John Byrd using ion semiconductor technology (Ion Torrent).  Baseline samples will be 
saved for future comparison with relapse samples.     
Samples will also be collected at 1 month for patients on ibrutinib, 9 months and at the time 
of relapse.  Samples obtained at 1 and 9 months will be paired with baseline samples and 
used to examine changes in gene or microRNA expression in cells or plasma microvesicles.  
These analyses will be performed using Nanostring technology, and will be run at Ohio State 
University.  Specifically, these samples will allow for validation of miRs and genes 
changing with ibrutinib, comparisons among subsets of patients with persistent 
lymphocytosis, and those who relapse later in therapy.  These studies will hopefully identify 
groups of patients most likely to benefit from ibrutinib and also mechanisms of primary and 
secondary resistance.  These samples will be saved in the Alliance Hematologic Malignancy 
Biorepository for future use.  
The eradication of MRD following chemotherapy and CIT is an independent predictor of 
PFS and OS;[10, 34] however, MRD has not been evaluated in the context of targeted 
therapies. This phase III trial has the potential to definitively determine whether MRD 
negativity is required for durable response with kinase inhibitors in CLL. MRD will be 
determined by high sensitivity 4 color flow cytometric analysis of the bone marrow using 
validated panels.  A sample will be classified as positive if 50 or more lymphocytes (out of 
500,000 total leukocyte events) are positive for CD5, CD19, CD43, and CD45 bright, and 
negative for CD10, CD79b, and CD81. Dr. Gerard Lozanski at Ohio State University will 
perform these studies. 
10.1.2 Objectives 
• 
To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH 
mutational status, or select DNA mutations predict outcomes or time to response in 
these three arms 
• 
To determine whether local FISH results for del(11q22.3) and del(17p13.1) are 
consistent with central analysis 
• 
To determine whether baseline microRNA and gene expression markers in cells or 
plasma microvesicles are correlated with clinical outcomes of interest (e.g. 
progression-free and alive at 2 years versus not) as well as to explore changes in 
microRNA expression from baseline to post-treatment time points, with a focus on 
those with persistent lymphocytosis and relapse 
• 
To determine whether eradication of MRD predicts longer duration of response with 
standard therapy and ibrutinib-based regimens 
10.1.3 Sample Requirements 

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Baseline 
Peripheral Blood: 4x10 mL acid citrate dextrose (ACD) tubes, 1x 5 mL heparin tube, 1 x 5 
mL EDTA tube  
Bone marrow: 1 x 10 mL EDTA tube 
Buccal cell sample: 50 mL sterile tube 
Day 1 Cycle 2 (patients on Arm B and C only) 
Peripheral Blood: 4x10 mL acid citrate dextrose (ACD) tubes  
Day 1 Cycle 9 
Peripheral Blood: 4x10 mL acid citrate dextrose (ACD) tubes 
Bone marrow: 1x10mL EDTA tube 
24 months 
Peripheral Blood: 4x10 mL acid citrate dextrose (ACD) tubes 
Bone marrow: 1x10 mL EDTA tube  
Time of Relapse/Progression 
Peripheral blood:  4x10 mL acid citrate dextrose (ACD) tubes, 1x10 mL heparin tube 
Bone marrow: 1 x 10 mL EDTA tube 
10.2 Geriatric Assessment in Alliance A041202 (Alliance A041202-EL1) 
10.2.1 Background 
It is widely accepted that chronologic age is not the optimal indicator on which to estimate 
functional status and ability to tolerate specific therapies or procedures.  The older patient 
population seen in CLL makes it especially important to evaluate patients based on criteria 
other than chronologic age. A measurement tool has been developed by the Alliance Cancer 
in the Elderly Committee which evaluates patients based on functional status has been 
shown to be feasible in the cooperative group setting.[35] This tool has been used both to 
describe the functional status of cohorts of patients and to predict chemotherapy-associated 
toxicity.[36] The assessment incorporates measures in six domains; Functional status, 
comorbidity, psychological state, social activity, social support, and nutrition.[37]  The 
following tools are included in the assessment: Activities of Daily Living, Instrumental 
Activities of Daily Living, Karnofsky Performance Status, Number of Falls in 6 months, 
timed 10-foot walk, comorbidity assessment from Older American Resources and Services 
Evaluation, Blessed Orientation-Memory-Concentration Test, Hospital Anxiety and 
Depression Scale, Medical Outcomes Study Social Activity and Social Support Surveys, 
Body Mass Index, and weight loss over 6 months. This evaluation will be used in the context 
of this study to describe the global functional status of the patients at baseline, evaluate 
prediction of chemotherapy-associated toxicities with targeted agents, and evaluate patients 
longitudinally with therapy. Longitudinal assessment will allow further exploration of 
tolerability of these agents, as well as changes in functional status that correlate with disease 
control and long-term toxicity.  This assessment will be optional for all patients, but 
institutions must offer the correlative study to all patients enrolling on the treatment study. 
10.2.2 Study Design 
The intent is to enroll 350 patients onto this substudy. To obtain the 350 patients, 
consecutive patients enrolled on the parent study will be asked to participate on this study 
until 350 patients are obtained or until accrual to the parent study has stopped, whichever 

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happens first. Patients will complete the geriatric functional assessment at baseline (between 
pre-registration and cycle 1 day 1), day 1 of cycle 6, and at the end of study (progression, 
study discontinuation for toxicity or patient choice) or at 2 years.  Median time to complete 
the assessment is 15 minutes for patients, and 5 minutes for research staff, who are required 
for the Karnofsky performance status assessment, a timed 10 foot walk, and the 6 question 
Blessed Orientation-Memory-Concentration Test.[35]   
Geriatric Assessment questionnaire booklets for A041202-EL1 are to be ordered prior to the 
registration of any patients. For booklet ordering instructions see Section 6.3. 
10.2.3 Objectives 
The Geriatric Functional Assessment will be used in the context of this trial to address the 
following questions: 
10.2.3.1 To describe the baseline functional status, comorbid medical conditions, and 
number of medications of older CLL patients who meet criteria for therapy 
Hypothesis:  Older patients with CLL who meet criteria for therapy will need 
assistance with instrumental activities of daily living, have multiple comorbid medical 
conditions, and be on medications for conditions besides leukemia.   
Rationale: As many CLL studies include predominantly younger patients, and 
functional status measurements are not routinely incorporated into CLL trials, there is 
little information about the functional status of the typical older CLL patient who 
requires therapy for disease.  While these patients will likely still overestimate the true 
functional status of the CLL population (because of self-selection for clinical trial 
participation, ability to travel to a tertiary center in some cases, and ECOG PS that 
allows study entry), it will provide valuable information regarding this patient 
population. 
Statistical Considerations:  The anticipated sample size for this aim is 350 patients. 
This will be a descriptive analysis. Summary statistics and corresponding 95% 
confidence intervals will be generated for baseline functional status, comorbid medical 
conditions, and the number of medications a patient is taking. 
10.2.3.2 To determine how functional status changes with therapy using baseline to 6 month 
evaluation and end of study / 2-year evaluation.  To determine whether this 
change is different among the treatment groups 
Hypothesis: Functional status will significantly improve with therapy.  The magnitude 
of change will be greater with ibrutinib-containing regimens. 
Rationale:  With disease control, it is very likely that functional status will 
improve.  However, functional status can also be limited because of treatment-
associated toxicity or the rigor of being on therapy (multiple doctor visits with blood 
draws, radiology, infusions), so it is important to balance therapy efficacy and 
tolerability.  Ibrutinib has been very well tolerated, so it will be interesting to 
investigate whether this tolerability translates into improved functional status for this 
group. 
Statistical Considerations:  It is assumed that 90% of the initial 350 patients will be 
assessed for functional status at 6 months and 60% will be assessed at 2 years; this 
corresponds to a 20% attrition rate we observed on other studies. With 315 patients 
assessed at 6 months (i.e. 90% of 350), a 0.367 standard deviation difference in 

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standardized 
means 
can 
be 
detected 
between 
patients 
treated 
with 
bendamustine+rituximab and patients treated with ibrutinib +rituximab with power of 
90% and a two-sided alpha level of 0.05. In general, a 0.5 standard deviation change 
in functional status score is considered clinically meaningful and so this aim has 
sufficient power to detect a clinically meaningful difference between the arms. This is 
a simplistic calculation and the more sophisticated analysis described below will likely 
have more power because it will analyze the changes across all timepoints. 
Analysis of covariance with repeated measures will be used to analyze the functional 
status changes between the two treatment arms if the attrition over time is relatively 
minimal. Treatment arm will be the independent variable (bendamustine+rituximab 
versus ibrutinib+rituximab) and the functional status score will be the dependent 
variable. Baseline comorbid conditions and socio-demographic factors will be entered 
as covariables. If attrition is considerable over the course of the substudy, a pattern 
mixture model will be used to analyze change in functional status over time by 
treatment arm, for each subset of patients maintained on the study for different lengths 
of time. [38, 39]Within the structure of the pattern mixture model, a random coefficient 
model will be used to control for other mediating factors including socio-demographic 
factors and baseline co-morbid conditions. Clinical significance of the findings will be 
further tested using logistic regression analysis to determine whether treatment arm is 
significantly predictive of those patients with a meaningful functional decline, defined 
as a drop of 0.50 standard deviations or greater in their baseline functional status score, 
at 6 months and 2 years. 
Although ANOVA with repeated measures will be the primary analysis if the amount 
of missing data < 20%, sensitivity analyses, including the use of pattern mixture 
modeling, will be conducted to determine the effect of “missingness” on the inferences. 
If the results are different using these two methods, the pattern mixture modeling 
approach will be used.  
10.2.3.3 To determine whether geriatric assessment variables known to be associated with 
chemotherapy toxicity in other disease groups can also predict therapy-associated 
toxicity in the CLL population 
Hypothesis:  A predictive model for chemotherapy adverse events (AEs) will be able 
to predict therapy-associated AEs in this patient population. 
Rationale:  Baseline variables identified in a predictive model for chemotherapy 
AEs[36] can also predict significant AEs (defined as grade 3+ AEs) associated with 
ibrutinib containing-regimens and confirm that specific geriatric assessment tools can 
predict AEs associated with cancer therapy in elderly patients. 
Statistical Considerations:  We will assess incidence of serious (grade 3 or higher) 
adverse events in each of the treatment arms; based on previous data, we expect a 50% 
grade 3+ AE rate with standard therapy, a 25% grade 3+ AE rate in the ibrutinib alone 
arm, and a 30% rate in the ibrutinib + rituximab arm. Toxicity associated with 
bendamustine+rituximab is expected to be primarily hematologic.[10] AEs associated 
with ibrutinib or ibrutinib + rituximab is expected to be hematologic as well as 
diarrhea, rash, and fever.[21, 22]   
The expected sample size for this aim is 350 patients. The primary analysis will be to 
use the various geriatric scores that were found to be predictive of serious adverse 
events in other patient populations (an AE of grade 3 or higher). This will be assessed 

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by determining whether the area under the curve (AUC) of a receiver operating curve 
(ROC) is statistically, significantly greater than 0.50, the value that is no better than 
chance. The analyses will be done for each arm separately, which will involve 
approximately 157 patients. There is approximately 90% power to detect an AUC of 
0.60 or greater, regardless of what the split is between patients with a serious AE and 
patients without a serious AE with a sample size of 157. AUCs that would be of interest 
are between 0.70 and 0.90. Hence, this study will have greater than 99% power to 
detect differences of this magnitude. This is an exploratory (NOT confirmatory 
analysis) and further studies will be warranted if we observe AUC values above 0.70. 
Models using baseline assessments will be used to predict who will experience a grade 
3 or higher adverse event. We will examine the associations between an occurrence of 
a grade 3+ (i.e. grade 3, 4, or 5) adverse event and the baseline geriatric assessment 
variables using logistic regression. These analyses will be done separately for each 
treatment arm as well as jointly using models that include treatment arm and a 
treatment/geriatric assessment interaction term. A comparison of those variables found 
to be statistically significantly associated with a grade 3+ AE for this patient population 
will be compared to those found to be associated in other patient populations. A level 
of significance of 0.05 will be used (no adjustment for multiple comparisons since we 
are determining whether associations found significant in other disease groups are also 
significant here). 
In addition, we will test any prognostic model that has been developed for other disease 
groups that use the geriatric assessment variables. To do this, we will develop a 
multivariable logistic regression model for predicting a grade 3+ AE using the variable 
in the prognostic model for other disease groups. We will then perform a receiver 
operating characteristic (ROC) analysis and determine whether the area under the 
curve (AUC) differs significantly from 0.5, which would indicate the model has 
predictive power. 
If existing models do not validate, we will develop a new prognostic model for AEs 
from the baseline assessments. All factors with univariable p-value less than 0.2 will 
be considered, including the potential for interactions of interest. The performance of 
the new model will be compared to existing models to determine whether it potentially 
has greater discriminatory ability by comparing the AUCs of each model. 
10.3 Evaluation 
of 
Candidate 
Pharmacogenetic 
Determinants 
of 
Ibrutinib 
or 
Ibrutinib/Rituximab Response (Alliance A041202-PP1) 
10.3.1 Background and Hypothesis 
Pharmacogenetic studies will focus on the hypothesized synergistic interaction of ibrutinib 
and rituximab. The tendency of ibrutinib to cause a peripheral lymphocytosis (perhaps due 
to disruption of bone marrow/lymph node homing mechanisms) combined with the rapid 
clearance of peripheral B-cells observed after rituximab treatment is the proposed basis of 
this synergy. Several germline polymorphisms can predict rituximab sensitivity. A 
polymorphism in FCGR3A, encoding the Fc-gamma receptor on natural killer (NK) cells, 
has been shown to affect rituximab response in follicular lymphoma and DLBCL, but not in 
CLL[40-43]. We hypothesize that the effects of this polymorphism on antibody-dependent 
cell mediated cytotoxicity (ADCC), i.e. NK-cell mediated destruction of rituximab coated 
cells, will be more pronounced in CLL with the addition of ibrutinib.  The three arms of this 
study provide controls to appropriately test this, since one arm has both agents, one has 
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effects specific to the proposed synergistic interaction between ibrutinib and rituximab can 
be assessed. Minimal residual disease (MRD) will be the primary endpoint. 
In addition to the primary hypothesis, other hypotheses to be tested include a C1QA SNP 
(rs172378), shown to predict rituximab response in FL, but never tested in CLL[44, 45] 
C1QA encodes a complement protein, and presumably affects complement dependent 
cytotoxicity (CDC), another mechanism by which rituximab kills B-cells. These studies will 
also include the investigation of the candidate gene variation as well as novel high density 
single-nucleotide polymorphisms (SNP) platforms available to survey the pattern of 
variation of the entire genome of an individual, allowing the identification of genes that have 
not previously related to the pharmacology of the drugs of interest or to a certain biological 
pathway. Currently, platforms with hundreds of thousands of SNPs have been extensively 
used in so called genome-wide associations studies (GWAS) and do not only provide 
information of the SNP pattern of an individual, but also on the quantitative pattern on copy 
number variation (including loss of heterozygosity, LOH). 
10.3.2 Objectives 
The primary objective is to assess whether the FCGR3A polymorphism (rs396991) is 
correlated with depth of response (MRD status) to ibrutinib plus rituximab after 8 cycles.   
The secondary objectives are to assess whether CIQA polymorphism (rs172378) is 
correlated with MRD status, CR rate, rapidity of response, and PFS. Thus, secondary 
endpoints will be CR rate, rapidity of response, and progression-free survival (PFS). 
10.3.3 Methods 
From the initial bone marrow aspirate, 0.5 mL will be used to culture fibroblasts to obtain 
germline DNA. If any patient who consents to PP1 is not able to have fibroblasts 
successfully cultured, a remaining portion of the LC1 buccal cell DNA sample may be used 
for this purpose. As a source of DNA for secondary correlative studies described below, 
whole blood will be obtained from consenting study participants at baseline, prior to receipt 
of study treatment. The blood will be sent to the Alliance Hematologic Malignancy 
Biorepository (HEME) for processing. Blood samples will be processed into plasma, PBL 
and DNA. If needed, B-cells can be removed by magnetic bead purification to eliminate 
CLL cells from the samples. DNA quality will be assessed by UV spectrophotometry and 
by agarose gel electrophoresis. All DNA samples will be stored at HEME until they are 
distributed to the appropriate laboratory for genotyping. For FCGR3A and C1QA SNPs, 
samples will be genotyped using previously established assays (Sequenom and Taqman, 
respectively). Phenotypic data will be extracted from the Alliance database by the Alliance 
Statistical Center. Center and statistical analyses will be conducted under the direction of 
the responsible Alliance primary statistician. 
11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium 
Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial 
contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% of 
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It is not necessary to change the doses due to changes in weight unless the calculated dose changes 
by ≥10%. 
11.1 Rituximab (IDEC-C2B8) 
Please refer to the FDA-approved package insert for rituximab for product information and a 
complete list of adverse events. 
AVAILABILITY 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 100 mg 
or 500 mg of rituximab solution, respectively, at a concentration of 10 mg/mL. Please refer to 
the agent’s package insert for additional information. 
STORAGE & STABILITY 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 mg/mL) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
PREPARATION 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final concentration 
of 1-4 mg/mL. Mix by inverting the bag gently. 
ADMINISTRATION 
Rituximab will be administered by IV infusion. Patients must be pretreated with acetaminophen 
and diphenhydramine (or equivalent antihistamine) on each day of antibody treatment. On days 
on which both ibrutinib and rituximab are given, ibrutinib will be taken first, followed by 
rituximab administration. 
Do not administer rituximab IV push or bolus. For the initial infusion, start at a rate of 50 
mg/hour; if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, 
to a maximum rate of 400 mg/hour. For subsequent infusions, if the patient tolerated the initial 
infusion, start at a rate of 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour 
increments every 30 minutes, to a rate of 400 mg/hour. If the patient did not tolerate the initial 
infusion, follow the initial infusion guidelines. If a reaction occurs, slow or stop the infusion.  If 
the reaction abates, restart infusion at 50% of the previous rate. These guidelines are 
recommended. Individual institutions may follow institutional guidelines for rituximab 
administration. 
TOXICITY 
The most serious adverse events associated with rituximab include severe infusion reactions, 
tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions consisting 
of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal reactions occurred 
within 24 hours of the first dose of rituximab. Because severe infusion reactions have been noted 
more frequently in patients with high leukocyte counts, such patients should be observed closely. 
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells. 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be the release of 
cytokines. If a reaction occurs, the infusion should be stopped until the symptoms resolve, and 

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then restarted at a 50% slower rate. Consider additional pre-medication with acetaminophen 650 
mg PO and diphenhydramine 50 mg PO/IV (or equivalent antihistamine). 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority of 
these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 1 
month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with rituximab. 
Recent reports describe JC virus reactivation leading to progressive multifocal 
leukoencephalopathy (PML) in patients who were receiving rituximab. Patients presenting with 
new neurologic findings (e.g., major changes in vision, unusual eye movements, loss of balance 
or coordination, confusion) should be evaluated for PML. 
A report in the literature described an increase in fatal infection in HIV-related lymphoma 
patients when rituximab was used in combination with CHOP chemotherapy, as compared to 
CHOP alone.  
11.2 Ibrutinib (PCI-32765, NSC # 748645, IND #117241) 
AVAILABILITY 
Ibrutinib is supplied by Pharmacyclics, Inc., and distributed by the CTEP, DCTD, NCI.  
Ibrutinib is supplied as hard gelatin capsules containing 140mg micronized ibrutinib and the 
following excipients:  microcrystalline cellulose; croscarmellose sodium; sodium lauryl sulfate; 
may contain magnesium stearate.  Capsules are packaged in high-density polyethylene (HDPE) 
bottles with an induction seal and a child resistant screw top cap.  Each bottle contains 92 
capsules. 
AGENT ORDERING AND AGENT ACCOUNTABILITY 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating investigators 
at each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management.   
Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
Investigator Brochure Availability 

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The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/   
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov   
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx    
• 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/    
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov   
• 
IB Coordinator:  IBCoordinator@mail.nih.gov    
• 
PMB email:  PMBAfterHours@mail.nih.gov   
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
STORAGE AND STABILITY 
Ibrutinib hard gelatin capsules should be stored at 15-25°C (59-77°F). Shelf life surveillance of 
the intact bottles is ongoing. 
ADMINISTRATION 
Ibrutinib is taken orally, with 8 ounces (approximately 240 mL) of water. The capsules should 
be swallowed intact, not less than 30 minutes before or 2 hours after a meal. Doses should be 
taken at about the same time each day. If the patient misses a dose, it can be taken as soon as 
possible on the same day with a return to the normal schedule the following day. The patient 
should not take extra capsules to make up the missed dose.   
TOXICITY 
For a comprehensive adverse events and potential risks list (CAEPR), please see Section 16.2. 
DRUG INTERACTIONS 
Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A4/5. Please see Appendix II 
for a list of strong inhibitors and inducers. 
Agents That May Increase ibrutinib Plasma Concentrations (CYP3A4/5 Inhibitors) 
Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A4/5 can 
increase ibrutinib exposure and should be avoided. Alternative agents with mild or no 
CYP3A4/5 inhibition should be considered. 
Co-administration of ketoconazole, a strong CYP3A4/5 inhibitor, in 18 healthy subjects, 
increased dose normalized exposure (Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, 
respectively.  Therefore, concomitant administration of ibrutinib with strong inhibitors of 
CYP3A4/5 (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, 
telithromycin, itraconazole, and nefazadone) should be avoided.  If a strong CYP3A4/5 inhibitor 
must be used, the Medical Monitor should be consulted before the use, and a dose reduction of 
ibrutinib to 140 mg daily or temporary hold of ibrutinib should be considered.  Subjects should 
be closely monitored for potential treatment-related toxicities.  The same dose of ibrutinib 

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administered prior to the temporary hold or dose reduction may be given upon reinitiation of 
ibrutinib after CYP3A4/5 use.  Moderate CYP3A4/5 inhibitors (aprepitant, erythromycin, 
fluconazole, verapamil, and diltiazem) should be used with caution.  If the benefit outweighs the 
risk and a moderate CYP3A4/5 inhibitor must be used, monitor subject for toxicity and follow 
dose modification guidance in the individual protocols, as needed.  Grapefruit juices and Seville 
oranges may also increase ibrutinib plasma concentrations and should be avoided for the 
duration of ibrutinib treatment.  
Agents That May Decrease ibrutinib Plasma Concentrations (CYP3A4/5 Inducers) 
Administration of ibrutinib with strong inducers of CYP3A4/5 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.  Strong CYP3A4/5 inducers 
(eg, carbamazepine, rifampin, phenytoin and St. John’s Wort) can decrease ibrutinib exposure 
and therefore should be avoided.  Alternative agents with less CYP3A4/5 induction should be 
considered.   
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with ECGs and electrolytes should be considered and if needed, a medical monitor 
may be contacted. 
Anticoagulation Therapy 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in patients requiring other anticoagulants or medications that inhibit platelet function.  
Patients with congenital bleeding diathesis have not been studied. 
11.3 Bendamustine 
Please refer to the FDA-approved package insert for bendamustine for product information and 
a complete list of adverse events. 
AVAILABILITY 
Bendamustine is supplied as a single-use vial containing 100 mg bendamustine HCL as white 
to off-white lyophilized powder 
STORAGE & STABILITY 
Bendamustine may be stored up to 25° C (77°F) with excursions permitted up to 30°C (86°F).  
Retain in original package until time of use to protect from light. 
ADMINISTRATION 
Bendamustine is administered by intravenous route over 30 minutes in 500 mL normal saline 
(to achieve a final concentration of 0.2-0.6 mg/mL). 
TOXICITY 
The most common side effect is bone marrow suppression. The most common non-hematologic 
adverse events in CLL (>15%) include pyrexia, nausea, and vomiting.  Other adverse reactions 
seen frequently include asthenia, fatigue, malaise/weakness, dry mouth, somnolence, cough, 
constipation, headache, mucosal inflammation, and stomatitis.   
Drug Interactions 
Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure of 
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12.0 ANCILLARY THERAPY 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc., when appropriate. All blood products should be irradiated and leukopore 
filtered to prevent transfusion-associated graft versus host disease.   
No prophylaxis is required for the administration of ibrutinib but may be administered if consistent 
with institutional guidelines. Institutional guidelines regarding supportive care related to 
bendamustine and rituximab infusions should be utilized.  A suggested regimen is provided below: 
Bendamustine: ondansetron 16 mg IV prior to each dose 
Rituximab: acetaminophen 650 mg PO and diphenhydramine 50 mg PO/IV (or equivalent 
antihistamine) 30 minutes prior to each dose 
Lymphocytosis 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts (i.e., ≥50% increase 
from baseline and above absolute count 5000/mcL), often associated with reduction of 
lymphadenopathy, has been observed in most patients (75%) with relapsed/refractory CLL/SLL 
treated with ibrutinib. A substantial increase in the number of circulating lymphocytes (e.g., > 
400,000/mcL) has been observed in a subset of patients. There have been isolated cases of leukostasis 
reported in patients treated with ibrutinib.  
A high number of circulating malignant cells (>400000/mcL) may confer increased risk. These 
patients should be closely monitored. Administer supportive care such as hydration and/or 
leukapheresis as indicated. Ibrutinib should be held if evidence of leukostasis until resolution of 
toxicity. 
12.1 Alliance Policy Concerning the Use of Growth Factors 
12.1.2 Epoetin Alfa / Darbepoietin Alfa 
Use of epoetin alfa / darbepoietin alfa in this protocol is prohibited. 
12.1.2 Filgrastim (G-CSF), pegfilgrastim, and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF), pegfilgrastim and sargramostim (GM-CSF) treatment is allowed per 
ASCO guidelines but not encouraged. 
2. Filgrastim/pegfilgrastim and sargramostim: 
a. may not be used prophylactically to avoid dose reductions or delays  
b. may not be used prophylactically because of concern about myelosuppression from 
prior chemotherapies 
3. For the treatment of febrile neutropenia the use of colony-stimulating factors (CSFs) should 
not be routinely instituted as an adjunct to appropriate antibiotic therapy. However, the use 
of CSFs may be indicated in patients who have prognostic factors that are predictive of 
clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction (sepsis 
syndrome) or fungal infection, as per the ASCO guidelines.  Investigators should therefore 
use their own discretion in using the CSFs in this setting.  
4. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources.  
12.2 CYP Inhibiting Drugs 
1. Concomitant use of strong CYP3A4/5 inducers or inhibitors is prohibited.  Patients on these 
inhibitors should not be entered onto the study. 

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2. If use of a strong CYP3A4/5 inducer or inhibitor is indicated during the conduct of the study, 
selection of an alternate concomitant medication with less potent enzyme inhibition 
potential is strongly recommended.  If a strong inducer or inhibitor is necessary, contact the 
study chair.  If a strong inhibitor is needed, ibrutinib will be temporarily held or dose-
reduced to 140 mg daily.  Patients should be closely monitored for potential treatment-
related toxicities.  
3. Moderate CYP3A4/5 inhibitors (such as aprepitant, erythromycin, fluconazole, verapamil, 
and diltiazem) should be used with caution. If a moderate CYP3A inhibitor must be used, 
reduce ibrutinib to 140 mg for the duration of the inhibitor use.  No dose adjustment is 
required in combination with mild inhibitors. 
4. Grapefruit juice and Seville oranges may also increase ibrutinib plasma concentrations and 
should be avoided for the duration of ibrutinib treatment.   
5. A list of strong CYP3A4/5 inducers and inhibitors is found in Appendix II.  
12.3 Surgery 
The following guidance should be applied during 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 serosanguineous drainage or the need for drainage 
tubes. 
• 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture 
[other than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should be 
held for at least 3 days prior to the procedure and should not be restarted for at least 3 
days after the procedure. For bone marrow biopsies that are performed while the subject 
is on ibrutinib, it is not necessary to hold ibrutinib for these procedures. 
• 
For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, or for at least 7 days after the urgent surgical procedure, 
whichever is longer. 
12.4 Permitted Concomitant Medications 
Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (e.g., joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that do 
not exceed 100 mg per day of prednisone or equivalent are permitted. 
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent.  
The following may be considered: localized hormonal or bone sparing treatment for non-B-cell 
malignancies, and localized radiotherapy for medical conditions other than the underlying B-
cell malignancies. 
12.5 Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) or other 
transporters, except OCT2.  Ibrutinib is a mild inhibitor of P-gp and BCRP.  Ibrutinib is not 
expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot be 
excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic dose. There is 
no clinical data available; therefore, to avoid a potential interaction in the GI tract, narrow 
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least 6 hours before or after ibrutinib.  Inhibition of the BCRP pathway may increase exposure 
to drugs that undergo BCRP mediated hepatic efflux, such as rosuvastatin. 
13.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
Criteria for response will utilize the Revised IWCLL 2008[28] for response which includes clinical, 
hematologic, and bone marrow features as derived from the initial 1996 guidelines[46].  
13.1 Response Criteria 
13.1.1 Complete response: Requires all of the following for a period of at least two months: 
• 
Absence of lymphadenopathy > 1.5 cm on physical exam and CT scan; 
• 
No hepatomegaly or splenomegaly on physical exam (a CT scan also may be used to 
assess); 
• 
No clonal B-cells in the blood by flow cytometry; 
• 
Normal CBC as exhibited by polymorphonuclear leukocytes ≥ 1,500/µL, platelets > 
100,000/µL, hemoglobin > 11.0 g/dL (untransfused); lymphocyte count < 5,000/µL; 
• 
Bone marrow aspirate and biopsy must be normocellular for age with < 30% of 
nucleated cells being lymphocytes. Lymphoid nodules may be present but must be T-
cell in origin. If these are demonstrated to be clonal B-cells, patients should be 
considered to be a partial response. Additionally, if bone marrow is positive by two 
color flow cytometry for CLL cells, it should be considered a partial response. If the 
marrow is hypocellular a bone marrow should be performed in 2-3 months. If blood 
counts (polymorphonuclear leukocytes < 1,500/µL, platelets < 100,000/µL) fail to 
recover at the time of the response evaluation but there is otherwise no evidence of CLL 
otherwise, a repeat determination should be performed at the time of count recovery 
(polymorphonuclear leukocytes ≥ 1,500/µL, platelets > 100,000/µL) but should not 
exceed 6 months. 
• 
Patients who fulfill the criteria for CR with the exception of a persistent cytopenia (CR 
with incomplete recovery, CRi) that is believed to be treatment related will be 
considered a CRi. As stated above, patients falling into this category should ideally 
undergo a repeat bone marrow when counts recover fully. If the bone marrow at this 
time reveals no CLL, these patients will be considered to be in complete remission at 
that time.  
• 
Patients who fulfill the criteria of CR with exception of having bone marrow lymphoid 
CLL nodules will be considered a nodular PR (nPR), and assessed prospectively for 
similarity to outcome with CR. 
• 
Patients who fulfill the criteria of CR with exception of not having a bone marrow 
biopsy performed will be considered a clinical CR. 
13.1.2 Partial Response: Requires a ≥ 50% decrease in peripheral lymphocyte count from pre-
treatment value, ≥ 50% reduction in lymphadenopathy of as many as 6 measurable lymph 
nodes, and/or ≥ 50% reduction in splenomegaly/hepatomegaly for a period of at least two 
months. Additionally, these patients must have one of the following: 
• 
Polymorphonuclear leukocytes ≥ 1,500/µL or 50% improvement from pre-treatment 
value 
• 
Platelets > 100,000/µL or 50% improvement from pre-treatment value 
• 
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• 
Patients who meet the criteria for PR with the exception of having less than a 50% 
reduction in peripheral lymphocyte count will be considered a partial response except 
persistent lymphocytosis (PR-L). These patients should continue to be followed on 
therapy and response status updated if the lymphocyte count does decrease by ≥ 50%. 
13.1.3 Progressive Disease: Because of the well-described lymphocytosis that occurs with 
ibrutinib, patients receiving ibrutinib will not be considered to have progressive disease if 
they have an increase in lymphocyte count without other disease related symptoms 
(increasing lymph nodes, splenomegaly, disease-associated constitutional symptoms).  
Progressive disease will be characterized by any one of the following events: 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes per microliter (in patients on Arm 1, or those on Arms 2 or 3 who are not 
receiving ibrutinib) 
• 
≥ 50% increase in the products of at least two lymph nodes on two consecutive 
determinations two weeks apart (at least one lymph node must be ≥ 2 cm), appearance 
of new palpable lymph nodes 
• 
≥ 50% increase in the size of the liver and/or spleen as determined by measurement 
below the respective costal margin, appearance of palpable hepatomegaly or 
splenomegaly which was not previously present 
• 
Transformation to a more aggressive histology (i.e., Richter’s syndrome or 
prolymphocytic leukemia with ≥ 56% prolymphocytes) 
• 
The progression of any cytopenia defines disease progression (unrelated to autoimmune 
cytopenia), as documented by a decrease of Hb levels >2 g/dL or to < 10 g/dL, or by a 
decrease of platelet counts > 50% or to < 100,000/µL, which occurs at least 3 months 
after treatment, if the marrow biopsy demonstrates an inﬁltrate of clonal CLL cells. 
During therapy, cytopenias cannot be used to deﬁne disease progression. 
13.1.4 Stable Disease  
Patients who do not fulfill the criteria for complete or partial response as defined above but 
do not exhibit progressive disease will be considered to have stable disease. 
13.2 Treatment-Related Lymphocytosis 
Similar to other agents targeting B-cell receptor 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[47]. 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts (i.e., ≥50% 
increase from baseline and above absolute count 5000/mcL), often associated with reduction of 
lymphadenopathy, has been observed in most patients (75%) with relapsed/refractory CLL/SLL 
treated with ibrutinib. This effect has also been observed in some patients (33%) with 
relapsed/refractory MCL treated with ibrutinib. This observed transient lymphocytosis is usually 
not associated with an adverse event and should not be considered progressive disease in the 
absence of other clinical findings. In both disease types, lymphocytosis typically occurs during 
the first few weeks of ibrutinib therapy (median time 1.1 weeks) and resolves within a median 
of 7.1 weeks in the MCL and 18.7 weeks in the CLL patients. 
A substantial increase in the number of circulating lymphocytes (e.g., > 400,000/mcL) has been 
observed in a subset of patients. There have been isolated cases of leukostasis reported in 
patients treated with ibrutinib.  

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14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1 Duration of Treatment 
14.1.1 
CR, PR, or SD  
Arm 1: Continue treatment for 6 cycles. Upon completing 6 cycles of treatment, Arm 1 
patients will be followed (in Arm 1 observation) at least every 3 cycles until progression. 
In the event that bendamustine and rituximab are discontinued for reasons other than 
progression, and the patient would like the option to crossover to ibruitnib alone in the 
future, then the patient will be followed (in Arm 1 observation) at least every 3 cycles 
until progression.  Patients with documented disease progression are eligible to cross over 
to single-agent ibrutinib upon documentation of disease progression. These patients will 
remain on ibrutinib  and follow the study calendar until second disease progression. After 
a second progression, patients will go on to survival follow up, followed every 6 months 
until 10 years from initial Step 1 registration. 
Arm 2: Continue treatment until disease progression, with patients followed at least every 
3 cycles until progression. After documented progression, patients will go on to survival 
follow up, followed every 6 months until 10 years from Step 1 registration. 
Arm 3: Continue rituximab until cycle 6, then continue ibrutinib until disease 
progression.  Patients will be followed at least every 3 cycles until progression. After 
documented progression, patients will go on to survival follow up, followed every 6 
months until 10 years from Step 1 registration. 
14.1.2 
Disease Progression: Remove from protocol therapy any patient with rapid disease 
progression.  
14.1.3 Follow Up Schedule 
Patient follow up is based on 28-day cycles.   
Patients on Arm 1 who complete 6 cycles of protocol treatment are required to be followed 
in Arm 1 observation (every 3 cycles beginning Day 1 of Cycle 6) until progression, at 
which point they may be eligible to crossover. See section 5.6 and 7.0 for more information. 
Patients on Arm 1 who discontinue bendamustine and rituximab prior to completion of 
Cycle 6 for reasons other than progression should be followed in Arm 1 observation if they 
would like to opportunity to crossover at disease progression. Should patients receive 
another therapy, then they will go on to clinical follow-up as outlined in the below 
paragraph. 
Patients who end treatment for reasons other than progression and subsequent treatment will 
go to clinical follow up (as outlined in Section 7.0), followed at least every 3 cycles from 
the date of discontinuation for up to 10 years from registration (Step 1).   
Patients who progress or receive a subsequent treatment will go to survival follow up (see 
Data Submission Schedule on A041202 Alliance and CTSU study page), followed every 6 
months from the date of discontinuation for 10 years from registration (Step 1).   
Patients who withdraw prior to starting any protocol treatment (with or without progression) 
will go to survival follow up, followed every 6 months for up to 10 years in observation 
from registration (Step1). 
14.1.4 Follow-up schedule for ineligible patients registered to the trial 
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A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible. 
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, 
provided the treating physician, study chair, and executive officer agree there are no safety 
concerns if the patient continues protocol treatment. All scans, tests, and data submission 
are to continue per Section 7.0. Notification of the local IRB may be necessary per local 
IRB policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial and have started treatment 
with subsequent discontinuation of study treatment, the same data submission requirements 
are to be followed per Section 7.0. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study 
intervention (regardless of eligibility), the follow-up requirements are specified below. 
Baseline, off treatment, and post-treatment follow up (i.e., relapse, progression, and 
survival) data submission required. See the Data Submission Schedule accompanying the 
All Forms Packet. 
14.2 Extraordinary Medical Circumstances  
If at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair, 
• 
Document the reason(s) for discontinuation of therapy, 
• 
Follow the patient for survival or secondary malignancy until death. 
15.0 STATISTICAL CONSIDERATIONS 
15.1 Overview and Study Design 
This is a randomized phase III trial designed to evaluate whether or not two different ibrutinib-
based therapeutic regimens improve progression-free survival (PFS) over standard of care 
(bendamustine + rituximab) in previously untreated, older (age ≥ 65 years) CLL patients who 
are symptomatic and require therapy by the IWCLL guidelines. This study will not be blinded. 
Treatments that are standard for younger CLL patients such as fludarabine-based regimens are 
often not adequately tolerated in older patients. As described earlier, recent studies have shown 
that in these older patients, bendamustine + rituximab is a tolerable and moderately effective 
regimen with a median PFS of approximately 3 years. Fischer et al found an overall median PFS 
in all patients of 33.8 months, where about half of patients were <65 years old. In looking at 
PFS by age group, those >70 years old had a median PFS of 37.6 months vs. 33.9 months for 
those <70 years. Many different treatment regimens are given to previously untreated CLL 
patients, but the combination of bendamustine + rituximab (BR) can be considered a standard 
regimen in this patient population and the best control arm against which to test novel targeted 
therapies. In this trial, we will formally test the superiority of two ibrutinib-base regimens 
(ibrutinib alone and ibrutinib + rituximab) each against this standard of care bendamustine + 
rituximab treatment arm. In addition, we will also compare the two ibrutinib-based regimens 
with each other (i.e. ibrutinib alone vs. ibrutinib + rituximab).  

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Primary Endpoint: The primary endpoint for all of the treatment arms in this phase III trial is 
PFS, where this will be defined as the time from study entry to the time of documented disease 
progression or death. All randomized patients meeting the eligibility criteria will be evaluable 
for progression-free status by intention to treat. Given the overall indolent nature of this disease, 
PFS is a meaningful endpoint, and has been shown to effectively correlate with OS benefit as 
well, such as that seen in the German CLL8 study. [5] 
Several secondary endpoints will also be evaluated in this study, including OS, time to 
progression, duration of response, ORR, CR, complete and nPR rate, MRD status, toxicity and 
tolerability, geriatric functional status and quality of life, and several correlative markers 
described below.  
Randomization: Patients will be randomized using dynamic allocation procedures to three arms 
in a 1:1:1 manner: bendamustine + rituximab (BR) vs. ibrutinib (I) vs. ibrutinib + rituximab 
(IR). Randomization will be stratified on Rai stage (intermediate vs. high) and presence of high-
risk FISH abnormalities (del(11q22.3) or del(17p13.1) vs. not). In addition, we will also stratify 
on ZAP-70 methylation status (methylated vs. not, using a 20% methylation cut point), which 
is hypothesized to be strongly associated with clinical outcomes in CLL.  
Study Design: The randomized phase III clinical trial design to be utilized in this study is 
described below. As noted above, patients will be randomized to one of three treatment arms: a 
control arm (bendamustine + rituximab) vs. ibrutinib alone vs. ibrutinib + rituximab. In an effort 
to limit patients assigned to the control arm, randomization will be done in a 1:1:1 manner to 
the three arms above, respectively. With these three treatment arms, there are three planned 
comparisons: (1) bendamustine + rituximab vs. ibrutinib alone; (2) bendamustine + rituximab 
vs. ibrutinib + rituximab; and (3) ibrutinib alone vs. ibrutinib + rituximab. In the unlikely event 
that one or both of the ibrutinib-based regimens are discontinued early due to early sufficient 
evidence of futility against the bendamustine + rituximab arm, the third comparison will not be 
conducted.  
The overall Type I error rate for this trial will be constrained at 0.05 and with 90% power for 
each of the one-sided tests of the ibrutinib-based regimens versus bendamustine plus rituximab 
and for the one-sided comparison of the ibrutinib alone versus ibrutinib plus rituximab arms.  
To adjust for the multiple pairwise comparisons between the arms, we will use a Bonferroni 
correction with an overall constraint of the Type I error rate to 0.05. Since we will primarily be 
conducting two main comparisons of interest (BR vs. I and BR vs. IR), each comparison will 
have a Type I error constraint of 0.025. It is of interest to maximize efficiency by comparing 
each of these arms against the common control arm, bendamustine + rituximab. However, we 
recognize that the experimental treatment arms are similar and can be considered related 
(ibrutinib alone, ibrutinib + rituximab) and thus that we in fact need to control for these multiple 
pairwise comparisons in addition to controlling error spending associated with multiple looks at 
the data. Since the comparison of I vs. IR arms is only of interest if both of them are found to 
be superior to the BR control arm, we will constrain the Type I error rate for that comparison to 
0.05. While we could use a more complex approach to correcting for our multiple comparisons 
that involves modeling joint distributions and involving step-up or step-down procedures, it was 
felt that the marginal gains in efficiency with slightly reduced sample sizes would not outweigh 
the complexity and multiple assumptions that would be required.  
Another assumption that we have for this design is that the overall accrual will be about 15 
patients per month. Based on data available for the bendamustine plus rituximab arm as well as 
recent data for current phase II trials of ibrutinib-based regimens, we have the following 
hypotheses for our comparisons of interest, assuming that these PFS distributions are 
exponentially distributed:  
bendamustine + rituximab vs. ibrutinib alone  

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PFS 2-yr estimates: 0.61 vs. 0.75 
PFS medians: 34 months vs. 58 months 
hazard ratio = 0.586 
bendamustine + rituximab vs. ibrutinib + rituximab  
PFS 2-yr estimates: 0.61 vs. 0.85  
PFS medians: 34 months vs. 102 months 
hazard ratio = 0.33 
(these are our assumptions for ibrutinib plus rituximab; however, we will have power to detect 
the same differential as with ibrutinib alone versus bendamustine plus rituximab) 
ibrutinib vs. ibrutinib + rituximab  
PFS 2-yr estimates: 0.75 vs. 0.85 
PFS medians: 58 vs. 102 months  
hazard ratio = 0.57 
We recognize that these hypothesized differentials of interest between the standard of care arm 
versus the ibrutinib-based regimens are quite large; however, it is felt that these improvements 
in PFS are necessary in order to more likely translate to corresponding improvements in OS. 
Note that with the comparisons of bendamustine plus rituximab versus either of the ibrutinib 
regimens, it makes sense to use a one-sided test for this. In other words, in our testing we only 
care if the ibrutinib-based regimens are specifically superior to the bendamustine plus rituximab 
arm. For the ibrutinib alone versus ibrutinib plus rituximab comparison, a one-sided test will 
also be used to be able to detect if PFS is significantly improved with the addition of rituximab 
to ibrutinib. Based on all of these considerations and constraints, this proposed study requires a 
total of 498 evaluable patients. This translates to 166 patients required for each treatment arm. 
We will plan to over-accrue by about 5% for a total accrual goal of 523 patients.  
15.2 Accrual time and study duration 
Based on our experience with cooperative group trials (e.g. CALGB 10404) run in this 
previously untreated CLL patient population as well as our experience in trials with ibrutinib-
based regimens, our expected monthly accrual rate is 15 patients per month, or equivalently 
about 180 patients per year. Since this study will not overlap with the other cooperative group 
trial (run through ECOG), we expect that this projected accrual rate is realistic. Therefore, we 
anticipate that this trial will require about 36 months to accrue the 523 patients required for this 
study. Overall, we will require a minimum of 24 months of follow up on all patients for a total 
study duration of about 60 months.  
15.3 Analysis Plan 
The primary endpoint of PFS will be compared in each of the planned pairwise comparisons as 
described above. Each of these efficacy analyses will utilize an intent-to-treat approach to the 
analyses, where patients will be analyzed in the arm to which they were randomized. Log-rank 
statistics will be used to compare the PFS distributions of the different treatment arms. The 
methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of 
the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, 
and PFS medians along with their 95% confidence intervals.  
Note that patients who are randomized to the BR treatment arm will be allowed to cross over to 
receive ibrutinib therapy once they have documentation of progression. Since patients who are 

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allowed to cross over will have had the event of interest for evaluation of the primary endpoint, 
this will not comprise our primary endpoint of progression-free survival in these comparisons.  
For each of the comparisons of BR vs. either of the ibrutinib regimens, we will conduct three 
interim evaluations, with the first planned interim analysis taking place after approximately 33% 
of events have occurred. After that, two more interim evaluations would be planned at 50% and 
75% of the planned full information (events) for this study. If in these interim evaluations 
sufficient evidence (per criteria outlined below) is observed that an ibrutinib-based arm is 
superior to the BR arm, then accrual to the BR may be suspended and terminated. Patients would 
still continue to be randomized to ibrutinib vs. ibrutinib+rituximab to fully evaluate that 
comparison. For the interim analysis related to the comparison of I vs. IR, we expect that the 
study will be fully accrued prior to seeing 50% of events required to perform the first interim 
analysis. Any interim analyses related to this comparison will be done to primarily identify if 
there is overwhelming evidence that the addition of rituximab to ibrutinib produces significantly 
superior results in terms of PFS. To preserve the Type I error rate control for each of these 
comparisons on superiority, the Lan-DeMets error spending rate function with the O’Brien-
Fleming boundaries is utilized. Futility boundaries have also been developed for the 
comparisons against control, where if at any of the planned interim analyses the hazard ratio is 
>1.05 in favor of the control arm, we will consult with the Alliance DSMB. If these boundaries 
are crossed, then the Alliance DSMB will determine if accrual to that arm should be suspended 
and/or if treatment of patients should be modified based on these results. The interim and final 
analysis boundaries and characteristics were generated using the East 5 clinical trial software 
program (version 5.4, Cytel Inc).  
Bendamustine + Rituximab vs. Ibrutinib  
Information 
fraction 
Cumulative 
events 
Alpha 
spent 
Beta 
spent 
Truncated 
boundary 
Estimated analysis time 
(months) 
0.33 
53 
0.0001 
0.005 
3.73 
25 
0.50 
80 
0.00153 
0.0119 
2.96 
31 
0.75 
120 
0.00965 
0.0356 
2.359 
40 
1.0 
159 
0.025 
0.1 
2.014 
50 
 
Ibrutinib alone vs. Ibrutinib + Rituximab 
Information 
fraction 
Cumulative 
events 
Alpha 
spent 
Beta 
spent 
Boundary to reject 
H0 
Estimated analysis time 
(months) 
0.50 
60 
0.00557 
0.0238 
2.538 
36 
0.75 
89 
0.0236 
0.0712 
2.016 
47 
1.0 
119 
0.05 
0.2 
1.72 
59 
15.4 Secondary Endpoint Analysis Plan 
Several secondary endpoints will be evaluated in the context of this proposed clinical trial.  
Best achieved response will be assessed for each treatment arm after one year as well as after 
two years given the potential for late and/or improved responses. Response rates will be assessed 
in multiple ways, where we will focus on the proportion of patients who achieve a biopsy-proven 
complete response (CR) and the proportion of patients who achieve any response to treatment 
(ORR) where we include partial responses, CRs as well as nPRs. We will assess the CR+nPR 
rate since nPRs have been shown to have improved time to event outcomes. Additionally, we 
will evaluate the proportion of patients who attain MRD negative status at time of CR 
documentation and at 2 years. Response and MRD negative status will be calculated for each 
arm, and will be estimated using the number of patients with the type of response of interest 

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divided by the total number of patients randomized to that treatment arm and the number of 
patients who achieve minimal residual disease divided by the total number randomized to that 
treatment arm, respectively. Assuming that the incidence of each type of response (CR, overall, 
or CR/nPR) as well as incidence of MRD is binomially distributed, we will calculate 
corresponding exact binomial 95% confidence intervals for the true response and MRD rates. 
This will also be performed for the cross over arm proposed in an ancillary manner. 
The Kaplan-Meier method will be used to estimate overall survival and time to progression 
distributions in this CLL population. Each of these variables will be measured from the date of 
registration to the date of the event (i.e., death or disease progression) or the date of last follow-
up to evaluate that event. Patients who are event-free at their last follow-up evaluation will be 
censored at that time point. In addition, any patients who go on to subsequent therapy prior to 
disease progression will be censored at that time.  
The Kaplan-Meier method will be used to estimate the duration of response in the CLL 
population. Duration of response is defined for all evaluable patients who have achieved an 
objective response (i.e., CR, nPR, PR) and will be calculated as the length of time from the date 
at which the patient’s objective status is first noted to be a response to the date that progression 
or death is documented (if one has occurred) or to the date of last follow-up (for those patients 
who have not progressed or died). These evaluations will also be performed for the cross over 
arm proposed. 
The Kaplan-Meier method will be used to estimate PFS and OS in patients who achieve a CR 
by two years, where we will assess differential PFS and OS based on MRD negative status at 
time of CR documentation. Additionally, at the 2-year time point, all responding patients will 
have MRD status evaluated. At both of these time points, hazard ratios and 95% confidence 
intervals for MRD negative versus positive patients will be calculated for PFS and OS. 
Toxicity and Tolerability: Frequency and severity of adverse events and tolerability of the 
regimen in each of the treatment arms will be collected and summarized using descriptive 
statistics. As per NCI CTCAE v4.0, the term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study treatment. The maximum 
grade for each type of toxicity will be recorded for each patient, and frequency tables will be 
reviewed to determine toxicity patterns. In addition, we will review all adverse event data that 
is graded as 3, 4, or 5 and classified as either “unrelated” or “unlikely to be related” to study 
treatment in the event of an actual relationship developing. The incidence of severe (grade 3+) 
adverse events or toxicities will be described. In particular, we will assess the proportion of 
patients who experience grade 3 or higher non-hematologic toxicity for each of the treatment 
arms. We will also assess tolerability of the regimens through assessing the number of patients 
who required dose modifications and/or dose delays. In addition, we will also capture the 
proportion of patients who go off treatment due to adverse reactions or even those who refuse 
further treatment for lesser toxicities that inhibit their willingness to continue participation on 
the trial. These tolerability measures will be assessed within each of the treatment arms and we 
will evaluate differences in these measures between the arms. All patients who have received at 
least one dose of any of the therapeutic agents in a treatment arm will be evaluable for toxicity 
and tolerability. This will also be performed for the cross over arm proposed. 
Functional Status measures and correlative endpoint analyses will also be analyzed in the 
context of this trial. Descriptions of these analyses are provided in Sections 10.1 and 10.2.  

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15.5 Correlative Science Statistical Considerations 
15.5.1 Statistical Considerations for A041202-LC1 
The correlative markers will be summarized quantitatively and graphically between 
treatment arms. In particular, we will assess several known prognostic factors for CLL at 
baseline (cytogenetics, FISH abnormalities, IgVH mutational status, ZAP-70 methylation 
status), as well as new biomarkers that may arise with continued research, and how these 
factors relate to the primary endpoint of PFS and secondary endpoints, including response 
rate and OS.  Since preliminary data on ibrutinib-based therapies suggest a low event rate, 
we will not only evaluate the differential distribution of these known prognostic factors for 
CLL using the log rank test for time to event data, but also in those who are progression-
free at two years versus those who are not.  Levels of difference that we are able to detect 
with at least 80% power will depend largely on the observed distribution of these factors in 
patients accrued on trial. Constraining overall Type I error to .05 and even with a Bonferroni 
correction for ten simultaneous comparisons, two-sided chi-square tests will have 80% 
power to detect differences of 20% or more in 2-year PFS rates (e.g. 65% vs. 85%, 73% vs. 
90%), even with incidences of a factor as small as 25%.  This is reasonable since it is 
expected that ~33% of patients will be identified as having ZAP-70 methylation >20%. 
Incidence rates of cytogenetic abnormality del(11q) are often near 25%, although incidence 
rates of del(17p) are typically lower (~8%), early studies with ibrutinib have shown quite 
favorable outcomes in this group of patients who typically do not respond to other treatment 
regimens and consequently, we anticipate that enrollment of patients in this high-risk group 
will be much higher and will not be a concern, similar to what we have seen in other trials 
with ibrutinib-based regimens.  Likewise, we anticipate that patients with complex 
karyotype will be over-represented, in part because complexity is associated with presence 
of del(17p), but also because incidence of complexity tends to be associated with older age.  
Log rank tests for these factors will have 80% power to detect differences in PFS 
distributions corresponding to similar 2-year PFS estimates. 
Not only will these markers be evaluated within each treatment arm, but they will also be 
evaluated in relation to progression-free survival across treatment arms through Cox 
regression models, adjusting for treatment arm in the model.  We will also assess the impact 
of these factors and how they may affect other clinical outcomes of interest and if these 
differ based on treatment received. In addition to known prognostic factors in CLL, we will 
also evaluate other correlative markers in baseline samples and in samples collected at 
relapse. DNA mutation markers will be explored in relation to clinical outcomes of interest 
as well as how they may change from baseline to time of relapse. Assessments of minimal 
residual disease (MRD) will be used in patients classified as CR to further evaluate their 
status as disease-free and if this further impacts their ability to remain progression-free and 
alive. Overall, given that this is a hematologic malignancy with accessible “tumor”, we 
expect to obtain evaluable samples on at least 90% of patients.  
For gene expression profiling and miR analysis by nanostring, baseline samples for patients 
in each treatment arm will be evaluated in relation to their progression-free status at 2 years 
to assess differential expression in those who achieve this clinical outcome of interest vs. 
those who do not. In addition, we will also assess achievement of CR by two years vs. not 
and identify those markers that have differential expression between these outcome groups. 
Both mRNA and miR expression data will be normalized and summarized using log base 2 
expression values for further analysis. A filtering step will be performed to remove probe 
sets/miRs for which the majority of expression values are below a noise level cutoff. 
Standard statistical methods (i.e. two-sided two-sample t-tests) will be used to determine 
differentially expressed genes and miRNAs, although we will make a correction for multiple 

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comparisons (using a univariate significance level of α=0.001 for gene expression and 
α=0.005 for miR expression to control the average number of false positives when screening 
across all probe sets and miRNAs). In analyses that focus on a short list of genes or miRNAs, 
identified apriori to have potential impact in CLL through previous work by our group (e.g. 
miR-155, miR-29c), there is at least 80% power to detect 1.5-fold changes in expression, 
assuming 85% of patients within a treatment arm are progression-free, a CV=0.5, and 
constraining overall Type I error to .05 with a Bonferroni correction for ten simultaneous 
comparisons.  If the CV is as large as 1.0 for some genes/miRNAs, 2-fold changes can be 
detected with at least 80% power.  In addition, we will evaluate changes in miR marker 
expression levels in pre- vs. post-treatment samples in those treated on the ibrutinib alone 
treatment arm, and how these changes may differ based on achievement of clinical outcomes 
of interest as well as between patients with vs. without persistent lymphocytosis. It is 
anticipated that approximately 20-25% of patients treated with single-agent ibrutinib will 
have persistent lymphocytosis at 9 months, resulting in approximately 35 paired samples to 
be screened for markers of resistance.  With n=35, there is at least 80% power to detect 1.65 
fold or 1.55 fold changes, respectively, for any gene or miRNA with CV<0.5; 2.40 or 2.15 
fold changes with CV<1.0 can be detected with at least 80% power for any gene or miRNA, 
respectively. These calculations allow for 1 false positive per 1000 features with gene 
expression data (i.e. α=0.001) and 5 false positive per 1000 features with miRNA data (i.e. 
setting  α=0.005).  Changes in miR marker expression from baseline to time of relapse will 
also be evaluated in all patients on either of the ibrutinib-based treatment arms who relapse.  
Finally, we will evaluate whether local FISH analysis is concordant with centralized FISH 
analysis for del(11q22.3) and del(17p13.1); i.e. each of these chromosomal abnormalities 
will be evaluated using FISH both locally and centrally at baseline, and the results will be 
compared for each patient. Since we are primarily interested in classification of having this 
abnormality vs. not, we will use a Kappa test to assess agreement of this classification for 
del(11q22.3) and del(17p13.1) for the local vs. centralized assessment. As noted earlier, 
based on our past experience with trials that include ibrutinib we expect that the rate of CLL 
patients with del(17p13.1) will be higher than what we typically see in CLL trials If we 
assume that we will see 25% of patients with the abnormality of interest, we will have at 
least 90% power to detect a significant difference from a near perfect concordance (H0: 
kappa=0.99) if the true Kappa is actually 0.96 or lower. Even if the rate of patients with 
del(17p13.1) is lower (10%), then we will still have 80% power to detect a significantly 
different rate of concordance if the true Kappa is 0.95 or lower. 
15.5.2 Statistical Considerations for A041202-EL1 
15.5.2.1 Objective 1: To describe the baseline functional status, comorbid medical 
conditions, and number of medications of older CLL patients who meet criteria 
for therapy 
The baseline measures for each of the components of the geriatric assessment will be 
summarized for the entire group of patients enrolled on the trial and for whom a 
geriatric assessment was completed as well as for each arm individually. The values 
among the arms will be compared to assess for the clinical and statistical differences. 
It is possible that imbalances can occur because the geriatric assessment is optional 
and so original randomization of the patients might be jeopardized. Categorical values 
will be compared with a chi-square test and continuous values will be compared with 
an ANOVA (if the distribution of the measurements is sufficiently normal) or a 
Kruskal-Wallis test (if the distribution of measurements is considerably skewed). 

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15.5.2.2 Objective 2: To determine how functional status changes with therapy using 
baseline to 6 month evaluation and end-of-study/2 year evaluation; to determine 
whether this change is different among the treatment groups 
This analysis will use the instruments that assess functional status: OARS MFAQ 
(IADL), MOS physical functioning, Karnofsky performance status rated by a health 
care professional, Karnofsky performance status rated by the patient, timed “Up and 
Go”, and number of falls in the last six months. For each measure and each patient, we 
will compute the differences at 6 months compared to baseline (6mo-B) and the 
differences at 2-years compared to baseline (2yr-B). These changes will be 
summarized with descriptive statistics and graphs for each arm. The first analysis will 
be to determine whether there was a change observed for each measure within a 
treatment arm. This will be determined by the Wilcoxon signed-rank test for each arm 
for continuous variables and McNemar’s test for categorical variables. We will do this 
for the 6-month endpoint and for the 2-year endpoint. The next analysis will be to 
determine whether the magnitude of the changes from baseline differ among the 
different treatment groups. This will be done using a Wilcoxon-Mann-Whitney test for 
continuous/ordinal values and a Fisher’s exact test or chi-square test for dichotomous 
variables.  A secondary analysis will be to do a comparison of 6mo-B and 2yr-B values 
between the subgroups of patients who are in remission at the end of 2 years and those 
who had progressed prior to 2 years. These comparisons will be made within each 
treatment arm as well as between treatment arms. There will be multiple comparisons 
made as part of the analysis plan for this aim and so we will make a partial correction. 
Specifically, we will not make a full Bonferroni correction but rather will reduce the 
level of significance from 0.05 to 0.01. In other words, differences will only be 
considered to be statistically significant for this aim if the p-value is less than 0.01. We 
feel this is appropriate because the intent of this aim is primarily exploratory. 
15.5.2.3 Objective 3: To determine whether geriatric assessment variables known to be 
associated with chemotherapy toxicity in other disease groups can also predict 
therapy-associated toxicity in the CLL population 
Detailed descriptions of hypotheses, expected sample sizes, power calculations and 
analysis plans for these objectives can be found in Section 10.2.3. 
15.5.3 Statistical Design for A041202-PP1 (Evaluation of Candidate Pharmacogenetic 
Determinants of Ibrutinib or Ibrutinib/Rituximab Response) 
The primary statistical objective for this study is to investigate the relationship between the 
FCGR3A SNP (rs396991) and response. The response phenotype will be quantified using 
MRD negativity status. We specifically hypothesize that in the rituximab-containing arms 
the T/T homozygotes will have a lower probability of achieving MRD negativity compared 
to the patients who have at least one copy of the G allele. We will use the Cochran–Mantel–
Haenszel statistic, stratified by treatment arm, assuming no third order interaction. 
The proposed clinical study aims to enroll a total of 523 patients. The primary analyses will 
be restricted to patients who self-report as non-Hispanic whites. Our previous genome-wide 
association studies have shown this to be a good surrogate marker for identifying a genetic 
European subset. We expect that 85% of patients registered the study will self-report as non-
Hispanic whites. We also expect that 85% of the patients will consent and usable samples 
to pharmacogenomic studies. The minimum expected sample size will be 377. We will 
genotype any patient who provides consent and a usable sample. 

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The relative allelic frequencies for rs396991 are highly variable in different racial groups 
(G is the minor allele in Africans and T is the minor allele in Asians). The relative genotypic 
frequencies for rs396991, assuming the study population is a similar population as in the 
NHLBI Exome Sequencing Project, are predicted to be: 0.12 G/G, 0.41 G/T, 0.47 T/T.  
For the power calculation, we will assume that the relative genotypic frequencies for the 
two groups are 0.47 (T/T) and 0.53 (G/T or G/G). We also assume that the response rates 
are 0.3 and 0.1 in arms 1 and 3 respectively. Within each arm, the MRD negativity will be 
expressed as the mixture piD=p0*0.47+p0*D*0.53 where p0 is the probability of achieving 
MRD negativity for the T/T group in this arm. The power, at the two-sided 0.05 level, is 0.8 
for D=2.05. 
As an exploratory analysis, we will consider genotype by rituximab interaction with respect 
to response. This will be carried out using a multiplicative logistic regression model 
incorporating all three arms.  We will also consider using other clinical outcomes (e.g., 
outcome, toxicity) as phenotypes. We will also consider molecular markers assayed on these 
patients as phenotypes (e.g., eQTLs). 
In addition, we may use the DNA collected to consider other candidate SNPs or to conduct 
a genome-wide association study (GWAS) to validate other or identify novel candidates, or, 
as next generation sequencing platforms become more cost effective, consider exome or 
whole-genome sequencing. 
 
15.6 Inclusion of Women and Minorities 
It is the intent of the Alliance to enroll patients regardless of gender or race. Both men and 
women of all races and ethnic groups are eligible for this study. In the development of this 
protocol, the possibility of inherent gender or racial/ethnic differences in treatment response has 
been considered.  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
11 
+ 
18 
= 
29 
Not Hispanic or Latino 
163 
+ 
331 
= 
494 
Ethnic Category: Total of all subjects 
174 
+ 
349 
= 
523 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
1 
= 
2 
Asian 
1 
+ 
3 
= 
4 
Black or African American 
12 
+ 
24 
= 
36 
Native Hawaiian or other Pacific Islander 
3 
+ 
1 
= 
4 
White 
157 
+ 
320 
= 
477 
Racial Category: Total of all subjects 
174 
+ 
349 
= 
523 
15.7 CDUS Reporting 
The Alliance Statistical Data Center will submit quarterly reports to CTEP by electronic means 
using the Clinical Data Update System (CDUS). 

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16.0 EXPEDITED ADVERSE EVENT REPORTING AND COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL 
RISKS LISTS 
16.1 Expedited Adverse Event Reporting 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below. Alliance investigators are required to notify the Investigational Drug Branch (IDB), the 
Alliance Central Protocol Program Office, the Study Chair, and their Institutional Review Board 
if a patient has an adverse event requiring expedited reporting. All such events must be reported 
in an expedited manner using the CTEP Adverse Event Reporting System (CTEP-AERS). The 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE. A copy of the CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Be sure to read this entire protocol section, as requirements are described in both the table and 
bullet points following the table below.  Note that the additional instructions or exclusions are 
protocol specific, and in the case of a conflict, the additional instructions or exclusions supersede 
the table. 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
A041202: Expedited Reporting Requirements for Adverse Events that Occur on Studies 
under an IND within 30 Days of the Last Treatment1, 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last treatment require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs that are at least possibly related to treatment 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization, and that are at 
least possibly related to treatment. 
• Grade 3 adverse events that are at least possibly related to treatment. 
Effective Date:  May 5, 2011 
 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements 
for Phase 3 Trials Utilizing an Agent Under an IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB, according to local IRB policies. 
• 
Alliance A041202 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) in this 
trial. 
• 
Treatment expected adverse events include those listed in Section 11.0, in the package 
inserts for bendamustine and rituximab, and in the CAEPR for ibrutinib (see Section 16.2, 
below). Note that the ASAEL column of the CAEPR for ibrutinib has been replaced with 
the specific protocol exceptions to expedited reporting (SPEER) list. This list now includes 
“expected” severity grades in addition to event terms. 
• 
All suspected and confirmed cases of fungal infections should be reported to CTEP within 
24 hours.  
• 
All new malignancies must be reported through CTEP-AERS whether or not they are 
thought to be related to either previous or current treatment. All new malignancies should 
be reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and 
in situ tumors. In CTCAE version 5.0, the new malignancies (both second and secondary) 
may be reported as one of the following: (1) Leukemia secondary to oncology 
chemotherapy, (2) Myelodysplastic syndrome, (3) Treatment-related secondary malignancy 
or (4) Neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-
AERS reports for new malignancies should include, tumor pathology, history of prior 
tumors, prior treatment/current treatment including duration, any associated risk factors or 
evidence regarding how long the new malignancy may have been present, when and how 
the new malignancy was detected, molecular characterization or cytogenetics of the original 
tumor (if available) and of any new tumor, and new malignancy treatment and outcome, if 
available.  

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• 
All pregnancies and suspected pregnancies occurring in female patients during therapy or 
within 90 days after completion of treatment on A041202 must be reported via CTEP-
AERS. Use the event term “pregnancy, puerperium, or perinatal condition-other, fetal 
exposure (grade 4).” 
o CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). In CTCAE v5.0, pregnancy loss is defined as “Death 
in utero,” and any pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal conditions SOC. A 
pregnancy should NOT be reported as a Grade 5 event under the Pregnancy, puerperium 
and perinatal conditions SOC as currently CTEP-AERS recognizes this event as a 
patient death. 
o The CTEP-AERS report should be amended for any neonatal deaths or complications 
occurring within 30 days of birth independent of attribution. Infant deaths occurring 
after 30 days considered to be related to in utero exposure to the agents used in this trial 
should be reported via CTEP-AERS. A neonatal death should be reported expeditiously 
as Grade 4, “Death neonatal” under the General disorders and administration SOC. 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical 
trial, e.g., cooperative group data reporting (see Section 6.1). 
16.2 Comprehensive Adverse Events and Potential Risks (CAEPR)  
16.2.1 Ibrutinib (PCI-32765, NSC # 748645) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list 
of events that are protocol specific exceptions to expedited reporting to NCI (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2082 patients. Below is the CAEPR 
for Ibrutinib (PCI-32765).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.6, January 29, 20181 
 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2082] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 

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 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2082] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Blood and lymphatic system 
disorders - Other 
(leukostasis)2  
  
 
Febrile neutropenia 
 
  
 
 
Leukocytosis2 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
 
 
Ventricular tachycardia 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Mucositis oral 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
 
 
Sudden death NOS 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection3 
  
 Infection3 (Gr 3) 
 
 
Infections and infestations - 
Other (bronchopulmonary and 
central nervous system 
infections)4  
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
INVESTIGATIONS 
  
 
Lymphocyte count 
increased2 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
 
Hyperuricemia 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  

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 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 5.0 Term) 
[n= 2082] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Muscle cramp 
 
  
 
Myalgia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
  
 
Neoplasms benign, 
malignant and unspecified 
(incl cysts and polyps) - 
Other (benign neoplasm of 
skin)5  
 
  
 
 
Treatment related secondary 
malignancy5 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
  
 
 
Peripheral sensory neuropathy   
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
 
 Pneumonitis6 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Skin and subcutaneous tissue 
disorders - Other 
(angioedema)7  
  
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)8  
 
 Skin and subcutaneous tissue 
disorders - Other (rash)8 (Gr 3) 
 
 
Stevens-Johnson syndrome 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
  
 
 
Hypotension 
  
 
Vascular disorders - Other 
(hemorrhage)9  
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Leukostasis and/or leukocytosis have been observed especially in patients with chronic lymphocytic leukemia (CLL) 
and mantle cell leukemia (MCL). 
 
3Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Fungal infections especially respiratory tract infections due to aspergillus and/or pneumocystis and central nervous 
system (CNS) infections due to aspergillus have been observed in clinical trials of ibrutinib. These reports may include 
incidents of presumptive fungal infections based on response to anti-fungal agents and/or radiographic evidence. 
 

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5Other malignant diseases have been observed in patients who have been treated with ibrutinib including solid tumors, 
skin cancer, and hematological malignancies. 
 
6Pneumonitis is included in the group term Interstitial Lung Disease (ILD) which also includes lung infiltration, 
bronchiolitis, pulmonary fibrosis, eosinophilc pneumonia, pulmonary toxicity, and alveolitis allergic. 
 
7Angioedema may be seen in association with the immune-related adverse event of anaphylaxis. 
 
8Rash may include but is not limited to the terms dermatitis, erythema, rash generalized, rash maculo-papular, rash 
pustular, rash pruritic, and urticaria. 
 
9It is possible that treatment with ibrutinib may increase the risk of hemorrhage which may occur anywhere in the 
body including CNS hemorrhage (including but not limitied to Intracranial hemorrhage, Intraventricular hemorrhage, 
and Subdural hematoma), Ecchymoses, Purpura (petechia), Gastrointestinal hemorrhage (including but not limited to 
Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, 
Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage), Genitourinary tract 
hemorrhage (including but not limited to Hematuria and Vaginal hemorrhage), Respiratory tract hemorrhage 
(including but not limited to Epistaxis), and Spontaneous hemorrhage. 
 
Adverse events reported on ibrutinib (PCI-32765) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that ibrutinib (PCI-32765) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic diathesis); Blood and lymphatic system disorders - Other (lymphadenitis); Blood and lymphatic system 
disorders - Other (pancytopenia); Hemolysis 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac disorders - Other (bundle branch block left); Cardiac disorders - Other (extrasystoles); Chest pain - cardiac; 
Heart failure; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Sinus bradycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain  
EYE DISORDERS - Dry eye; Eye disorders - Other (eye discharge); Eye disorders - Other (macular edema); Eye 
disorders - Other (ocular hyperemia); Eye disorders - Other (retinal hemorrhage); Eye pain; Floaters; Glaucoma; 
Keratitis; Periorbital edema; Photophobia; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Cheilitis; Colitis; Dyspepsia; Enterocolitis; 
Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gluteal 
intramuscular bleed); Gastrointestinal disorders - Other (irritable bowel syndrome); Gastrointestinal disorders - Other 
(tongue discoloration); Oral dysesthesia; Oral pain; Pancreatitis; Periodontal disease; Small intestinal obstruction; 
Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like symptoms; Gait 
disturbance; General disorders and administration site conditions - Other (early satiety); General disorders and 
administration site conditions - Other (multiple organ dysfunction syndrome); General disorders and administration 
site conditions - Other (sensation of foreign body); General disorders and administration site conditions - Other 
(temperature intolerance); Generalized edema; Injection site reaction; Localized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response syndrome) 
INFECTIONS AND INFESTATIONS - Conjunctivitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related reaction; Injury, poisoning 
and procedural complications - Other (excoriation) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT corrected interval prolonged; INR 
increased; Investigations - Other (cardiac murmur); Investigations - Other (increase CRP); Lymphocyte count 
decreased; Weight gain; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hyperphosphatemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypoglycemia; 
Hypokalemia; 
Hypomagnesemia; 
Hyponatremia; 

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Hypophosphatemia; Metabolism and nutrition disorders - Other (cachexia); Metabolism and nutrition disorders - 
Other (hypoproteinemia); Metabolism and nutrition disorders - Other (lactose intolerance) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Flank 
pain; Generalized muscle weakness; Joint effusion; Joint range of motion decreased; Musculoskeletal and connective 
tissue disorder - Other (groin pain); Musculoskeletal and connective tissue disorder - Other (muscle rigidity); 
Musculoskeletal and connective tissue disorder - Other (pain in jaw); Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Dysgeusia; Encephalopathy; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other (mental impairment); Nervous system 
disorders - Other (parosmia); Nervous system disorders - Other (PML); Paresthesia; Reversible posterior 
leukoencephalopathy syndrome; Somnolence; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Insomnia; Restlessness 
RENAL AND URINARY DISORDERS - Cystitis noninfective; Renal and urinary disorders - Other (calculus 
bladder); Renal and urinary disorders - Other (polyuria); Urinary frequency; Urinary retention; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dyspareunia; Reproductive system and breast 
disorders - Other (hematospermia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Hiccups; Laryngeal 
inflammation; Pleural effusion; Productive cough; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (nasal ulcer); Sinus disorder; Sinus pain; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Nail discoloration; Nail loss; 
Photosensitivity; Pruritus; Skin atrophy; Skin hyperpigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hot flashes; Thromboembolic event; Vascular disorders - Other (peripheral 
coldness) 
 
Note: Ibrutinib (PCI-32765) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
16.3 Adverse Event List for Commercial Agents 
For a complete list of adverse events and potential risks for rituximab and bendamustine, 
please refer to the FDA-approved package labeling for both drugs. 
16.3.1 Rituximab 
The most serious adverse events associated with rituximab include severe infusion reactions, 
tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions 
consisting of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, ventricular fibrillation or cardiogenic shock may be fatal. Most 
reported fatal reactions occurred within 24 hours of the first dose of rituximab. Because 
severe infusion reactions have been noted more frequently in patients with high leukocyte 
counts, such patients should be observed closely. 
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells. 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson 
syndrome and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 
weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be the release of 
cytokines. If a reaction occurs, the infusion should be stopped until the symptoms resolve, 
and then restarted at a 50% slower rate. Consider additional pre-medication with 
acetaminophen 650 mg PO and diphenhydramine 50 mg PO/IV (or equivalent 
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Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority 
of these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and 
approximately 1 month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with rituximab. 
Recent reports describe JC virus reactivation leading to progressive multifocal 
leukoencephalopathy (PML) in patients who were receiving rituximab. Patients presenting 
with new neurologic findings (e.g., major changes in vision, unusual eye movements, loss 
of balance or coordination, confusion) should be evaluated for PML. 
A report in the literature described an increase in fatal infection in HIV-related lymphoma 
patients when rituximab was used in combination with CHOP chemotherapy, as compared 
to CHOP alone.  
16.3.2 Bendamustine 
The most common side effect is bone marrow suppression. The most common non-
hematologic adverse events in CLL (>15%) include pyrexia, nausea, and vomiting.  Other 
adverse reactions seen frequently include asthenia, fatigue, malaise/weakness, dry mouth, 
somnolence, cough, constipation, headache, mucosal inflammation, and stomatitis. 
16.4 Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor.  These events will be reported to the Sponsor via CTEP-
AERS within 24 hours of awareness following the procedure described above for SAEs and will 
require enhanced data collection.  All Events of Special Interest will be submitted within 24 
hours of awareness even if they do not meet serious criteria. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*.  
• 
Any treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 
or higher AE per CTCAE. 
 

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17.0 REFERENCES 
1. 
Rai, K.R., et al., Fludarabine compared with chlorambucil as primary therapy for chronic 
lymphocytic leukemia. N Engl J Med, 2000. 343(24): p. 1750-7. 
2. 
Cartovsky, D., S. Richards, and E. Maututes, et al., Assessment of fludarabine plus 
cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 Trial): a 
radomised controlled trial. Lancet, 2007. 370(9583): p. 230-239. 
3. 
Flinn, I.W., et al., Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine 
for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. 
J Clin Oncol, 2007. 25(7): p. 793-8. 
4. 
Byrd, J.C., et al., Randomized phase 2 study of fludarabine with concurrent versus sequential 
treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic 
leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood, 2003. 101(1): 
p. 6-14. 
5. 
Hallek, M., et al., Addition of rituximab to fludarabine and cyclophosphamide in patients with 
chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 376(9747): p. 
1164-74. 
6. 
Eichhorst, B.F., et al., First-line therapy with fludarabine compared with chlorambucil does not 
result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood, 
2009. 114(16): p. 3382-91. 
7. 
Woyach, J.A., et al., Impact of Age on Outcomes Following Initial Therapy with Various 
Chemotherapy and Chemoimmunotherapy Regimens in Patients with Chronic Lymphocytic 
Leukemia (CLL): Results of CALGB Studies. ASH Annual Meeting Abstracts, 2011. 118(21): p. 
289-. 
8. 
Hillmen, P., et al., Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic 
Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study. ASH 
Annual Meeting Abstracts, 2010. 116(21): p. 697-. 
9. 
Foa, R., et al., A Phase II Study of Chlorambucil Plus Rituximab Followed by Maintenance Versus 
Observation In Elderly Patients with Previously Untreated Chronic Lymphocytic Leukemia: 
Results of the First Interim Analysis. ASH Annual Meeting Abstracts, 2010. 116(21): p. 2462-. 
10. 
Fischer, K., et al., Bendamustine in combination with rituximab for previously untreated patients 
with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic 
Lymphocytic Leukemia Study Group. J Clin Oncol, 2012. 30(26): p. 3209-16. 
11. 
Dal Porto, J.M., et al., B cell antigen receptor signaling 101. Mol Immunol, 2004. 41(6-7): p. 599-
613. 
12. 
Deglesne, P.A., et al., Survival response to B-cell receptor ligation is restricted to progressive 
chronic lymphocytic leukemia cells irrespective of Zap70 expression. Cancer Res, 2006. 66(14): p. 
7158-66. 
13. 
Bernal, A., et al., Survival of leukemic B cells promoted by engagement of the antigen receptor. 
Blood, 2001. 98(10): p. 3050-7. 
14. 
Vetrie, D., et al., The gene involved in X-linked agammaglobulinaemia is a member of the src family 
of protein-tyrosine kinases. Nature, 1993. 361(6409): p. 226-33. 
15. 
Tsukada, S., et al., Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked 
agammaglobulinemia. Cell, 1993. 72(2): p. 279-90. 
16. 
Rawlings, D.J., et al., Mutation of unique region of Bruton's tyrosine kinase in immunodeficient 
XID mice. Science, 1993. 261(5119): p. 358-61. 
17. 
Herman, S.E., et al., Bruton tyrosine kinase represents a promising therapeutic target for treatment 
of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 2011. 117(23): 
p. 6287-96. 

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18. 
Fowler, N., et al., The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity 
In Patients with Relapsed/Refractory B-Cell Malignancies: Results From a Phase I Study. ASH 
Annual Meeting Abstracts, 2010. 116(21): p. 964-. 
19. 
Pollyea, D.A., et al., A Phase I Dose Escalation Study of the Btk Inhibitor PCI-32765 in Relapsed 
and Refractory B Cell Non-Hodgkin Lymphoma and Use of a Novel Fluorescent Probe 
Pharmacodynamic Assay. ASH Annual Meeting Abstracts, 2009. 114(22): p. 3713-. 
20. 
Byrd, J., et al., Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 
in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim 
results of a phase Ib/II study. J Clin Oncol (ASCO Annual Meeting Abstracts), 2011. 29: p. 
Abstract 6508. 
21. 
Byrd, J.C., et al., The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) promotes 
High Response Rate, Durable Remissions, and is Tolerable in Treatment Naïve (TN) and Relapsed 
or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) Patients  including Patients with High-
risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study Durable 
Remissions, and is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic 
Lymphocytic Leukemia (CLL) Patients  including Patients with High-risk (HR) Disease: New and 
Updated Results of 116 Patients in a Phase Ib/II Study.ASH Annual Meeting, 2012. 
22. 
Burger, J.A., et al., The Btk Inhibitor Ibrutinib (PCI-32765) in Combination with Rituximab Is Well 
Tolerated and Displays Profound Activity in High-Risk Chronic Lymphocytic Leukemia (CLL) 
Patients. ASH Annual Meeting Abstracts, 2012. 120(21): p. 187-. 
23. 
Calin, G.A., et al., A MicroRNA signature associated with prognosis and progression in chronic 
lymphocytic leukemia. N Engl J Med, 2005. 353(17): p. 1793-801. 
24. 
Kluiver, J., et al., Regulation of pri-microRNA BIC transcription and processing in Burkitt 
lymphoma. Oncogene, 2007. 26(26): p. 3769-76. 
25. 
Mraz, M., et al., miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 
abnormalities. Leukemia, 2009. 23(6): p. 1159-63. 
26. 
Tan, A.D., Novotny, et al, A patient-level meta-analytic investigation of the prognostic significance 
of baseline quality of life (QOL) for overall survival (OS) among 3,704 patients participating in 24 
North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology 
clinical trials. J Clin Oncol, 2008. 26. 
27. 
Sloan JA, L.H., Sargent DJ, Satele D, Schaefer PL, Haylard MY, Grothey A, Garces YI, Brown 
PD, Loprinzi CL, Buckner JC. , A patient-level pooled analysis of the prognostic significance of 
baseline fatigue for overall survival (OS) among 3,915 patients participating in 43 North Central 
Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. 
J Clin Oncol, 2009. 27(507s). 
28. 
Hallek, M., et al., Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a 
report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute-Working Group 1996 guidelines. Blood, 2008. 111(12): p. 5446-56. 
29. 
Puente, X.S., et al., Whole-genome sequencing identifies recurrent mutations in chronic 
lymphocytic leukaemia. Nature. 475(7354): p. 101-5. 
30. 
Quesada, V., et al., Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 
gene in chronic lymphocytic leukemia. Nat Genet. 44(1): p. 47-52. 
31. 
Wang, L., et al., SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J 
Med. 365(26): p. 2497-506. 
32. 
Fabbri, G., et al., Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 
mutational activation. J Exp Med. 208(7): p. 1389-401. 
33. 
Rossi, D., et al., Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: 
association with progression and fludarabine-refractoriness. Blood. 118(26): p. 6904-8. 
34. 
Bottcher, S., et al., Minimal residual disease quantification is an independent predictor of 
progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis 
from the randomized GCLLSG CLL8 trial. J Clin Oncol. 30(9): p. 980-8. 

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35. 
Hurria, A., et al., Implementing a geriatric assessment in cooperative group clinical cancer trials: 
CALGB 360401. J Clin Oncol. 29(10): p. 1290-6. 
36. 
Hurria, A., et al., Predicting chemotherapy toxicity in older adults with cancer: a prospective 
multicenter study. J Clin Oncol. 29(25): p. 3457-65. 
37. 
Hurria, A., et al., Developing a cancer-specific geriatric assessment: a feasibility study. Cancer, 
2005. 104(9): p. 1998-2005. 
38. 
Hogan, J.W. and N.M. Laird, Mixture models for the joint distribution of repeated measures and 
event times. Stat Med, 1997. 16(1-3): p. 239-57. 
39. 
Little, R.J., Pattern-mixture models for multivariate incomplete data. Journal of the American 
Statistical Association, 1993. 88: p. 125-134. 
40. 
Cartron, G., et al., Therapeutic activity of humanized anti-CD20 monoclonal antibody and 
polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood, 2002. 99(3): p. 754-8. 
41. 
Farag, S.S., et al., Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to 
rituximab in B-cell chronic lymphocytic leukemia. Blood, 2004. 103(4): p. 1472-4. 
42. 
Kim, D.H., et al., FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP 
therapy for diffuse large B-cell lymphoma. Blood, 2006. 108(8): p. 2720-5. 
43. 
Dall'Ozzo, S., et al., Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A 
polymorphism on the concentration-effect relationship. Cancer Res, 2004. 64(13): p. 4664-9. 
44. 
Racila, D.M., et al., Homozygous single nucleotide polymorphism of the complement C1QA gene 
is associated with decreased levels of C1q in patients with subacute cutaneous lupus 
erythematosus. Lupus, 2003. 12(2): p. 124-32. 
45. 
Racila, E., et al., A polymorphism in the complement component C1qA correlates with prolonged 
response following rituximab therapy of follicular lymphoma. Clin Cancer Res, 2008. 14(20): p. 
6697-703. 
46. 
Cheson, B.D., et al., National Cancer Institute-sponsored Working Group guidelines for chronic 
lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood, 1996. 87(12): p. 
4990-7. 
47. 
Stevenson, F.K., B-cell receptor signaling in chronic lymphocytic leukemia. Blood, 2011. 118(16): 
p. 4313-4320. 
 
 

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APPENDIX I 
PATIENT MEDICATION DIARY 
 
Today’s date ______________________________ 
Agent: Ibrutinib 
Patient Name__________________ (initials acceptable) Patient Study ID ________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each 4 week-period while you take ibrutinib. 
2. 
You will take ibrutinib on days 1-28.  
3. 
Record the date, the number of capsules of each size you took, and when you took them. Record doses as soon as 
you take them; do not batch entries together at a later time. 
4. 
If you have any comments or notice any side effects, please record them in the Comments column. If you make a 
mistake while you write, please cross it out with one line, put your initials next to it, and then write the corrected 
information next to your initials.  Example: 10:30 am SB 9:30 am 
5.    Take ibrutinib at least 30 minutes before eating or at least 2 hours after a meal. The capsules are not meant to be 
opened or dissolved. If you miss a dose, it can be taken as soon as possible on the same day with a return to the 
normal schedule the following day. Do not take extra capsules to make up a missed dose. 
6. 
Please return this form and the bottle with any leftover capsules to your physician when you go for your next 
appointment. 
 
Day 
Date 
Time of dose 
# of capsules taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 

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Day 
Date 
Time of dose 
# of capsules taken 
Comments 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Physician’s Office will complete this section: 
 
1. Date patient started protocol treatment___________________________________________________ 
 
2. Date patient was removed from study ____________________________________________________ 
 
3. Patient’s dose cohort ____________________________________________________________________ 
 
4. Total number of capsules taken this month (each size) _________________________________________ 
 
5. Physician/Nurse/Data Manager’s Signature _________________________________________________ 
 
Patient’s signature 
______________________________________________________________________________ 
 
 

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APPENDIX II 
INDUCERS AND INHIBITORS CYP3A4/5 
 
A strong inhibitor is one that causes a >5-fold increase in plasma AUC values or >80% decrease in 
clearance.  Strong inducers and inhibitors are in bold. 
 
CYP3A4/5 inducers 
CYP3A4/5 inhibitors 
Efavirenz 
Cyclosporine 
Nevirapine 
Indinavir 
 
Miconazole 
Barbiturates 
Nelfinavir 
Carbamazepine 
Poscanazole 
Glucocorticoids 
Ritonavir 
Modafinil 
Clarithromycin 
Oxcarbazepine 
Itraconazole 
Phenobarbital 
Ketoconazole 
Phenytoin 
Nefazodone 
Pioglitazone 
Saquinavir 
Rifabutin 
Telithromycin 
Rifampin 
Voriconazole 
St. John's wort 
 
Troglitazone 
Aprepitant 
 
Atazanavir 
 
Caffeine 
 
Clotrimazole 
 
Conivaptan 
 
Cimetidine 
 
Delavirdine 
 
Desipramine 
 
Diltiazem 
 
Efavirenz 
 
Erythromycin 
 
Fluconazole 
 
Fosaprepitant 
 
Grapefruit juice 
 
Haloperidol 
 
Isoniazid 
 
Metronidazole 
 
Nicardipine 
 
Norfloxin 
 
Quinidine 
 
Tetracycline 
 
Verapamil 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
78 
APPENDIX III REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
A translator may be used to administer the assessment. Additionally, since CCTG is participating 
in A041202, a French version of the assessment has been provided on the following page. 
 
 
 
 
How would you describe: 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
79 
Fatigue/Uniscale Évaluation 
 
Instructions: S'il vous plaît, pour chaque article ci-dessous, encerclez le numéro (0-10) qui vous 
décrit le mieux. 
 
Comment décririez-vous : 
 
 
1. Votre niveau de fatigue moyen au cours de la dernière semaine, aujourd'hui inclus? 
  
0  
1  
2  
3  
4  
5  
6  
7 
 8  
9  
10  
Aucune fatigue  
 
La pire fatigue possible 
 
 
 
 
 
 
 
2. Votre qualité de vie globale dans la semaine écoulée, y compris aujourd'hui? 
 
 0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
Aussi mauvaise  
 
 
 
 
 
 
Aussi bonne 
que possible   
 
 
 
 
 
 
que possible 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
80 
APPENDIX IV COLLABORATIVE AGREEMENTS PROVISIONS 
 
The ibrutinib supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between Pharmacyclics (hereinafter referred to as 
“Collaborator”) and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Ibrutinib may not be used for any purpose outside the scope of this protocol, nor can ibrutinib be 
transferred or licensed to any party not participating in the clinical study.  Collaborator data for 
ibrutinib are confidential and proprietary to Collaborator and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing Agents contain confidential 
information and should not be shared or distributed without the permission of the NCI.  If a copy 
of this protocol is requested by a patient or patient’s family member participating on the study, 
the individual should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data 
by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter 
be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, 
all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, 
or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 

ALLIANCE A041202 
 
Version Date 03/20/2019
 
Update #08 
 
81 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ 
media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

ALLIANCE A041202 
 
 
Version Date 03/20/2019
 
Update #08 
 
82 
 
APPENDIX V 
GERIATRIC ASSESSMENT (A041202-EL1) MEASURES

 
 
Version Date 03/20/2019
 
Update #08 
 
83 
A Randomized Phase III Study of Bendamustine Plus Rituximab 
Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in 
Untreated Older Patients with Chronic Lymphocytic Leukemia 
(CLL) 
 
 
Self Assessment Measure - Patient Questionnaire 
 
Assessment Period  
 
 Prior to Treatment (between pre-registration and start of cycle 1) 
 
 Day 1 of Cycle 6 
 
 Progression or 2 years 
 
 
 
 
 
 
 
Responsible person name (Physician, Nurse, or CRA) _________________________________________ 
 
 
Date Completed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
Patient Study ID Number: __________ 
 
 
 
 
 
 
 
 
Patient Initials: ________________ 
 
L 
F 
M 
 
 
 
 
 
 
Study Number:  A041202   

ALLIANCE A041202 
 
PATIENT INFORMATION SHEET 
Patient Completed – Patient Questionnaire 
Version Date 03/20/2019 
84 
Update #08 
 
Page 1 of 13 
 
 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet is to be completed prior to your first treatment, on day 1 of cycle 6, and at 
progression or 2 years. 
 
2. The booklet contains 12 set of questions: 
a. Background information 
b. Daily activities questionnaire 
c. Physical activities questionnaire 
d. Current health rating questionnaire 
e. Falls questionnaire 
f. Your health questionnaire 
g. Mental Health questionnaire 
h. Social activities questionnaire 
i. 
Social support questionnaire 
j. 
Spirituality/religion questionnaire 
k. Your feelings questionnaire 
l. 
Questions concerning the questionnaire 
 
 
3. Directions on how to complete each set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions  
 
5. Bring the booklet with you to your next clinical visit.  It is very important that you return the 
booklet to us, whether you finish the study or not. 
 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 
 
 

ALLIANCE A041202 
 
PATIENT INFORMATION SHEET 
Patient Completed – Patient Questionnaire 
Version Date 03/20/2019 
85 
Update #08 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 2 of 13 
 
 
Patient Instructions:  If you are unable to complete the questionnaire, a member of your health care 
team will assist you. Please do not have a family member complete the questionnaire for you. 
 
 
A. BACKGROUND INFORMATION 
1. What is the highest grade you finished in school? (Mark one with an X). 
 8th grade or less 
 
 
 
 Vocational/technical school 
 9-11th grade  
 
 
 Bachelor’s degree 
 High school graduate/GED  
 Advanced degree 
 
 Associate degree/some college 
 
 I prefer not to answer 
 
 
2. What is your marital status? (Mark one with an X.) 
 
 
 Married 
 
 
 Separated 
 
 
 Domestic partnership 
 Never married 
 
 
 Widowed 
 
 
 I prefer not to answer 
 
 
 Divorced 
 
 
3. With whom do you live? (Mark all that apply with an X.) 
 
 Spouse / partner 
 
 
 
 Parent(s)/ parent(s)-in-law 
 
 Girlfriend / boyfriend 
 
 
 Live alone 
 
 Children aged 18 years or younger 
 
 Other specify ________________ 
 
 Children aged 19 years or older 
 
 Other relative specify ________________ 
 
 
4. What is your current employment status?  (Mark one with an X.) 
 
 Employed 32 hours or more per week 
 Unemployed 
 
 Employed less than 32 hours per week 
 Retired 
 
 Homemaker  
 
 
 Full-time student 
 
 Disabled 
 
 
 
 
 Part-time student 
 
 On medical leave 
 
 
 
 Other specify ________________ 
 
 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 3 of 13 
 
B. DAILY ACTIVITIES* 
 
PATIENT INSTRUCTIONS: Indicate your response by marking an X in one box per question. 
 
1. Can you use the telephone… 
 without help, including looking up and dialing; 
 with some help (can answer phone or dial operator in an emergency, but need a special phone or 
help in getting the phone number or dialing); or 
 are you completely unable to use the telephone? 
 
2. Can you get to places out of walking distance… 
 without help (can travel alone on buses, taxis, or drive your own car); 
 with some help (need someone to help you or go with you when traveling); or 
 are you unable to travel unless emergency arrangements are made for a specialized vehicle like 
an ambulance? 
 
3. Can you go shopping for groceries or clothes (assuming you have transportation) … 
 without help (taking care of all shopping needs yourself, assuming you have transportation); 
 with some help (need someone to go with you on all shopping trips); or 
 are you completely unable to do any shopping? 
 
4. Can you prepare your own meals… 
 without help (plan and cook full meals yourself); 
 with some help (can prepare some things but unable to cook full meals yourself); or 
 are you completely unable to prepare any meals? 
 
5. Can you do your housework… 
 without help (can clean floors, etc); 
 with some help (can do light housework but need help with heavy work); or 
 are you completely unable to do any housework? 
 
6. Can you take your own medicines… 
 without help (in the right doses at the right time); 
 with some help (able to take medicine if someone prepares it for you and/or reminds you to take 
it); or 
 are you completely unable to take your medicines? 
 
7. Can you handle your own money… 
 without help (write checks, pay bills, etc.); 
 with some help (manage day-to-day buying but need help with managing your checkbook and 
paying your bills); or 
 are you completely unable to handle money? 
 
 
 
* OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
Page 4 of 13 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
C. PHYSICAL ACTIVITIES*  
 
1. The following items are activities you might do during a typical day. Does your health limit you in 
these activities?  (Mark an X in the box on each line that best reflects your situation.) 
 
 
Activities 
Limited  
a lot 
Limited  
a little 
Not limited  
at all 
a. Vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports 
 
 
 
b. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
 
 
 
c. Lifting or carrying groceries 
 
 
 
d. Climbing several flights of stairs 
 
 
 
e. Climbing one flight of stairs 
 
 
 
f. Bending, kneeling, or stooping 
 
 
 
g. Walking more than a mile 
 
 
 
h. Walking several blocks 
 
 
 
i. Walking one block 
 
 
 
j. Bathing or dressing yourself 
 
 
 
 
 
 
* MOS, Physical Functioning Scale – Stewart, A.L. and Ware, J.E., 1992 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 5 of 13 
 
 
 
D. CURRENT HEALTH RATING* 
 
Which one of the following phrases best describes you at this time? (Mark one with an X.) 
 
 Normal, no complaints, no symptoms of disease 
 
 Able to carry on normal activity, minor symptoms of disease 
 
 Normal activity with effort, some symptoms of disease 
 
 Care for self, unable to carry on normal activity or do active work 
 
 Require occasional assistance but able to care for most of personal needs 
 
 Require considerable assistance for personal care 
 
 Disabled, require special care and assistance 
 
 Severely disabled, require continuous nursing care 
 
* Patient KPS – Loprinzi, C.L., et al., 1994 
 
 
 
E. FALLS 
 
How many times have you fallen in the last 6 months?  __ __ __ 
 
 
 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 6 of 13 
 
F. YOUR HEALTH  
 
1. Your General Health* 
 
Patient Instructions: Do you have any of the following illnesses at the present time, and if so, how much 
does it interfere with your activities: Not at All, A Little or A Great Deal? (Mark an X in the box that 
best reflects your answer.) 
 
 
 
If you have this illness:  
How much does it interfere with your 
activities? 
Illness 
No 
Yes 
 
Not  
at all 
A little 
A great 
deal 
a. Other cancers or leukemia 
 
 
→ 
 
 
 
b. Arthritis or rheumatism 
 
 
→ 
 
 
 
c. Glaucoma 
 
 
→ 
 
 
 
d. Emphysema or chronic bronchitis 
 
 
→ 
 
 
 
e. High blood pressure 
 
 
→ 
 
 
 
f. Heart trouble 
 
 
→ 
 
 
 
g. Circulation trouble in arms or legs 
 
 
→ 
 
 
 
h. Diabetes 
 
 
→ 
 
 
 
i. Stomach or intestinal disorders 
 
 
→ 
 
 
 
j. Osteoporosis 
 
 
→ 
 
 
 
k. Liver disease 
 
 
→ 
 
 
 
l. Kidney disease 
 
 
→ 
 
 
 
m. Stroke 
 
 
→ 
 
 
 
n. Depression 
 
 
→ 
 
 
 
 
 
* OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 7 of 13 
 
 
2. How is your eyesight (with glasses or contacts)?  (Mark one with an X.) 
 Excellent 
 
 Good  
 Fair 
 
 
 Poor  
 
 Totally blind 
 
3. How is your hearing (with a hearing aid, if needed)? (Mark one with an X.) 
 Excellent 
 
 Good  
 Fair 
 
 
 Poor  
 
 Totally deaf 
 
4. Do you have any other physical problems or illnesses (other than listed in questions 1-4) at the 
present time that seriously affect your health? 
 No 
 
 Yes   (If yes), specify _________________________________________________ 
 
(If yes), how much does this interfere with your activities?  (Mark one with an X.) 
 
 
 Not at all 
 
 Somewhat  
 A great deal 
  
 
 
* OARS IADL – Fillenbaum, G.G. and Smyer, M.A., 1981 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
 
Page 8 of 13 
 
G. MENTAL HEALTH QUESTIONNAIRE* 
 
INSTRUCTIONS: These questions are about how you have been feeling within the past month. 
Please mark an “X” in the box on each line that best reflects your situation.  
 
How much of the time during the 
past month: 
All  
of the 
Time 
Most 
of the 
Time 
A Good 
Bit of the 
Time 
Some  
of the 
Time 
A Little 
of the 
Time 
None 
of the 
Time 
1. has your daily life been full of 
things that were interesting to you? 
 
 
 
 
 
 
2. did you feel depressed? 
 
 
 
 
 
 
3. have you felt loved and wanted? 
 
 
 
 
 
 
4. have you been a very nervous 
person? 
 
 
 
 
 
 
5. have you been in firm control of 
your behavior, thoughts, emotions, 
feelings? 
 
 
 
 
 
 
6. have you felt tense or “high-
strung”? 
 
 
 
 
 
 
7. have you felt calm and peaceful? 
 
 
 
 
 
 
8. have you felt emotionally stable? 
 
 
 
 
 
 
9. have you felt downhearted and 
blue? 
 
 
 
 
 
 
10. have you felt restless, fidgety, or 
impatient? 
 
 
 
 
 
 
11. have you been moody, or brooded 
about things? 
 
 
 
 
 
 
12. have you felt cheerful, lighthearted? 
 
 
 
 
 
 
13. have you been in low or very low 
spirits? 
 
 
 
 
 
 
14. have you been a happy person? 
 
 
 
 
 
 
15. did you feel you had nothing to 
look forward to? 
 
 
 
 
 
 
16. have you felt so down in the dumps 
that nothing could cheer you up? 
 
 
 
 
 
 
17. have you been anxious or worried? 
 
 
 
 
 
 
* MHI-17 – Stewart, A.L. and Ware, J.E., 1992 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 9 of 13 
 
H. SOCIAL ACTIVITIES* 
 
1. During the past 4 weeks, how much time has your physical health or emotional problems interfered 
with your social activities (like visiting with friends, relatives, etc.)?  
(Mark one with an X.) 
 
 All of the time 
 Most of the time 
 Some of the time 
 A little of the time 
 None of the time 
 
 
2. Compared to your usual level of social activity, has your social activity during the past 6 months 
decreased, stayed the same, or increased because of a change in your physical or emotional condition?  
(Mark one with an X.) 
 
 Much less socially active than before 
 Somewhat less socially active than before 
 About as socially active as before 
 Somewhat more socially active as before 
 Much more socially active than before 
 
 
3. Compared to others your age, are your social activities more or less limited because of your physical 
health or emotional problems? (Mark one with an X.) 
 
 Much more limited than others 
 Somewhat more limited than others 
 About the same as others 
 Somewhat less limited than others 
 Much less limited than others 
 
 
 
* MOS, Social Activities – Stewart, A.L. and Ware, J.E., 1992 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
 
Page 10 of 13 
 
I. SOCIAL SUPPORT* 
 
INSTRUCTIONS: People sometimes look to others for companionship, assistance or other types of 
support. How often is each of the following kinds of support available to you if you need it? (Mark 
an X in the box on each line that best reflects your situation.) 
 
 
None  
of the 
Time 
A 
Little 
of the 
Time 
Some  
of the 
Time 
Most  
of the 
Time 
All  
of the 
Time 
1. Someone to help you if you were confined to 
bed. 
 
 
 
 
 
2. Someone you can count on to listen to you 
when you need to talk. 
 
 
 
 
 
3. Someone to give you good advice about a 
crisis. 
 
 
 
 
 
4. Someone to take you to the doctor if you 
needed it. 
 
 
 
 
 
5. Someone to give you information to help you 
understand a situation. 
 
 
 
 
 
6. Someone to confide in or talk to about 
yourself or your problem. 
 
 
 
 
 
7. Someone to prepare your meals if you were 
unable to do it yourself. 
 
 
 
 
 
8. Someone whose advice you really want. 
 
 
 
 
 
9. Someone to help you with daily chores if you 
were sick. 
 
 
 
 
 
10. Someone to share your most private worries 
and fears with. 
 
 
 
 
 
11. Someone to turn to for suggestions about how 
to deal with a personal problem. 
 
 
 
 
 
12. Someone who understands your problems. 
 
 
 
 
 
 
 
* MOS Social Support Survey – Sherbourne, C.D. and Stewart, A.L., 1991 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
 
Page 11 of 13 
 
J. SPIRITUALITY/RELIGION* 
 
Directions: Please answer the following questions about your religious beliefs and/or involvement. 
(Please mark an “X” in the box on each line that best reflects your situation.)  
 
1. How often do you attend church, synagogue, or other religious meetings? (Mark one with an X.) 
 More than once per week 
 Once a week 
 A few times a month 
 A few times a year 
 Once a year or less 
 Never 
 
2. How often do you spend time in private religious activities, such as prayer, meditation or Bible study?  
(Mark one with an X.) 
 More than once a day 
 Daily 
 Two or more times per week 
 Once a week 
 A few times a month 
 Rarely or never 
 
The following section contains 3 statements about religious belief or experience.  Please mark the extent 
to which each statement is true or not true for you. 
 
3. In my life, I experience the presence of the Divine (i.e., God). (Mark one with an X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
 
4. My religious beliefs are what really lie behind my whole approach to life. (Mark one with an X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
 
5. I tried hard to carry my religion over into all other dealings in my life. (Mark one with an X.) 
 Definitely true of me 
 Tends to be true 
 Unsure 
 Tends not to be true 
 Definitely not true 
 
* DUREL: Duke University Religion Index – Koenig et al., 1997 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
 Page 12 of 13 
 
 
K. YOUR FEELINGS* 
 
1. Do you often feel sad or depressed? (Mark one with an X.) 
 
 No     
 Yes 
 
 
2. How would you describe your level of anxiety, on the average? Please circle the number (0-10) best 
reflecting your response to the following that describes your feelings during the past week, including 
today.  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No anxiety  
Anxiety as bad 
as it can be 
 
* Mahoney et al., 1994; LASA – Locke et al., 2007 
 
 
 

ALLIANCE A041202 
 
Self Assessment Measure – Patient Questionnaire 
 
Page 13 of 13 
 
L. QUESTIONS CONCERNING THE QUESTIONNAIRE 
 
1. Were there any questions difficult to understand?  
 No     
 Yes 
(If yes), which questions were they? 
 
 
 
 
 
2. Was the time it took to answer all the questions too long, just right or too short? 
 Too short  →  How long would you have liked the questionnaire to be?   __ __ minutes 
 Just right 
 Too long →  How long would you have liked the questionnaire to be?   __ __ minutes 
 
 
Which items would you remove? 
 
 
 
 
 
 
3. Did you find any of the questions upsetting? 
 No     
 Yes 
(If yes), which questions were they? 
 
 
 
 
 
 
 
Could you tell me why they were upsetting? 
 
 
 
 
 
 
4. Do you think the questionnaire left out any questions that were important to ask? 
 
 
 
 
 
 
 
Thank you for your participation

ALLIANCE A041202 
 
A Randomized Phase III Study of Bendamustine Plus Rituximab 
Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in 
Untreated Older Patients with Chronic Lymphocytic Leukemia 
(CLL) 
 
 
Health Care Professional Questionnaire 
 
Assessment Period  
 
 Prior to Treatment (between pre-registration and start of cycle 1) 
 
 Day 1 of Cycle 6 
 
 Progression or 2 Years 
 
 
This form completed by  
   Physician (check one) 
 Yes     
 No 
   Nurse (check one)    
 
 Yes     
 No 
   CRA (check one) 
 Yes     
 No 
 
 
 
 
Date Completed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
Patient Study ID Number: __________ 
 
 
 
 
 
 
 
 
Patient Initials: ________________ 
 
L 
F 
M 
 
 
 
 
 
 
Study Number:  A041202   

ALLIANCE A041202 
HEALTHCARE PROFESSIONAL INFORMATION SHEET 
Health Care Professional Completed Questionnaire 
________________________________________________________________________ 
Version Date: 03/20/2019 
99 
 
 
 
 
          Update #08 
 
Page 1 of 5 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your patients’ functional status, cognition, and nutrition.   
 
1. This booklet is to be completed prior to the patient’s first treatment, on day 1 of cycle 6, and at 
progression or 2 years. 
 
2. The booklet contains 6 set of questions: 
I. Form information 
II. Functional status (Karnofsky Performance Status, Timed “Up and Go”) 
III. Cognition (Blessed Orientation-Memory-Concentration Test) 
IV. Scoring  
V. Nutrition 
VI. Questions regarding questionnaires 
 
3. This booklet should be completed by a Nurse, CRA or physician. 
 
4. Directions on how to complete each set of questions are written on the top of the page. 
 
5. Please enter the booklet data into Medidata Rave when finished. 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 
 
 
 
 
 
 

ALLIANCE A041202 
 
Healthcare Professional Questionnaire 
______________________________________________________________________________ 
Version Date: 03/20/2019 
100 
Update #08 
Page 2 of 5 
II. Functional Status 
A. Karnofsky Performance Status (Healthcare professional rated)* 
 
INSTRUCTIONS: Please rate your assessment of patient’s Karnofsky Performance Status as of date this 
form is completed. (Scale is listed below.) 
 
__ __ __ % 
 
% 
CRITERIA 
100 
Normal: no complaints; no evidence of disease. 
90 
Able to carry on normal activity; only minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, but unable to carry on normal activity or do active work. 
60 
Requires occasional assistance, but is able to care for most personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospitalization is indicated although death not imminent. 
20 
Very sick; hospitalization necessary; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
* Physician KPS – Karnofsky, D.A. and Burchenal, J.H., 1949 
 
 
B. Timed “Up and Go”** 
 
INSTRUCTIONS: The timed “Up and Go” measures, in seconds, the time it takes for an individual to stand up 
from a standard arm chair (approximate seat height of 46 cm [approximately 1.5 ft]), walk a distance of 3 meters 
(approximately 10 feet), turn, walk back to the chair, and sit down again. The subject wears his/her regular footwear 
and uses their customary walking aid (none, cane, walker, etc.) No physical assistance is given. The subject starts 
with his back against the chair, his arm resting on the chair’s arm, and his walking aid in hand.  He is instructed that 
on the word “go”, he is to get up and walk at a comfortable and safe pace to a line on the floor 3 meters 
(approximately 10 feet) away, turn, and return to the chair and sit down again. The subject walks through the test 
once before being timed in order to become familiar with the test. Either a wrist watch with a second hand or a stop-
watch can be used to time the performance. 
 
 
 
Time to perform “Up and Go”  __ __ . __ seconds 
 
 
** Timed “Up and Go” – Podsiadio, D. and Richardson, S., 1991 
 

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III. Cognition 
This section is only completed prior to treatment (between pre-registration and start of cycle 1) and on day 1 of 
cycle 6 
 
BLESSED ORIENTATION-MEMORY-CONCENTRATION TEST* 
 
Patient’s 
Response 
Maximum 
errors 
                                         Final 
Score          Weight          score 
1. What year is it now? 
[without looking at a calendar] 
__ __ __ __ 
1 
__ __        x       4       =      __ __ 
2. What month is it now? 
[without looking at a calendar] 
__ __ 
1 
__ __        x       3        =      __ __ 
Memory Phrase: 
Repeat this phrase after me: ‘John 
Brown, 42 Market Street, Chicago’ 
 
 
 
3. About what time is it? 
[within 1 hour] 
__ __ : __ __ 
(24-hour clock) 
1 
__ __   x             3        =      __ __ 
4. Count backwards 20 to 1. 
 
2 
__ __   x           2        =      __ __ 
5. Say the months in reverse order. 
 
2 
__ __   x           2        =      __ __ 
6. Repeat the Memory Phrase. 
 
5 
__ __   x           2        =      __ __ 
 
 
 
 
              TOTAL SCORE:     __ __ 
 
Scoring: For items 1 to 3, the response is either correct (score 0) or incorrect (score 1). For items 4 to 6, add one 
point for each error (item 4 and 5 maximum error is 2; for item 6, maximum error is 5); total all scores in “Final 
Score” column. Data from participants found to have gross cognitive impairment as determined by the Orientation-
Memory-Concentration Score ≥11 will be excluded from the analysis. Maximum score = 28. 
 
* Blessed OMC – Katzman, R., et al., 1983; Kawas, C., et al., 1995 
 
IV. Scoring 
This question is only applicable to the BOMC-Test in Section III. 
 
1. Did the patient score greater than or equal to 11 on the Blessed Orientation-Memory-Concentration Test? 
 No 
 Yes (If yes, notify the patient’s treating physician.) 
 
This question is only applicable to question #1 in “Section K. Your Feelings” from the Patient Questionnaire. 
 
2. How did the patient answer the question “Do you often feel sad or depressed?” in the Patient  Questionnaire 
(Section K)? 
 No 
 Yes (If yes, notify the patient’s treating physician.) 

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V. Nutrition 
 
Height (from patient’s chart)    __ __ _ cm 
 
Weight (from patient’s chart)    __ __ __ kg 
 
Weight approximately 6 months ago (from patient’s chart or patients self report)  __ __ __ kg 
 
 
VI. Questions Regarding Questionnaires 
 
A. Were any of the questionnaires in the Geriatric Assessment – Healthcare Professional Questionnaire  
difficult 
for you to administer? 
 
 Yes     
 No 
 
 
If no, please proceed to the next question. 
(If yes), please indicate which questionnaire was difficult to administer (Mark all that apply with an X.) 
 
 Karnofsky Performance Status (KPS) Healthcare Professional Rated 
 
 Timed Up and Go 
 
 Blessed Orientation-Memory-Concentration Test 
 
 Other 
               If other, specify _________________________________ 
 
B. Were any of the questionnaires in the Geriatric Assessment – Patient Questionnaire difficult for the patient 
 
to complete? 
 
 Yes     
 No 
 
 
If no, please proceed to the next question.  
 
(If yes), please indicate which questionnaire(s) was difficult for the patient to complete (Mark all that apply 
 
with an X.) 
 Background Information  
 Daily Activities  
 Physical Activities  
 Current Health Rating  
 Falls  
 Your Health  
 
 Mental Health  
 Social Activity  
 Social Support  
 Spirituality/Religion 
 Your Feelings 
 
 
 

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C. Was the patient able to complete “Geriatric Assessment – Patient Questionnaire” on his/her own? 
 Yes     
 No 
 
 
If yes, please proceed to the next question. 
(If no), reason not completed on his/her own (select the primary reason) 
 
 Not literate (does not read or write) 
 Visual problem 
 Fatigue 
 Questions too difficult (above the patient’s reading ability) 
 Other, specify_________________________________________________ 
 
 
D. Length of time to complete both the Patient and Healthcare Professional Questionnaires 
Length of time to complete healthcare professional questionnaire 
__ __ __ minutes 
Length of time to complete patient questionnaire 
__ __ __ minutes 
Total length of time to complete both questionnaires 
__ __ __ minutes 
 
 
 
 
 
 
 
 
 
 
Completed by ____________________________ 
Date form completed __ __ / __ __ / __ __ __ __ 
 
(Last name, First name) 
 
 
 
        M  M       D  D        Y   Y    Y   Y 
 
 
 
 
 
 
 
 
 

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