A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (&gt;/= 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: National Cancer Institute (NCI)

1 
Update #12 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO A041702 
_________________________________________ 
 
A RANDOMIZED PHASE III STUDY OF IBRUTINIB PLUS OBINUTUZUMAB VERSUS IBRUTINIB PLUS 
VENETOCLAX AND OBINUTUZUMAB IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
X Editorial/Administrative changes 
 
 
Activation 
 
 
 
 
 
 
Eligibility changes 
 
 
Closure 
 
 
 
 
 
 
Therapy/Dose Modifications/Study Calendar changes 
 
 
Suspension  
 
 
 
 
 
 
Scientific/Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Correlative Science/BioMS changes 
 
 
 
 
 
 
 
 
X Informed Consent changes  
 
 
 
 
 
 
 
 
X Other: Updated CAEPR for Venetoclax 
 
 
 
 
 
 
The changes included in this update to A041702 have been made in response to the NCI Action Letter 
from Dr. Steven Gore (steven.gore@nih.gov). This Action Letter is posted on the A041702 study page 
on the CTSU website. A revised CAEPR for Venetoclax drug with new risks has been added to the 
protocol. Therefore, the model consent form has been revised to incorporate the new risks, consistent 
with the NCI Model Consent Template instructions. 
 
No recommended level of IRB review is provided by the Alliance as the CIRB is the IRB of record for 
this trial. This amendment must be implemented within 30 days after posting. 
 
A consent form addendum will need to be signed by all patients currently receiving treatment or having 
treatment held with Venetoclax. Please refer to the amendment application and CIRB guidelines for 
further instructions. 
 
 

2 
 
 
UPDATES TO THE PROTOCOL: 
 
Title Page 
• 
The Protocol Coordinator contact has been updated. 
• 
The Data Manager contact has been updated. 
 
Section 9.4.3 (Comprehensive Adverse Events and Potential Risks list (CAEPR) for Venetoclax 
(ABT-199, NSC 766270)) 
This section has been revised to include the updated venetoclax CAEPR (Version 2.2, July 22, 2025) 
provided by CTEP. Changes from Version 2.1 to Version 2.2 include the following: 
 
• The SPEER grades have been updated. 
 
• 
Added New Risk:  
• 
Rare but Serious: Hepatobiliary disorders - Other (drug-induced liver injury) 
• 
Also Reported on Venetoclax Trials But With Insufficient Evidence for Attribution: 
Alanine aminotransferase increased; Cataract; Colitis; Creatinine increased; Delirium; 
Esophageal pain; Esophageal ulcer; Fall; Generalized muscle weakness; Leukemia 
secondary to oncology chemotherapy; Metabolism and nutrition disorders - Other 
(hypervolemia); Mucositis oral; Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) - Other (Richter’s syndrome); Pain in extremity; Pneumonitis 
 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on Venetoclax Trials But With Insufficient 
Evidence for Attribution: Back pain; Hyperphosphatemia 
 
• 
Decrease in Risk Attribution:  
• 
Changed to Less Likely from Likely: Anemia; Fatigue 
• 
Changed to Also Reported on Venetoclax Trials But With Insufficient Evidence for 
Attribution from Less Likely: Hypertension; Hypophosphatemia 
 
_____________________________________________________________________________________ 
 
UPDATES TO THE MODEL CONSENT: 
What risks can I expect from taking part in this study? 
Based on the updated CAEPR described above, the following changes have been made to the NCI 
condensed risk profile for venetoclax: 
 
• 
Added New Risk: 
• 
Rare: Damage to the liver which may cause yellowing of eyes and skin, swelling 
 
• 
Decrease in Risk Attribution: 
• 
Changed to Occasional from Common: Anemia which may require blood transfusion; 
Tiredness 

3 
 
• 
Changed to Also Reported on Venetoclax Trials But With Insufficient Evidence for 
Attribution from Occasional (i.e. Removed from Risk Profile): High blood pressure which 
may cause headaches, dizziness, blurred vision 
 
• 
Provided Further Clarification: 
• 
Pain in joints (under Occasional) is now reported as Pain (under Occasional) 
 
_____________________________________________________________________________________ 
 
INFORMED CONSENT ADDENDUM: 
A new informed consent addendum has been added to reflect the new or additional information 
for Venetoclax with this update. This addendum is intended to be signed by all patients currently 
receiving treatment or having treatment held with Venetoclax. 
 
 
A replacement protocol document, model consent, and informed consent addendum have been 
issued. 
This study remains closed to new patient accrual. 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 

1 
Version Date 11/07/2025 
 
Update #12 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A041702 
 
A RANDOMIZED PHASE III STUDY OF IBRUTINIB PLUS OBINUTUZUMAB VERSUS IBRUTINIB PLUS 
VENETOCLAX AND OBINUTUZUMAB IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
NCI-supplied agents: Ibrutinib (NSC #748645) 
Venetoclax (NSC #766270) 
Obinutuzumab (NSC #793436) 
IND #: 
 
IND Holder: DCTD 
 
ClinicalTrials.gov Identifier: NCT03737981 
Study Chair 
Jennifer Woyach, MD 
The Ohio State University 
Tel: 614-685-5667   Fax: 614-293-4812 
jennifer.woyach@osumc.edu 
Community Oncology Co-chair 
Leukemia Correlative Study Co-
Chair & Leukemia Correlative 
Science Committee Chair 
Leukemia Committee Co-Chair 
Elie Dib, MD 
St. Joseph Mercy Hospital 
Tel: 734-712-3456 
Elie_dib@ihacares.com 
John C. Byrd, MD  
University of Cincinnati 
Tel: 513-558-0858 
Byrd2jc@ucmail.uc.edu 
Geoffrey L. Uy, MD 
Washington University School of 
Medicine 
Tel: 800-600-3606 
guy@wustl.edu 
Leukemia Committee Co-Chair 
Cancer in the Older Adults Co-
Chair 
Pathology Co-Chair 
Wendy Stock, MD 
University of Chicago 
Tel: 773-834-8982 
wstock@medicine.bsd.uchicago.edu 
Aminah Jatoi, MD 
Mayo Clinic 
Tel: 507-284-4918 
Jatoi.aminah@mayo.edu 
Cecelia Miller, PhD 
The Ohio State University 
Tel: 614-366-3908 
cecelia.miller@osumc.edu 
SWOG Study Champion 
ECOG-ACRIN Study 
Champion 
Primary 
Statistician 
Cancer in the Older Adults 
Statistician 
Brian T. Hill, PhD 
Cleveland Clinic 
Tel: 216-445-9451 
Hillb2@ccf.org 
Wei Ding, MD, PhD 
Mayo Clinic 
Tel: 507-266-0792  
Ding.wei@mayo.edu 
Jun (Vivien) Yin, 
PhD  
Tel: 507-538-6252 
yin.jun@mayo.edu 
Jennifer Le-Rademacher, PhD 
Tel:507-284-4402 
Le-
Rademacher.Jennifer@mayo.edu 
Secondary Statistician 
Protocol Coordinator 
Data Manager 
Gabriela Perez 
Tel: 507-293-9454 
Perezburbano.gabriela@mayo.edu 
Jayke Giese 
leukemiaprotocols@alliancenctn.org 
Korrie Powell 
Powell.Korrie@mayo.edu 
 
In Memory of Dr. Arti Hurria 
 
Participating NCTN Groups: Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-
ACRIN Cancer Research Group, NRG / NRG Oncology, SWOG / SWOG

A041702 
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Update #12 
Study Resources 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/ 
 Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
A041702 Nursing Contact 
Ilene Galinsky, MSN, ANP-C 
Dana-Farber Cancer Institute 
Tel: 617-632-3902 
Email: igalinsky@partners.org 
 
Alliance Hematologic Malignancy Biorepository 
The Arthur G. James Cancer Hospital  
& Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-688-4754 
AllianceLTB@osumc.edu 
A041702 Pharmacy Contact 
Caroline Harvey, RPh. 
Dana-Farber Cancer Institute 
Tel: 617-632-3786   
caroline_harvey@dfci.harvard.edu 
 
Drug Distribution Contact 
NCI Pharmaceutical Management Branch 
Tel: 240-276-6575 
PMBAfterHours@mail.nih.gov 
 
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, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
pharmacovigilance@allianceNCTN.org 
Questions regarding specimens/specimen 
submissions: 
Alliance Hematologic Malignancy Biorepository  
Questions regarding drug supply 
NCI PMB 
Questions regarding drug administration 
Pharmacy Contact 
 
 
 
 
 

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Update #12 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
https://www.ctsu.org, and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (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 log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
For clinical questions (i.e. patient eligibility or treatment-related)  
Study Chair, Nursing Contact, Protocol Coordinator, and (where applicable) Data Manager 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 
 

A041702 
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Update #12 
 
A RANDOMIZED PHASE III STUDY OF IBRUTINIB PLUS OBINUTUZUMAB VERSUS IBRUTINIB PLUS 
VENETOCLAX AND OBINUTUZUMAB IN UNTREATED OLDER PATIENTS (≥ 65 YEARS OF AGE) WITH 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
 
Pre-registration eligibility criteria (see Section 3.2) (Step 0) 
-CLL or SLL diagnosis 
-Central blood submission for correlates & FISH (see Section 
6.2) 
 
Registration eligibility criteria (see Section 3.3) (Step 1) 
-Diagnosis with CLL or SLL in accordance with 2018 IWCLL 
criteria 
-Intermediate or high-risk Rai stage CLL or SLL 
-Criteria met for treatment as defined by 2018 IWCLL 
guidelines 
-No prior therapy for CLL (except palliative steroids or 
treatment of autoimmune complications per Section 3.3.3) 
-Age ≥ 65 years  
-ECOG performance status 0-2 
-No comorbid conditions or other active diseases per Section 
3.3.7  
-Not taking concomitant medications as outlined in Section 
3.3.8 
-No known allergy to mannitol 
-No prior significant hypersensitivity to rituximab 
-No major surgery within 10 days or minor surgery within 7 days 
 
Re-registration eligibility criteria (See Section 3.4) (Step 2)  
- Completion of first 14 cycles of therapy and remain on ibrutinib 
- Receipt of central BM MRD results and completion of response evaluation 
Required Initial Laboratory Values for 
Registration (Step 1) 
Absolute Neutrophil Count (ANC) ≥ 
1,000/mm3 except if due to bone marrow 
involvement 
Platelet Count (untransfused) ≥ 30,000/mm3 
except if due to bone marrow involvement 
Calc. Creatinine Clearance ≥ 40 mL/min (by 
Cockcroft-Gault) 
Bilirubin ≤ 1.5 x upper limit of normal (ULN) 
except if due to liver involvement, hemolysis, 
or Gilbert’s disease 
AST / ALT  ≤ 2.5 x upper limit of normal 
(ULN) except if due to liver involvement 

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Update #12 
RE-REGISTRATION (Step 2) 
SCHEMA 
1 Cycle = 28 Days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients will be followed for 10 years from study 
registration (Step 1) or until death, whichever comes first. Please refer to the full protocol 
text for a complete description of the eligibility criteria and treatment plan
PRE-REGISTRATION (STEP 0) 
REGISTRATION/RANDOMIZATION (STEP 1) 
Central specimen submission for FISH (see Sec 6.2), 
Local assessment of Rai Stage (see Sec 3.3), & 
confirmation of eligibility (see Sec 3.3) 
Arm 1 
Ibrutinib 420 mg PO daily days 1-28 for 15 
cycles  
Obinutuzumab 100 mg IV 100 mg on C1D1, 
900 mg on C1D2, 1000 mg on Cycle1D8 & 
C1D15, C2-6D1 
Arm 2 
Ibrutinib 420 mg PO daily days 1-28 for 15 cycles 
Obinutuzumab 100 mg IV 100 mg on C1D1, 900 
mg on C1D2, 1000 mg on C1D8 & C1D15, C2-6D1 
Venetoclax 20 mg daily PO beginning C3D1, dose 
escalated weekly to a final dose of 400 mg on C4D1, 
then 400 mg daily PO C4D1-C14D28 
Any response except 
BM MRD- CR 
(BM MRD+ CR, PR, PRL, 
SD) 
BM MRD - CR 
Observation q3 
cycles for 6 years 
from registration 
(step 1), then q6 
cycles until 
progression 
Ibrutinib 420 mg PO 
daily days 1-28 until 
progression or 
unacceptable adverse 
events 
Ibrutinib 420 mg PO daily days 1-28 until 
progression or unacceptable adverse events 
C15D1 Response Assessment Specimen submission 
for central BM MRD & local response assessment & 
labs performed per Sec 5.0., 
 
At the same time, 
Continue Ibrutinib 420 mg PO daily C15D1-D28. 
C15D1 Response Assessment Specimen submission 
for central BM MRD & local response assessment & 
labs performed per Sec 5.0.  
 
At the same time, 
Continue Ibrutinib 420 mg PO daily C15 D1-D28.  

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Update #12 
Arm 1 Ibrutinib Obinutuzumab 
 
 
Cycle 1 D1-28 
C2 
 
 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 
C14 
C15 
Day 1 
D2 
D8 
D15 
D1 
D1 
D1 
D1 
D1 
Ibrutinib  
420 mg daily 
Obinutuzumab 
 
100 
mg 
900 
mg 
1000 
mg 
1000 
mg 
1000 
mg 
1000 
mg 
1000 
mg 
1000 
mg 
1000 
mg 
 
 
 
 
 
 
 
 
 
 
Arm 2 Ibrutinib, Venetoclax, and Obinutuzumab 
 
Cycle 1 D1-28 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
C12 
C13 
C14 
C15 
Day 1 
D2 
D8 
D15 
Ibrutinib   
PO 
420 mg daily 
Obinutuzumab 
IV 
 
100 
mg 
900 
mg 
1000 
mg 
1000
mg 
Day 1 
1000 
mg 
D1 
1000 mg 
D1 
1000 
mg 
D1 
1000 
mg 
D1 
1000 
mg 
 
 
 
 
 
 
 
 
 
Venetoclax  
PO 
 
 
 
 
 
20 mg 
daily, 
dose 
escalated 
weekly* 
 
400 mg daily 
 
 
* Arm 2 Venetoclax Dose Escalation  
Cycle 3 
Cycle 4 
Day 1 – 7 
D8 - 14 
D15-21 
D22 - 28 
D1 - 7 
20 mg 
50 mg 
100 mg 
200 mg 
400 mg 

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Update #12 
 
Table of Contents 
1.0 
BACKGROUND ........................................................................................................................ 10 
1.1 
Initial therapy for CLL in older patients .................................................................................. 10 
1.2  
Ibrutinib as Initial Therapy for CLL ........................................................................................ 10 
1.3 
Venetoclax in CLL .................................................................................................................. 11 
1.4 
Justification for addition of venetoclax ................................................................................... 11 
1.5 
Justification for Correlative Studies ........................................................................................ 13 
1.6 
Impact of the trial .................................................................................................................... 13 
2.0 
OBJECTIVES ............................................................................................................................ 13 
2.1 
Primary objective .................................................................................................................... 13 
2.2 
Secondary objectives ............................................................................................................... 13 
2.3 
Correlative science objectives ................................................................................................. 13 
3.0 
PATIENT SELECTION .............................................................................................................. 13 
3.1 
On-study guidelines ................................................................................................................. 14 
3.2 
Pre-registration eligibility criteria (Step 0) .............................................................................. 14 
3.3 
Registration eligibility criteria (Step 1) ................................................................................... 14 
3.4 
Eligibility criteria for re-registration (Step 2) ......................................................................... 18 
4.0 
PATIENT REGISTRATION ....................................................................................................... 18 
4.1 
CTEP Registration Procedures ................................................................................................ 18 
4.2 
CTSU Registration Procedures ............................................................................................... 19 
4.3 
Patient pre-registration requirements (Step 0) ......................................................................... 21 
4.4 
Patient registration requirements (Step 1) ............................................................................... 21 
4.5 
Patient re-registration requirements (Step 2) ........................................................................... 22 
4.6 
Patient Registration/Randomization Procedures ..................................................................... 22 
4.7 
Stratification Factors and Treatment Assignments .................................................................. 23 
5.0 
STUDY CALENDAR .................................................................................................................. 24 
6.0 
DATA AND SPECIMEN SUBMISSION ....................................................................................... 27 
6.1 
Data Collection and Submission ............................................................................................. 27 
6.2 
Specimen collection and submission ....................................................................................... 28 
7.0 
TREATMENT PLAN/INTERVENTION ...................................................................................... 29 
7.1 
Cycle 1 through Cycle 14 Day 28 ........................................................................................... 30 
7.2 
After Cycle 15 Day 28 ............................................................................................................. 34 
8.0 
DOSE AND TREATMENT MODIFICATIONS ............................................................................ 34 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care...................................... 34 
8.2 
Dose Modifications ................................................................................................................. 37 
9.0 
ADVERSE EVENTS .................................................................................................................. 40 

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Update #12 
9.1 
Routine Adverse Event Reporting ........................................................................................... 40 
9.2 
CTCAE Routine Reporting Requirements .............................................................................. 41 
9.3 
Expedited Adverse Event Reporting (RAVE-CTEP-AERS) .................................................. 42 
9.4 
CAEPRs .................................................................................................................................. 45 
9.5 Adverse Events of Special Interest ................................................................................................... 54 
10.0 
DRUG INFORMATION ............................................................................................................. 55 
10.1 
General Considerations: .......................................................................................................... 55 
 
 
 
 
 
 
10.5 
NCI-supplied Agent Ordering, Accountability, Inventory, IB Availability, and Contacts ..... 59 
11.0 
MEASUREMENT OF EFFECT ................................................................................................... 60 
11.1 
Complete response .................................................................................................................. 60 
11.2 
Complete response with incomplete recovery (CRi) ............................................................... 60 
11.3 
Clinical CR (CCR) .................................................................................................................. 61 
11.4 
Nodular PR (nPR) ................................................................................................................... 61 
11.5 
Partial Response ...................................................................................................................... 61 
11.6 
Partial response except persistent lymphocytosis (PRL) ......................................................... 61 
11.7 
Progressive Disease (PD) ........................................................................................................ 61 
11.8 
Stable Disease.......................................................................................................................... 62 
12.0 
END OF TREATMENT/INTERVENTION ................................................................................... 62 
12.1 
Duration of Protocol Treatment .............................................................................................. 62 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention ............................................ 63 
12.3 
Follow-up ................................................................................................................................ 63 
12.4 
Extraordinary Medical Circumstances .................................................................................... 64 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention
 
64 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 64 
13.1 
Study design ............................................................................................................................ 64 
13.2 
Statistical design and analysis for the primary endpoint ......................................................... 65 
13.3 
Sample size, accrual time, and study duration ........................................................................ 67 
13.4 
Supplementary analysis plans ................................................................................................. 67 
13.5 
Monitoring the study ............................................................................................................... 69 
13.6 
Study reporting ........................................................................................................................ 70 
13.7 
Inclusion of women and minorities ......................................................................................... 70 
14.0 
CORRELATIVE AND COMPANION STUDIES .......................................................................... 72 
14.1 
Laboratory Correlative Studies ............................................................................................... 72 

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15.0 
REFERENCES .......................................................................................................................... 74 
APPENDIX I CHILD-PUGH SCORE ....................................................................................................... 76 
APPENDIX II HOWARD CRITERIA FOR TLS GRADING ............................................................................ 77 
APPENDIX III COLLABORATIVE AGREEMENT ......................................................................................... 78 
APPENDIX IV IBRUTINIB PATIENT MEDICATION DIARY ........................................................................ 80 
APPENDIX V VENETOCLAX PATIENT MEDICATION DIARY .................................................................... 84 
APPENDIX VI PATIENT DRUG INFORMATION HANDOUT AND WALLET CARDS ................................... 88 
 
 
 
 
 

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Update #12 
1.0 
BACKGROUND 
1.1 
Initial therapy for CLL in older patients 
The optimal initial therapy for older adults with CLL is not established.  Ibrutinib is FDA 
approved in the up-front setting based on data showing excellent activity and durable remissions 
with this agent [1] as well as the RESONATE-2 study [2], which showed both a PFS and OS 
advantage for ibrutinib over chlorambucil (median PFS for chlorambucil 18.9 months vs not 
reached for ibrutinib; 24 month OS 85% for chlorambucil vs 98% for ibrutinib).  Response rates 
were high in this study, with an overall response rate (ORR) of 86% and complete response 
(CR) rate of 4%. A041202, a randomized phase III trial comparing ibrutinib to standard 
chemoimmunotherapy (bendamustine plus rituximab) has been completed but results not yet 
reported, yet the hematology community has adopted ibrutinib as a standard of care for this 
patient population. This trial and others are also investigating ibrutinib in combination with 
CD20 antibody compared with ibrutinib as a single agent.  While no mature data from 
randomized studies are available, it is clear that ibrutinib given with CD20 antibody is safe, and 
is certain to be at least as effective as ibrutinib given as a single agent.  Therefore, either ibrutinib 
alone or in combination with CD20 antibody can be considered a standard of care for the 
frontline treatment of CLL. Of the clinically available CD20 antibodies, obinutuzumab is the 
most effective, and can produce complete responses alone and in combination with other agents. 
To ensure that our standard of care arm is the most effective comparator, we have chosen the 
combination of ibrutinib and obinutuzumab for this study.  
While ibrutinib is highly effective in previously untreated CLL patients, there do remain 
disadvantage to this therapy.  Specifically, the low rate of complete response (CR) and need for 
continuous administration.  While data does not exist to prove that a CR with ibrutinib is superior 
to a PR, the fact that mutations in B cell specific genes (BTK and PLCG2) are acquired during 
therapy and drive resistance to this agent [3] suggests that elimination of all CLL cells would 
decrease the likelihood of mutation acquisition and therefore clinical progression.  As well, no 
data exist relative to discontinuation, even in patients with deep remission.  While ibrutinib is 
generally well tolerated, some toxicities such as hypertension are more common over time, and 
continuous administration has other obvious disadvantages including cost.  
Currently, a number of studies have been designed with the goal of discontinuation of ibrutinib 
therapy by administration of combinations with either chemotherapy or additional targeted 
therapies.  However, no studies have been undertaken to this point to randomize patients to 
continue versus discontinue ibrutinib.   
1.2  
Ibrutinib as Initial Therapy for CLL 
1.2.1 
 Efficacy 
Ibrutinib (PCI-32765, Imbruvica™) is a first-in-class, orally-administered, covalently- 
binding small molecule inhibitor of BTK currently under development for the treatment of 
B-cell malignancies. Ibrutinib is approved by the U.S. Food and Drug Administration 
(FDA) for the treatment of patients with CLL/SLL and Waldenstrom’s Macroglobulinemia 
and for mantle cell lymphoma (MCL) patients who have received at least one prior therapy.  
Ibrutinib has been highly effective as initial therapy for CLL.  The first study to test this 
approach, PCYC 1102, showed a 5 year PFS of 92% [4]. As well, the phase III 
RESONATE-2 study showed a 24 month PFS with this agent. [5]  Combinations with 
ibrutinib and monoclonal antibodies as well have showed exceptional efficacy. In a phase 
II study of ibrutinib in combination with rituximab for patients with high risk CLL (either 
treatment-naïve or relapsed), PFS at 18 months was 78%.  Another study of ibrutinib in 
combination with ofatumumab for patients with relapsed disease showed a 12 month PFS 

A041702 
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Version Date 11/07/2025 
 
Update #12 
of 83.1%. [6]Overall, these data show that ibrutinib alone or in combination with CD20 
monoclonal antibodies produce durable remissions.  However, even in the front-line 
setting, very few patients achieve a complete response, so indefinite duration of therapy is 
required. 
1.2.2 
Safety 
Ibrutinib alone and in combination with antibodies has consistently demonstrated 
acceptable safety parameters. In the RESONATE-2 study, the most common adverse 
events (>20% of patients) included diarrhea, fatigue, nausea, and cough.  High grade (grade 
≥3) toxicities included hypertension (14%), atrial fibrillation (6%) and bleeding (4%).  
Discontinuation due to adverse events was relatively rare over the short follow-up. [2]   
Long term follow-up of ibrutinib studies has shown relatively few cumulative toxicities, 
although rate of hypertension does tend to increase over time on drug. [7]  Infectious 
toxicities tend to decrease over time.  
1.3 
Venetoclax in CLL 
1.3.1 
Efficacy 
Venetoclax has demonstrated considerable efficacy in CLL, both alone and in combination 
with ibrutinib or monoclonal antibody therapy.  In the phase I study in relapsed or 
refractory CLL, the response rate was 79%.  Remarkably, complete remissions occurred in 
20% of patients. Median PFS was 25 months in the dose escalation cohort, and 15 month 
PFS was 66% in the expansion cohort of patients treated at 400 mg daily. [8]  Single agent 
venetoclax has also shown efficacy in patients with relapsed CLL who possess 
del(17p13.1), where the response rate was 79.4%, with a CR rate of 8%.  12 month PFS 
was 72%. [9] 
Venetoclax has also been studied in combination with monoclonal antibodies.  In a phase 
1b study of venetoclax in combination with rituximab, OFF was 86%, with a 51% CR rate.  
Of 25 patients who attained a CR, 80% were minimal residual disease negative.  2 year 
PFS was 82%. [10] More recently, the MURANO study compared venetoclax plus 
rituximab to bendamustine plus rituximab in patients with relapsed/refractory CLL.  PFS 
was superior for venetoclax + rituximab, with 2 year PFS of 82.8%. [11] 
1.3.2 
Safety 
Venetoclax has been well tolerated across studies.  In the phase study, adverse events seen 
in >20% of patients included diarrhea, upper respiratory tract infection, nausea, 
neutropenia, 
fatigue, 
cough, 
pyrexia, 
anemia, 
headache, 
constipation, 
and 
thrombocytopenia.  The most significant toxicity seen with venetoclax is tumor lysis 
syndrome, which occurred in 18% of patients in the phase I setting.  This risk has been 
reduced by slow ramp-up to the desired dose as well as stratification and supportive care 
based upon tumor lysis syndrome risk. [8] 
1.4 
Justification for addition of venetoclax 
Venetoclax is a rational drug to combine with ibrutinib given preclinical data suggesting synergy 
[12] [13] as well as extraordinary clinical results as a single agent including impressive CR rates 
even in the relapsed population. [8] [9]  The combination of ibrutinib with venetoclax and 
obinutuzumab is currently under investigation in the phase I/II setting in both treatment-naïve 
and relapsed/refractory CLL.  12 patients were initially treated in the Phase Ib portion of the 
study, where the recommended Phase II dose was determined to be the FDA labeled doses for 
each drug. [14]  There were no dose limiting toxicities, and no patient discontinued therapy. 

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Toxicities generally were as expected for each drug given individually.  The Phase II portion 
included an additional 50 patients (25 treatment-naïve, 25 relapsed/refractory).  Median age was 
59, but patients on the study were up to age 77.  All toxicities are presented in Table 1 below.  
Hematologic toxicity was most frequent with the majority of patients experiencing 
thrombocytopenia (80%) and/or neutropenia (76%). The most frequent non-hematologic 
toxicities were hypertension (70%), infusion related reactions (66%), bruising (52%), myalgia 
(50%), and nausea (50%). Grade 3-4 toxicities were largely hematologic with 56% experiencing 
grade 3-4 neutropenia and 34% grade 3-4 thrombocytopenia. The only frequently occurring non-
hematologic grade 3-4 toxicity was hypertension (32%).  
The median follow-up for the study was 18.0 months (range 0-24.8) for the RR cohort and 20.6 
months (range 7.4-23.9) for the TN cohort. At mid-therapy assessment 23/25 of the RR patients 
remained on study and all had achieved a response. Three patients achieved CR, 3 a CR with 
incomplete marrow recovery, and 17 a partial remission. The ORR in RR patients at mid-therapy 
was 92% (95% CI: 74-99%). Twenty-three (92%) RR patients tested for mid-therapy MRD, 
with 16 (70%) MRD negative in both the blood and marrow. Two patients had MRD in the 
blood only, 2 in the marrow only, and 3 in both the blood and the marrow. Mid-therapy 
responses for the TN cohort have previously been reported (Rogers ASH 2017). To date in 21 
(84%) TN patients completed treatment through C14 and 23 (92%) RR remain on study with 21 
completing treatment. No patients in either cohort had progressive disease. There was one death 
from neutropenia and colitis in a TN patient.  
Table 1: Treatment related adverse event [1] 
 
 
Based on previous trials showing a survival advantage for initial therapy even in the setting of 
active agents for second line therapy, [2] [15] we believe that investigation of a combination of 
our most active agents in the up-front setting is justified.  As a secondary endpoint this trial will 
collect OS data.   

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1.5 
Justification for Correlative Studies 
Limited data exist in the treatment-naïve setting to inform how traditional (cytogenetics, IGHV 
mutational status) or novel (DNA mutations) prognostic studies impact response to 
ibrutinib/obinutuzumab or ibrutinib/obinutuzumab/venetoclax in the front-line setting.  With the 
high response rates and durable remissions seen with these combinations, it will require a large 
trial with extended follow up to gather meaningful data.  Therefore, this study has the unique 
opportunity to collect biomarkers that will impact our understanding of prognostic studies 
associated with these drugs.  As well, there are no data to determine mechanisms of resistance 
associated with ibrutinib/obinutuzumab/venetoclax, and again the efficacy of this agent makes 
a large study required to begin to understand these mechanisms.  Because the importance of the 
data to be obtained is so high, and risk to the patients is minimal, correlative laboratory studies 
will be required for all patients.     
1.6 
Impact of the trial 
The proposed trial will establish the standard of care for initial therapy of older adults with CLL. 
It also has the potential to diminish drug costs significantly for patients who attain BM MRD- 
status and can go off therapy.  As well, data regarding discontinuation of ibrutinib is applicable 
to the relapsed setting as well as other diseases where ibrutinib is used.   
2.0 
OBJECTIVES 
2.1 
Primary objective  
To compare the progression-free survival (PFS) between control treatment and experimental 
treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus 
ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.  
2.2 
Secondary objectives 
2.2.1 
To compare BM MRD- CR rates, MRD- rates, and depth of response, and depth of response 
at Cycle 15 Day 1 between patients treated with IO versus IVO. 
2.2.2 
To compare overall survival (OS) between the control and experimental treatment 
strategies: IO with IM versus IVO regardless of IM or observation. 
2.2.3 
To compare the 5-year PFS and OS for the control and experimental treatment strategies: 
IO with IM versus IVO regardless of IM or observation. 
2.2.4 
To describe the toxicity profile for each of the treatment strategies and by each treatment 
course. 
2.3 
Correlative science objectives 
2.3.1 
To compare MRD status between blood and bone marrow at the end of induction 
treatment/Cycle 15 Day 1 to determine whether blood MRD can be used as a surrogate to 
bone marrow MRD with these treatment regimens. 
2.3.2 
To compare peripheral blood MRD status by standard central flow cytometry to next 
generation sequencing (NGS) using ClonoSeq technique to determine the agreement in 
MRD negativity of the two techniques. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  

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3.1 
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.  
Physicians should consider whether any of the following may render the patient inappropriate 
for 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. 
• 
Patients may not have an active intercurrent disease or concurrent malignancy that is 
expected to limit survival to <5 years.  
• 
Patients who cannot swallow oral formulations of the agents. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study and for women 18 months 
after obinutuzumab treatment and for men 180 days after obinutuzumab treatment 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). 
3.2 
Pre-registration eligibility criteria (Step 0) 
___ 
3.2.1 
CLL or SLL diagnosis 
Patients must have been diagnosed with CLL (> 5000 B-cells per uL of peripheral blood 
at any point during the course of their disease) or Small lymphocytic lymphoma (SLL) 
with <5000 B-cells per µL of blood but with disease-associated lymphadenopathy.  
___ 
3.2.2 
Central FISH blood submission 
This blood submission is mandatory prior to registration/randomization to perform FISH 
centrally that will be used for stratification. It should be obtained as soon after pre-
registration as possible. See Sections 4.4 and 6.2 for more information. 
3.3 
Registration eligibility criteria (Step 1) 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
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 one week later would 
be considered Day 7. 
___ 
3.3.1 
Documentation of disease 
Patients must be diagnosed with CLL or SLL in accordance with 2018 IWCLL criteria [28] 
that includes all of the following: 

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• 
≥5x109 B lymphocytes (5000/μL) in the peripheral blood measured by flow 
cytometry at any point in the course of the disease or less peripheral blood 
involvement but disease-associated lymphadenopathy. 
• 
On local morphologic review, the leukemic cells must be small mature 
lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes. 
• 
Neoplastic 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. 
___ 
3.3.2 
Staging and indication for therapy 
• 
Patients must be intermediate or high-risk Rai stage CLL or SLL 
Intermediate Risk (Formerly Stage 
I/II) 
Lymphadenopathy  
and/or   
hepatomegaly or splenomegaly 
without anemia or thrombocytopenia 
High Risk (Formerly Stage III/IV) 
Splenomegaly  
and/or  
Anemia (hemoglobin <11g/dL) not 
attributable to autoimmune hemolytic 
anemia  
and/or  
Thrombocytopenia (plt <100 x109/L) 
not attributable to autoimmune 
thrombocytopenia 
• 
Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines[16] 
which includes at least one of the following criteria: 
o Evidence of marrow failure as manifested by the development or worsening of 
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia 
or thrombocytopenia) 
o Massive (≥6 cm below the costal margin), progressive or symptomatic 
splenomegaly 
o Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy 
o Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an 
increase of ≥ 50% over a 2 month period 
o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy 
o Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, 
spine) 
o Constitutional symptoms, which include any of the following: 
▪ 
Unintentional weight loss of 10% or more within 6 months 
▪ 
Significant fatigue 

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▪ 
Fevers >100.5 degrees F for 2 weeks or more without evidence of 
infection 
▪ 
Night sweats ≥1 month without evidence of infection 
___ 
3.3.3 
Prior treatment 
• 
Patients must not have had prior therapy for CLL/SLL (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/SLL 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. 
___ 
3.3.4 
Age ≥ 65 years 
___ 
3.3.5 
ECOG performance status 0-2 
___ 
3.3.6 
Required initial laboratory values  
Absolute Neutrophil Count (ANC) 
≥ 1,000/mm3 except if due to bone 
marrow involvement 
Platelet Count (untransfused) 
≥ 30,000/mm3 except if due to bone 
marrow involvement 
Calc. Creatinine Clearance 
 
≥ 40 mL/min (by Cockcroft-Gault) 
Bilirubin 
≤ 1.5 x upper limit of normal (ULN) 
except if due to liver involvement, 
hemolysis, or Gilbert’s disease 
AST / ALT  
≤ 2.5 x upper limit of normal (ULN) 
except if due to liver involvement 
___ 
3.3.7 
Comorbid conditions or other active diseases 
• 
Patients must not have any history of Richter’s transformation or prolymphocytic 
leukemia (prolymphocytes in blood > 55%). 
• 
If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be 
undetectable on suppressive therapy if indicated. 
• 
Please note: 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, must have hepatitis serologies and hepatitis B DNA monitored 
periodically by the treating physician. 
• 
If history of hepatitis C virus (HCV) infection, must be treated with undetectable 
HCV viral load 
• 
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.   
• 
Patients who have had a myocardial infarction, intracranial bleed, or stroke within 
the past 6 months are not eligible.   

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• 
Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral 
therapy with undetectable viral load within 6 months are eligible for this trial 
___ 
3.3.8 
Concomitant medications 
• 
Patients must not be receiving active systemic anticoagulation with heparin or 
warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior 
to registration on the study.  
• 
Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed 
on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 
14 days prior to registration on the study. See Section 8.1.9 for more information. 
• 
Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. 
Patients must discontinue the drug 14 days prior to registration on the study. See 
Section 8.1.10 for more information. 
• 
Patients must not require more than 20 mg prednisone or equivalent corticosteroid 
daily. 
• 
Patients must not have uncontrolled active systemic infection requiring 
intravenous antibiotics. 
___ 
3.3.9 
Central FISH blood results 
Central FISH blood results are mandatory prior to registration/randomization for it will be 
used for stratification. See Sections 4.4 and 6.2 for more information. 
___ 
3.3.10 Other  
• 
Patients must be able to swallow capsules and not have the following conditions: 
disease significantly affecting gastrointestinal absorption, resection of the stomach 
or small bowel, partial or complete bowel obstruction.  
• 
Patients must not have a known allergy to mannitol. 
• 
Patients must not have prior significant hypersensitivity to rituximab (not 
including infusion reactions). 
• 
Patients may not have had major surgery within 10 days prior to registration, or 
minor surgery within 7 days prior to registration. Examples of minor surgery 
include dental surgery, insertion of a venous access device, skin biopsy, or 
aspiration for a joint. The decision about whether a surgery is major or minor can 
be made at the discretion of the treating physician.  
• 
Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase 
for prophylaxis/treatment of TLS. 

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3.4 
Eligibility criteria for re-registration (Step 2) 
___ 
3.4.1 
Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib 
therapy.  
___ 
3.4.2 
Receipt of central BM MRD results. 
___ 
3.4.3 
Response assessment completed per Section 5.0. 
4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
IVR—MD, DO, or international equivalent; 
NPIVR—advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
AP—clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such 
as the Roster Update Management System (RUMS), OPEN, Rave; acting as a primary 
site contact, or with consenting privileges 
Associate (A)—other clinical site staff involved in the conduct of NCI-sponsored trials; and 
Associate Basic (AB)—individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
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 Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 

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Addition to a site roster; 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
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. 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS).  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 

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• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Holds the appropriate CTEP registration type for the protocol. 
4.2.1 
Additional site registration requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Downloading site registration documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and its associated investigators and staff on a 
participating roster. To view/download site registration forms:Log in to the CTSU 
members’ website (https://www.ctsu.org) using your CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A041702. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.3 
Submitting regulatory documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 

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4.2.4 
Checking site registration status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
- 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.2.5 
Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website. The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site receiving 
an approved site registration status and enrolling patients to the study. To maintain an approved 
site registration status the CI must re-sign the DTL at least annually and when a new version of 
the DTL is released; and to activate new task assignments requiring CI sign-off. Any individual 
at the enrolling site on a participating roster may initiate the site DTL. Once the DTL is 
submitted for CI approval, only the designated DTL Administrators or the CI may update the 
DTL. Instructions on completing the DTL are available in the Help Topics button in the DTL 
application and include a Master Task List, which describes DTL task assignments, CI signature, 
and CTEP registration requirements. 
4.3 
Patient pre-registration requirements (Step 0) 
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. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
4.4 
Patient registration requirements (Step 1) 
Pre-registration (Step 0) completed: All patients are REQUIRED to be pre-registered to 
A041702 in order to complete patient registration (Step 1) and to submit peripheral blood to the 
Alliance Hematologic Malignancy Biorepository (HEME) for FISH to be performed at The 
Ohio State University (see Section 6.2), with FISH results used for stratification. After patient 
pre-registration with specimen submission, sites will be notified of FISH results via email within 
7-10 business days of specimen receipt at the Alliance Biorepository (HEME). Once patient 
registration eligibility is confirmed (See Section 3.3) the patient may be registered (Step 1) in 
OPEN. Registration must occur within 36 business days of receipt of FISH results.  
FISH for stratification: All patients are REQUIRED to be pre-registered to A041702 in order 
to submit peripheral blood to the Alliance Hematologic Malignancy Biorepository (HEME) for 
FISH performed at The Ohio State University (see Section 6.2.2). The FISH results will be used 
for stratification.  

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4.5 
Patient re-registration requirements (Step 2) 
• 
Day 1 of Cycle 15 response assessment:  The patient must have successfully completed 
fourteen cycles of therapy on Arm 1 (Ibrutinib/Obinutuzumab) or Arm 2 
(Ibrutinib/Venetoclax/Obinutuzumab) and remain on ibrutinib therapy in order to be re-
registered. Response assessment should be performed per Section 5.0 and specimens 
submitted per Section 6.2. Re-registration should be performed by Cycle 15 Day 21 to 
allow for agent ordering and provision by CTEP (see Section 10.1). 
• 
All patients are required to submit blood and bone marrow for central MRD. Sites will 
be notified of bone marrow MRD results via email within 7-10 business days of 
specimen receipt at Alliance HEME Biorepository. Response assessment (including 
CT) must be performed per Section 5.0. Follow OPEN enrollment procedures as 
detailed in Section 4.7 to register the patient to Step 2. Sites will be notified via email 
of the treatment assignment according to the following: 
o Patients randomized to Arm 1: At re-registration, these patients will be 
automatically assigned to ibrutinib maintenance  
o Patients randomized to Arm 2 who are determined to have any response 
except BM MRD- (centrally) CR (locally): At re-registration, these patients 
will be automatically assigned to ibrutinib maintenance. 
o Patients randomized to Arm 2 who are determined to be BM MRD- 
(centrally) and determined to be CR (locally): At re-registration, these 
patients will be automatically assigned to observation.  
4.6 
Patient Registration/Randomization Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
Corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 

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Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.7 
Stratification Factors and Treatment Assignments 
Step 1 randomization: 
• 
Rai stage (intermediate vs. high) 
• 
High-risk FISH abnormality del(17p13.1) (present vs. absent).  
Step 2 re-registration: 
• 
Initially randomized to Arm 1 
• 
Initially randomized to Arm 2 and any response except BM MRD- CR 
• 
Initially randomized to Arm 2 and a response of BM MRD- CR  
 

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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals  
− 
Peripheral blood flow cytometry to meet pre-registration eligibility criteria (see Section 
3.2.1) may be completed at any time prior to pre-registration. 
o IGHV mutational status needs to be performed prior to registration, but results are 
not required to register the patient. May be completed any time prior to registration 
− 
To be completed ≤ 14 DAYS before registration: All laboratory studies (except those listed 
below), history and physical. 
− 
To be completed ≤ 60 DAYS before registration: Peripheral blood and bone marrow flow 
cytometry, bone marrow aspirate and biopsy, CT scan, HBsAg, HBsAb, Hep C, HB core 
antibody, Serum immunoglobulins, Beta 2 microglobulin. If a bone marrow biopsy was 
performed as standard of care within this window, a repeat is not necessary and no research 
aspirate needs to be sent. 
 
Prior 
to 
Pre-
Reg 
Prior 
to 
Reg 
 
 
C1 
D1 
 
 
 
 
 
 
C2-6 
D1 
 
C9 D1, 
C12 
D1, 
C15 
 D1 
 
 
C16D1, then D1 
q 3 cycles for 6 
years from 
registration 
(Step 1), then q 6 
cycles* 
Clinical 
follow-
up 
** 
Clinical 
disease 
progression
*** 
Tests & Observations**** 
 
 
 
 
 
 
 
 
History & progress notes  
 
X 
 
X 
X 
X 
X 
X 
Physical examination and node 
measurements 
 
X 
 
X 
X 
X 
X 
X 
Height  
 
X 
 
 
 
 
 
 
Weight / body surface area 
 
X 
X 
X 
X 
X 
 
X 
Performance status 
 
X 
X 
X 
X 
X 
 
X 
Solicited baseline abnormalities/AEs 
 
X 
X 
X 
X 
X 
 
X 
Laboratory Studies**** 
 
 
 
 
 
 
 
 
Complete blood count (CBC) 
 
X 
X 
X 
X 
X 
X 
X 
Serum creatinine, BUN 
 
X 
X 
X 
X 
A 
 
 
Serum electrolytes (Na/K)  
 
X 
X 
X 
X 
 
 
 
Uric acid / phosphate / Ca++F 
 
X 
X 
 
 
 
 
G 
AST, ALT, alk. phos., bilirubin, albumin 
 
X 
 
X 
X 
A 
 
 
LDH 
 
X 
X 
X 
X 
 
 
X 
Beta-2-microglobulin 
 
X 
 
 
 
 
 
 
Direct antiglobulin test (Coomb’s test) 
 
X 
 
 
 
 
 
 
HBsAg, HBsAb, Hep C, HB core 
antibody  
 
X(1) 
 
 
 
 
 
 

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Update #12 
Serum immunoglobulins (IgG, IgA, IgM) 
 
X 
 
B 
B 
C 
C 
 
IGVH mutational status 
X 
 
 
 
 
 
 
 
TLS risk assessment 
 
 
D 
 
 
 
 
 
Venetoclax TLS monitoring labs 
 
 
 
E 
 
 
 
 
Staging**** 
 
 
 
 
 
 
 
 
Peripheral whole blood for central FISH 
& cytogenetics 
 
X(2) 
 
 
 
 
 
 
CT scan (chest, neck, abdomen, & pelvis) 
& bilateral measurements of largest nodes 
 
X 
 
B(3) 
B 
C 
C 
X 
Peripheral blood flow cytometry 
F 
F(4) 
 
B(4) 
B(4) 
X(4) 
 
X(4) 
Bone marrow aspirate (including flow 
cytometry) & biopsy   
 
X(5) 
 
B 
B 
 
 
 
Peripheral whole blood and bone marrow 
aspirate for central BM MRD 
 
 
 
B 
B 
 
 
 
Correlative studies: (Mandatory for all 
patients) 
 
 
 
 
 
 
 
 
Peripheral whole blood, bone marrow 
aspirate and buccal samples for  
correlative studies 
Whole blood required prior to registration, at the end of treatment during Day 1 of 
Cycle 15,Day 1 of Cycle 22, every Day 1 of 6 cycles beginning C22 until 6 years from 
registration (Step 1), then every 12 cycles, at discontinuation of treatment, and 
relapse/progression. Bone marrow aspirate required prior to registration, at the end 
of initial treatment Day 1 of Cycle 15, and at discontinuation of treatment. If bone 
marrow was performed as standard of care prior to study pre-registration but within 
the time window, research aspirate does not need to be sent. Buccal cell sample 
required prior to treatment. See Section 6.2 
 
* 
Testing schedule is Cycle 16 Day 1, then on Day 1 of every 3 cycles until 6 years after the date of 
study registration (Step 1), then on Day 1 of every 6 cycles until progression, or 10 years from study 
registration, whichever occurs first. Following the completion of therapy, each cycle has a window of 
+/- 14 days. 
** Clinical follow-up is defined for patients who discontinue protocol therapy (either prior to re-registration 
or after re-registration with ibrutinib) in the absence of clinical disease progression to CLL (see Section 
12.3.2 for definition and requirements). Clinical follow-up is required every 3 cycles (from date of 
discontinuation of protocol therapy) until 6 years have elapsed from study registration (Step 1), then every 
6 cycles thereafter until progression, or until 10 years from study registration, whichever occurs first. Each 
of these observations has a +/- 30 day window. 
*** After documentation of clinical disease progression to CLL, survival follow-up is required every 6 
months until death or 10 years have elapsed from registration (Step 1), whichever occurs first. 
**** 
Tests & observations and laboratory studies can be performed +/- 7 calendar days to Day 1 of the 
specified cycle.  CT scans and bone marrow biopsy may be completed +/- 7 calendar days from the 
beginning of the specified cycle.  
 
1 
All patients should be screened for hepatitis B prior to registration. Patients who test positive for 
hepatitis B should be screened with hepatitis B DNA testing every 3 cycles and should be considered 
for prophylactic antiviral therapy. 
2 
Peripheral whole blood for central FISH testing is required for all patients at the pre-registration 
assessment.  Results must be received in order to register the patient.  
3 
CT scans for high TLS risk patients should be repeated prior to C3D1 if treating physician thinks 
patient may no longer fall in the high-risk category; if low/med risk, treatment should be modified 
accordingly. 

A041702 
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Update #12 
4 
Peripheral blood flow cytometry must include an assessment of number of CLL cells per uL, absolute 
B-cell counts (CD19+ & CD5+), and T-cell count.   
5 
Bone marrow aspirate at baseline should include flow cytometry. Panel should include:  assessment of 
number of CLL cells per uL, absolute B-cell counts (CD19+ & CD5+), and T-cell count. If bone 
marrow biopsy was completed within the timeframe but prior to study participation and the flow 
cytometry was not included, the bone marrow does not need to be repeated. 
 
 
A For patients who continue on ibrutinib therapy only. 
B For patients who complete Cycles 1-14, perform only on Cycle 15 Day 1. For patients who discontinue 
protocol therapy in Cycles 1-14 for reasons other than clinical disease progression to CLL, perform only at 
the end of treatment during Step 1 (+/- 14 calendar days). Local flow cytometry is only required on 
baseline bone marrow (not at Cycle 15 Day 1). 
C Perform every 12 cycles. For all patients, including those assigned to ibrutinib and those assigned to 
Observation after re-registration, perform on Day 1 of Cycles 28, 40, etc. For patients in clinical follow-
up, perform every 12 cycles beginning with the initial response assessment after therapy discontinuation.  
Obtain immunoglobulins during follow-up as clinically indicated. 
D Venetoclax risk assessment is required C1D1.  Requirements are outlined in Section 7.1.2. If the treating 
physician suspects that risk category has changed prior to day 1 of venetoclax (due to 
ibrutinib/obinutuzumab), CT scans may be repeated and risk reassessed prior to venetoclax administration. 
E Venetoclax TLS monitoring labs include creatinine, potassium, calcium, uric acid, and phosphate. 
These labs must be performed on Cycle 3 Days 1, 8, 15, 22 and Cycle 4 Day 1.  These tests should be 
performed on the schedule outlined in Section 7.1.2. 
F 
Perform prior to pre-registration rather than prior to registration if diagnosis of CLL has not already been 
confirmed. 
G Obtain serum uric acid, phosphate, and calcium during follow-up as clinically indicated. 
 
 
 
 

A041702 
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Update #12 
6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website  under Data Management > Rave Home 
and click to accept the invitation in the Tasks pane located in the upper right corner of the 
iMedidata screen. Site staff 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 eLearning link in the Tasks pane 
located in the upper right corner of the iMedidata screen. If an eLearning is required for a study 
and has not yet been taken, the link to the eLearning will appear under the study name in the 
Studies pane located in the center of the iMedidata screen; once the successful completion of 
the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or 
by contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.   
6.1.1 
Supporting documentation to be submitted to the Alliance 
This study requires supporting documentation as outlined below: 

A041702 
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Version Date 11/07/2025 
 
Update #12 
• 
Baseline: Peripheral blood flow and bone marrow report, H&P with lymph node 
sizes documented on physical exam, and CT report. The Central FISH Review 
results form is to be added as ‘Other’ supporting documentation.  
• 
Cycle 15 Day 1: Peripheral blood flow and bone marrow report, H&P with lymph 
node sizes documented on physical exam, CT report; if protocol therapy is 
discontinued during Cycles 1-14 for reasons other than clinical disease progression to 
CLL, submit instead at the end of treatment (+/- 14 calendar days). The Central Bone 
Marrow and Peripheral Blood MRD results are to be added as ‘Other’ supporting 
documentation. 
• 
C16D1 and every third cycle after C15D1 response assessment: Peripheral blood 
flow reports 
• 
Every 12 cycles after C16D1: CT reports 
• 
Progression (Either before or after C15D1 response assessment): H&P with lymph 
node sizes documented on physical exam, CT report, and, if performed, bone 
marrow report. 
Supporting documentation is to be submitted via Rave. 
6.1.2 
Data Quality Portal   
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent 
forms, forms with current status and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
6.2 
Specimen collection and submission  
The Alliance A041702 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing and shipping. The manual can be found on the BioMS and CTSU 
websites. Questions regarding the CSM should be address to the contacts specified in the 
manual. 
For all patients registered to Alliance A041702: Submission of blood for central FISH testing is 
required for all patients at the pre-registration assessment and prior to registration. Submission 
of bone marrow and blood for central BM MRD for Cycle 15 Day 1 assessment is required for 
all patients; if protocol therapy is discontinued during Cycles 1-14 for reasons other than clinical 
disease progression to CLL, submit within 14 days of discontinuation of therapy.  
 
 

A041702 
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Update #12 
 
Prior to 
registration 
Day 1 
Cycle 15 * 
Day 1 q 6 cycles 
Beginning C22 
until 6 years from 
registration (Step 
1), then q 12 
cycles**  
Discontinuation 
of Treatment*** 
Relapse/ 
Progression 
**** 
Mandatory for all patients registered to A041702: 
Bone marrow aspirate 
(EDTA/lavender top) 
10 mL 
10 mL2 
 
10 mL 
  
 
Peripheral blood (acid 
citrate dextrose/ ACD-A) 
40 mL 
40 mL 
40 mL 
40 mL 
40 mL 
Peripheral blood (sodium 
heparin) 
5 mL1 
5 mL 
5 mL 
5 mL 
5 mL 
Buccal cell sample (kit 
provided) 
X 
 
 
 
 
 
* 
For patients who have completed 14 cycles of treatment, bone marrow and 
peripheral blood may be submitted +/- 7 business days from Cycle 15 Day 1. 
** 
Submit +/- 7 business days. 
*** 
For patients who have discontinued treatment during Cycles 1-14 for reasons 
other than clinical disease progression to CLL,1, blood and bone marrow must 
be submitted within +/- 14 business days of discontinuation of therapy.  
**** 
The relapse/progression specimen is not required if the discontinuation of 
therapy specimen submissions were submitted within the previous 2 months. 
1 
Peripheral whole blood for central FISH testing is required for all patients at 
the pre-registration assessment and within 36 business days prior to 
registration. 
2 
MRD assessment will be performed, and the specimen MUST be submitted no 
later than 7 business days after Day 1 of Cycle 15 to allow for re-registration 
by Cycle 15 Day 21 and for agent ordering and provision by CTEP (Section 
10.1). See Section 4.6 for more information. 
7.0 
TREATMENT PLAN/INTERVENTION 
For questions regarding treatment, please see the study contacts page.  
It is acceptable for individual antibody 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 therapy 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 

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Update #12 
up to 7 days before the protocol-defined date for major life events. Documentation to justify this 
delay should be provided. 
7.1 
Cycle 1 through Cycle 14 Day 28 
Prior to registration, all patients should meet eligibility criteria and undergo centralized FISH 
testing.  Central FISH results as well as Rai stage must be documented on the 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 ≤ 14 days after registration (Step 1). 
7.1.1 
Arm 1: Ibrutinib/Obinutuzumab 
Treatment on Arm 1 consists of ibrutinib 420 mg PO daily on days 1-28 of each of fifteen 
28-day cycles.  Obinutuzumab is administered IV at 100 mg on cycle 1 day 1, 900 mg on 
cycle 1 day 2, 1000 mg cycle 1 days 8 and 15, and 1000 mg day 1 of cycles 2-6. 
• 
Recommended/prohibited ancillary therapy is outlined in Section 8.1. 
• 
Premedication: No premedication is required for ibrutinib. Premedication for 
obinutuzumab per institutional guidelines is permitted, however, recommended 
premedication is the following: 
o 20 mg dexamethasone IV or 80 mg methylprednisolone IV at least 1 hour 
prior (first 2 doses, then may be discontinued at treating physician 
discretion). 
o 650-1000 mg acetaminophen at least 30 minutes prior. 
o Anti-histamine (e.g. 50 mg Benadryl) at least 30 minutes prior (first 2 
doses, then may be discontinued at treating physician discretion).  
• 
Tumor Lysis Syndrome (TLS), including fatal cases, has been reported in patients 
receiving obinutuzumab. Patients with high tumor burden, high circulating 
lymphocyte count (>25 x 10 9 /L) or renal impairment are at greater risk for TLS 
and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics 
(e.g., allopurinol or rasburicase) and hydration prior to the infusion of 
obinutuzumab. 
• 
During the initial days of obinutuzumab treatment, monitor the laboratory 
parameters of patients considered at risk for TLS per institutional standards. For 
treatment of TLS, correct electrolyte abnormalities, monitor renal function and 
fluid balance, and administer supportive care, including dialysis as indicated. 
• 
Drug administration: Full administration guidelines are outlined in Section 10.1. 
Ibrutinib should be administered at least 30 minutes prior to obinutuzumab on 
cycle 1 day 1. Thereafter, the order of administration may be altered per 
institutional guidelines. 
• 
Patients on ibrutinib should keep a daily drug administration record with dates and 
times taken (see Appendix IV, 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. 

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Update #12 
• 
Dose modifications/dose delays after cycle 1 are outlined in Section 8.2. 
7.1.2 
Arm 2: Ibrutinib/Venetoclax/Obinutuzumab 
Treatment on this arm consists of ibrutinib 420 mg PO daily, on days 1-28 of each of 15 
28-day cycles.  Obinutuzumab is administered IV at 100 mg on cycle 1 day 1, 900 mg on 
cycle 1 day 2, 1000 mg cycle 1 days 8 and 15, and 1000 mg day 1 of cycles 2-6.  Venetoclax 
is taken PO starting at 20 mg daily on cycle 3 day 1, and dose escalated once weekly (50 
mg starting C3D8, 100 mg starting C3D15, 200 mg starting C3D22, 400 mg starting C4D1) 
to a final dose of 400 mg daily beginning on cycle 4 day 1 and continuing to the end of 
cycle 14. Venetoclax should be taken with a meal (and both venetoclax and ibrutinib should 
be taken with water). 
• 
Recommended/prohibited ancillary therapy is outlined in Section 8.1.  
• 
Premedication:  
o No premedication is required for ibrutinib.  
o Venetoclax premedication TLS prophylaxis is shown in Table 2 
below.  
o Premedication for obinutuzumab per institutional guidelines is 
permitted, however, recommended premedication is as follows: 
▪ 
20 mg dexamethasone IV or 80 mg methylprednisolone IV at least 
1 hour prior (first 2 doses, then may be discontinued at treating 
physician discretion). 
▪ 
650-1000 mg acetaminophen at least 30 minutes prior. 
▪ 
Anti-histamine (e.g. 50 mg Benadryl) at least 30 minutes prior 
(first 2 doses, then may be discontinued at treating physician 
discretion).  
• 
Tumor Lysis Syndrome (TLS), including fatal cases, has been reported in 
patients receiving obinutuzumab. Patients with high tumor burden, high 
circulating lymphocyte count (>25 x 10 9 /L) or renal impairment are at greater 
risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-
hyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to the 
infusion of obinutuzumab. 
• 
During the initial days of obinutuzumab treatment, monitor the laboratory 
parameters of patients considered at risk for TLS per institutional standards. 
For treatment of TLS, correct electrolyte abnormalities, monitor renal function 
and fluid balance, and administer supportive care, including dialysis as 
indicated. 
• 
Drug administration: Ibrutinib should be administered at least 30 minutes prior 
to obinutuzumab on cycle 1 day 1. Venetoclax should be given at least 60 
minutes prior to obinutuzumab. Thereafter, the order of administration may be 
altered per institutional guidelines.  
• 
A 2-hour window is allowed for the 24-hour post dose draw required with each 
venetoclax ramp up in C3/ARM2. For the earlier draws (within 12 hours post 
dose), a 1-hour window is allowed.  

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Update #12 
• 
Venetoclax TLS risk category will be assessed at C1D1 according to the 
guidelines in Table 2 below.  For patients at high risk for TLS or those at 
medium risk with CrCl <80ml/min, the first dose of 20 mg venetoclax and 50 
mg venetoclax should be administered in the hospital setting.  If desired by the 
treating physician, risk category assessment can be repeated prior to C3D1.  
Patients who are initially at high or medium risk but then decrease risk upon 
reassessment can be treated as an outpatient. Patients can be discharged after 
review of 24-hour post dose labs and if no evidence of TLS. 
• 
Patients on ibrutinib and venetoclax should keep a daily drug administration 
record with dates and times taken (see Appendix IV and Appendix V, Patient 
Medication Diary).  
• 
If a dose of ibrutinib or venetoclax is missed, it can be taken as soon as possible 
on the same day (< 8 hours after the missed dose) with a return to normal 
schedule the following day. Vomited doses should not be made up. Any 
remaining study drug must be returned at the next scheduled visit. Dose 
modifications/dose delays after cycle 1 are outlined in Section 8.2. 
Adapted from Venetoclax package insert: 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 
5- week ramp-up phase. Changes in blood chemistries consistent with TLS that require 
prompt management can occur as early as 6 to 8 hours following the first dose of venetoclax 
and at each dose increase. 
Table 2 below describes the recommended TLS prophylaxis and monitoring during 
VENCLEXTA treatment based on tumor burden determination from clinical trial data. 
 
 
 
 
 
 
 
 
Table 2. Recommended TLS Prophylaxis Based on Tumor Burden from Clinical 
Trial Data (consider all patient co-morbidities before final determination of 
prophylaxis and monitoring schedule) 
Tumor Burden 
Prophylaxis 
Blood Chemistry Monitoringc,d 

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Update #12 
Hydrationa 
Anti- 
hyperuricemics 
Setting and Frequency of Assessments 
Low 
All LN <5 
cm AND 
ALC <25 
x109/L 
Oral 
(1.5-2 L) 
Allopurinolb 
Outpatient 
• Pre-dose, 6 to 8 hours, 24 hours at first dose 
of 20 mg and 50 mg 
• Pre-dose at subsequent ramp- up doses 
Medium 
Any LN 5 cm to 
<10 cm OR 
ALC ≥25 
x109/L 
Oral (1.5-2 
L) and consider 
additional 
intravenous 
Allopurinol 
Outpatient 
• Pre-dose, 6 to 8 hours, 24 hours at first dose 
of 20 mg and 50 mg 
• Pre-dose at subsequent ramp- up doses 
• Consider hospitalization for patients with 
CrCl 
<80ml/min at first dose of 20 mg and 50 mg; see 
below for monitoring in hospital 
High 
Any 
LN 
≥10 
cm 
OR 
ALC ≥25 x109/L 
AND any 
LN ≥5 cm 
Oral (1.5-2 
L) and 
intravenous (150-
200 mL/hr as 
tolerated) 
Allopurinol; 
consider 
rasburicase if 
baseline uric acid 
is elevated 
In hospital at first dose of 20 mg and 50 mg 
• Pre-dose, 4, 8,12 
and 24 hours Outpatient at subsequent ramp-
up doses 
Pre-dose, 6 to 8 hours, 24 hours 
ALC = absolute lymphocyte count; LN = lymph node. 
aAdminister intravenous hydration for any patient who cannot tolerate oral hydration. 
bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax. cCorrect abnormal blood 
chemistries prior to administering venetoclax 
dFor patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose. 
7.1.3 
Cycle 15 Day 1 through Cycle 15 Day 28 
Following the completion of 14 cycles, all patients will receive a 15th cycle of ibrutinib 
therapy as they undergo restaging and response assessment including central evaluation of 
BM MRD. See sections 4.5, 5.0 and 6.2 for more information. All patients are required to 
re-register (Step 2). Patients will be assigned follows to subsequent treatment beginning 
Day 1 of Cycle 16 as follows: 
• 
All patients initially randomized to Arm 1 Ibrutinib/Obinutuzumab will be 
assigned to Ibrutinib.   
• 
All patients initially randomized to Arm 2 (Ibrutinib/Venetoclax/Obinutuzumab) 
and who do not achieve a BM MRD negative CR will be assigned to Ibrutinib. 
• 
Patients 
who 
are 
initially 
randomized 
to 
Arm 
2 
(Ibrutinib/Venetoclax/Obinutuzumab) and who do achieve a BM MRD negative 
CR will be assigned to Observation.  

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7.2 
After Cycle 15 Day 28 
7.2.1 
Ibrutinib  
Treatment on this arm will consist of ibrutinib 420 mg daily starting cycle 16 day 1 and 
continuing until disease progression or until criteria in Section 12.1 are met. 
7.2.2 
Observation 
Treatment on this arm will consist of observation every 3 cycles for 6 years from 
registration (84 cycles), then every 6 cycles thereafter until disease progression, until 
criteria in Section 12.1 are met, or 10 years from study registration (whichever comes first) 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other agent which would be considered treatment 
for CLL or impact the primary endpoint. 
8.1.2 
Patients should receive full supportive care while on this study, 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. All blood products and 
concomitant medications such as antidiarrheals, analgesics, and/or antiemetics 
received from the first day of study treatment administration until 30 days after the 
final dose will be recorded in the medical records.  Monoclonal antibodies to treat or 
prevent COVID-19 are allowed on the study. 
8.1.3 
No infectious prophylaxis is required for the administration of ibrutinib or 
venetoclax but may be administered if consistent with institutional guidelines. 
Premedication for TLS with venetoclax dose escalation is outlined in Table 2 in 
Section 7.1.2. Institutional guidelines regarding supportive care related to 
obinutuzumab infusions should be utilized.  Patients with absolute lymphocyte 
count >25,000/μL should receive prophylaxis with allopurinol for at least 7 days 
prior to the start of therapy.  A suggested regimen for premedication for 
obinutuzumab is provided below: 
• 
20 mg dexamethasone IV or 80 mg methylprednisolone IV at least 1 hour prior 
(first 2 doses, then may be discontinued at treating physician discretion). 
• 
650-1000 mg acetaminophen at least 30 minutes prior. 
• 
Anti-histamine (e.g. 50 mg Benadryl) at least 30 minutes prior (first 2 doses, then 
may be discontinued at treating physician discretion).  
8.1.4 
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 

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and/or leukapheresis as indicated. Ibrutinib should be held if evidence of leukostasis until 
resolution of leukostasis symptoms, and then ibrutinib can be restarted.  
8.1.5 
Antiemetics may be used at the discretion of the attending physician, with the 
exception of steroids above. 
8.1.6 
Diarrhea management is per the discretion of the treating physician. Diarrhea could 
be managed conservatively with medications such as loperamide. 
Patients with severe diarrhea should be assessed for intravenous hydration and correction 
of electrolyte imbalances. 
8.1.7 
Alliance Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol. 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology Clinical Practice 
Guideline Update.  J Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical 
Oncology – American Society of Hematology Clinical Practice Guideline Update on the 
Use of Epoetin and Darbepoetin in Adult Patients with Cancer.  J Clin Oncol 28:4996-
5010, 2010. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
White Blood Cell Growth Factors (Includes:  filgrastim (G-CSF), pegfilgrastim tbo-
filgrastim, and sargramostim (GM-CSF)) and other FDA approved white blood cell growth 
factor biologics) may not be used prophylactically to avoid dose reductions, delays or to 
allow for dose escalations specified in the protocol, but may be used in cases of prolonged 
or recurrent neutropenia or in a patient who has had neutropenia with previous cycles. If 
White blood cell growth factors are used, they must be obtained from commercial sources. 
Selection of white blood cell growth factor products should be per institutional guidelines.   
8.1.8 
Hypersensitivity/infusion reactions 
Treat hypersensitivity and infusion reactions as per institutional standards. 
8.1.9 
CYP3A Inhibitors 
Chronic concomitant treatment with strong inhibitors of CYP3A is not recommended. 
Strong CYP3A inhibitors are contraindicated with ibrutinib at all times. Ibrutinib should 
be dose reduced to 140 mg daily when administered with a moderate CYP3A inhibitor. 
Strong CYP3A inhibitors are also contraindicated during the venetoclax ramp up and must 
be used with caution during steady state venetoclax dosing. Venetoclax dose should be 
reduced by 75% if administered with a strong CYP3A inhibitor and by 50% if administered 
with moderate CYP3A inhibitors or with P-gp inhibitors. 
The following drugs are EXAMPLES of strong inhibitors of CYP3A and are not allowed 
during treatment with ibrutinib.  
 
 
Boceprevir 
Clarithromycin 
Cobicistat 
Idelalisib 
Conivaptan 
Danoprevir/Ritonavir Elvitegravir/Ritonavir Indinavir 

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Itraconazole 
Ketoconazole 
Mibefradil 
Lopinavir/Ritonavir 
Nefazodone 
Nelfinavir 
Ritonavir 
Paritaprevir/Ritona
vir combindations 
Posaconazole 
Saquinavir 
Telaprevir 
Telithromycin 
Tipranavir/Rit
onavir 
Voriconazole 
 
 
 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to inhibit CYP3A. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist.  
Grapefruit and Seville oranges may increase ibrutinib and venetoclax plasma 
concentrations and should be avoided for the duration of ibrutinib therapy. 
8.1.10 CYP3A4 Inducers 
Chronic concomitant treatment with strong inducers of CYP3A is not allowed during on 
this trial. The following drugs are EXAMPLES of strong inducers of CYP3A and are not 
allowed during treatment with ibrutinib or venetoclax. 
• 
Rifampin 
• 
Carbamazepine 
• 
Avasimibe 
• 
Enzalutamine 
• 
Mitotane 
• 
Phenytoin 
• 
St. John’s wort 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist.  
8.1.11 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) 

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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. 
8.1.12 Permitted Concomitant Medications 
• 
Short courses (<4 weeks) 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 <4 weeks 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. 
8.1.13 Other malignancies 
Patients diagnosed with other malignancies may remain on therapy in many cases.  Therapy 
may always be continued during workup for another cancer and until the initiation of new 
therapy.  In general, patients may continue therapy if the therapy for another cancer 
includes surgery, radiation, or hormonal therapy.  Please contact the study chair in 
individual cases to determine whether protocol therapy can continue. 
8.1.14 Hepatitis B Reactivation  
Hepatitis B reactivation has been reported with obinutuzumab as well as ibrutinib.  Patients 
with chronic hepatitis B are eligible for the protocol as long as viral load is undetectable.  
These patients should be monitored every 3 cycles for hepatitis B reactivation with hepatitis 
B DNA testing, and should be considered for prophylactic antiviral therapy.  Monitoring 
and prophylaxis should continue at least 6 months following completion of therapy. 
Patients with evidence of reactivation of hepatitis B should immediately discontinue 
obinutuzumab and ibrutinib and be treated for hepatitis B in conjunction with appropriate 
specialists.  
8.1.15 COVID-19 Vaccine 
Patients are encouraged to receive COVID 19 vaccination. Vaccination status will not 
interfere with trial participation. 
8.2 
Dose Modifications 
AERS reporting may be required for some adverse events (See Section 9.0) 
8.2.1 
Dose Modifications for Hematologic Toxicity 
Dose modifications should be made based on day 1 values for each cycle, or the presence 
of significant bleeding or febrile neutropenia. Hematologic toxicity for the purpose of dose 
modifications will be graded according to 2018 IWCLL criteria[16], which account for 
pretreatment cytopenias. These are graded as follows: 

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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%-74% 
≥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. 
Dose Level 
Ibrutinib 
Venetoclax 
Obinutuzumab 
1 (starting dose) 
420 mg 
400 mg 
1000 mg 
-1 
280 mg 
300 mg 
No obinutuzumab 
-2 
140 mg 
200 mg 
No obinutuzumab 
-3 
No ibrutinib 
100 mg 
No obinutuzumab 
-4 
No ibrutinib 
No venetoclax 
No obinutuzumab 
• 
For grade 3 or 4 hematologic toxicity, significant bleeding, or febrile neutropenia, 
the treating investigator should attempt to assign causality to one or more agents.  
This may be done in conjunction with the Alliance Study Chair if desired. Grade 
3 neutropenia does not require dose interruption or modification unless 
accompanied by fever, and lymphopenia/lymphocytosis do not require dose 
modification or interruption. Grade 3 or higher hypertension does not require dose 
interruption or modification if blood pressure is managed medically. For other 
grade 3/4 hematologic toxicities, the causative agent(s) should be held until 
toxicity returns to ≤ grade 1 (or baseline), while other drugs should remain at 
original doses and schedule. All drugs should be held if causality is unable to be 
attributed to an individual or group of agents.  For the first occurrence, drug may 
be restarted at the original dose.  For the second occurrence and beyond, dose 
reduce by 1 level. If all three drugs were held then all three drugs need to be dose 
reduced.  Consider the use of intermittent growth factor for grade 3 or 4 
neutropenia.  
• 
Drugs may be held for up to 28 consecutive days for drug-related toxicity. If drug-
related toxicity persists, the offending drug must be discontinued permanently.  
There is no time limit to hold drugs for unrelated toxicity in the absence of 
progressive disease. 
• 
Patients who are dose-reduced and are stable for 3 cycles may have dose escalated 
1 level each cycle.  
• 
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 

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(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 by the treating physician. 
Administer supportive care such as hydration and/or leukapheresis as indicated. 
Ibrutinib should be held if evidence of leukostasis until resolution of symptoms, 
and can then be restarted. 
8.2.2 
Dose Modifications for Non-Hematologic Toxicity  
Dose Level 
Ibrutinib 
Venetoclax 
Obinutuzumab 
1 (starting dose) 
420 mg 
400 mg 
1000 mg 
-1 
280 mg 
300 mg 
No obinutuzumab 
-2 
140 mg 
200 mg 
No obinutuzumab 
-3 
No ibrutinib 
100 mg 
No obinutuzumab 
-4 
No ibrutinib 
No venetoclax 
No obinutuzumab 
 
• 
For grade 3 or 4 non-hematologic toxicity at possibly, probably, or definitely 
related to an individual agent, hold that agent until toxicity returns to ≤ grade 1 (or 
baseline).  For a first occurrence, drug may 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.  All 
drugs should be held if causality is unable to be attributed to an individual or group 
of agents. 
• 
Drug may be held for up to 28 consecutive days for drug-related toxicity. If drug-
related toxicity persists, the offending drug must be discontinued permanently. 
There is no time limit to hold drugs for unrelated toxicity in the absence of 
progressive disease.  
• 
Aspergillus infection has been reported in patients taking ibrutinib. Any patient 
diagnosed with aspergillus or other disseminated fungal infection should have 
ibrutinib withheld until fungal infection is resolved and preferably until antifungal 
therapy is complete. 
• 
For infusion reactions attributable to obinutuzumab, supportive care should be 
provided per institutional protocols.  Obinutuzumab can be continued without dose 
modification.  However, at the discretion of the treating physician and with study 
chair approval, obinutuzumab can be discontinued for severe infusion reactions. 
• 
Obinutuzumab should be discontinued in the case of progressive multifocal 
leukoencephalopathy (PML) or development of hepatitis B reactivation. 
• 
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 non-warfarin 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 I to determine whether dose modifications are warranted 
according to the following instructions.  For patients who develop mild liver 

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Update #12 
impairment while on study (Child-Pugh class A), the recommended dose is 140 
mg daily (two capsules).  For patients who develop moderate liver impairment 
while on study (Child-Pugh class B), the recommended dose is 70 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. 
• 
For any 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 ONLY 
AFTER discussion with the study chair. 
• 
For blood chemistry changes or symptoms suggestive of TLS: 
• 
Withhold the next day’s dose. If it resolves within 24-48 hours of last dose, 
resume at the same dose. 
• 
For any blood chemistry changes requiring more than 48 hours to resolve, 
resume at a reduced dose. 
• 
For any events of clinical TLS, resume at a reduced dose following resolution. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. For the specific AE of tumor 
lysis syndrome, grading will be performed both according to CTCAE criteria and Howard criteria, 
where the TLS will also be categorized as laboratory or clinical. Howard criteria can be found in 
Appendix II. Attribution to protocol treatment for each adverse event must be determined by the 
investigator and reported on the required forms. Please refer the NCI Guidelines: Adverse Event 
Reporting Requirements for further details on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
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 according to the study calendar in Section 5.0. For this trial, the Form, “Adverse Events” 
is used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class (SOC) 
Neutrophil count decreased 
Investigations 
Hypertension 
Vascular disorders 
Atrial fibrillation 
Cardiac disorders 

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Infections (grade 3-5 only) 
Infections and infestations 
Platelet count decreased 
Investigations 
Rash maculopapular 
Skin and subcutaneous tissue disorders 
Arthralgia 
Musculoskeletal and connective tissue disorders 
Edema limbs 
General disorders and administration site conditions 
Bruising 
Injury, poisoning and procedural complications 
Tumor lysis syndrome 
Metabolism and nutrition disorders 
Fatigue 
General Disorders and administration site conditions 
Diarrhea 
Gastrointestinal disorders 
  
9.1.1 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting. Sites must initiate all AEs for this study in 
Medidata Rave.     
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each treatment 
course or reporting period and is used to collect AEs that start during the period or persist 
from the previous reporting period. AEs that occur 30 Days after the Last Administration 
of the Investigational Agent/Intervention are collected using the Late Adverse Event form. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs that 
meet reporting requirements. The CRA completes the report by accessing CTEP-AERS via 
a direct link on the Medidata Rave Expedited Reporting Evaluation form. Contact the 
CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if you have 
any issues submitting an expedited report in CTEP-AERS. 
In the rare occurrence that 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 that was phoned in must be entered immediately into CTEP-AERS using the 
direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 

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Update #12 
• 
Study specific documents: Protocols > Documents> Protocol Related Documents> 
Adverse Event Reporting; and   
• 
Additional resources: Resources > CTSU Operations Information> User Guides & 
Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date. 
b) 
Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (RAVE-CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Alliance Central Protocol 
Operations Program, the Study Chair, and their Institutional Review Board if a patient has a 
reportable serious adverse event. 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.  
The 
CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE.  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
• 
Note:  All deaths on study require both routine and expedited reporting regardless 
of causality.  Attribution to treatment or other cause should be provided. 

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Alliance A041702 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. 
≤ Grade 4 anemia, neutropenia, thrombocytopenia, and hospitalization resulting from these 
do not require CTEP-AERS, but should be submitted as part of study results. All other 
grade 3, 4, or 5 adverse events that precipitate hospitalization or prolong an existing 
hospitalization must be reported via CTEP-AERS. 
New primary malignancies should be reported using Medidata Rave.  
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
All new malignancies must be reported via 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/acute myelogenous leukemia, and in situ tumors.  
Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlines in each protocol. 
Second Malignancy: 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
reporting unless otherwise specified. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or 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 

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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 limited to Intracranial hemorrhage, Intraventricular hemorrhage, 
and Subdural hematoma), Ecchymoses, Purpura (petechia), Eye disorders - Other (eye hemorrhage), Eye disorders - 
Other (retinal hemorrhage), 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); Febrile neutropenia; 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 - Blurred vision; Dry eye; Eye disorders - Other (eye discharge); Eye disorders - Other (macular 
edema); Eye disorders - Other (ocular hyperemia); Eye pain; Floaters; Glaucoma; Keratitis; Periorbital edema; 
Photophobia; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Cheilitis; Colitis; 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) 
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 (CRP increased); Lymphocyte count 
decreased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hyperphosphatemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypoglycemia; 
Hypokalemia; 
Hypomagnesemia; 
Hyponatremia; 

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4Gastrointestinal perforation may occur in Gastrointestinal lymphomas and may include: Colonic perforation, 
Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal 
perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infusion related reactions, including high-grade hypersensitivity reactions, may occur during or immediately after 
administration of obinutuzumab; clinical manifestations may include as, fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty breathing (dyspnea), bronchospasm and hypoxia. 
 
6Anaphylaxis (immediate-onset hypersensitivity) with symptoms including dyspnea, bronchospasm, hypotension, 
urticaria, and tachycardia as well as late-onset hypersensitivity (serum sickness) with symptoms including chest pain, 
diffuse arthralgia, and fever, which may be life-threatening have been observed in obinutuzumab trials. 
 
7Infection may include viral, bacterial and fungal infections in any organ system under the INFECTIONS AND 
INFESTATIONS SOC. 
 
8Neutrophil count decreased (neutropenia) may be of late onset, prolonged, and in rare cases, life threatening or fatal. 
 
Adverse events reported on Obinutuzumab (Gazyva) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Obinutuzumab (Gazyva) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
GASTROINTESTINAL DISORDERS - Dyspepsia; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Flu like symptoms; 
Malaise 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Blood lactate dehydrogenase increased 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypokalemia; Metabolism and nutrition disorders 
- Other (vitamin D deficiency) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (neuropathy peripheral); Paresthesia; 
Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Anxiety; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hiccups; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis 
 
Note: Obinutuzumab (Gazyva) 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. 
 
9.4.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Venetoclax 
(ABT-199, NSC 766270) 
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.pd
f for further clarification. Frequency is provided based on 4751 patients. Below is the 
CAEPR for Venetoclax (ABT-199). 

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Adverse events reported on Venetoclax (ABT-199) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Venetoclax (ABT-199) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (coronary artery disease); Heart failure; 
Myocardial infarction; Sinus tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
EYE DISORDERS - Cataract 
GASTROINTESTINAL DISORDERS - Abdominal pain; Belching; Colitis; Dry mouth; Dyspepsia; Dysphagia; 
Esophageal pain; Esophageal ulcer; Gastrointestinal disorders - Other (Crohn's disease); Mucositis oral; Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema limbs; Flu-like 
symptoms; General disorders and administration site conditions - Other (general physical health deterioration); 
General disorders and administration site conditions - Other (multiple organ dysfunction syndrome); Injection site 
reaction; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatic function abnormal) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Infusion-related reaction; Injury, 
poisoning and procedural complications - Other (laceration) 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; Creatinine increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (failure to thrive); Metabolism and nutrition disorders - Other (hypervolemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified (incl 
cysts and polyps) - Other (acute myeloid leukemia); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (Richter's syndrome); Treatment-related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Intracranial hemorrhage; Ischemia cerebrovascular; 
Nervous system disorders - Other (neuropathy peripheral); Peripheral sensory neuropathy; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Ovarian rupture 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Aspiration; Dyspnea; 
Epistaxis; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pneumonitis; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (asphyxia) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Pruritus; Rash acneiform; Rash maculo-papular 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Venetoclax (ABT-199) 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. 
9.5 Adverse Events of Special Interest 
Non drug Specific AESIs (applicable to all Roche / GNE studies): 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law and based on the following observations: - Treatment-emergent ALT or 
AST > 3 x baseline value in combination with total bilirubin > 2 x ULN (of which 
> 35% is direct bilirubin) - Treatment-emergent ALT or AST > 3 x baseline value 
in combination with clinical jaundice 

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• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below - Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected 
AESIs specific to Venclexta (Venetoclax): 
• 
Tumor lysis syndrome (irrespective of seriousness) 
AESIs specific to Gazyva (Obinutuzumab): 
• 
Tumor lysis syndrome (irrespective of seriousness) 
• 
Second Malignancy 
10.0 DRUG INFORMATION 
10.1 
General Considerations: 
Investigators ordering and/or dispensing supplied agents at any time for study treatment must 
be currently registered with PMB, DCTD, NCI. A registered investigator must co-sign for other 
non-registered personnel prescribing the supplied agents. 
10.1.1 Contraception 
Men must use a barrier method while on treatment with obinutuzumab and for 180 days 
after the last dose of obinutuzumab. 
Women taking obinutuzumab must be advised to use contraceptives for 18 months after 
obinutuzumab treatment. 
10.2 
Ibrutinib (NSC 748645, IND 
 IND holder CTEP/DCTD/NCI)  
Investigators ordering and/or dispending supplied agents at any time for study treatment must 
be concurrently registered with PMB, DCTD, and NCI. A registered investigator must co-sign 
for other non-registered personnel prescribing the supplied agents. See Section 10.5 for agent 
ordering, agent accountability, agent inventory records, investigator brochure availability, and 
useful links and contacts information for all NCI-supplied agents 
Procurement and Availability  
Ibrutinib is supplied by Pharmacyclics, Inc., and distributed by the Pharmaceutical Management 
Branch, CTEP/DCTD/NCI. Do not use commercial supply. 
Formulation   
Ibrutinib is supplied as hard gelatin capsules containing micronized ibrutinib and the following 
excipients:  microcrystalline cellulose; croscarmellose sodium; sodium lauryl sulfate; may 
contain magnesium stearate.  Capsules are manufactured as 140mg in a size 0, gray, hard gelatin 
capsule. Capsules are packaged in high-density polyethylene (HDPE) bottles with an induction 
seal and a child resistant screw top cap.  Each bottle contains 92 or 120 capsules.  Ibrutinib 
capsules are to be dispensed in their original containers. 
Storage   
The recommended storage condition for ibrutinib capsules is 15°C to 25°C (59°F to 77°F) with 
excursions permitted to 30°C (86°F). 

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Stability 
Shelf life surveillance of the intact bottles is ongoing. 
Administration 
Orally, with 8 ounces (approximately 240ml) of water.  The capsules are to be swallowed intact.  
Doses are to be taken at about the same time each day.  If a dose is missed, it should be taken as 
soon as possible on the same day with a return to the normal schedule the following day.  Patients 
should not take extra capsules to make up the missed dose. 
Drug Interactions 
Ibrutinib is primarily metabolized by CYP3A4.  Grapefruit and Seville orange juices should be 
avoided. 
 
Adverse Events 
For a comprehensive adverse events and potential risks list (CAEPR), please see Section 9.4.1. 
10.3 
Obinutuzumab (NSC 793436, IND 
 IND holder CTEP/DCTD/NCI)   
Investigators ordering and/or dispending supplied agents at any time for study treatment must 
be concurrently registered with PMB, DCTD, and NCI. A registered investigator must co-sign 
for other non-registered personnel prescribing the supplied agents. See Section 10.5 for agent 
ordering, agent accountability, agent inventory records, investigator brochure availability, and 
useful links and contacts information for all NCI-supplied agents 
Procurement and Availability  
Obinutuzumab is supplied by Genentech, and distributed by the Pharmaceutical Management 
Branch, CTEP/DCTD/NCI. Do not use commercial supply. 
Formulation   
Obinutuzumab is provided as a single 1000 mg dose liquid concentrate with a strength of 25 
mg/mL. It is supplied in 50 mL glass vials containing 40 mL of the 25 mg/mL liquid concentrate. 
In addition to the antibody, the liquid also contains histidine/histidine-HCl, trehalose, poloxamer 
188 and highly purified water (HPW). HPW meets the specified limits for water for injections 
(WFI) according to USP. 
Storage   
2°C and 8°C, protected from light. If a storage temperature excursion is identified, promptly 
return obinutuzumab to 2°C - 8°C and quarantine the supplies.  Provide a detailed report of the 
excursion (including documentation of temperature monitoring and duration of the excursion) 
to PMBAfterHours@mail.nih.gov for determination of suitability for use. 
Stability 
For microbiological stability, the diluted GAZYVA infusion solution should be used 
immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution 
may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours followed by 48 
hours at room temperature (total prepared infusion stability of 72 hours).  Please note that the 
product does not contain preservatives and safeguards should be in place to prevent microbial 
contamination if the product is not used immediately. 
Preparation 
Dilute into a 250 mL 0.9% sodium chloride PVC or non- PVC polyolefin infusion bag. 
Obinutuzumab can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL.  Do not 

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use other diluents such as dextrose (5%).  Mix diluted solution by gentle inversion. Do not shake 
or freeze. Institutional methods of preparation are acceptable, including diluting the first dose 
in 100ml NS. 
Administration 
Intravenous infusion 
Chronic Lymphocytic Leukemia 
Loading dose (Cycle 1 only), 100 mg infused at 25 mg/hr with no increase in infusion rate. The 
100 mg dose of obinutuzumab given on Day 1 of Cycle 1 can also be administered in 100 mL 
NS. 
Day 2 (Cycle 1 only) – dose should be started at 50 mg/hr and can be increased in increments 
of 50 mg/hr every 30 minutes to maximum infusion rate of 400 mg/hr 
Subsequent infusions – if no infusion reaction with previous infusion and final infusion rate > 
100 mg/hr, then all subsequent infusions can start at 100 mg/hr and increase every 30 minutes 
to maximum of 400 mg/hr 
Drug Interactions 
No formal drug-drug interaction studies have been performed, although limited drug interaction 
sub-studies have been undertaken for obinutuzumab with bendamustine, 
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), and FC (fludarabine, 
cyclophosphamide) and chlorambucil. Co-administration with obinutuzumab had no effect on 
the pharmacokinetics of bendamustine, FC, chlorambucil or the individual components of 
CHOP; in addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP 
on the pharmacokinetics of obinutuzumab. A risk for interactions with concomitantly used 
medicinal products cannot be excluded. 
Adverse Events 
For a comprehensive adverse events and potential risks list (CAEPR), please see Section 9.4.2. 
 
10.4 
Venetoclax (NSC 766270, IND 
 IND holder CTEP/DTCD/NCI) 
Investigators ordering and/or dispending supplied agents at any time for study treatment must 
be concurrently registered with PMB, DCTD, and NCI. A registered investigator must co-sign 
for other non-registered personnel prescribing the supplied agents. See Section 10.5 for agent 
ordering, agent accountability, agent inventory records, investigator brochure availability, and 
useful links and contacts information for all NCI-supplied agents 
Procurement and Availability  
Venetoclax is supplied by Abbvie/Genentech, and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI. Do not use commercial supply. 
Formulation   
Venetoclax tablets are supplied as oblong, bi-convex pale yellow or beige tablets that contain 
10 mg, 50 mg or 100 mg venetoclax as the active ingredient. Each tablet also contains the 
following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium 
stearyl fumarate, and calcium phosphate dibasic. In addition, the 100 mg coated tablets include 
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dioxide.  Each tablet is debossed with “V” on one side and a “10”, “50” or “100” corresponding 
to the tablet strength on the other side. 
The 10 mg and 50 mg supplies will be provided in blister cards.  Each 10 mg blister card will 
contain 16 tablets, while each 50 mg blister card will contain 8 tablets.  The 100 mg tablets will 
be supplied in 32 count bottles. 
Storage   
Store between 15° to 30°C (59° to 86°F). 
If a storage temperature excursion is identified, promptly return venetoclax to between 15° to 
25°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability 
Stability studies are ongoing. 
Administration 
Tablets should be taken orally once daily, at approximately the same time, with a meal and 
water.  Do not chew, crush, or break tablets. 
If a dose is missed by less than 8 hours, take the missed dose right away and take the next dose 
as usual.  If a dose is missed by more than 8 hours, the patient should wait and take the next 
dose at the usual time. 
Patients should not take an additional dose if they vomit after taking venetoclax.  They should 
take the next dose at the usual time the following day. 
Drug Interactions 
Venetoclax is predominantly metabolized by CYP3A4/5.  Concomitant use of venetoclax with 
strong inhibitors of CYP3A at initiation and during ramp-up phase is contraindicated.  For 
patients who have completed the ramp-up phase and are on a steady daily dose, reduce the dose 
by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the venetoclax 
dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of 
the inhibitor 
Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors.  If a moderate CYP3A 
inhibitor or a P-gp inhibitor must be used, reduce the dose by at least 50%.  Resume the dose 
that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after 
discontinuation of the inhibitor.  If a narrow therapeutic index P-gp substrate must be used, it 
should be taken at least 6 hours before venetoclax.  
Avoid concomitant use with strong CYP3A inducers or moderate CYP3A inducers. 
Venetoclax may cause a significant increase in Cmax and AUC of warfarin.  International 
normalized ratio (INR) should be monitored closely in patients receiving warfarin. 
Venetoclax had no large effect on QTc interval (i.e., > 20 ms) and there was no relationship 
between venetoclax exposure and change in QTc interval. 
Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) 
do not affect venetoclax bioavailability. 
Avoid grapefruit products, Seville oranges, and starfruit during treatment 
Adverse Events 

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For a comprehensive adverse events and potential risks list (CAEPR), please see Section 9.4.3. 
10.5 
NCI-supplied Agent Ordering, Accountability, Inventory, IB Availability, and Contacts 
Investigators ordering and/or dispending supplied agents at any time for study treatment must 
be concurrently registered with PMB, DCTD, and NCI. A registered investigator must co-sign 
for other non-registered personnel prescribing the supplied agents. 
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 
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 
1. CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/   
2. NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov   
3. PMB Online Agent Order Processing (OAOP) Application: 
https://ctepcore.nci.nih.gov/OAOP/pages/login.jspx   
4. PMB Policies and Guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
5. CTEP Identity and Access Management (IAM) Account: 
https://ctepcore.nci.nih.gov/iam/   
6. CTEP Associate Registration and IAM Account Help: ctepreghelp@ctep.nci.nih.gov    
7. IB Coordinator: IBCoordinator@mail.nih.gov    

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8. 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) 
11.0 MEASUREMENT OF EFFECT 
Criteria for response will utilize the Revised 2018 IWCLL [16] for response which includes clinical, 
hematologic, and bone marrow features as derived from the initial 1996 guidelines[21].  
There are 8 possible response categories: complete response (CR), CR with incomplete recovery 
(CRi), clinical CR (CCR), nodular partial response (nPR), partial response (PR), PR with persistent 
lymphocytosis (PRL), stable disease (SD), and progressive disease (PD). Once a CR/CRi/CCR is 
achieved, response cannot worsen and be recorded as nPR/PR/PRL/SD at a subsequent assessment; 
likewise, once nPR/PR/PRL is achieved, response cannot worsen and be recorded as SD at a 
subsequent assessment. The criteria for each response category are described in detail below. 
11.1 
Complete response 
Requires all of the following on response evaluation testing and then clinical stability 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  
• 
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. 
CR should continue to be reported as CR at each subsequent clinical assessment until 
documentation of PD.  
11.2 
Complete response with incomplete recovery (CRi) 
• 
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.  
• 
A CRi assessment can continue to be reported as CRi or improve to CR at a 
subsequent clinical assessment, until documentation of PD.  

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11.3 
Clinical CR (CCR) 
• 
Patients who fulfill the criteria of CR with exception of not having a bone marrow 
biopsy performed will be considered a clinical CR. 
• 
A CCR assessment can continue to be reported as CCR, be recorded as CRi, or 
improve to CR at a subsequent clinical assessment, until documentation of PD. 
11.4 
Nodular PR (nPR) 
• 
Patients who fulfill the criteria of CR with exception of having bone marrow 
lymphoid CLL nodules will be considered a nodular PR (nPR). 
• 
A nPR assessment can continue to be reported as nPR or improve to 
CR/CRi/CCR/CRi at a subsequent clinical assessment, until documentation of PD. 
11.5 
Partial Response 
Requires a ≥ 50% decrease in peripheral lymphocyte count from pre-treatment value (in those 
patients with lymphocytosis pre-treatment), ≥ 50% reduction in lymphadenopathy of as many 
as 6 measurable lymph nodes, and/or ≥ 50% reduction in splenomegaly/hepatomegaly by 
physical exam on response evaluation testing and then clinical stability 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 
• 
Hemoglobin > 11.0 g/dL (untransfused) or 50% improvement from pre-treatment value 
• 
A PR assessment can continue to be reported as PR or improve to 
CR/CRi/CCR/nPR at a subsequent clinical assessment, until documentation of PD 
11.6 
Partial response except persistent lymphocytosis (PRL) 
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%. 
A PRL assessment can continue to be reported as PRL or improve to 
CR/CRi/CCR/nPR/PR at a subsequent clinical assessment, until documentation of PD.  
11.7 
Progressive Disease (PD) 
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) (See Section 8.2 for more 
information).  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), 
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• 
≥ 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. 
11.8 
Stable Disease  
Patients who do not fulfill the criteria for complete or partial response as defined above (CR, 
CRR, CRi, nPR, PR, PR-L) but do not exhibit progressive disease will be considered to have 
stable disease. 
A 
SD 
assessment 
can 
continue 
to 
be 
reported 
as 
SD 
or 
improve 
to 
CR/CRi/CCR/nPR/PR/PRL at a subsequent clinical assessment, until documentation of 
PD. 
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Please see the study calendar (Section 5.0) and the treatment section (Section 7.0) for treatment 
and following up time periods. 
12.1.1 Cycle 1 through Cycle 15 Day 28 
Arm 1: Continue obinutuzumab through cycle 6 and ibrutinib until the end of Cycle 15.  
Patients who complete 14 cycles of protocol therapy will undergo Day 1 of Cycle 15 
response assessment and staging. During this time, all patients will complete Cycle 15 of 
ibrutinib therapy. All patients will then continue with ibrutinib maintenance until disease 
progression as described in Section 12.1.2.  
Arm 2: Continue obinutuzumab through Cycle 6, and ibrutinib and venetoclax until the 
end of Cycle 14.  Patients who complete 14 cycles of protocol therapy will undergo Day 1 
of Cycle 15 response assessment, central BM MRD and staging per Section 5.0 and 6.2. 
During this time, all patients will complete Cycle 15 of ibrutinib therapy.  
• 
Patients who are determined to have BM MRD+ (performed centrally) disease will 
continue ibrutinib maintenance until disease progression as described in Section 
12.1.2.  
• 
Patients who are determined to have BM MRD- (performed centrally) disease but 
without CR (determined locally) will continue ibrutinib maintenance therapy until 
disease progression as described in Section 12.1.2.  
• 
Patients who are BM MRD- and with CR will be continue to Observation until 
disease progression as described in Section 12.1.2. 

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12.1.2 After Cycle 15 Day 28 
Ibrutinib: Continue ibrutinib until disease progression, with patients followed every 3 
cycles for 6 years from registration (Step 1) and every 6 cycles thereafter until progression. 
See Section 5.0. 
Observation: Patients who go on to observation will be followed per Section 5.0 every 3 
cycles for 6 years from registration (Step 1) and every 6 cycles thereafter until disease 
progression.  
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression (if applicable) 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Patients who are treated according to the scheduled protocol therapy (as described in 
Section 7.0) will follow the study calendar outlined in Section 5.0. After documented 
progression of CLL (at any stage, on any arm), patients will go on to survival follow up, 
followed every 6 months until 10 years from Step 1 registration.  
12.3.2 Follow-up for Patients Who Stop Study Treatment Early  
Patients who stop due to toxicity at any point during therapy will go to clinical follow up 
(see column in Section 5.0), until disease progression. At that time, patients go to survival 
follow up, followed every 6 months until 10 years from registration (Step 1).   
Patients who receive non-protocol CLL-directed therapy will go to clinical follow up 
(as outlined in Section 5.0) until disease progression. At that time, patients go to survival 
follow up (see Data Submission Schedule on A041702 Alliance and CTSU study page), 
followed every 6 months until 10 years from registration (Step 1).  
Patients who stop study treatment early to receive a non-protocol therapy unrelated 
to their CLL diagnosis will go to clinical follow up (as outlined in Section 5.0), until 
disease progression. At that time, patients go to survival follow up, followed every 6 
months until 10 years from registration (Step 1). 

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Follow up for 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 from registration (Step1). 
12.3.2 Follow-up for Specimen Submission 
Specimen submission must continue during all treatment stages, observation and clinical 
follow-up. Specimen submission are not required if patient is in survival follow-up.   
12.4 
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: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
 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 as 
if the patient were eligible. 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, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
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. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study design 
This is a randomized, open label, multi-center phase III trial designed to evaluate whether the 
treatment strategy of ibrutinib/venetoclax/obinutuzumab (IVO) followed by ibrutinib 
maintenance (IM) for patients without BM MRD- CR and IM discontinuation for patients with 
BM MRD- CR improves progression-free survival (PFS) over ibrutinib/obinutuzumab (IO) 
followed by IM in previously untreated, older (age ≥ 65 years) CLL patients who are 
symptomatic and require therapy by the IWCLL guidelines. This trial implements a group 

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sequential design with two interim analyses for superiority and three interim analyses for futility 
using the O’Brien-Fleming version of the Lan Demets alpha-spending and beta-spending 
functions, respectively, to control the type I and II error rates. The sample size calculation was 
conducted using EAST version 6.4 software (Cytel Inc.). 
13.2 
Statistical design and analysis for the primary endpoint 
13.2.1 Primary endpoint 
The primary endpoint in this phase III trial is progression-free survival (PFS), which will 
be defined from randomization date until the earlier of disease progression or death from 
any cause, censoring patients alive and progression-free at the date of last known clinical 
assessment. If a patient begins a subsequent, non-protocol CLL therapy, we will collect 
reason for beginning subsequent treatment. If the reason for beginning a non-protocol CLL 
treatment prior to a documented progression is due to symptomatic disease or clinical 
deterioration, then this will be considered an event for PFS at the last assessment date prior 
to start of non-protocol therapy. Alternatively, if the reason for beginning a non-protocol 
CLL treatment prior to a documented progression is due to some other reason (e.g., 
experiences an adverse event and chooses to begin a different therapy), clinical data will 
be carefully reviewed on a case-by-case basis and it will be determined whether to treat as 
an event for PFS or censor at the last assessment date prior to start of non-protocol therapy. 
Using an intent-to-treat approach, all randomized patients will be included in the analysis 
of the primary endpoint in the arm to which they were randomized. 
13.2.2 Statistical design 
Patients will be randomized using dynamic allocation procedures in a 1:1 manner to the 
two treatment arms: IO vs. IVO. Randomization will be stratified on Rai stage 
(intermediate vs. high) and high-risk FISH abnormality del(17p13.1) (present vs. absent).  
The primary goal of this phase III trial is to determine whether the experimental treatment 
strategy of IVO followed by IM for patients without BM MRD- CR and IM discontinuation 
for patients with BM MRD- CR has superior PFS compared to the control treatment 
strategy of IO followed by IM for all patients. We will test the null hypothesis that the 
hazard ratio is equal to 1.0 versus the alternative hypothesis that the hazard ratio is equal 
to 0.55 in favor of the experimental treatment strategy. Assuming exponential parameters 
for control and experimental treatment strategy groups are 0.071 and 0.039, respectively, 
this corresponds to a median PFS of 9.717 years vs. 17.667 years and is equivalent to 5-
year PFS rates of 70% vs. 82.187%. Based on design assumptions, the 70% PFS rate at 5 
years assumed for the control treatment strategy group corresponds with data available 
from a randomized phase III trial, in which previously untreated patients aged 65 years or 
older received ibrutinib until disease progression or unacceptable toxic effects and had a 
PFS estimate at 18 months of 90%.2 
There is 90% power for this one-sided log-rank test of superiority with the experimental 
treatment strategy versus the control treatment strategy using a group sequential design and 
constraining the one-sided type I error to 0.025 (i.e., two-sided error of 0.05). This design 
requires 128 events and translates to 431 total evaluable patients when assuming uniform 
accrual over 3 years and a minimum follow-up of 5 years.  
This design includes two interim analyses for superiority when 50% and 75% of the 
expected number of events have been observed and three interim analyses for futility when 
25%, 50%, and 75% of the expected number of events have been observed. Decision rules 
for interim and final analyses were determined using the O’Brien-Fleming version of the 
Lan Demets alpha-spending and beta-spending functions.  

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13.2.3 Analysis plan 
The primary endpoint of PFS will be compared between the experimental and control 
treatment strategy groups using a stratified log-rank test (stratified on Rai stage, 
intermediate vs. high, and del(17p13.1) by FISH, present vs. absent). The Kaplan-Meier 
method will be used to estimate PFS distributions. Five-year PFS estimates, medians, and 
corresponding hazard ratios will be provided with 95% confidence intervals for each 
treatment strategy. All patents randomized to a treatment arm will be included in the 
analysis of the primary endpoint.  
13.2.4 Interim analysis decision rules 
For the primary comparison of PFS between experimental and control treatment strategies, 
there will be three interim evaluations. The first planned interim analysis will occur after 
approximately 25% of the expected number of events have been observed. This is 
equivalent to 32 events and is anticipated shortly prior to year 3 of the study. After that, 
two more interim evaluations are planned after approximately 50% and 75% of the 
expected number of events are observed. All interim evaluations will include an assessment 
of futility to identify if there is strong evidence of worse outcome with the experimental 
treatment strategy (per criteria outlined below). If at any of the planned interim analyses 
the futility boundary is crossed, then the Alliance DSMB will determine whether accrual 
should be suspended, treatment modified, or trial terminated based upon review of the data. 
Only the second and third interim evaluations will include an assessment of superiority to 
avoid stopping the trial too early without adequate follow-up of patients who discontinue 
IM as part of the experimental treatment strategy. If, at these planned interim analyses, the 
superiority boundary is crossed (per criteria outlined below), then the Alliance DSMB will 
determine whether the trial can be stopped with early release of results based upon review 
of the data. For all interim analyses, the z-statistic from the one-sided stratified log-rank 
test will be compared to the boundary values determined by the trial design. The interim 
analysis boundaries and characteristics were generated using EAST version 6.4 software 
(Cytel Inc.). 
13.2.5 Final analysis decision rules 
The final analysis comparing PFS between experimental and control treatment strategies 
is to be conducted after 128 events are observed or all patients are followed for at least 5 
years (whichever occurs first). This analysis of PFS will be conducted using the remaining 
alpha and beta following the interim analyses where the overall one sided alpha level is 
0.025 and the overall beta level is 0.10. If at the final analysis the z-statistic from the one-
sided stratified log-rank test is less than -2.014 and in favor of the experimental treatment 
strategy group, then the experimental treatment strategy will be declared a success; 
otherwise the control treatment strategy will be preferred in this patient population. The 
final analysis boundaries and characteristics were generated using EAST version 6.4 
software (Cytel Inc.). 
Boundary rules for comparison of PFS between experimental and control treatment 
strategies 
Information 
Fraction 
Cumulative 
Events 
Cumulative 
Alpha spent 
Cumulative 
Beta spent 
Superiority 
Boundary 
Z (HR) 
Futility 
Boundary 
Z (HR) 
Estimated 
Analysis 
Time (Yrs) 
0.25 
32 
0 
0.00095 
NA 
1.415 (1.649) 
2.9 
0.50 
64 
0.00153 
0.01942 
-2.963 (0.477) 
-0.319  (0.923) 
4.4 

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0.75 
96 
0.00965 
0.05632 
-2.359 (0.618) 
-1.289 (0.769) 
6.1 
1.0 
128 
0.025 
0.09837 
-2.014 (0.700) 
-2.014 (0.700) 
8.0 
Boundaries use the O’Brien Fleming version of the Lan-Demets stopping rules. The 
superiority boundary rule is not applicable (NA) at the first interim analysis and the 
incremental crossing probability at each subsequent analysis under the alternative 
hypothesis is 0.284, 0.434, and 0.183, respectively. The incremental futility crossing 
probability at each analysis under the null hypothesis is 0.078, 0.548, 0.279, and 0.072, 
respectively. The futility boundaries are not binding.  
13.3 
Sample size, accrual time, and study duration 
13.3.1 Sample size 
The statistical design is fully described in Section 13.2. The study design requires 431 total 
evaluable patients (n ≈ 215 randomized to each arm). With 5% overaccrual to account for 
ineligibilities, cancellations, and major violations, the target accrual is 454 patients. 
13.3.2 Accrual rate and accrual duration 
From cooperative group trial A041202, a phase III trial that enrolled previously untreated 
CLL patients aged 65 years or older, the screening rate was 22 patients per month and the 
accrual rate was 18 patients per month. For A041702, a successor study which will enroll 
previously untreated CLL patients aged 65 years or older, we estimate lower screening and 
accrual rates of 15 and 13 patients per month, respectively, over 3 years. If there are no 
major issues of patient safety and the study does not stop early at the time of interim 
analyses, the maximum expected study duration is 8 years when all patients have been 
followed a minimum of approximately 5 years. 
13.3.3 Primary endpoint completion date for ClinicalTrials.gov reporting 
For the purpose of ClinicalTrail.gov reporting, the primary endpoint completion date 
(PECD) for this study is approximately 5 years after the randomization of the last patient. 
13.4 
Supplementary analysis plans 
With the exception of toxicity and tolerability measures, which will be limited to patients 
who begin treatment on either arm, analyses will include all randomized patients.  
In a sensitivity analysis of the primary endpoint, PFS will be defined from randomization 
date until the earlier of disease progression or death from any cause, censoring patients 
alive and progression-free at the date of last known clinical assessment, without taking into 
consideration the start of non-protocol CLL therapy. PFS using this modified definition 
will be compared between the experimental and control treatment strategy groups using a 
stratified log-rank test (stratified on Rai stage, intermediate vs. high, and del(17p13.1) by 
FISH, present vs. absent). The Kaplan-Meier method will be used to estimate PFS 
distributions. Five-year PFS estimates, medians, and corresponding hazard ratios will be 
provided with 95% confidence intervals for each treatment strategy. Differences in five-
year PFS estimates between the treatment strategies will be tested using a stratified chi-
square test based on the complementary log-log transformation of the Kaplan-Meier 
estimates.  
Best achieved response, up through the Cycle 15 Day 1 response assessment, will be 
determined. Response criteria are defined in Section 11.0 and for the purposes of recording 
best 
response 
will 
be 
categorized 
according 
to 
the 
following 
hierarchy: 
CR/CRi/CCR/nPR/PR/PRL/SD/PD. BM MRD negative will be defined as <1 CLL cell per 

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10,000 leukocytes in the bone marrow. BM MRD- CR rate will be calculated, and will be 
estimated using the number of patients meeting the BM MRD- CR criteria divided by the 
total number of patients randomized to each of the treatment arms (IO, IVO). Assuming 
that the incidence of BM MRD- CR is binomially distributed, we will calculate 
corresponding binomial 95% confidence intervals for the true rates. The stratified Cochran-
Mantel-Haenszel test will be used to compare the BM MRD- CR rates between treatment 
arms (stratified on Rai stage, intermediate vs. high, and del(17p13.1) by FISH, present vs. 
absent). Similar analysis methods will be used to compare MRD- rates (BM and PB) 
between treatment arms. Specific to the comparison of MRD- rates, sensitivity analyses 
will be carried out conditional on the number of patients who submit a sample for MRD 
and with an informative MRD result, and by exploring the impact of missing data through 
techniques such as worst-case scenario or tipping-point analyses. In addition, the degree of 
response will be summarized with frequencies and percentages in two ways: first using 
physical exams with CT scans and second using physical exams only to categorize 
response. Lastly, PFS and OS landmarked at Cycle 16 Day 1 will be described by MRD 
response status and by treatment course using Cycle 15 Day 1 MRD and response 
assessments. 
OS is defined from randomization date until death from any cause, censoring patients alive 
at the date of last contact. The Kaplan-Meier method will be used to estimate the OS 
distribution for each treatment strategy. Estimates at 5 years will be calculated with 
corresponding 95% confidence intervals, and differences in these estimates between the 
treatment strategies will be tested using a stratified chi-square test based on the 
complementary log-log transformation of the Kaplan-Meier estimates. Comparisons in OS 
curves between experimental and control treatment strategies will use a stratified log-rank 
test (stratified on Rai stage, intermediate vs. high, and del(17p13.1) by FISH, present vs. 
absent). Hazard ratios with 95% confidence intervals will be estimated from the 
corresponding, stratified proportional hazard model. 
Toxicity and tolerability measures will be monitored regularly. Frequency and severity of 
adverse events and tolerability for each treatment strategy group will be summarized using 
descriptive statistics. As per NCI CTCAE v5.0, 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. We will also assess tolerability through assessing the number of patients who 
require dose modifications and/or dose delays, and the proportion of patients who go off 
treatment due to adverse events. Further, toxicity and tolerability measures will be assessed 
by treatment course. All patients who have received at least one dose of any of the 
therapeutic agents in a treatment regimen will be evaluable for toxicity and tolerability. 
Proportional hazard models will be used in a multivariable analysis to identify baseline 
variables associated with PFS/OS and logistic regression models will be used in a 
multivariable analysis to identify baseline variables associated with response and/or 
specific toxicities of interest. Baseline variables will include but not be limited to presence 
of complex karyotype (>3 abnormalities), presence of TP53 mutations, and nodal size (> 
10 cm). 

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13.5 
Monitoring the study 
13.5.1 Adverse event stopping rule 
A safety monitoring rule will be applied to guide accrual suspension decisions based on 
unacceptable toxicity. The safety monitoring rule will be evaluated for all patients who 
begin treatment and during the time period prior to ibrutinib maintenance or observation. 
The safety rule will signal whether the proportion of patients who permanently discontinue 
therapy due to grade 3 or higher adverse events (including patients who died during active 
treatment) is significantly higher with IVO vs. IO. It is not anticipated that the percentage 
of patients who discontinue IO therapy due to grade 3 or higher adverse events will be 
more than 10-15%. The safety rule corresponds to a two-sample test of proportions with 
85% power to detect an increase of 10 percentage points (i.e., 10% vs. 20%) with 454 
patients, while constraining the overall one-sided type I error to 0.05. It uses a z-statistic 
based on the difference in two proportions and pooling the variance, with interim analyses 
planned after each successive group of approximately 45 patients are evaluated for the 
safety endpoint at roughly 1 year. To control the type I error rate across these comparisons, 
the Pocock version of the Lan-Demets error spending function was utilized. If this 
boundary is crossed, the data will be reviewed more closely and shared with the NCI as 
well as the Alliance DSMB so that consensus regarding temporary suspension of accrual, 
protocol modifications, or in the worst case scenario, decision to close the trial early may 
be made. The interim analysis and boundary characteristics were generated using the EAST 
version 6.4 software (Cytel Inc.) The boundary is shown below on the z-scale and on the 
effect scale (i.e., difference in proportions for the IVO versus IO treatment arms). 
 
 

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Information 
Fraction 
Cumulative 
Sample Size 
Approximate 
Analysis Time 
(Months) 
Cumulative 
Alpha Spent 
Boundary on 
the Z scale 
Corresponding 
Boundary on 
the Treatment 
Effect Scale 
0.10 
45 
18 
0.008 
2.412 
0.260 
0.20 
91 
21 
0.015 
2.363 
0.180 
0.30 
136 
25 
0.021 
2.317 
0.144 
0.40 
182 
29 
0.026 
2.280 
0.123 
0.50 
227 
33 
0.031 
2.250 
0.108 
0.60 
272 
37 
0.035 
2.225 
0.098 
0.70 
318 
40 
0.039 
2.204 
0.090 
0.80 
363 
44 
0.043 
2.187 
0.083 
0.90 
409 
48 
0.047 
2.171 
0.078 
1.00 
454 
52 
0.050 
2.158 
0.073 
 
13.5.2 Accrual monitoring stopping rule  
Accrual will be monitored closely with monthly reports. Investigators will evaluate accrual 
after the first year of study activation. If accrual during this time period is less than 50% of 
what was projected to meet accrual goals, the study team will work together with the Data 
Monitoring Committee and the National Cancer Institute to plan for modifications, 
including the potential for closure. 
13.5.3 Monitoring of non-protocol CLL therapy 
Reasons for starting non-protocol CLL therapy in the absence of a documented progression 
will be described in study reports provided to the Alliance DSMB. In addition, the 
proportion of patients who start non-protocol CLL therapy in the absence of a documented 
progression will be summarized and compared between treatment arms. A Fisher’s exact 
test will be used to identify if there is an imbalance in the proportions that may compromise 
the primary endpoint, and the study team will work together with the DSMB and the NCI 
to plan for possible modifications. 
13.6 
Study reporting 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patients-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31, and 
October 31. Instructions for submitting data using the CDUS can be found on the CTEP website 
(https://ctep.cancer.gov/reporting/cdus.html). 
Note: If your study has been assigned to CUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above. If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
via CTEP-AERS.  
13.7 
Inclusion of women and minorities 
It is the intent of the Alliance to enroll patients regardless of sex 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 sex or racial/ethnic differences in treatment response has been considered.  

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summarize the number of PFS events when they occur and will estimate Kaplan-Meier 
curves to illustrate PFS distributions.  
 
 

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15.0 REFERENCES 
1. 
Byrd, J.C., et al., Three-year follow-up of treatment-naive and previously treated patients with 
CLL and SLL receiving single-agent ibrutinib. Blood, 2015. 125(50616): p. 2497-506. 
2. 
Burger, J.A., et al., Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. 
N Engl J Med, 2015. 373(25): p. 2425-37. 
3. 
Woyach, J.A., et al., Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. 
N Engl J Med, 2014. 370(24): p. 2286-94. 
4. 
O'Brien, S., et al., Ibrutinib for patients with relapsed or refractory chronic lymphocytic 
leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet 
Oncol, 2016. 17(10): p. 1409-1418. 
5. 
Barr, P., et al., Updated Efficacy and Safety from the Phase 3 Resonate-2 Study: Ibrutinib As 
First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic 
Leukemia/Small Lymphocytic Leukemia Blood (ASH Annual Meeting Abstracts), 2016. 128: p. 
Abstract 234. 
6. 
Jaglowski, S.M., et al., Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab 
in chronic lymphocytic leukemia: a phase 1b/2 study. Blood, 2015. 126(7): p. 842-50. 
7. 
O'Brien, S., et al., Five-year experience with single agent ibrutinib in patients with previously 
untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. 
Blood (ASH Annual Meeting Abstracts), 2016: p. Abstract 233. 
8. 
Roberts, A.W., et al., Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic 
Leukemia. N Engl J Med, 2016. 374(4): p. 311-22. 
9. 
Stilgenbauer, S., et al., Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 
17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol, 2016. 17(6): p. 768-78. 
10. 
Seymour, J.F., et al., Venetoclax plus rituximab is superior to bendamustine plus rituximab in 
patients with relapsed/refractory chronic lymphocytic leukemia-results from a pre-planned 
interim analysis of the randomized phase 3 MURANO study. Blood (ASH Annual Meeting 
Abstracts), 2017: p. Abstract LBA-2. 
11. 
Seymour, J.F., et al., Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic 
leukaemia: a phase 1b study. Lancet Oncol, 2017. 18(2): p. 230-240. 
12. 
Cervantes-Gomez, F., et al., Pharmacological and Protein Profiling Suggests Venetoclax (ABT-
199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia. Clin Cancer Res, 
2015. 21(16): p. 3705-15. 
13. 
Woodland, R.T., et al., Regulation of B cell survival in xid mice by the proto-oncogene bcl-2. J 
Immunol, 1996. 156(6): p. 2143-54. 
14. 
Rogers, K.A., et al., Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and 
refractory chronic lymphocytic leukemia. Blood, 2018. 132(15): p. 1568-1572. 
15. 
Goede, V., et al., Obinutuzumab plus chlorambucil in patients with CLL and coexisting 
conditions. N Engl J Med, 2014. 370(12): p. 1101-10. 
16. 
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. 
17. 
De Francesco, M.A., et al., Different sequence strains of Streptococcus agalactiae elicit various 
levels of cytokine production. Immunol Invest, 2008. 37(8): p. 741-51. 
18. 
Micallef, M.A. and M.L. Garg, Anti-inflammatory and cardioprotective effects of n-3 
polyunsaturated fatty acids and plant sterols in hyperlipidemic individuals. Atherosclerosis, 
2009. 204(2): p. 476-82. 
19. 
This 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. 

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20. 
Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
21. 
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. 
22. 
Woyach, J.A., et al., BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic 
Leukemia. J Clin Oncol, 2017. 35(13): p. 1437-1443. 

 
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APPENDIX I 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. 
 
 
 
 
 
 
 
 

 
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APPENDIX II HOWARD CRITERIA FOR TLS GRADING 
 
Definitions of Laboratory and Clinical TLS* 
Metabolic Abnormality 
Criteria for Classification of 
Laboratory TLS 
Criterial for Classification of 
Clinical TLS 
Hyperuricemia 
Uric acid >8.0mg/dl 
-- 
Hyperphosphatemia 
Phosphorous >4.5 mg/dl 
-- 
Hyperkalemia 
Potassium >6.0 mmol/l 
Cardiac dysrhythmia or sudden 
death probably of definitely 
caused by hyperkalemia 
Hypocalcemia 
Corrected calcium <7.0 mg/dl or 
ionized calcium <1.12** 
Cardiac dysrhythmia, sudden 
death, seizure, neuromuscular 
irritability, hypotension, or heart 
failure probably or definitely 
caused by hypocalcemia. 
Acute kidney injury*** 
-- 
Increase in the serum creatinine 
level of 0.3 mg/dl 
(26.5µmol/l)(or a single value 
>1.5 times the upper limit of the 
age-appropriate normal range if 
no baseline creatinine 
measurement is available) or the 
presence of oliguria, defined as 
an average urine output of 
<0.5mg/kg/hr for 6 hours) 
 
* In laboratory TLS, two or more metabolic abnormalities must be present during the same 24 hour period 
within 3 days before the start of therapy or up to 7 days afterward. Clinical TLS requires the presence of 
laboratory TLS plus an increased creatinine level, seizures, cardiac dysrhythmia, or death 
** The corrected calcium level in mg/dl = measured calcium in mg/dl + 0.8 x (4-albumin in g/dl) 
*** Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dl or a period of 
oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical 
TLS. 
 
 
Taken from: Howard, SC, Jones DP, Pui C-H. “The tumor lysis syndrome.” NEJM 2011:364:1844-54. 
 
 

 
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APPENDIX III COLLABORATIVE AGREEMENT 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) 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” (https://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. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) 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: https://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”0. 
 
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 Collaborators 
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 
(https://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 
application, 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. 
 

 
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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. 
 
6. Any manuscripts reporting the results for this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for the 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 the 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 ncicteppubs@mail.nih.gov. The Regulator 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. 
 
 
 

 
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APPENDIX IV IBRUTINIB PATIENT MEDICATION DIARY 
Version #02 
Today’s Date: ________________________________________ Agent: __________________________ 
Patient Name (initial acceptable): ________________________ Patient Study ID: __________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 4 week-period while you take your 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 is out with one line, put your initials 
next to it, and then write the corrected information next to your initials. Examples: 10:30am SB 
9:30AM 
5. Take ibrutinib with 8 ounces (approximately 240ml) of water. The capsules are to be swallowed 
intact. Take your dose about the same time each day. If a dose is missed, it should be taken as 
soon as possible within 8 hours of the missed dose on the same day with a return to the normal 
schedule the following day. Do not take extra capsules to make up the missed dose.  
6. Please return this form to your physician when you go for your next appointment. 
Cycle #: ________________ 
Day 
Date 
Time of Dose 
# of capsules 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 

 
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Day 
Date 
Time of Dose 
# of capsules 
Comments 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
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: _____________________________________ 
 
Patients Signature: ______________________________________________________________ 
 

 
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APÉNDICE IV DIARIO DE MEDICACIÓN DEL PACIENTE CON IBRUTINIB 
Versión n.º 02 
Fecha de hoy: ________________________________________ Agente: __________________________ 
Nombre del paciente (inicial aceptable): _________________________  
Identificación del estudio del paciente: __________________ 
 
INSTRUCCIONES PARA EL PACIENTE: 
1. Complete un formulario por cada período de 4 semanas mientras toma su ibrutinib. 
2. Tomará ibrutinib los días 1 a 28. 
3. Registre la fecha, la cantidad de cápsulas de cada tamaño que tomó y cuándo las tomó. Registre 
las dosis tan pronto como las tome; no agrupe las entradas juntas en un momento posterior. 
4. Si tiene algún comentario o nota algún efecto secundario, regístrelo en la columna Comentarios. 
Si comete un error al escribir, táchelo con una línea, coloque sus iniciales al lado y luego escriba 
la información corregida junto a sus iniciales. Ejemplos: 10:30 a.m. SB 9:30 a.m. 
5. Tome ibrutinib con 8 onzas (aproximadamente 240 ml) de agua. Las cápsulas deben tragarse 
intactas. Tome su dosis aproximadamente a la misma hora todos los días. Si se olvida una dosis, 
debe tomarse lo antes posible dentro de las 8 horas posteriores a la dosis olvidada el mismo día y 
volver al horario normal al día siguiente. No tome más cápsulas para alcanzar la dosis olvidada.  
6. Entregue este formulario a su médico cuando vaya a su próxima cita. 
Ciclo N.º: _______ 
Día 
Fecha 
Hora de la dosis 
Cantidad de 
cápsulas 
Comentarios 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 

 
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17 
 
 
 
 
Día 
Fecha 
Hora de la dosis 
Cantidad de 
cápsulas 
Comentarios 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
El consultorio del médico completará esta sección: 
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: 
 
 
Firma del paciente: ______________________________________________________________ 
 
 
 

 
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APPENDIX V VENETOCLAX PATIENT MEDICATION DIARY 
Version #02 
Today’s Date: ________________________________________ Agent: __________________________ 
Patient Name (initial acceptable): ________________________ Patient Study ID: __________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 4 week-period while you take your venetoclax. 
2. You will take venetoclax 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 is out with one line, put your initials 
next to it, and then write the corrected information next to your initials. Examples: 10:30am SB 
9:30AM 
5. Take venetoclax with 8 ounces (approximately 240ml) of water. The capsules are to be 
swallowed intact. Take your dose about the same time each day. If a dose is missed, it should be 
taken as soon as possible within 8 hours of the missed dose on the same day with a return to the 
normal schedule the following day. Do not take extra capsules to make up the missed dose.  
6. Please return this form to your physician when you go for your next appointment. 
Cycle #: ________________ 
 
Day 
Date 
Time of Dose 
# of capsules 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 

 
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Day 
Date 
Time of Dose 
# of capsules 
Comments 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
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: _____________________________________ 
 
Patients Signature: ______________________________________________________________ 
 

 
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APÉNDICE V DIARIO DE MEDICACIÓN DEL PACIENTE DE VENETOCLAX 
Versión n.º 02 
Fecha de hoy: ________________________________________ Agente: __________________________ 
Nombre del paciente (inicial aceptable): _________________________  
Identificación del estudio del paciente: __________________ 
INSTRUCCIONES PARA EL PACIENTE: 
1. Complete un formulario por cada período de 4 semanas mientras toma su venetoclax. 
2. Tomará venetoclax los días 1 a 28. 
3. Registre la fecha, la cantidad de cápsulas de cada tamaño que tomó y cuándo las tomó. Registre 
las dosis tan pronto como las tome; no agrupe las entradas juntas en un momento posterior. 
4. Si tiene algún comentario o nota algún efecto secundario, regístrelo en la columna Comentarios. 
Si comete un error al escribir, táchelo con una línea, coloque sus iniciales al lado y luego escriba 
la información corregida junto a sus iniciales. Ejemplos: 10:30 a.m. SB 9:30 a.m. 
5. Tome venetoclax con 8 onzas (aproximadamente 240 ml) de agua. Las cápsulas deben tragarse 
intactas. Tome su dosis aproximadamente a la misma hora todos los días. Si se olvida una dosis, 
debe tomarse lo antes posible dentro de las 8 horas posteriores a la dosis olvidada el mismo día y 
volver al horario normal al día siguiente. No tome más cápsulas para alcanzar la dosis olvidada.  
6. Entregue este formulario a su médico cuando vaya a su próxima cita. 
Ciclo N.º: _______ 
 
Día 
Fecha 
Hora de la dosis 
Cantidad de 
cápsulas 
Comentarios 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 

 
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16 
 
 
 
 
17 
 
 
 
 
Día 
Fecha 
Hora de la dosis 
Cantidad de 
cápsulas 
Comentarios 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
El consultorio del médico completará esta sección: 
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: 
 
 
Firma del paciente: ______________________________________________________________ 
 
 
 
 

 
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APPENDIX VI PATIENT DRUG INFORMATION HANDOUT AND WALLET CARDS 
Version #03 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug combination of ibrutinib, venetoclax, and obinutuzumab.  This clinical trial is sponsored 
by the National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
Both ibrutinib and venetoclax interact with a certain specific enzyme in your liver.  The enzyme(s) 
in question is/are CYP3A, where ibrutinib and venetoclax are primarily broken down by CYP3A 
enzymes, and therefore may be affected by other drugs that inhibit or induce this enzyme.   
Venetoclax also may interact with certain transport proteins that help move drugs in and out of cells.  
The protein in question is P-gp and venetoclax may be moved in and out of cells by this protein.   
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
Ibrutinib, venetoclax, and obinutuzumab may interact with other drugs which can cause side effects. 
For this reason, it is very important to tell your study doctors of any medicines you are taking before 
you enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When you 
talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
Ibrutinib and venetoclax must be used very carefully with other medicines that use certain liver 
enzymes.  Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers to review any medicines and herbal supplements that are considered strong 
inhibitors or inducers of CYP3A. 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) 
may contain ingredients that could interact with your study drug.  Speak to your 
doctors or pharmacist to determine if there could be any side effects.  
• 
Avoid grapefruit products, Seville oranges, and starfruit during treatment 
• 
Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or 
discontinuing 
any 
medicine. 
 
Your 
study 
doctor’s 
name 
is 

 
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_____________________________________ and he or she can be contacted at 
_____________________________________. 
 

 
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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
combination of ibrutinib, venetoclax, and obinutuzumab.  This clinical 
trial is sponsored by the NCI.  Ibrutinib and venetoclax may interact 
with drugs that are processed by your liver. Because of this, it is very 
important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
Ibrutinib and venetoclax interact with CYP3A, and must be used 
very carefully with other medicines that interact with this enzyme.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered strong 
inducers/inhibitors of CYP3A.    
➢ 
Before prescribing new medicines, your regular health care 
providers should check a frequently updated medical reference, 
such as with the FDA, for a list of drugs to avoid, or contact 
your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

 
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APÉNDICE VI VOLANTE DE INFORMACIÓN SOBRE EL FÁRMACO PARA EL PACIENTE Y TARJETA PARA 
BILLETERA 
Versión n.º 03 
Información para los pacientes, sus cuidadores y el equipo de atención médica ajeno al estudio 
sobre posibles interacciones con otros fármacos y suplementos herbales  
El paciente ____________________________ está inscrito en un ensayo clínico que usa la 
combinación de fármacos experimentales en estudio ibrutinib, venetoclax y obinutuzumab.  Este 
ensayo clínico está patrocinado por el Instituto Nacional del Cáncer.  Este formulario está dirigido al 
paciente, pero incluye información importante para otras personas que atienden a este paciente.  
 
Esto es lo que usted como proveedor de atención médica debe saber: 
Tanto el ibrutinib como el venetoclax interactúan con una determinada enzima específica en su 
hígado.  La enzima en cuestión es CYP3A, donde ibrutinib y venetoclax son degradados 
principalmente por las enzimas CYP3A y, por lo tanto, pueden verse afectados por otros fármacos 
que inhiben o inducen esta enzima.   
Venetoclax también puede interactuar con ciertas proteínas de transporte que ayudan a que los 
fármacos entren y salgan de las células.  La proteína en cuestión es P-gp y el venetoclax puede entrar 
y salir de las células mediante esta proteína.   
 
Al paciente: Lleve este papel a sus citas médicas y guarde la tarjeta de información adjunta en 
su billetera.   
Ibrutinib, venetoclax y obinutuzumab pueden interactuar con otros fármacos que pueden causar 
efectos secundarios. Por esta razón, es muy importante que informe a los médicos del estudio sobre 
cualquier medicamento que esté tomando antes de inscribirse en este ensayo clínico.  También es 
muy importante que informe a sus médicos si deja de tomar algún medicamento habitual o si 
comienza a tomar un nuevo medicamento mientras participa en este estudio.  Cuando hable con sus 
médicos sobre sus medicamentos actuales, incluya los medicamentos que compra sin receta (remedio 
de venta libre) o cualquier suplemento a base de hierbas como la hierba de San Juan.  Es útil llevar 
con usted los envases de los medicamentos o una lista actualizada de los medicamentos. 
Muchos proveedores de atención médica pueden hacer recetas de medicamentos.  Debe informar a 
todos sus proveedores de atención médica (médicos, asistentes médicos, enfermeras profesionales, 
farmacéuticos) que está participando en un ensayo clínico.  
 
Esto es lo que usted y ellos deben saber:  
Ibrutinib y venetoclax deben usarse con mucho cuidado con otros medicamentos que usan ciertas 
enzimas hepáticas.  Antes de que usted se inscriba en el ensayo clínico, su médico del estudio 
trabajará con sus proveedores de atención médica habituales para revisar cualquier medicamento y 
suplemento herbal que se consideren inhibidores o inductores potentes de CYP3A. 
• 
¡Tenga mucho cuidado!  Los medicamentos de venta libre (incluidos los 
suplementos herbales) pueden contener ingredientes que podrían interactuar con el 
fármaco del estudio.  Hable con sus médicos o farmacéuticos para determinar si 
podría haber algún efecto secundario.  

 
Alliance A041702 
 
92 
Version Date 11/07/2025 
 
Update #12 
• 
Evite los productos de toronja, naranjas de Sevilla y carambola durante el 
tratamiento. 
• 
Su proveedor de atención médica habitual debe consultar una fuente de consulta 
médica actualizada con frecuencia o llamar al médico del estudio antes de recetar 
cualquier medicamento nuevo o de suspender algún medicamento que esté 
tomando. 
 
El 
nombre 
de 
su 
médico 
del 
estudio 
es 
_____________________________ 
y 
se 
lo/la 
puede 
contactar 
en 
_________________________________. 
 

 
Alliance A041702 
 
93 
Version Date 11/07/2025 
 
Update #12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TARJETA PARA LA BILLETERA CON 
INFORMACIÓN SOBRE EL FÁRMACO DEL 
ESTUDIO    
Usted está inscrito en un ensayo clínico que usa la combinación de 
fármacos experimentales en estudio ibrutinib, venetoclax y 
obinutuzumab.  Este ensayo clínico está patrocinado por el NCI.  
Ibrutinib y venetoclax pueden interactuar con fármacos que son 
procesados por su hígado. Por eso, es muy importante que: 
➢ Informe a sus médicos si deja de tomar algún medicamento o si 
comienza a tomar algún medicamento nuevo. 
➢ Informe a todos sus proveedores de atención médica (médicos, 
asistentes médicos, enfermeras profesionales o farmacéuticos) que está 
participando en un ensayo clínico. 
➢ Consulte con su médico o farmacéutico siempre que necesite usar 
un medicamento de venta libre o un suplemento herbal. 
 
Ibrutinib y venetoclax interactúan con CYP3A y deben usarse con 
mucho cuidado con otros medicamentos que interactúan con esta 
enzima.  
➢ Antes de que usted se inscriba en el ensayo clínico, su médico del 
estudio trabajará con sus proveedores de atención médica 
habituales para revisar cualquier medicamento y suplemento herbal 
que se consideren inductores/inhibidores potentes de CYP3A.    
➢ 
Antes de recetar nuevos medicamentos, sus proveedores de 
atención médica habituales deben consultar una referencia 
médica actualizada con frecuencia, como la de la FDA, para 
obtener una lista de medicamentos que deben evitarse, o 
comunicarse con su médico del estudio.   
➢ El nombre de su médico del estudio es 
_____________________________ y se lo puede contactar 
en_________________________________.