Conditions: Recurrent Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Small Lymphocytic Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This is an open-label non-randomized two-center phase 2 study evaluating the safety and efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or refractory CLL/SLL.

Detailed description:
The primary objective of this study is to evaluate the efficacy of concurrent therapy with ibrutinib and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

The secondary objectives of this study are to define the safety, tolerability, and dose-limiting toxicity (DLT) within 28 days of completion of dose-escalation.

Arms:
arm 1: Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Venetoclax
Intervention descriptions: intervention 1: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1. intervention 2: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).

Protocol document:
Prot_SAP_001.pdf: 
IRB-36705 
 
 
Steven E Coutre, MD  
 
Protocol 10691 dated 27 AUG  2020 
 
Page 1 of 111  
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TITLE:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed or Refractory 
Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
 
 
 
NCT03045328 
Coordinating Center of a Multi-Center Study 
Stanford Cancer Institute (SCI) 
875 Blake Wilbur Dr 
Stanford, CA  94305 
Protocol Director / Principal Investigator:  
Steven Edward Coutre, MD 
875 Blake Wilbur Dr,  
Stanford, CA  94305  
Phone 650-498-6000 / Fax 650-724-5203 
coutre@stanford.edu  
Investigators at other Sites: 
Steven Rosen, MD 
City of Hope National Medical Center 
1500 East Duarte Rd 
Duarte, CA  91010 
 
srosen@coh.org 
Tanya Siddiqi, MD 
City of Hope National Medical Center 
1500 East Duarte Rd 
Duarte, CA  91010 
tanyasiddiqi@coh.org  
SCI Biostatistician: 
SCI Study Coordinator: 
Alex McMillan, PhD  
Senior Research Scientist 
Stanford University 
alexmcm@stanford.edu 
Pamela Clay, CRC 
800 Welch Road; FC2C51 
Stanford, CA  
 
pclay@stanford.edu  
Regulatory Information  


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Table of Contents 
1 
OBJECTIVES, ENDPOINTS, AND OUTCOMES ......................................................... 17 
1.1 
Objectives .................................................................................................................. 17 
1.1.1 
Primary Objectives ................................................................................................ 17 
1.1.2 
Secondary Objectives ........................................................................................... 17 
1.1.3 
Exploratory Objectives .......................................................................................... 17 
1.2 
Endpoints (summary) ................................................................................................ 17 
1.2.1 
Primary Endpoint(s) ............................................................................................... 17 
1.2.2 
Secondary Endpoint(s) .......................................................................................... 17 
1.3 
Study Design ............................................................................................................. 18 
1.3.1 
Overview ............................................................................................................... 18 
1.3.2 
Randomization ...................................................................................................... 18 
1.3.3 
Number of Participants .......................................................................................... 18 
1.4 
ClinicalTrials.gov Registration, Outcomes, and Results ............................................ 18 
1.4.1 
Interventional model .............................................................................................. 18 
1.4.2 
Masking ................................................................................................................. 18 
1.4.3 
Type of Primary Objective / Outcome ................................................................... 18 
1.4.4 
Outcomes Measures for ClinicalTrials.gov Results Reporting .............................. 18 
1.5 
Regulatory Status of Study Agents ........................................................................... 19 
1.5.1 
Venetoclax ............................................................................................................. 19 
1.5.2 
Ibrutinib .................................................................................................................. 19 
2 
BACKGROUND ............................................................................................................ 20 
2.1 
Study Disease ........................................................................................................... 20 
2.1.1 
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ........................... 20 
2.1.2 
Treatment Options ................................................................................................. 20 
2.1.3 
Role of BTK and Bcl-2 Family Proteins in CLL/SLL .............................................. 21 
2.2 
Study Drugs ............................................................................................................... 22 
2.2.1 
Venetoclax ............................................................................................................. 22 
2.2.2 
Ibrutinib .................................................................................................................. 22 
2.3 
Rationale ................................................................................................................... 23 
2.3.1 
Primary Purpose of the Study ............................................................................... 23 
3 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ............................ 24 


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3.1 
Inclusion Criteria ........................................................................................................ 24 
3.2 
Exclusion Criteria ...................................................................................................... 25 
3.3 
Informed Consent Process ........................................................................................ 27 
3.4 
Eligibility Verification Procedures .............................................................................. 27 
3.5 
Study Timeline ........................................................................................................... 27 
3.5.1 
Completion of Study .............................................................................................. 27 
3.5.2 
Study Follow-up Post-completion .......................................................................... 28 
4 
TREATMENT PLAN ...................................................................................................... 29 
4.1 
Study Drug Administration ......................................................................................... 29 
4.2 
Toxicity Management ................................................................................................ 29 
4.3 
General Concomitant Medication and Supportive Care Guidelines .......................... 29 
4.3.1 
Prophylaxis and Management of Tumor Lysis Syndrome ..................................... 29 
4.3.2 
Permitted Concomitant Medications ...................................................................... 36 
4.3.3 
Concomitant Medications to be Used with Caution ............................................... 36 
4.3.4 
Prohibited Concomitant Medications ..................................................................... 38 
4.3.5 
Guidelines for Ibrutinib Management with Surgeries or Procedures ..................... 39 
4.4 
Duration of Therapy ..................................................... Error! Bookmark not defined. 
4.5 
Duration of Follow-up ................................................................................................ 39 
4.6 
Criteria for Removal from Study ................................................................................ 40 
4.6.1 
Removal from Study Treatment ............................................................................ 40 
4.6.2 
Removal from Study .............................................................................................. 40 
4.7 
Study Risk Information .............................................................................................. 40 
4.8 
Risk Mitigation ........................................................................................................... 40 
5 
STUDY DRUG INFORMATION ..................................................................................... 41 
5.1 
Study Drug Venetoclax .............................................................................................. 41 
5.1.1 
Name ..................................................................................................................... 41 
5.1.2 
Formulation ........................................................................................................... 41 
5.1.3 
Study Cohorts / Arms / Groups ............................................................................. 41 
5.1.4 
Mechanism of Action ............................................................................................. 41 
5.1.5 
Non-clinical and Clinical Pharmacokinetics ........................................................... 41 
5.1.6 
Summaries of Non-Clinical Pharmacology and Toxicology Studies ...................... 42 
5.1.7 
Summaries of Clinical Studies ............................................................................... 43 
5.1.8 
Major Route of Elimination .................................................................................... 44 


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5.1.9 
Safety Profile ......................................................................................................... 45 
5.1.10 
Rationale for the Starting Dose and Regimen Selected ........................................ 47 
5.1.11 
Maximum Allowable Dose/ Overdose ................................................................... 47 
5.1.12 
Treatment Duration ............................................................................................... 47 
5.2 
Study Drug Ibrutinib ................................................................................................... 48 
5.2.1 
Names ................................................................................................................... 48 
5.2.2 
Formulation ........................................................................................................... 48 
5.2.3 
Study Cohorts ........................................................................................................ 48 
5.2.4 
Mechanism of Action ............................................................................................. 48 
5.2.5 
Non-Clinical and Clinical Pharmacokinetics .......................................................... 48 
5.2.6 
Summaries of Non-Clinical Pharmacology and Toxicology Studies ...................... 49 
5.2.7 
Summaries of Clinical Studies ............................................................................... 49 
5.2.8 
Major Route of Elimination .................................................................................... 50 
5.2.9 
Safety Profile ......................................................................................................... 50 
5.2.9.11  Hypertension ......................................................................................................... 53 
5.2.9.12  Rationale for the Starting Dose and Regimen Selected ....................................... 54 
5.2.9.13  Maximum Allowable Dose / Overdose .................................................................. 54 
5.2.9.14  Treatment Duration ............................................................................................... 54 
5.3 
Study Drug Supply .................................................................................................... 55 
5.3.1 
Venetoclax Drug Supply ........................................................................................ 55 
5.3.2 
Ibrutinib Drug Supply ............................................................................................. 55 
5.4 
Venetoclax and Ibrutinib Accountability ..................................................................... 55 
6 
DOSE MODIFICATIONS AND DISCONTINUATION ................................................... 55 
6.1 
Venetoclax Dose Modification ................................................................................... 55 
6.2 
Ibrutinib Dose Modification ........................................................................................ 56 
6.3 
Dose Modification for Both Venetoclax and Ibrutinib ................................................. 57 
6.4 
Treatment Discontinuation ........................................................................................ 58 
7 
ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 59 
7.1 
Adverse Events Definition ......................................................................................... 59 
7.1.1 
Serious Adverse Events Definition ........................................................................ 60 
7.2 
Adverse Event Reporting .......................................................................................... 60 
7.3 
Safety Monitoring ...................................................................................................... 62 
7.4 
Adverse Events of Special Consideration ................................................................. 62 


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7.4.1 
Second Malignancy vs Secondary Malignancy ..................................................... 62 
7.4.2 
Other Adverse Events of Special Considerations ................................................. 63 
7.5 
Case Report Forms (CRFs) for Adverse Event Reporting ........................................ 64 
8 
CORRELATIVE / SPECIAL STUDIES .......................................................................... 65 
8.1 
Pharmacokinetics Assessments: Collected at Stanford Cancer Institute Site ONLY 65 
8.2 
Biomarker Assessments ............................................................................................ 65 
9 
TREATMENT ASSESSMENTS AND STUDY CALENDAR ......................................... 66 
9.1 
Study Treatment Schedule ........................................................................................ 66 
9.1.1 
Screening Phase ................................................................................................... 66 
9.1.2 
Treatment Phase ................................................................................................... 66 
9.2 
Study Procedures and Assessments ........................................................................ 67 
9.2.1 
Study Assessments ............................................................................................... 67 
9.2.2 
Efficacy Evaluations .............................................................................................. 68 
9.2.3 
Study Diagnostics / Procedures ............................................................................ 69 
9.3 
Table of Assessments / Study Calendar ................................................................... 73 
9.4 
End-of-Study ............................................................................................................. 76 
9.4.1 
Study Discontinuation ............................................................................................ 76 
9.4.2 
Publication of Study Results .................................................................................. 76 
9.5 
Follow-up ................................................................................................................... 76 
10 
REGULATORY CONSIDERATIONS ............................................................................ 77 
10.1 Institutional Review Board (IRB) Approval of Protocol .............................................. 77 
10.2 Protocol Compliance and Deviations ........................................................................ 77 
10.2.1 
Compliance with the Protocol ................................................................................ 77 
10.2.2 
Protocol Deviations ............................................................................................... 77 
10.2.3 
Protected Subject Health Information Authorization .............................................. 77 
10.3 Data and Safety Monitoring Plan ............................................................................... 78 
10.3.1 
Data Management Plan ......................................................................................... 78 
10.4 Investigator Responsibilities ...................................................................................... 79 
10.5 Protocol Amendments ............................................................................................... 79 
10.6 Publication of Study Results ...................................................................................... 79 
11 
STATISTICAL CONSIDERATIONS .............................................................................. 80 
11.1 Statistical Design ....................................................................................................... 80 
11.1.1 
Treatment Assignment .......................................................................................... 80 


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11.2 Endpoints .................................................................................................................. 80 
11.2.1 
Primary Endpoint ................................................................................................... 80 
11.2.2 
Secondary Endpoint(s) .......................................................................................... 80 
11.2.3 
Exploratory Endpoint(s) ......................................................................................... 81 
11.3 Interim analyses ........................................................................................................ 81 
11.4 Primary Analysis ........................................................................................................ 82 
11.4.1 
Primary Analysis Population .................................................................................. 82 
11.4.2 
Sample Size .......................................................................................................... 82 
11.4.3 
Accrual estimates .................................................................................................. 83 
11.4.4 
Safety Analysis ...................................................................................................... 83 
11.4.5 
Pharmacokinetic Analysis ..................................................................................... 83 
12 
REFERENCES .............................................................................................................. 84 
13 
APPENDICES ............................................................................................................... 86 
13.1 Appendix A.  Participant Eligibility Checklist ............................................................. 86 
13.2 Appendix B.  ECOG Status Scores ........................................................................... 91 
13.3 Appendix C.  Inhibitors and Inducers of CYP3A ........................................................ 91 
13.4 Appendix D.  Modified 2008 IWCLL Criteria for Tumor Response ............................ 94 
13.5 Appendix E.  Recommendations for Initial Management of Electrolyte Abnormalities 
and Prevention of Tumor Lysis Syndrome (TLS) ...................................................... 95 
13.6 Appendix F.  Clinical and Laboratory Definition of Tumor Lysis Syndrome .............. 99 
13.7 Appendix G.  Template for Protocol Amendments .................................................. 100 
13.8 Appendix H.  Drug Order Form for Venetoclax ....................................................... 101 
13.9 Appendix I.  Drug Order Form for Ibrutinib .............................................................. 103 
13.10 Appendix J.  Drug Diary for Ibrutinib ....................................................................... 105 
13.11 Appendix K.  Drug Diary for Venetoclax .................................................................. 107 


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Protocol Synopsis 
Study Title 
An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed or 
Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic 
Leukemia 
Study Design 
This is an open-label non-randomized two-center phase 2 study 
evaluating the safety and efficacy of concurrent therapy with ibrutinib and 
venetoclax in subjects with relapsed or refractory CLL/SLL.   
Screening, including CT scans and bone marrow aspirate and biopsy, 
must be performed within 28 days of study drug initiation.  Ibrutinib 
420 mg PO daily will be initiated on Week 1.  Intra-patient dose ramp-up 
of venetoclax will be initiated at Week 9 at 20 mg PO daily with the dose 
increasing weekly to 50 mg; 100 mg; 200 mg; and 400 mg as per 
FDA-approved dosing guidelines. Upon completion of ibrutinib + 
venetoclax combination treatment at Week 117, participants will have 
completed the trial and may transition off-study to receive commercial 
ibrutinib at the discretion of the investigator. 
Restaging CT/MRI imaging must be performed at Week 9, Week 38, 
Week 62, and within 1 month of completion of therapy at Week 117.  
Study visits will be conducted on Day 1 of each of the following weeks:  
Week 1; Week 5; Week 9 through Week 14; Week 18;  Week 22;  
Week 26; Week 30; Week 38; and every 12 weeks thereafter, until study 
completion. 
If an investigator has determined that a subject should discontinue the 
study, or a subject voluntarily withdraws, a Final Visit will be conducted 
as well as a 30-Day Safety Follow-Up.  If the subject is discontinued from 
the study due to toxicities attributable to either study drug, additional 
Follow-Up Visits will be conducted as clinically appropriate until 
satisfactory clinical resolution of the adverse event. 
Study Phase 
Phase 2  
Study Duration 
117 weeks of treatment and up to 1 month of follow up to complete final 
assessment. 
Primary Objective(s) 
The primary objective of this study is to evaluate the efficacy of 
concurrent therapy with ibrutinib and venetoclax in patients with relapsed 
and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic 
leukemia (SLL). 
Primary Endpoint(s) 
Complete response rate (CR)  
Secondary Objectives To define the safety and tolerability of combination therapy with ibrutinib 
and venetoclax. 


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Protocol 10691 dated 27 AUG  2020 
 
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Secondary 
Endpoint(s) 
For the combination of venetoclax and ibrutinib: 
• 
Overall response rate (ORR)  
• 
Duration of response (DOR) 
• 
Time-to-progression (TTP) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS)  
• 
Rate of minimal residual disease (MRD) negativity in the bone 
marrow 
• 
Safety:  
o Frequency, severity, and relatedness of AEs 
o Frequency, severity and management of TLS 
o Frequency of AEs requiring discontinuation of study drug or dose 
reductions, or leading to death 
Exploratory 
Objectives 
• 
Time to next CLL treatment (TNT) 
• 
Change in mutation landscape at time of progression 
• 
Pharmacokinetics of ibrutinib and venetoclax when administered in 
combination 
Indication 
Relapsed or refractory CLL/SLL patients 
Investigational Drug  
Venetoclax in combination with ibrutinib  
Dose 
Venetoclax will be administered PO with single daily doses QD starting at 
Week 9.  Venetoclax dose increments will proceed weekly from  
20 mg → 50 mg → 100 mg → 200 mg → 400 mg.  
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.  Subjects will receive 420 mg ibrutinib PO daily. 
Sample Size 
22 subjects  
Summary of 
Eligibility Criteria 
Inclusion Criteria 
• 
Voluntarily sign and date an informed consent form (ICF) with 
authorization to use protected health information (in accordance with 
national and local subject privacy regulations) and approved by the 
Institutional Review Board (IRB) prior to initiation of any study specific 
procedures 
• 
Diagnosis of chronic lymphocytic leukemia CLL) or small lymphocytic 
leukemia (SLL) meeting IWCLL criteria, and relapsed after or 
refractory to at least 1 prior treatment  
• 
Measurable nodal disease by computed tomography (CT) 
Laboratory 
• 
Adequate hematologic function independent of transfusion and 


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growth factor support for at least 7 days prior to screening, (except for 
pegylated G-CSF (pegfilgrastim) and darbepoetin which require at 
least 14 days prior to screening) defined as the following.  
o Absolute neutrophil count > 750 cells/mm3 (0.75 x 109/L)  
o Platelet count > 30,000 cells/mm3 (30 x 109/L) without transfusion 
support; evidence of mucosal bleeding; a known bleeding 
episode within 3 months of screening; or a history of a 
bleeding disorder  
o Hemoglobin > 8.0 g/dL 
If the bone marrow evaluation shows heavy infiltration with 
underlying disease, growth factor support may be administered to 
achieve the eligibility criteria. 
• 
Adequate hepatic and renal function defined as:  
o Serum aspartate transaminase (AST) or alanine transaminase 
(ALT) ≤ 2.5 x upper limit of normal (ULN)  
o Estimated Creatinine Clearance ≥ 30 mL/min (24-hour measured 
GFR or modified Cockcroft-Gault)  
o Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to 
Gilbert’s syndrome or of non-hepatic origin)  
• 
PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN  
Demographic  
• 
Men and women ≥ 18 years of age  
• 
Eastern Cooperative Oncology Group (ECOG) performance status of 
0, 1, or 2  
Ethical/Other  
• 
Female subjects who are of non-reproductive potential 
(ie, post-menopausal by history - no menses for ≥ 1 year; OR history 
of hysterectomy; OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy). 
OR 
• 
Female subjects of childbearing potential must have a negative 
serum pregnancy test upon study entry 
• 
Male and female subjects must agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], 
sexual abstinence, or sterilized partner) during the period of therapy 
and for 90 days after the last dose of study drug 
Exclusion Criteria 
• 
Prior treatment with either ibrutinib or venetoclax  
• 
Vaccinated with live, attenuated vaccine(s) within 28 days prior to 
first dose of study drug 
• 
Received an allogeneic stem cell transplant within the past 1 year  
(if over 1 year post-allogeneic transplant, must not have 
active cGVHD) 


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• 
Richter’s transformation confirmed by biopsy  
• 
Active uncontrolled autoimmune cytopenias  
Concurrent Conditions 
• 
Chemotherapy ≤ 21 days prior to first administration of study 
treatment and/or monoclonal antibody ≤ 4 weeks prior to first 
administration of study treatment.  
• 
History of other malignancies, except:  
o Malignancy treated with curative intent and with no known active 
disease present for ≥ 3 years before the first dose of study drug, 
and felt to be at low risk for recurrence by treating physician  
o Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease  
o Adequately treated carcinoma in situ without evidence of disease  
• 
Concurrent systemic immunosuppressant therapy 
[eg, cyclosporine A, tacrolimus, etc, or chronic administration 
(> 14 days) of > 20 mg/day of prednisone] within 28 days of the 
first dose of study drug  
• 
Recent infection requiring systemic treatment that was completed 
≤ 14 days before the first dose of study drug  
• 
Unresolved toxicities from prior anti-cancer therapy, defined as 
having not resolved to Common Terminology Criteria for Adverse 
Event (CTCAE, v4.03), Grade ≤ 1, or to the levels dictated in the 
inclusion/exclusion criteria except for alopecia  
• 
Known bleeding disorders (eg, von Willebrand’s disease) or 
hemophilia  
• 
History of stroke or intracranial hemorrhage within 6 months prior to 
first dose of study drug 
• 
Known history of human immunodeficiency virus (HIV) or active with 
hepatitis C virus (HCV) or hepatitis B virus (HBV).   
Subjects who are positive for hepatitis B core antibody or hepatitis B 
surface antigen must have a negative polymerase chain 
reaction (PCR) result before enrollment in order to meet eligibility for 
this criterion.  Those who are PCR-positive will be excluded. 
• 
Any uncontrolled active systemic infection  
• 
Major surgery within 4 weeks of first dose of study drug  
• 
Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise the 
subject’s safety or put the study outcomes at undue risk  
• 
Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as 
defined by the New York Heart Association Functional Classification; 
or a history of myocardial infarction, unstable angina, or acute 
coronary syndrome within 6 months prior to screening  
• 
Unable to swallow capsules; malabsorption syndrome;  disease 


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significantly affecting gastrointestinal function; resection of the 
stomach or entire small bowel; symptomatic inflammatory bowel 
disease or ulcerative colitis; or partial or complete bowel obstruction  
• 
Concomitant use of warfarin or other Vitamin K antagonists  
• 
Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor 
or inducer within 7 days prior to the first dose of ibrutinib or subjects 
who require continuous treatment with a strong cytochrome P450 
CYP3A inhibitor or inducer (see Appendix C)  
• 
Lactating or pregnant  
• 
Unwilling or unable to participate in all required study evaluations 
and procedures  
• 
Unable to understand the purpose and risks of the study  
• 
Subjects with chronic liver disease with hepatic impairment 
Child-Pugh class B or C 
Treatment and 
Procedural Summary 
Ibrutinib 420 mg PO daily will be initiated on Week 1 Day 1.  Venetoclax 
will be initiated at 20 mg PO daily on Week 9 Day 1 and increased every 
7 days to 50 mg; 100 mg; 200 mg; and 400 mg. Upon completion of 
ibrutinib + venetoclax combination treatment at Week 117, participants 
will have completed the trial and may transition off-study to receive 
commercial ibrutinib at the discretion of the investigator. 
Ibrutinib and Venetoclax Dose and Schedule 
Week 
Ibrutinib 
Venetoclax 
1 
420 
0 
9 
420 
20 
10 
420 
50 
11 
420 
100 
12 
420 
200 
13 to 117 
420 
400 
Safety Plan 
Adverse event (AE) monitoring; vital signs; physical examination; ECG; 
and laboratory values will be assessed.  Guidelines for tumor lysis 
syndrome (TLS) management are provided.  Chemistry labs (including 
potassium; calcium; uric acid; phosphorus; and creatinine) will be 
performed pre-dose;  8 hours;  and 24 hours post-dose for the first and 
each escalated venetoclax dose and additionally as deemed necessary 
to monitor TLS. 
Statistical 
Considerations 
All efficacy analyses will be performed using the intent-to-treat (ITT) 
population.   
Primary Efficacy Analysis:   
Complete Response Rate 
The proportion of subjects with a complete response (per investigator 
assessment) will be calculated for all subjects based on IWCLL criteria. A 
95% confidence interval based on binomial distribution will be 
constructed for the calculated CR rate. 


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Secondary Efficacy Analysis: 
Overall Response Rate 
The proportion of subjects with an overall response (per investigator 
assessment) will be calculated for all subjects based on IWCLL criteria.  
A 95% confidence interval based on binomial distribution will be 
constructed for the calculated ORR. 
Duration of Response 
Duration of response will be defined as the number of days from the date 
of first response per investigator assessment to the earliest recurrence or 
PD per investigator assessment.  If a subject is still responding, then the 
subject's data will be censored at the date of the subject's last available 
clinical disease assessment.  For subjects who never experienced 
response, the subject's data will be censored on the date of enrollment.  
Duration of response will be analyzed by Kaplan-Meier methodology 
using data for all enrolled subjects who receive study treatment.  Median 
duration of response will be calculated and the corresponding 95% 
confidence interval will be presented. 
Time-to-progression 
Time-to-progression will be defined as the number of days from the date 
of first dose to the date of earliest disease progression (per the 
investigator assessment).  All disease progression will be included 
regardless whether the event occurred while the subject was taking study 
drug or had previously discontinued study drug.  If the subject does not 
experience disease progression, then the data will be censored at the 
date of the last available disease assessment.  TTP will be analyzed by 
Kaplan-Meier methodology using data for all enrolled subjects.  Median 
time TTP will be calculated and 95% confidence interval for median time 
TTP will be presented. 
Progression-Free Survival 
Progression-Free Survival will be defined as the number of days from the 
date of first dose to the date of earliest disease progression (per the 
investigator assessment) or death.  All disease progression will be 
included regardless whether the event occurred while the subject was 
taking study drug or had previously discontinued study drug.  If the 
subject does not experience disease progression or death, then the data 
will be censored at the date of the last disease assessment.  PFS will be 
analyzed by Kaplan Meier methodology using data for all dosed subjects.  
Median PFS time will be calculated and 95% confidence interval for 
median PFS time will be presented. 
Overall Survival 
Overall survival will be defined as the number of days from the date of 
first dose to the date of death for all dosed subjects.  The data for 
subjects who did not die will be censored at the date of last study visit or 
the last known date to be alive, whichever is later.  OS will be analyzed 


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by Kaplan-Meier methodology using data from all dosed subjects.  
Median time survival will be calculated and 95% confidence interval for 
the median time survival will be presented. 
Rate of Minimal Residual Disease (MRD) Negativity in the Bone Marrow 
MRD negativity will be defined as less than one CLL cell per 10,000 
leukocytes (or below 10-4) on bone marrow-based flow cytometry.  Rate 
of MRD negativity will be defined as the proportion of subjects who have 
MRD negativity on bone marrow assessment.  Ninety-five percent (95%) 
confidence intervals based on the binomial distribution will be provided. 
Safety Endpoints and Analysis  
A safety analysis will be performed for all dosed subjects unless 
otherwise indicated.  For the entire study, AEs will be evaluated and 
summarized.  Laboratory test results and vital signs will be explored for 
trends and summarized as appropriate.   
Endpoints:  
• 
Frequency, severity, and relatedness of AEs 
• 
Frequency, severity and management of TLS 
• 
Frequency of AEs requiring discontinuation of study drug or dose 
reductions, or leading to death  
Exploratory Efficacy Analysis:  
Pharmacokinetics 
Pharmacokinetic samples for ibrutinib will be collected on the first day of 
ibrutinib dose administration (Week 1 Day1) and each day when dosed in 
combination with a newly escalated dose of venetoclax in all subjects 
enrolled in the study at Stanford University. 
Pharmacokinetic samples for venetoclax will be collected at 8 hours 
post-dose on the day of the first venetoclax dose administration and for 
each new escalated dose in all subjects enrolled in the study at Stanford 
University.  Pharmacokinetic samples will be collected for the dose 
ramp-up stage.   
Values for the pharmacokinetic parameters for ibrutinib and venetoclax 
including the maximum observed plasma concentration (Cmax), the time 
to Cmax (peak time, Tmax), the area under the plasma concentration-time 
curve (AUC) from 0 to the time of the last measurable concentration 
(AUCt) and AUC over a 24-hour dose interval (AUC0-24) will be 
determined.  Additional analyses may be performed if useful in the 
interpretation of the data. 
Time to Next Anti-CLL Treatment 
Time to next anti-CLL treatment will be defined as the number of days 
from the date of the first dose of ibrutinib to the date of first dose of new 
non-protocol anti-leukemia therapy (NPT) or death from any cause.  For 


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subjects who did not take NPT, the data will be censored at the last 
known date to be free of NPT.  TTNT will be analyzed by Kaplan-Meier 
methodology using data for all dosed subjects.  Median TTNT time will be 
calculated. 
Change in mutation landscape at time of progression 
BTK mutation analysis (NeoGenomics) will be performed at baseline and 
at time of progression. 
Interim Analysis 
No interim analysis for efficacy is planned.  


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Protocol Schema 
Figure 1.  Administration of Ibrutinib and Venetoclax 
8 weeks ibrutinib alone:  
Week 1 Day 1 
 
Week 8 Day 7 
 
5 weeks venetoclax dose-escalation:  
Week 9 Day 1 
 
Week 13 Day 7 
 
2 years combined therapy:  
Week 14 Day 1 
 
Week 117 Day 7 
 
 
Ibrutinib 420 mg PO daily 
Ibrutinib 420 mg PO daily 
Venetoclax 400 mg PO daily 
Ibrutinib 420 mg PO daily 
Venetoclax dose escalated weekly 


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List of Abbreviations and Definitions of Terms 
AE 
Adverse event 
IgH 
Immunoglobulin heavy chain  
AESI 
Adverse events of special interest 
IRB 
Institutional review board 
ALC 
Absolute lymphocyte count 
IV 
Intravenous 
AML 
Acute myeloid leukemia  
IVRS 
Interactive-voice response system 
ANC 
Absolute neutrophil count 
IWRS 
Interactive web response system 
AUC 
Area under curve (exposure) 
IWCLL 
NCI-WG 
International Workshop on Chronic 
Lymphocytic Leukemia National Cancer 
Institute-Working Group 
BCR 
B-cell receptor 
LTLS 
Laboratory Tumor Lysis Syndrome 
BTK 
Bruton’s tyrosine kinase 
MCL 
mantle cell lymphomas  
CBC 
Complete blood count 
MRD 
Minimal residual disease 
CLL 
Chronic lymphocytic leukemia 
NCI 
National Cancer Institute  
Cmax 
Maximum concentration of drug 
NHL 
non-Hodgkin's Lymphoma 
CRF 
Case report form (paper or electronic) 
ORR 
Overall response rate  
CR 
Complete response 
OS 
Overall survival 
CT 
Computed tomography 
PD 
Pharmacodynamics  
CTCAE 
Common Terminology Criteria for 
Adverse Events 
PFS 
Progression-free survival 
CTEP 
Cancer Therapy Evaluation Program 
pK 
Pharmacokinetics  
CTLS 
Clinical tumor lysis syndrome 
PO 
Oral 
DCF 
Data Clarification Form 
PR 
Partial Response 
DLBCL 
Diffuse large B-cell lymphoma 
SAE 
Serious adverse event 
DLT 
Dose-limiting Toxicity 
SCI 
Stanford Cancer Institute 
DMC 
Data monitoring committee 
SLL 
 Small lymphocytic lymphoma 
DSM-IV 
Diagnostic and Statistical Manual of 
Mental Disorders (4th edition) 
SRC 
Scientific Review Committee 
ECG 
Electrocardiogram 
TLS 
Tumor lysis syndrome 
eDC 
Electronic data capture 
Tmax 
Median time to maximum plasma 
concentration  
FL 
Follicular lymphomas  
TPN 
Total parenteral nutrition 
GCP 
Good Clinical Practice 
Tmax 
Median time to maximum plasma 
concentration 
HBsAg 
Hepatitis B surface antigen 
TTNT 
Time to Next anti-cancer Treatment  
HIV 
Human immunodeficiency virus 
TTP 
Time-to-progression  
ICF 
Informed Consent Form 
ULN 
Upper limit of normal  
ICH 
International Conference on 
Harmonization 
USP 
United States Pharmacopeia 
 


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1 OBJECTIVES, ENDPOINTS, AND OUTCOMES  
1.1 Objectives  
1.1.1 Primary Objectives  
The primary objective of this trial is to evaluate the efficacy of orally-administered venetoclax 
combined with ibrutinib in patients with CLL/SLL who have been previously treated with at least 
one agent but who are naïve to ibrutinib and venetoclax.   
1.1.2 Secondary Objectives  
The secondary objectives of this trial are to define the safety and tolerability of combination 
therapy with venetoclax and ibrutinib in relapsed and refractory CLL/SLL patients who have not 
been previously treated with either venetoclax or ibrutinib. 
1.1.3 Exploratory Objectives   
• 
To determine the time to next treatment.   
• 
To perform BTK mutation analysis (NeoGenomnics) to identify potential mechanisms of 
resistance.   
• 
To evaluate the pharmacokinetics of ibrutinib and venetoclax when administered in 
combination. 
1.2 Endpoints (summary) 
Endpoints for this study are presented in greater detail in Section 11.2 Endpoints.   
1.2.1 Primary Endpoint(s)  
Complete response rate (CR)  
1.2.2 Secondary Endpoint(s)  
Secondary Endpoints include: 
• 
Overall response rate (ORR) 
• 
Duration of response (DOR) 
• 
Time-to-progression (TTP) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Rate of minimal residual disease (MRD) negativity in the bone marrow 
• 
Safety 
o Frequency, severity, and relatedness of AEs 
o Frequency, severity and management of TLS 
o Frequency of AEs requiring discontinuation of study drug or dose reductions, or 
leading to death 


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1.3 Study Design 
1.3.1 Overview 
This is a Phase 2, open-label, non-randomized 2-center study that will evaluate the safety and 
efficacy of orally administered venetoclax combined with ibrutinib in patients with relapsed or 
refractory CLL/SLL and no prior treatment with either ibrutinib or venetoclax. 
Table 1.  Planned intra-patient dose ramp-up of venetoclax 
Week 
Venetoclax 
(mg/day) 
Ibrutinib 
(mg/day) 
1 
0 
420 
9 
20 
420 
10 
50 
420 
11 
100 
420 
12 
200 
420 
13-117 
400 
420 
1.3.2 Randomization  
This is an open-label study.  Participants will not be blinded or randomized to study treatment. 
1.3.3 Number of Participants  
A total of twenty-two (22) participants will be enrolled in this study. 
1.4 ClinicalTrials.gov Registration, Outcomes, and Results  
1.4.1 Interventional model  
The intervention model of this study is a single group study.   
1.4.2 Masking  
This is an open-label, non-randomized study.   
1.4.3 Type of Primary Objective / Outcome  
The primary outcome of this study is to evaluate the efficacy of concurrent therapy with ibrutinib 
and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and 
small lymphocytic leukemia (SLL).  
1.4.4 Outcomes Measures for ClinicalTrials.gov Results Reporting 
1.4.4.1 Primary Outcome(s)  
• 
Primary Outcome Measure:  The primary outcome for this study, for the purposes of 
Clinical Trials.gov registration and results reporting, is the complete response rate.  
• 
Primary Outcome Measure Title:  Complete response rate when venetoclax is used 
in combination with 420 mg/day ibrutinib to treat chronic lymphocytic leukemia (CLL) and 
small lymphocytic leukemia (SLL).  


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• 
Time Frame:  The time frame for assessment of the primary outcome / primary endpoint 
is 62 weeks.  
• 
Safety Issue:  Does not assess a safety issue.   
1.4.4.2 Secondary Outcome(s) 
• 
Overall response rate (ORR) based on IWCLL NCI-WG criteria 
• 
Duration of response (DOR) defined as the number of days from the date of first 
response per investigator assessment to the earliest recurrence or progressive disease 
per investigator assessment 
• 
Time-to-progression (TTP) defined as the number of days from the date of first dose 
(date of enrollment if not dosed) to the date of earliest disease progression (per the 
investigator assessment) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Rate of minimal residual disease (MRD) negativity in the bone marrow 
• 
Safety 
o Frequency, severity, and relatedness of AEs 
o Frequency, severity and management of TLS 
o Frequency of AEs requiring discontinuation of study drug or dose reductions, or 
leading to death 
1.5 Regulatory Status of Study Agents  
The indication described in this study is considered investigational relative to the approved 
indications.  Regulatory authorization to conduct this study is pursuant to IND 131,600 
submitted by Steven E Coutre, MD. 
1.5.1 Venetoclax  
Venetoclax is approved for marketing in the United States, as Venclexta for the indication of 
treatment of chronic lymphocytic leukemia (CLL) with 17p deletion, after at least one prior 
therapy.  
Venetoclax manufacturer AbbVie Inc has submitted to FDA a Letter of Authorization of 
Cross-reference to their IND 110,159 on behalf of this study.  
1.5.2 Ibrutinib 
Ibrutinib is approved for marketing in the United States, as Imbruvica for the indication of 
treatment of FDA for the treatment of CLL regardless of the presence or absence of the 
17p deletion, and also to treat mantle cell lymphoma (MCL) after one prior therapy;  relapsed or 
refractory marginal zone lymphoma (MZL);  chronic graft-vs-host disease (GvHD) after failure of 
1 or more systemic lines of therapy;  or Waldenström’s macroglobulinemia (WM).  .  
Ibrutinib manufacturer Pharmacyclics LLC has submitted to FDA a Letter of Authorization of 
Cross-reference to their ibrutinib IND 102,688 on behalf of this study.  Ibrutinib continues to be 
studied in other disease settings.  


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2 BACKGROUND 
2.1 Study Disease 
2.1.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
Chronic lymphocytic leukemia (CLL), and its analogous disease small lymphocytic leukemia 
(SLL), is a lymphoproliferative disorder characterized by progressive accumulation of 
monoclonal, small, mature-appearing CD5+ B-cells in peripheral blood, bone marrow, and 
secondary lymphoid organs.  It is the most common form of leukemia in adults in the Western 
World, accounting for approximately 30% of all leukemias.1  Chronic lymphocytic leukemia 
primarily affects elderly individuals; however, approximately one third of patients are less than 
60 years of age at diagnosis.2  It is currently estimated that annually approximately 15,000 
people will be diagnosed with CLL in the United States, and that almost 4,500 individuals will die 
of the disease.3  In Europe, CLL accounts for approximately 30% of all leukemias in adults with 
a reported age-standardized incidence rate of 3.79 per 100,000 individuals (for CLL/SLL) in the 
years 2000 to 2002.4  The approximate 5-year survival rate for patients with CLL is 73%.5  CLL 
presents with a variable clinical course.  Approximately one-third of patients have indolent 
disease with prolonged median survival that does not require treatment, and die of causes 
unrelated to disease.  Another third have an initial indolent phase that is followed by rapid 
progression of the disease requiring therapy.  The remaining third have aggressive disease and 
require treatment at the time of diagnosis.  Chronic lymphocytic leukemia patients will often 
have compromised bone marrow reserve due to their underlying disease.  The principal 
complication of CLL is immunodeficiency related to myelosuppression and as a result, infection 
is the major cause of death in patients with CLL.  
2.1.2 Treatment Options 
The current practice for early stage CLL patients is to take an expectant approach, while those 
with advanced stage disease who require treatment receive combination regimens.  
Chlorambucil, in use for several decades, can induce partial remissions in advanced CLL, but 
does not improve survival when used in asymptomatic early-stage CLL.6 Fludarabine, approved 
as a second-line agent, improves response rates, progression-free survival (PFS), and in 
combination with cyclophosphamide and rituximab (FCR), overall survival (OS) compared to 
fludarabine and cyclophosphamide alone.7-10 As such, FCR has emerged as the first line 
therapy in young patients with CLL.  In 2008, bendamustine, an alkylator and antimetabolite, 
was approved as first line therapy for CLL, based on improvement in PFS versus chlorambucil.  
For patients over the age of 65-70, FCR is not tolerated; other therapies, such as chlorambucil ± 
rituximab, or bendamustine ± rituximab are commonly used in the up-front setting.  For patients 
with del(17p13.1) none of these traditional approaches work effectively. 
Standard chemotherapeutic options for CLL cause significant immune suppression and 
myelosuppression are not well tolerated by the elderly population and have not consistently 
offered survival advantage.  Treatment decisions for patients with CLL are made based on 
considerations such as age, clinical stage, expected survival, and anticipated toxicities.  With 
the notable exception of allogeneic stem cell transplantation, CLL is currently an incurable 
disease, despite good initial responses to chemoimmunotherapy.  Nonetheless, globally access 
to allogeneic stem cell transplant and/or clinical trials is limited, and treatment options for 
relapsed disease tend to have increased toxicity and reduced antitumor activity. 


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2.1.3 Role of BTK and Bcl-2 Family Proteins in CLL/SLL 
B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to antigen.  
Antigen binding induces receptor aggregation and the clustering and activation of multiple 
tyrosine kinases, which in turn activate further downstream signaling pathways.11   
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from mutations 
and translocations acquired during normal B-cell development.12 Several lines of evidence 
suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies.   
The protein Bruton’s tyrosine kinase (BTK) is a Tec-family kinase that is exclusively expressed 
in B-cells and participates in the BCR signaling pathway.  The upstream Src-family kinases Blk, 
Lyn and Fyn13,14 activate BTK which in turn phosphorylates and activates phospholipase-Cγ 
(PLCγ); this leads to Ca2+ mobilization and activation of NFκB, MAP kinase and Akt pathways.15 
There is strong evidence that lymphomas require BCR signaling.  A functional B-cell receptor is 
maintained, even as the non-expressed immunoglobulin heavy chain (IgH) is involved in 
oncogenic translocations.16  Patients whose tumor cells developed resistance to anti-idiotype 
therapy did not produce BCR-negative tumor populations as a resistance strategy, indicating 
that the BCR provides important survival signals for lymphoma cells.17  Selective knockdown of 
BCR components by siRNA causes apoptosis in B-cell lymphoma cell lines.18 During recent 
years, evidence has accumulated consistent with signaling via the BCR being important in CLL 
with two small molecule inhibitors of BTK and PI3K approved in 2014 in the US for relapsed 
CLL patients.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease 
X-linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic 
diseases are characterized by reduced BCR signaling and a failure to generate mature B-cells.  
The BTK protein is expressed in most hematopoietic cells except T-cells and natural killer cells, 
but the selective effect of BTK mutations suggests that its primary functional role is in antigen 
receptor signaling in B-cells.19   
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 
oncogene was first identified in follicular lymphoma where the t(14;18) chromosomal 
translocation results in significant over-expression of the protein in B-cells.  The Bcl-2 family of 
genes encodes a family of closely related proteins that possess either pro-apoptotic or 
anti-apoptotic activity and share up to four Bcl-2 Homology domains.20-23  Bcl-2 overexpression 
is a major contributor to the pathogenesis of some types of lymphoid malignancies.  Bcl-2 is 
also overexpressed in acute and chronic leukemias. Chronic lymphocytic leukemia (CLL) is a 
genetic disease where the microRNAs miR15a and miR16-1 that negatively regulate the 
transcription of Bcl-2 are deleted or down regulated, resulting in uncontrolled expression of 
Bcl-2.24,25  


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2.2 Study Drugs 
2.2.1 Venetoclax 
Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that binds 
with > 500-fold higher affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to other Bcl-2 family 
proteins Bcl-XL (Ki – 48 nM) and Bcl-w (Ki – 245 nM).26 Overexpression of anti-apoptotic Bcl-2 
family proteins is associated with increased resistance to chemotherapy, and antagonism of the 
action of these proteins might enhance response to such therapy and overcome resistance.  
Anti-apoptotic Bcl-2 family members are associated with tumor initiation, disease progression, 
and drug resistance, making them compelling targets for antitumor therapy. 
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma and 
leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs), 
diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias (AMLs).  Venetoclax 
was especially potent against cell lines expressing high levels of Bcl-2.  Leukemia and 
lymphoma cell lines bearing the t(14;18) translocation were significantly more sensitive to 
venetoclax than non-mutated cell lines. 
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines derived 
from acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL).  The drug was 
also active in a model of disseminated ALL. 
Venetoclax is approved by the US Food and Drug Administration (FDA) for the treatment of  
1) Chronic lymphocytic leukemia (CLL) in patients with 17p deletion who have received at 
least one prior therapy, and  
2) CLL in patients with 17p deletion 
More information on the nonclinical, pharmacology, and clinical data for venetoclax can be 
found in Section 5 of this protocol and in the current version of the venetoclax package insert 
and Investigator’s Brochure. 
2.2.2 Ibrutinib 
Ibrutinib is a potent, first-in-class, orally-administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream BCR signaling pathways and thus 
prevents B-cell proliferation.  In vitro, ibrutinib inhibits purified BTK and selected members of the 
kinase family with 10-fold specificity compared with non-BTK kinases.   
Ibrutinib (Imbruvica) is approved by the US Food and Drug Administration (FDA) for the 
treatment of  
1) Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy 
based on overall response rate,  
2) Chronic lymphocytic leukemia (CLL),  
3) CLL in patients with 17p deletion,  
4) Waldenström’s macroglobulinemia,  
5) Marginal zone lymphoma (MZL) in patients who have received at least one prior 
anti-CD20-based therapy, and  


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6) Chronic graft-vs-host disease (GVHD) after failure of one or more lines of systemic 
therapy. 
Ibrutinib is currently under investigation in various indications.   
This study uses the FDA—approved dose of ibrutinib for patients with CLL/SLL 
(420 mg/day oral).  More information on the nonclinical, pharmacology, and clinical data for 
ibrutinib can be found in Section 5 of this protocol and in the current version of the ibrutinib 
package insert and Investigator’s Brochure. 
2.3 Rationale 
The optimal approach to CLL/SLL treatment with the multiple agents that are available and in 
development remains an open question.  While the default approach continues to be serial 
treatment with different agents at the time of disease progression, concurrent treatment offers 
the possibility of deeper and more durable responses.  Targeting multiple mediators of 
malignancy simultaneously with highly-active; well-tolerated therapies has the potential to 
eliminate CLL clones that may be resistant to a particular therapy and prevent the emergence of 
resistance through single escape mutations. 
The combination of ibrutinib and venetoclax is compelling for multiple reasons.  Both are well 
tolerated with high response rates as single agents.  Multiple lines of evidence show activation 
of apoptosis in CLL cells in response to ibrutinib and the effect of venetoclax have the potential 
to dramatically enhance this response.  Combination therapy with traditional 
chemoimmunotherapy has achieved higher rates of complete response than monotherapy with 
either antibodies or alkylators alone and a combination of targeted agents has the potential to 
achieve this goal, particularly in bone marrow response and in prolonging the duration of 
response. 
The regimen is designed to start therapy with ibrutinib, and then ramp-up the dose of venetoclax 
as per FDA-approved dosing guidelines, followed by continue treatment along with the standard 
CLL/SLL dose of ibrutinib. 
2.3.1 Primary Purpose of the Study  
Treatment:  The clinical trial described in this protocol is designed to determine whether CR 
rates can be improved in patients with relapsed or refractory CLL/SLL when venetoclax is used 
concurrently with ibrutinib. 


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3 PARTICIPANT SELECTION AND ENROLLMENT 
PROCEDURES 
Subjects with relapsed or refractory CLL per IWCLL criteria without prior treatment with 
venetoclax or ibrutinib will be selected for this study.  Subjects must undergo screening 
including CT and bone marrow aspirate and biopsy within 28 days prior to initial study drug 
administration.  
3.1 Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all the following inclusion criteria. 
1. Voluntarily sign and date an informed consent form (ICF) with authorization to use 
protected health information (in accordance with national and local subject privacy 
regulations) and approved by the Institutional Review Board (IRB) prior to initiation of 
any study specific procedures. 
2. Diagnosis of chronic lymphocytic leukemia CLL) or small lymphocytic leukemia (SLL) 
meeting IWCLL/NCI-WG criteria, and relapsed after or refractory to at least 
1 prior treatment. 
3. Measurable nodal disease by computed tomography (CT). 
Laboratory 
4. Adequate hematologic function independent of transfusion and growth factor support for 
at least 7 days prior to screening [except for pegylated G-CSF (pegfilgrastim) and 
darbepoetin which require at least 14 days prior to screening defined as the following.   
o Absolute neutrophil count > 750 cells/mm3 (0.75 x 109/L).  
o Platelet count > 30,000 cells/mm3 (30 x 109/L) without transfusion support; 
evidence of mucosal bleeding; a known bleeding episode within 3 months of 
screening; or a history of a bleeding disorder.   
o Hemoglobin > 8.0 g/dL. 
If the bone marrow evaluation shows heavy infiltration with underlying disease, growth 
factor support may be administered after screening and prior to the first dose of therapy. 
5. Adequate hepatic and renal function defined as: 
o Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤ 2.5 x upper limit of normal (ULN). 
o Estimated Creatinine Clearance ≥ 30 mL/min (24-hour measured GFR or 
modified Cockcroft-Gault) 
o Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin) 
6. PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN. 
Demographic 
7. Men and women ≥ 18 years of age. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 


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Ethical/Other 
9. Females:  
o Female subjects who are of non-reproductive potential (ie, post-menopausal by 
history - no menses for ≥ 1 year; OR history of hysterectomy; OR history of 
bilateral tubal ligation; OR history of bilateral oophorectomy).   
OR 
o Female subjects of childbearing potential must have a negative serum pregnancy 
test upon study entry.  
10. Male and female subjects must agree to use highly effective methods of birth control 
(eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine 
devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and 
for 90 days after the last dose of study drug 
3.2 Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Prior treatment with either venetoclax or ibrutinib. 
2. Vaccinated with live, attenuated vaccine(s) within 28 days prior to first dose of 
study drug  
3. Received an allogeneic stem cell transplant in the past 1 year (if over 1 year post 
allogeneic transplant, must not have active cGVHD). 
4. Richter’s transformation confirmed by biopsy. 
5. Active uncontrolled autoimmune cytopenias  
Concurrent Conditions 
6. Chemotherapy ≤ 21 days prior to first administration of study treatment and/or 
monoclonal antibody ≤ 4 weeks prior to first administration of study treatment. 
7. History of other malignancies, except:   
• 
Malignancy treated with curative intent and with no known active disease present 
for ≥ 3 years before the first dose of study drug, and felt to be at low risk for 
recurrence by treating physician. 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
• 
Adequately treated carcinoma in situ without evidence of disease.   
8. Concurrent systemic immunosuppressant therapy [eg, cyclosporine A, tacrolimus, etc, or 
chronic administration (> 14 days) of > 20 mg/day of prednisone] within 28 days of the 
first dose of study drug. 


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9. Recent infection requiring systemic treatment that was completed ≤ 14 days before the 
first dose of study drug.  
10. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, v4.03), Grade ≤ 1, or to the 
levels dictated in the inclusion/exclusion criteria except for alopecia. 
11. Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. 
12. History of stroke or intracranial hemorrhage within 6 months prior to first dose of 
study drug. 
13. Known history of human immunodeficiency virus (HIV) or active with hepatitis C 
virus (HCV) or hepatitis B virus (HBV).   
Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen 
must have a negative polymerase chain reaction (PCR) result before enrollment in order 
to meet eligibility for this criterion.  Those who are PCR-positive will be excluded. 
14. Any uncontrolled active systemic infection. 
15. Major surgery within 4 weeks of first dose of study drug. 
16. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes 
at undue risk. 
17. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to screening. 
18. Unable to swallow capsules; malabsorption syndrome; disease significantly affecting 
gastrointestinal function; resection of the stomach or small bowel; symptomatic 
inflammatory bowel disease or ulcerative colitis; or partial or complete bowel obstruction. 
19. Concomitant use of warfarin or other Vitamin K antagonists. 
20. Received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7 days prior to 
the first dose of ibrutinib, OR subjects who require continuous treatment with a strong 
cytochrome P450 CYP3A inhibitor or inducer (see Appendix C)  
21. Lactating or pregnant. 
22. Unwilling or unable to participate in all required study evaluations and procedures. 
23. Unable to understand the purpose and risks of the study. 
24. Subjects with chronic liver disease with hepatic impairment Child-Pugh class B or C 


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3.3 Informed Consent Process 
Prior to participation in any study-specific procedure, including any invasive screening 
procedures, all candidates for participation will be provided a consent form describing the study.  
This consent form will provide sufficient information to make an informed decision regarding 
participation.   
• 
If the person providing consent is fluent in English, the prospective subject must sign the 
IRB-approved informed consent. 
• 
If the subject is considered “non-English speaking,” and the “Short Form” consent 
process will be used, the IRB-approved English consent form (aka, the 
“Summary Form”) will be signed by the person obtaining consent (POC) and the witness; 
and a Short Form in the language of the person providing consent will be signed by the 
subject and the witness.   
The participant will be provided with a copy of the signed and dated consent document prior to 
any study procedure.  The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time. 
The informed consent form (ICF) and consent process must comply with the US regulations 
(§ 21 CFR Part 50) as well as country specific national regulations and/or local laws.  The 
Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail.  This process must be documented in the subject’s source record.   
3.4 Eligibility Verification Procedures 
To verify patient eligibility, the following documents should be completed by the study team and 
faxed or e-mailed (secure) to the Stanford Cancer Institute (SCI) Study Coordinator:  
• 
Copy of required laboratory tests/procedures 
• 
Signed patient consent form 
• 
HIPAA authorization form 
• 
Eligibility screening worksheet 
The SCI Study Coordinator will have the Principal Investigator review the eligibility packet and if 
eligible, will: 
• 
Assign a patient study number 
• 
Fax or e-mail the patient study number to the participating site 
3.5 Study Timeline 
3.5.1 Completion of Study 
Participants will complete this study if he or she has not been lost to follow up and has not 
withdrawn consent prior to the end of study or has died before the end of the study. 


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The study will be complete when the last subject being treated has completed the last dose of 
study medications and up to 1 month of follow up to complete the final assessment.  
3.5.2 Study Follow-up Post-completion 
This study will not follow patients after completion of therapy. Upon completion of ibrutinib + 
venetoclax combination treatment at Week 117, participants will have completed the trial and 
may transition off-study to receive commercial ibrutinib at the discretion of the investigator. 


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4 TREATMENT PLAN 
4.1 Study Drug Administration  
Study participants will start treatment in the outpatient setting with ibrutinib 420 mg PO daily on 
Week 1 Day 1 of treatment.  After completion of 8 weeks of treatment with ibrutinib, they will 
subsequently begin co-administration of venetoclax once daily with the daily dose increased 
every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).  The dosing 
schedule is depicted in Table 1 in Section 1.3.1. 
Venetoclax will be administered orally once daily continuously from the time of treatment 
initiation with venetoclax.  Each dose should be taken with approximately 240 mL of water 
(8 ounces) within 30 minutes after the completion of breakfast or the subject’s first meal of the 
day with an effort to take venetoclax at the same time of day daily.  Venetoclax should be taken 
at the same time as ibrutinib. 
Ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily.  The capsules are 
to be taken around the same time each day with 8 ounces (approximately 240 mL) of water.  
The capsules should be swallowed intact and subjects should not attempt to open capsules or 
dissolve them in water.  The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville 
oranges should be avoided for the duration of the study (see Appendix C). 
If a dose of either study drug is not taken at the scheduled time, it can be taken as soon as 
possible on the same day with a return to the normal schedule the following day.  The subject 
should not take extra capsules to make up the missed dose. 
4.2 Toxicity Management 
Adverse event management and dose modifications are outlined in Section 6 
Dose Modifications.   
4.3 General Concomitant Medication and Supportive Care Guidelines 
4.3.1 Prophylaxis and Management of Tumor Lysis Syndrome 
There is a potential for tumor lysis syndrome (TLS) in subjects affected by hematologic 
malignancies, especially in those with bulky disease; elevated pretreatment lactate 
dehydrogenase (LDH) levels; elevated leukocyte count; renal dysfunction; and dehydration. 
In response to the events of TLS reported in the Phase 1 studies in subjects with diagnosis of 
relapsed or refractory CLL treated with venetoclax monotherapy or in combination with an 
anti-CD20 antibody, an extensive review of the safety data was performed across all CLL trials 
in January of 2013.  These clinical data suggest that size of baseline lymph nodes is a risk 
factor for TLS, with larger lymph nodes resulting in increased risk.  In addition, creatinine 
clearance of ≤ 80 mL/min at Screening was identified as a risk factor for TLS.  Data analyses 
have resulted in development of three risk categories, listed below.   
• 
Risk category for an individual patient is determined upon study entry.   


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o A detailed description of risk factors for developing tumor lysis following 
treatment with venetoclax is available in the current Investigator's Brochure.  
Refer to Appendix F for laboratory and clinical definitions of TLS. 
• 
TLS Prophylaxis and Monitoring Checklist will be completed throughout the lead-in 
period to ensure proper TLS prophylaxis measures. 
o The section below describes the management of patients throughout dosing 
based on their risk factors for developing TLS identified upon study entry.   
For tumor lysis syndrome prophylaxis, all subjects enrolling into the study will be classified into 
3 risk categories based on the tumor burden prior to venetoclax administration.  The tumor 
burden assessed by the nodal disease and absolute lymphocyte count at Screening will be used 
to define each category as described below. 
Table 2.  TLS Risk Categories 
Risk Categories for 
Developing TLS 
TLS Risk Category Criteria 
Low 
All measurable lymph nodes with the largest diameter < 5 cm  
AND ALC < 25 × 109/L 
Medium 
Any measurable lymph node with the largest diameter ≥ 5 cm and < 10 cm,  
OR ALC ≥ 25 × 109/L 
High 
Any measurable lymph node with the largest diameter ≥ 10 cm, 
OR ALC ≥ 25 × 109/L AND any measurable lymph node with the 
largest diameter ≥ 5 cm but < 10 cm 
4.3.1.1 First Dose of Venetoclax at 20 mg and at 50 mg 
Tumor lysis syndrome prophylaxis must be initiated in all subjects irrespective of their TLS risk 
category prior to the first dose of venetoclax at 20 mg and at 50 mg.  Tumor lysis syndrome 
prophylaxis includes: 
• 
An oral agent to reduce the uric acid level (eg, allopurinol) to be initiated at least 
72 hours prior to dosing.  Treatment may need to be continued for up to 5 weeks based 
on the ongoing risk of TLS development.  Subjects allergic to allopurinol must use 
another uric acid reducer. 
• 
Oral hydration consisting of fluid intake of 1.5 to 2 L per day starting at least 48 hours 
prior to the start of treatment for all subjects prior to first dose and at all subsequent dose 
increment steps and continued for at least 24 hours after dosing and all the chemistries 
laboratory values remain within ULN. 
• 
Serum chemistry and hematology laboratory samples must be drawn anytime within 
72 hours prior to first dose and electrolyte values should be reviewed and not 
demonstrate any clinically significant abnormalities prior to the first dose of venetoclax to 
keep the treatment on schedule.  If clinically significant laboratory abnormalities are 
observed in this baseline laboratory assessment, first dose of venetoclax must be 
delayed until resolution and initiate management per Appendix E, (Recommendations for 
Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 


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Syndrome [TLS]), and if needed, patient should receive additional prophylactic treatment 
prior to the initiation dosing. 
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS risk 
category as follows: 
I.  Low Risk Category 
Subjects in Low Risk category can begin venetoclax lead-in period in the outpatient setting if 
there is no indication to hospitalize. 
• 
For subjects who are unable to maintain adequate oral hydration, IV hydration of 1.5 to 
2 L is recommended in the outpatient setting on D1 of 20 mg and 50 mg dose to assure 
this full amount of hydration is achieved.  For subjects in patients for whom volume 
overload is considered a significant risk, hospitalization should be considered. 
• 
Chemistry and hematology laboratory tests are to be performed within 72 hours before 
the first dose of venetoclax.  The investigator must review these laboratory values.  The 
investigator's decision to proceed with venetoclax treatment initiation may be based on 
these laboratory values.   
• 
Chemistry laboratory tests must be performed STAT at 0 hour (pre-dose), 8, and 
24* hours post-dose after the first dose of venetoclax at 20 mg and at 50 mg.  Pre-dose 
laboratory values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration.  Results from pre-dose 
laboratory values are not required to be available prior to initiating venetoclax treatment.  
Subjects must remain at the hospital, or clinic, until the investigator has reviewed the 
8-hour laboratory values. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose chemistry laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
• 
If any significant laboratory changes are observed within the first 24 hours after initiation 
of dosing, see Appendix E (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]) for procedures to follow.  
These laboratory values must be reviewed in real time by the investigator. 
• 
Additional laboratory assessments may be performed per investigator discretion. 
• 
Hematology laboratory tests must be performed 24* hours post-dose after the first dose 
of venetoclax at 20 mg and at 50 mg. 
* All 24 hour post-dose laboratory assessments may be taken within a 2-hour window if 
necessary. 
II.  Medium Risk Category 
Subjects in Medium Risk category who have creatinine clearance ≥ 80 mL/min will receive their 
initial doses of venetoclax at 20 and 50 mg as outpatients. 
Subjects in the Medium Risk category who have creatinine clearance of < 80 mL/min and/or 
higher tumor burden may be handled as high-risk subjects per investigator discretion for the first 
dose of venetoclax at 20 mg and 50 mg (Refer to section for high-risk subjects below). 


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• 
Subjects will receive IV hydration of 1.5 to 2 L in the outpatient setting on D1 of 20 mg 
and 50 mg dose in addition to oral hydration as stated above.  For subjects in whom 
volume overload is considered a significant risk, hospitalization should be considered. 
• 
Chemistry and hematology laboratory tests are to be performed within 72 hours before 
the first dose of venetoclax.  The investigator must review these laboratory values.  The 
investigator's decision to proceed with venetoclax treatment initiation may be based on 
these laboratory values. 
• 
Chemistry laboratory tests must be performed STAT at 0 hour (pre-dose), 8, and 
24* hours after the first dose of venetoclax at 20 mg and at 50 mg.  Pre-dose laboratory 
values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration. 
• 
Results from pre-dose laboratory values are not required to be available prior to initiating 
venetoclax treatment.  Subjects must remain at the hospital, or clinic, until the 
investigator has reviewed the 8-hour laboratory values. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose chemistry laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
• 
If any significant laboratory changes are observed within the first 24 hours after initiation 
of dosing, see Appendix E, (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]) for procedures to follow. 
• 
Additional laboratory assessments may be performed per investigator discretion. 
• 
Hematology laboratory tests must be performed 24* hours post-dose after the first dose 
of venetoclax at 20 mg and at 50 mg. 
* All 24 hour post-dose laboratory assessments may be taken within a 2-hour window if 
necessary. 
III.  High-risk Category 
Hospitalization and monitoring starting the night before administration of the first dose of 20 mg 
and 50 mg of venetoclax and continued till at least 24 hours post-dose chemistry laboratory 
values are reviewed by the investigator. 
• 
Chemistry and hematology laboratory tests to be performed upon admission the night 
before first dose of venetoclax.  The investigator's decision to proceed with venetoclax 
treatment initiation will be based on these laboratory values. 
• 
Nephrology (or other acute dialysis service) consultation should be considered upon 
admission per institutional standards at investigators' discretion to ensure emergency 
dialysis is available and the appropriate staff is aware and prepared to handle any 
necessary intervention for TLS.  Telemetry should also be considered.  IV hydration 
must be started the night before dosing and continued for 24 hours after dose. 
• 
Rasburicase must be administered per regional standards or institutional guidelines for 
subjects with elevated uric acid level at baseline (> ULN) or rapidly rising uric acid level 
as prophylaxis prior to the initial dose of venetoclax.).  For patients with a 


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contraindication to rasburicase (ie, glucose-6-phosphate dehydrogenase [G6PD] 
deficiency), the TLS risk-mitigation plan must be reviewed with the Principal Investigator. 
• 
Chemistry laboratory tests must be performed STAT at 0 (pre-dose, within 4 hours 
before venetoclax administration), 4, 8, 12 and 24* hours after the first dose of 
venetoclax at 20 mg and 50 mg.  These laboratory values must be reviewed in real time 
by the investigator.  Pre-dose laboratory values will be collected and used as baseline to 
assess potential electrolyte abnormalities occurring post venetoclax administration. 
• 
Prophylactic reductions for potassium, inorganic phosphorus and/or uric acid above of 
normal range prior to dosing are recommended. 
• 
If any significant laboratory changes are observed within the first 24 hours after initiation 
of dosing, see Appendix E, (Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]), for additional laboratory 
assessments and management guidelines. 
• 
Hematology laboratory tests performed pre-dose (within 4 hours before venetoclax 
administration) and 24* hours post-dose after the first dose of venetoclax at 20 mg and 
50 mg. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
* All 24 hour laboratory assessments may be taken within 2-hour window if necessary. 
For all dose escalations, laboratory values for subject management must be reviewed prior to 
the subject’s next dose.  Based upon the laboratory values, the subject may continue dosing, 
may need to hold dose until resolution of laboratory abnormalities, may require additional 
post-dose laboratory checks or may require hospitalization for further monitoring.  Please see 
Appendix E, (Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS]) for appropriate procedures to follow. 
4.3.1.2  Dose Escalation of Venetoclax to 100 mg, 200 mg, and 400 mg 
All subjects, irrespective of their risk category, must receive the following TLS prophylaxis 
measures prior to subsequent dose increases of venetoclax: 
• 
Continue administration of an oral uric acid reducer as indicated above. 
• 
Oral hydration consisting of fluid intake of approximately 1.5 to 2 L/day starting at least 
48 hours days prior to each dose increment.  IV hydration is encouraged at subsequent 
dose increases for subjects who are unable to maintain such oral hydration.  IV 
hydration will be in the outpatient setting on the day of dose increment.  For patients in 
whom volume overload is considered a significant risk, hospitalization should be 
considered. 
• 
Chemistry and Hematology laboratory tests must be performed within 72 hours and the 
investigator must review results prior to each dose escalation.  For subjects 
demonstrating any clinically significant laboratory abnormalities, additional prophylactic 
treatment should be administered prior to dosing (see Appendix E, Recommendations 


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for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome [TLS]). 
Additional TLS prophylaxis and monitoring procedures are tailored to the individual TLS risk 
category as follows: 
I.  Low Risk Category 
Subjects in Low Risk category will receive the subsequent dose escalations (100, 200 and 
400 mg) as outpatients. 
• 
Chemistry and Hematology laboratory tests will be performed at STAT at 0 hour 
(pre-dose), 8 and 24 hours after dose administration.  These laboratory values must be 
reviewed in real time by the investigator.  Pre-dose laboratory values will be collected 
and used as baseline to assess potential electrolyte abnormalities occurring post 
venetoclax administration. 
• 
Subjects must remain at the hospital, or clinic, until the investigator has reviewed the 
8-hour laboratory values. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose chemistry laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
• 
Additional laboratory assessments may be performed per investigator discretion. 
II.  Medium Risk Category 
Subjects in Medium Risk category may receive their subsequent dose escalations in the 
outpatient setting.  Subjects with creatinine clearance < 80 mL/min and/or higher tumor burden 
may be hospitalized per investigator's discretion. 
For subjects who receive their subsequent dose escalations in the outpatient setting, 
• 
Chemistry and Hematology laboratory tests will be performed 0 (pre-dose), 8 and 
24 hours post dose administration.  These laboratory values must be reviewed in real 
time by the investigator.  Pre-dose laboratory values will be collected and used as 
baseline to assess potential electrolyte abnormalities occurring post venetoclax 
administration. 
• 
Subjects must remain at the hospital, or clinic, until the investigator has reviewed the 
8-hour laboratory values. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose chemistry laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
• 
Additional laboratory assessments may be performed per investigator discretion. 
For subjects who are hospitalized during subsequent dose escalations,  
• 
Chemistry and Hematology laboratory tests will be performed upon admission.  
Chemistry tests will be performed STAT at 0 hour (pre-dose), 4, 8, 12 and 24 hours post 


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dose.  These laboratory values must be reviewed in real time by the investigator.  
Pre-dose laboratory values will be collected and used as baseline to assess potential 
electrolyte abnormalities occurring post venetoclax administration. 
• 
IV hydration should be started with a target of approximately 2 L per day or as clinically 
appropriate for patients who are hospitalized. 
• 
Hematology laboratory tests will be performed 24 hours post-dose. 
• 
The 24-hour post-dose laboratory results must be reviewed by the investigator prior to 
the subject leaving the hospital or receiving any additional doses of the study drug. 
III.  High-risk Category 
High-risk subjects may receive the subsequent dose increases as outpatients.  Subjects with 
creatinine clearance < 80 mL/min may be hospitalized per investigator discretion.  
Hospitalization will begin the evening prior to the dose of venetoclax and continue for 24 hours 
after dose administration. 
For subjects who are hospitalized during subsequent dose escalations,  
• 
Chemistry and Hematology laboratory tests will be performed upon admission.  
Chemistry tests will be performed STAT at 0 hour (pre-dose); 4; 8; 12; and 24 hours 
post-dose.  These laboratory values must be reviewed in real time by the investigator.  
Pre-dose laboratory values will be collected and used as baseline to assess potential 
electrolyte abnormalities occurring post venetoclax administration. 
• 
IV hydration should be started with a target of approximately 2 L per day or as clinically 
appropriate for patients who are hospitalized. 
• 
Hematology laboratory tests will be performed 24 hours post-dose. 
• 
The 24-hour post-dose laboratory results must be reviewed by the investigator prior to 
the subject leaving the hospital or receiving any additional doses of the study drug. 
For subjects who are not hospitalized,  
• 
Chemistry and Hematology laboratory tests will be performed pre-dose (within 72 hours), 
and at 8 and 24 hours post dose administration.  These laboratory values must be 
reviewed in real time by the investigator.  Pre-dose laboratory values will be collected 
and used as baseline to assess potential electrolyte abnormalities occurring post 
venetoclax administration. 
• 
Intravenous hydration (1.5 to 2 L) will be given in the outpatient setting with a target of 
approximately 2 L per day or as clinically appropriate. 
• 
Subjects must remain at the hospital, or clinic, until the investigator has reviewed the 
8-hour laboratory values. 
• 
Day 2 dose should not be administered until the investigator reviews the 24 hours 
post-dose chemistry laboratory values. 
• 
If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same 
dose will be continued until Day 7 in the outpatient setting. 
• 
Additional laboratory assessments may be performed per investigator discretion. 


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Any subject, who at any dose level develops clinically significant electrolyte abnormalities must 
have their subsequent venetoclax dose held until the electrolyte abnormalities resolve.  
Electrolyte changes should undergo aggressive management and further monitoring as per 
Appendix E, (Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome [TLS]).  The subject may resume dosing based on a risk 
assessment (including tumor burden status), as determined by the investigator.  All subjects 
must receive the intended dose for at least 7 days before increasing to the next higher dose.  
4.3.2 Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc) 
are permitted.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 
growth factors (erythropoietin) is permitted per institutional policy and in accordance with the 
ASCO guidelines.27 Transfusions may be given in accordance with institutional policy.  
Short courses (≤ 14 days) of steroid treatment for non-cancer related medical reasons (eg, joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that 
do not exceed 100 mg per day of prednisone or equivalent are permitted.  
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.  
Treatment for autoimmune cytopenias are permitted for < 14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent.  
4.3.3 Concomitant Medications to be Used with Caution 
4.3.3.1  CYP3A Inhibitors / Inducers 
Ibrutinib is metabolized primarily by CYP3A4.  Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure, and therefore strong 
CYP3A inhibitors should be avoided. 


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Table .  Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A Inhibitors 
Patient 
Population 
Co-administered Drug 
Recommended Ibrutinib Dose 
for the Duration of the Inhibitor 
Usea 
B-Cell 
Malignancies 
Mild CYP3A inhibitors 
420 mg or 560 mg once daily per 
indication. No dose adjustment 
required. 
Moderate CYP3A inhibitors 
280 mg once daily. 
Voriconazole 200 mg twice 
daily 
Posaconazole suspension 
100mg once daily, 100 mg 
twice daily, or 200 mg twice 
daily  
140 mg once daily. 
Other strong CYP3A inhibitors 
Posaconazole at higher 
dosesb  
Avoid concomitant use and 
consider alternative with less 
CYP3A inhibitory potential. 
If these inhibitors will be used 
short-term (such as anti-infectives 
for seven days or less), interrupt 
ibrutinib. 
If the benefit outweighs the risk, 
and long-term dosing with a 
CYP3A inhibitor is required (more 
than seven days), reduce ibrutinib 
dose to 140 mg once daily for the 
duration of the inhibitor use. 
a. 
 Monitor for adverse reactions to IMBRUVICA and interrupt or modify dose as recommended (see Dosage and 
Administration). 
b. 
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, 
posaconazole IV injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily). 
• 
No dose adjustment is required in combination with mild inhibitors.  
• 
Avoid grapefruit and Seville oranges during ibrutinib treatment as these contain 
moderate inhibitors of CYP3A.  
Avoid concomitant use of systemic strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St John’s Wort).  Consider alternative agents with less CYP3A induction.  
A list of common CYP3A inhibitors and inducers is provided in Appendix C.  For further 
information, please refer to the current version of the ibrutinib Investigator Brochure and the 
examples of inhibitors, inducers, and substrates found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This website is continually revised and 
should be checked frequently for updates.  


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4.3.3.2  Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib or 
Venetoclax 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates.  However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose.  There is no clinical data available; therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib. 
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak 
OATP1B1 inhibitor in vitro.  To avoid a potential interaction in the gastrointestinal tract, 
co-administration of narrow therapeutic index P-gp substrates such as digoxin with venetoclax 
should be avoided.  If a narrow therapeutic index P-gp substrate must be used, it should be 
taken at least 6 hours before venetoclax. 
4.3.3.3  QT-Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered. 
4.3.3.4  Antiplatelet Agents and Anticoagulants 
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet 
function.  Supplements such as fish oil and vitamin E preparations should be avoided during 
treatment with ibrutinib.  In an in vitro platelet function study, inhibitory effects of ibrutinib on 
collagen-induced platelet aggregation were observed.  Bleeding events of any grade, including 
bruising and petechiae, occurred in subjects treated with ibrutinib.  Subjects with congenital 
bleeding diathesis have not been studied.  Ibrutinib should be held at least 3 to 7 days pre- and 
post-surgery, depending upon the type of surgery and the risk of bleeding.  For guidance on 
ibrutinib and the use of anticoagulants during procedures/surgeries, see Section 4.3.5.  
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
should be monitored closely for signs and symptoms of bleeding and the risks and benefits of 
continuing ibrutinib treatment should be considered.  
4.3.4 Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying disease are prohibited.  Corticosteroids for 
the treatment of non-cancer related reasons for longer than 14 days and/or at doses > 100 mg 
of prednisone or its equivalent are prohibited. 
Use of strong CYP3A inhibitors is contraindicated during venetoclax initiation and dose 
ramp-up.  Subjects may not consume grapefruit or grapefruit products, Seville oranges 
(including marmalade containing Seville oranges) or star fruit within the 3-day period prior to the 
first venetoclax administration and until the last day of treatment is completed due to possible 
CYP3A mediated metabolic interaction.  
Erythropoietic growth factors (eg, erythropoietin) and neutrophil growth factors (eg, filgrastim 
and peg-filgrastim) may be administered per standard practice.  


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4.3.5 Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:  
4.3.5.1  Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should not 
be restarted for at least 3 days after the procedure.  For bone marrow biopsies that are 
performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures.  
4.3.5.2  Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should 
be held at least 7 days prior to the intervention (except for emergency procedures) and should 
be held at least 7 days after the procedure and restarted at the discretion of the investigator 
when the surgical site is reasonably healed without serosanguinous drainage or the need for 
drainage tubes. 
4.4 Duration of Therapy 
Upon completion of ibrutinib + venetoclax combination treatment at Week 117, participants will 
have completed the trial and may transition off-study to receive commercial ibrutinib at the 
discretion of the investigator. In the absence of treatment delays due to adverse event(s), 
combination treatment may continue through Week 117, or until one of the following criteria 
applies: 
• 
Disease progression or relapse 
• 
Unacceptable drug-related adverse event(s)  
• 
Patient decides to withdraw from the study  
• Investigator decision that discontinuation is in the best interests of the patient 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Pregnancy 
4.5 Duration of Follow-up 
Patients will be followed until end of treatment; withdrawal of consent; or death, whichever 
occurs first.  Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.   


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4.6 Criteria for Removal from Study 
4.6.1 Removal from Study Treatment 
Patients will be removed from study treatment when any of the criteria listed in Section 4.4 
applies.  The reason for treatment termination and the date the patient was removed must be 
documented in the Case Report Form (CRF).   
4.6.2 Removal from Study 
Withdrawal from the study including termination of all follow-up will occur if: 
• 
The subject is lost to follow-up following reasonable effort from study staff to contact the 
subject 
• 
The subject withdraws consent for follow-up observation 
• 
The subject dies 
• 
The study is terminated 
Documentation of the reason for withdrawal and withdrawal of full (treatment and all further 
contact) or partial (withdrawal of consent to treatment but not to follow-up visits) consent will be 
must be documented in the Case Report Form (CRF). 
4.7 Study Risk Information 
Risks of the study drugs are described within the venetoclax and ibrutinib 
Investigator’s Brochures and FDA-approved labeling for each.  
4.8 Risk Mitigation 
Risk mitigation will include safety assessments during clinic visits at weeks 1; 5; and 9 (ibrutinib 
treatment only); then weekly for 4 weeks during the venetoclax dose ramp-up; then, during the 
venetoclax + ibrutinib stage, every 4 weeks through Week 30; then at Week 38, Week 62, and 
every 12 weeks thereafter.  Safety assessments will include hematology; serum chemistry; 
physical exam with vital signs, weight, and ECOG performance status; and subject interviews 
for adverse events and concomitant medications. 


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5 STUDY DRUG INFORMATION 
5.1 Study Drug Venetoclax 
5.1.1 Name 
Study drug venetoclax is approved by the US Food and Drug Administration (FDA) as 
Venclexta.  The approved uses of venetoclax are described at Section 2.2.1 Venetoclax.  
5.1.2 Formulation 
The venetoclax tablets will be packaged in high-density polyethylene (HDPE) plastic bottles or 
blister packs to accommodate the study design.  Each container will be labeled per local 
regulatory requirements.  Tablets are formulated with 10 mg, 50 mg and 100 mg doses. 
Blister Packs will contain study drug for one week plus one extra day.  Subjects will be 
instructed to take the extra day's dose (noted with an "X" on the Blister Pack) only if directed by 
the investigator. 
5.1.3 Study Cohorts / Arms / Groups  
This is a single-arm, open label study.  All participants will receive ibrutinib for 8 weeks, then 
begin dose-escalation with venetoclax as described elsewhere in the protocol. 
5.1.4 Mechanism of Action 
Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that binds 
with > 500-fold higher affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to other Bcl-2 family 
proteins Bcl-XL (Ki – 48 nM) and Bcl-w (Ki – 245 nM).  Overexpression of anti-apoptotic Bcl-2 
family proteins is associated with increased resistance to chemotherapy, and antagonism of the 
action of these proteins might enhance response to such therapy and overcome resistance.  
Anti-apoptotic Bcl-2 family members are associated with tumor initiation, disease progression, 
and drug resistance, making them compelling targets for antitumor therapy. 
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma and 
leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs), 
diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias (AMLs).  Venetoclax 
was especially potent against cell lines expressing high levels of Bcl-2.  Leukemia and 
lymphoma cell lines bearing the t(14;18) translocation were significantly more sensitive to 
venetoclax than non-mutated cell lines. 
5.1.5 Non-clinical and Clinical Pharmacokinetics  
In vitro studies have shown that venetoclax is metabolized primarily by CYP3A4; thus, 
co-administration of venetoclax with drugs that inhibit CYP3A4 (such as ketoconazole) is 
predicted to cause a significant increase in the exposure of venetoclax and will be undertaken 
with caution.  In a phase-I dose-escalation trial in patients with relapsed/refractory NHL, after a 
single dose administration with a high-fat meal, venetoclax reached Cmax at approximately 
7 hours with a terminal half-life of about 15 hours.  Food increased venetoclax exposure by 
approximately 3-fold.  


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5.1.6 Summaries of Non-Clinical Pharmacology and Toxicology Studies  
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines derived 
from acute lymphoblastic leukemia (ALL) and Non-Hodgkin's Lymphoma (NHL).  The drug was 
also active in a model of disseminated ALL. 
5.1.6.1  Non-Clinical Toxicology Studies 
The nonclinical toxicology of venetoclax has been evaluated in repeated-dose studies in mice 
and dogs with up to 4 weeks of once daily oral dosing (and with 4-week recovery periods) and in 
dogs with 2 weeks of dosing (18-week recovery period); safety pharmacology studies 
(cardiovascular, neurofunctional, and pulmonary); and in genetic toxicity tests (Ames and in vitro 
chromosome aberrations assays).   
The primary toxicities associated with venetoclax administration included effects on the 
hematologic system (lymphocytes and red blood cell parameters) in mice and dogs and on the 
male dog reproductive system.  There was no evidence of genotoxicity of venetoclax.  
A severely toxic dose (STD10) was not identified in mice up to and including the top dose of 
600 mg/kg/day (overall mean AUC0-24 = 91.5 μg•hr/mL and Cmax = 7.2 μg/mL).  In dogs, the 
highest non-severely toxic dose (HNSTD) was 150 mg/kg/day, but due to overlapping 
exposures between the mid and high doses, the HNSTD was defined as the mid dose of 
50 mg/kg/day (overall mean AUC0-24 = 472 μg•hr/mL and Cmax = 27.4 μg/mL). 
Venetoclax causes decreases in circulating lymphocytes and lymphocytes in lymphoid tissue.  
After 4 weeks of dosing, the lymphocyte effects were reversible or partially reversible in the 
mouse but generally were less reversible in the dog at the end of a 4-week recovery period.  
However, in a 2-week dog study focused on lymphocyte recovery over an extended (18-week) 
period, reversibility of lymphocyte effects was demonstrated.  Immunophenotyping was used to 
assess changes in peripheral blood lymphocyte subsets (ie, mature T-cells, helper T-cells, 
cytotoxic T-cells, and mature B-cells).  At the end of the 18-week recovery period, both total and 
lymphocyte subset counts returned to within range of baseline and control values, and all effects 
on lymphoid tissue reversed.  The venetoclax–related decreases in lymphocytes in blood and 
lymphoid tissues are considered pharmacologically mediated and non-adverse. 
Additional hematological effects of venetoclax treatment included reversible decreases in red 
blood cell parameters (primarily, hematocrit and hemoglobin concentration) in mice and dogs.  
The decreases in red cell parameters were adverse only at the high dose levels in the 4-week 
studies (ie, at 600 mg/kg/day in mice and at 150 mg/kg/day in dogs, but all red cell parameters 
were reversible at the end of a 4-week recovery period.  Effects on both lymphocytes and red 
cell mass are readily monitored in subjects. 
Dogs at the high dose of 150 mg/kg/day in the 4-week study had clinical signs of itching and 
swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  Most of 
the animals (8 of 10 dogs) were affected.  The clinical signs were mild to moderate in severity, 
transient and sporadic in occurrence, and were absent during the recovery period.  The swelling 
reactions were observed after the first dose in 3 dogs, and therefore not consistent with 
drug-induced immediate (IgE-mediated, Type I) hypersensitivity; however, other 
immune-mediated mechanisms could be involved.  Although the basis for the swelling reactions 
was not established, there were no signs of anaphylaxis.  Any occurrences of swelling reactions 
in patients can be monitored and treated. 


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In an ongoing 9-month chronic toxicity study of dogs with venetoclax, hypopigmented (white) 
facial hair was observed after approximately 3 months of dosing (ongoing study Abbvie 
R&D/12/384).  The finding was limited to the mid and high doses (6 and 20 mg/kg/day), and was 
observed in both males and females.  Evidence from Bcl-2 knockout mouse (bcl-2-/-) studies 
indicates that hair hypopigmentation is consistent with the pharmacological effect of Bcl-2 
functional loss, and occurs due to loss of hair follicle melanocytes dependent on Bcl-2 for 
survival.28 A dedicated physical examination of the skin and extensive ophthalmic examinations 
determined that pigmentation of the skin and in the eye (particularly in the iris and fundus) 
appears unaffected.  The potential for development of white (hypopigmented) hair in humans is 
unknown. 
Venetoclax was tested in a battery of safety pharmacology assays and produced no effects in 
central nervous system/neurobehavioral, or respiratory studies in mice at oral doses up to 
600 mg/kg.  In an anesthetized dog cardiovascular model given intravenous doses of 
venetoclax, mild reductions in myocardial contractility (maximum rate of rise of left ventricular 
pressure [dP/dtmax]:  –6% to –13%) and cardiac output (–11% to –19%) were observed at 
plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, respectively.  However, no effect on 
blood pressure, heart rate, or electrocardiogram (ECG) parameters were observed relative to 
baseline or controls in either the anesthetized dog study or in the conscious dog cardiovascular 
study using telemeterized animals at maximum drug concentrations of 46 μg/mL and 16 μg/mL, 
respectively. 
Nonclinical safety pharmacology and toxicology evaluations of venetoclax, as well as nonclinical 
and human studies of related anti-apoptotic Bcl-2 family protein inhibitors, suggest potential 
mechanism-based toxicities may include lymphopenia and neutropenia,29 signs of tumor lysis, 
reduction in red cell mass, decreased spermatogenesis, skin swelling, and hair 
hypopigmentation.  Thrombocytopenia has not been observed in toxicology studies in mice and 
dogs.  These findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL sparing) 
inhibitor.  Consequently, thrombocytopenia is not expected to be a dose-limiting toxicity (DLT) 
clinically. 
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be found 
in the current version of the Investigator's Brochure. 
5.1.6.2  Carcinogenesis, Mutagenesis, Impairment of Fertility 
Male dog reproductive effects consisted of markedly reduced numbers of spermatogonia in the 
testes at all venetoclax dose levels after 4 weeks of dosing, with progression to severe 
decreases in the numbers of all germ cells in testes during the 4-week recovery period.  Male 
mice did not have testicular changes associated with venetoclax administration.  The 
translatability of the testicular findings in dogs to humans is unknown, but this change may be 
related to venetoclax pharmacology, as one or more members of the Bcl-2 family of proteins 
play a role in spermatogenesis.30-32 In view of the potential treatment benefits of venetoclax, this 
finding is anticipated not to impact the treatment of subjects with advanced hematologic 
malignancies.  
5.1.7 Summaries of Clinical Studies  
As of 28 November 2015, data available in the AbbVie and Genentech/Roche clinical databases 
include a total of 1662 subjects who have been exposed to at least 1 dose of venetoclax in the 
oncology and immunology development programs.  A total of 1498 oncology subjects have data 


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available in AbbVie and Genentech/Roche studies as of 28 November 2015.  Of these 1498, 
935 subjects had CLL/small lymphocytic leukemia (SLL), 346 subjects had NHL, 115 subjects 
had MM, 102 had AML.  An additional 66 subjects were healthy volunteers.  A total of 564 
oncology subjects received the drug as monotherapy, 933 received the drug in combination with 
other therapies, and 1 subject received venetoclax as a single dose in a DDI study and did not 
re-enroll into a subsequent monotherapy study.  Additionally, 98 subjects were exposed to at 
least 1 dose of venetoclax in the AbbVie immunology study, Study M13-093, as of 
28 November 2015. 
Preliminary efficacy results are available for subjects with CLL/SLL, NHL, MM, and AML as 
listed below.  Preliminary data indicate that venetoclax continues to show promising efficacy in 
oncology subject populations. 
• 
In venetoclax monotherapy Study M12-175 (as of 25 August 2015), the overall remission 
rate (ORR; investigator-assessed) in Arm A (R/R CLL/SLL) in the Dose-Escalation and 
Safety Expansion Cohorts was 79%.33 The ORR (investigator-assessed) in Arm B (R/R 
NHL) was 38% for FL subjects and 18% for DLBCL subjects (Dose-Escalation and 
Safety Expansion Cohorts). 
• 
In venetoclax monotherapy Study M13-982 (as of 30 April 2015), the ORR 
(IRC-assessed) for R/R CLL subjects was 74%. 
• 
In venetoclax monotherapy Study M14-032 (as of 25 August 2015), the ORR for R/R 
CLL subjects in Arm A (ibrutinib-resistant) was 42% and in Arm B (idelalisib-resistant) 
was 29%. 
• 
In Study M13-365 (as of 28 October 2015) the ORR for R/R CLL/SLL subjects treated 
with venetoclax + rituximab was 86%. 
• 
In Study M12-630 (as of 17 September 2015), the ORR for R/R NHL subjects treated 
with venetoclax + BR was 67%. 
• 
In Study M13-367 (as of 17 September 2015), the ORR for R/R MM subjects treated 
with venetoclax was 24% in t(11;14)-positive subjects and 4% in t(11;14)-negative 
subjects. 
• 
In Study M12-901 (as of 17 September 2015), the ORR for R/R MM subjects treated 
with venetoclax and bortezomib/dexamethasone was 100% in bortezomib-naïve 
subjects, 71% in bortezomib-sensitive subjects, and 17% in bortezomib-refractory 
subjects. 
• 
In Study M14-212 (as of 07 October 2014), the ORR for AML subjects treated with 
venetoclax monotherapy was 19%. 
• 
In Study M14-358 (as of 19 September 2015), the ORR for AML subjects was 77%. 
• 
In Study M14-387 (as of 28 November 2015), the ORR for AML subjects was 44%. 
For the most comprehensive clinical information regarding venetoclax, refer to the current 
version of the Investigator's Brochure. 
5.1.8 Major Route of Elimination  
Following oral administration in mouse, rat, dog, and human, venetoclax and its metabolites 
were cleared primarily via biliary excretion and fecal elimination, with minimal renal clearance.  


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5.1.9 Safety Profile  
The preliminary clinical data of venetoclax monotherapy in subjects with CLL/SLL, MCL and 
NHL have shown a favorable benefit to risk ratio in Study M12-175.  As of 3 February 2014, a 
total of 153 subjects have been enrolled in Study M12-175, and had data available for the study 
(95 in Arm A and 58 in Arm B).  The most common adverse events in Arm A (CLL/SLL subjects) 
were diarrhea (38.9%), neutropenia (37.9%), nausea (34.7%), upper respiratory tract 
infection (30.5%), fatigue (27.4%), and cough (20.0%).  The most common adverse events in 
Arm B (NHL subjects) were nausea (32.8%), diarrhea (24.1%), and fatigue and upper 
respiratory tract infection (20.7% each). 
The most common adverse events reported for all subjects in the study were nausea (34.0%), 
diarrhea (33.3%), neutropenia (29.4%), upper respiratory tract infection (26.8%), and 
fatigue (24.8%).  The most common events Grade 3 or above reported in Arm A (CLL/SLL 
subjects) were neutropenia (34.7%) and anemia (10.5%), and in Arm B (NHL subjects) were 
anemia (15.5%) and neutropenia (10.3%).  Overall, Grade 3 or 4 adverse events reported in 
> 5% of patients were anemia, neutropenia, febrile neutropenia, thrombocytopenia, 
hyperglycemia, and tumor lysis syndrome (TLS).  These adverse events were mostly consistent 
with complications commonly observed in heavily pretreated patients with R/R CLL/SLL.  Febrile 
neutropenia was the most common serious adverse event observed with venetoclax 
monotherapy treatment (7.0%); all events resolved on supportive treatment, and none resulted 
in discontinuation from the study.  The only other serious adverse event reported in more than 
2 subjects was TLS (11.0%) for venetoclax as a single agent.  A comprehensive safety review 
identified risk factors for developing TLS from Study M12-175 as well as Study M13-365 
(venetoclax in combination with rituximab), resulting in implementation of a modified 
dose-escalation regimen and revised TLS risk management procedures in ongoing studies in 
various hematologic malignancies. 
5.1.9.1  Tumor Lysis Syndrome (TLS) 
TLS is considered an important identified risk and is predominantly seen in the CLL population 
with high tumor burden.  Primary CLL cells are essentially dependent on Bcl-2 for survival and 
are exquisitely sensitive to the Bcl-2 specific inhibitor venetoclax, and the on-target 
pharmacological effect can cause rapid reduction in size of tumor (debulk) and may pose a risk 
of TLS. 
The management of the risk of TLS with venetoclax has evolved over time. In Study M12-175 
(June 2011), substantial anti-tumor activity was observed in the first 3 subjects with CLL 
following a single dose of venetoclax of 100 to 200 mg.  Within 24 hours, reductions in palpable 
lymphadenopathy were observed in all 3 subjects and dramatic reductions in lymphocyte count 
(> 95%) were observed in the 2 subjects with pretreatment lymphocytosis.  This rapid response 
resulted in TLS in all 3 subjects, mainly characterized by increases in potassium, phosphate, 
and LDH levels which resolved without clinical complications in all 3 subjects. 
Subsequently, the initial venetoclax dose for CLL subjects was reduced to 50 mg, and 
2 to 3 weekly ramp-up steps were introduced to reach the final cohort dose.  In addition, in all 
subjects, intensified monitoring and standard TLS prophylaxis measures were mandated, 
including protocol-specified laboratory tests, hydration, and treatment to prevent hyperuricemia. 
In the subsequent cohorts, a CLL subject developed TLS and acute renal failure requiring 
dialysis.  This subject presented with elevated potassium and ECG changes indicating possible 
myocardial infarction.  Subsequently, a cardiac catheterization was performed.  The acute renal 


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failure may have also been due to the radiographic dye in the setting of TLS.  Hospitalization of 
CLL/SLL subjects with the first dose of venetoclax became mandatory following the report of 
this serious adverse event. 
In December 2012, 2 fatal adverse events in the setting of TLS were reported in subjects with 
CLL/SLL.  The first death (in Study M13-365) occurred within 24 hours after the subject received 
his first dose of 50 mg venetoclax.  The second death (in Study M12-175) occurred within 
48 hours after the subject had escalated to the final dose of 1200 mg/daily of venetoclax, the 
highest dose administered in the venetoclax program to date.  Following the report of 2 fatal 
adverse events in the setting of TLS in December 2012, the clinical program was halted and a 
comprehensive review of all safety data available from studies with venetoclax revealed: 
• 
The highest risk period for developing TLS is at initiation of venetoclax.  The risk is 
reduced as the tumor burden decreases. 
• 
Subjects with TLS appeared to have had a higher venetoclax exposure than subjects 
without TLS.  To reduce the initial exposure for all subjects to that of subjects not 
experiencing TLS (Cmax ≤ 0.23 μg/mL), trial simulation data indicated that subjects 
should receive 20 mg as a starting dose. 
• 
Bulky lymph nodes ≥ 5 cm and elevated screening ALC ≥ 38.9 × 109/L were identified as 
risk factors for TLS following administration of venetoclax. Screening CrCl < 80 mL/min 
was also identified as a contributing factor.  These TLS risk factors are not unique to 
venetoclax and have been previously identified in the literature. 
• 
The 2 subjects who had fatal CTLS (Subject 167 in Study M12-175, and Subject 5503 in 
Study M13-365) had nodes greater than or approximately equal to 10 cm in size. 
Based on the analyses and discussion with regulatory authorities, the clinical program was 
reinitiated in May 2013 with a modified venetoclax dosing regimen and enhanced TLS 
prophylaxis and monitoring measures: frequent blood draws, uric acid reducing agents 
≥ 72 hours prior to first dose, and site education plan.  Repeat analysis in January 2014 
performed to evaluate the effectiveness of revised measures indicated a marked reduction in 
severity and frequency of TLS when compared to the previous analysis.  None of the subjects 
experienced any serious (including fatal) or non-serious event of CTLS or laboratory TLS 
(LTLS) or had study treatment discontinued because of TLS.  The revised dosing regimen, 
which includes a more gradual increase in dose, likely led to gradual debulking of the tumor and 
played a key role in mitigating the risk.  Based on the results of this interim analysis, following 
revisions were made in May 2014: 
• 
All subjects starting venetoclax treatment at 20 mg QD for 1 week followed by gradual 
weekly titration up to the 400 mg QD dose. 
• 
More personalized approach for prophylaxis and monitoring measures, where subjects 
with low and medium risk for TLS could receive venetoclax on an out-patient basis with 
post-dose laboratory monitoring at 8 and 24 hours.  Subjects at high risk for TLS were 
hospitalized for their initial dose at 20 mg and 50 mg and then managed on an 
out-patient basis. 
• 
Oral uricosurics starting 72 hours prior and oral hydration starting 48 hours prior to 
starting venetoclax; additional IV fluids for high and medium risk subjects.  Rasburicase 
is recommended for subjects at high risk, especially those with high baseline values. 


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• 
Reassessment of tumor burden based on current ALC followed by less intensive 
prophylaxis and monitoring was allowed, based on the investigator's discretion. 
From May 2014 to 25 August 2015, a total of 105 subjects have received venetoclax following 
the above measures in monotherapy CLL Study M13-982 (safety expansion cohort) and Study 
M14-032. Adverse events of TLS are reported in 4/105 (3.8%) subjects, with no events of CTLS. 
Hyperkalemia (or blood potassium increased) was the most common laboratory adverse event 
relevant to TLS, and was reported in 17/105 (16.2%; one Grade 3 event) of subjects. 
Hyperphosphatemia was reported in 15/105 (14.3%, 22 Grade 3 events) subjects; 
hypocalcaemia in 10/105 (9.5%) subjects, and hyperuricemia in 9/105 (8.6%) subjects. All 
adverse events related to clinical chemistries resolved with standard electrolyte management 
without any clinical consequences. 
Current recommendations for TLS prophylaxis and monitoring in CLL are summarized in 
Section 4.3.1. 
5.1.10 Rationale for the Starting Dose and Regimen Selected  
Daily oral dosing of venetoclax at 400 mg has been well tolerated in CLL patients previously as 
mono-agent therapy; higher doses have also been tested in other malignancies though without 
significantly increased efficacy in CLL/SLL.  Implementation of intra-patient dose-escalation with 
venetoclax, pre-treatment TLS risk categorization, and enhanced prophylactic guidance and 
monitoring for TLS has eliminated the significant tumor lysis that was previously seen with 
initiation of venetoclax therapy at higher doses.  A similar use of intra-patient dose-escalation for 
venetoclax in this study will allow rapid identification of the maximal tolerable dose while 
maintaining high sensitivity for adverse events and dose-limiting toxicities.   
5.1.11 Maximum Allowable Dose/ Overdose 
The maximum allowed dose of venetoclax in this study is 400 mg. 
Any dose of study drug more than that specified in this protocol is considered an overdose.  
Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be 
reported as a Serious Adverse Event in the appropriate time frame and documented as clinical 
sequelae to an overdose.   
There is no specific antidote for venetoclax. In the event of an overdose, subjects should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 7 for further information regarding AE reporting. 
5.1.12 Treatment Duration 
Treatment duration of venetoclax for this study is 2 years in combination with ibrutinib.  


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5.2 Study Drug Ibrutinib  
5.2.1 Names 
Study drug ibrutinib is approved by the US Food and Drug Administration (FDA) as Imbruvica.  
The approved uses of ibrutinib are described at Section 2.2.2 Ibrutinib.  
5.2.2 Formulation 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  All 
formulation excipients are compendial and are commonly used in oral formulations.  Refer to the 
ibrutinib Investigator's Brochure for a list of excipients. 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drug will be dispensed in child-resistant packaging.  Study drug labels will contain information to 
meet the applicable regulatory requirements. 
The first dose of ibrutinib will be delivered in the clinic on Day 1, after which subsequent dosing 
is typically on an outpatient basis.  Unused ibrutinib dispensed during previous visits must be 
returned to the site and drug accountability records updated at each visit. 
Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
5.2.3 Study Cohorts 
All study participants will receive ibrutinib daily starting at Week 1 Day 1 at the FDA-approved 
dose for CLL/SLL. 
5.2.4 Mechanism of Action 
Ibrutinib was designed as a selective and covalent inhibitor of Bruton’s tyrosine kinase (BTK).34 
In vitro, ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this 
position.  When added directly to human whole blood, ibrutinib inhibits signal transduction from 
the B-cell receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM 
stimulation followed by CD69 expression.35 
For more detailed and comprehensive information regarding pharmacology, refer to the current 
Investigator’s Brochure. 
5.2.5 Non-Clinical and Clinical Pharmacokinetics 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased, with substantial inter-subject variability.  The mean half-life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours.  Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
overnight fasting with median time to Tmax delayed from 2 to 4 hours.  Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with 
approximately 15 times lower inhibitory potency compared to ibrutinib.  The metabolite-to-parent 


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AUC ratio ranged from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was less 
than 2-fold of first dose exposure. 
Data from clinical Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated 
from the plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain 
maximal pharmacodynamic activity for 24 hours post dose at dose levels ≥ 2.5 mg/kg.  In Study 
PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 
560 mg continuous dosing cohort were all above 90% at either 4 or 24 hours after drug 
administration. 
5.2.6 Summaries of Non-Clinical Pharmacology and Toxicology Studies 
For the most comprehensive nonclinical information regarding ibrutinib, refer to the current 
version of the Investigator's Brochure. 
5.2.6.1  Non-Clinical Toxicology Studies 
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system or respiratory system in rats at any dose tested.  Further, no treatment-related 
corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). 
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in patients administered the dose of 560 mg daily, respectively. 
5.2.6.2  Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with ibrutinib have not been conducted in animals.  In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
5.2.7 Summaries of Clinical Studies 
The initial study of ibrutinib in relapsed/refractory CLL patients demonstrated an ORR of 90% 
but only a 7% CR rate with a median treatment duration of 23 months.36 For the most 
comprehensive clinical information regarding ibrutinib, refer to the current version of the 
Investigator's Brochure. 


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5.2.8 Major Route of Elimination 
The results of human mass balance study of [14C]-ibrutinib conducted in 6 healthy male subjects 
demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally-excreted, whereas 
approximately 80% is recovered in feces.  Subjects with mild and moderate renal insufficiency 
(creatinine clearance > 30 mL/min) were eligible to enroll in Study PCYC-1102-CA in which 
pharmacokinetic (PK) assessments were included.  No dose adjustment is needed for mild or 
moderate renal impairment (greater than 30 mL/min creatinine clearance).  There is no data in 
patients with severe renal impairment or patients on dialysis.  In a hepatic impairment study, 
data showed an increase in ibrutinib exposure.  Following single dose administration, the AUC 
of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to 
subjects with normal liver function.  The safety of ibrutinib in patients with hepatic impairment is 
currently in progress. 
5.2.9 Safety Profile 
Pooled safety data for a total of 1,971 subjects treated with various therapies in combination 
with ibrutinib from 17 studies that have completed primary or final analysis included in the CSR 
as of 12 November 2019 are summarized below. Therapies used in combination with ibrutinib in 
these studies, included BR (bendamustine and rituximab), FCR (fludarabine, 
cyclophosphamide, and rituximab), cytarabine, azacytidine, dexamethasone, durvalumab, 
ofatumumab, lenalidomide with EPOCH-R (cyclophosphamide, doxorubicin, etoposide, 
vincristine, prednisone +/- rituximab), nivolumab, Obinutuzumab, rituximab, carfilzomib +/- 
dexamethasone, pomalidomide and dexamethasone and R-CHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone). 


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Table 3.  Most frequently reported TEAEs in subjects receiving ibrutinib in combination 
therapy (N = 1,971) 
Most frequently reported 
TEAEs > 20% 
Most frequently reported 
Grade 3 or 4 TEAEs > 3% 
Most frequently reported 
Serious TEAEs > 2% 
Neutropenia 
Diarrhea 
Nausea 
Thrombocytopenia 
Fatigue 
Anemia 
Pyrexia 
Cough 
Upper respiratory tract 
infection 
Constipation 
Neutropenia 
Thrombocytopenia 
Febrile neutropenia 
Pneumonia 
Hypertension 
Neutrophil count decreased 
Anemia 
Fatigue 
Diarrhea 
Platelet count decreased 
Hypokalemia 
Lymphocyte count decreased 
White blood cell count 
decreased 
Atrial fibrillation 
Hyponatremia 
Leukocytosis 
Leukopenia 
Lymphocyte count increased 
Febrile neutropenia 
Pneumonia 
Atrial fibrillation 
Pyrexia 
Anemia 
For more detailed information, refer to the current version of the IB. 
5.2.9.1  Bleeding-related Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and 
without thrombocytopenia.  These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and some major hemorrhagic events, some fatal, including 
gastrointestinal bleeding, intracranial hemorrhage and hematuria.  Use of ibrutinib in subjects 
requiring other anticoagulants or medications that inhibit platelet function increases the risk of 
major bleeding.  A higher risk for major bleeding was observed with anticoagulant than with 
antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when 
co-administered with ibrutinib. Monitor for signs and symptoms of bleeding. Subjects with 
congenital bleeding diathesis have not been studied.  See Section 4.3.3.4 for guidance on 
concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See Section 4.3.5 
for guidance on ibrutinib management with surgeries or procedures.  In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were 
observed, refer to Section 4.3.3.4. Supplements such as fish oil and vitamin E preparations 
should be avoided.  
Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of 
surgery and the risk of bleeding. 


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5.2.9.2  Cardiac Arrhythmias 
Atrial fibrillation, atrial flutter and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset of 
dyspnea) should be evaluated clinically, and if indicated, have an ECG performed.  For cardiac 
arrhythmias that persists, consider the risks and benefits of ibrutinib treatment and follow the 
protocol dose modification guidelines. 
5.2.9.3  Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) 
were reported in subjects treated with ibrutinib.  Monitor complete blood counts monthly. 
5.2.9.4  Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, 
vomiting, and constipation.  These events are rarely severe and are generally managed with 
supportive therapies including antidiarrheals and antiemetics.  Subjects should be monitored 
carefully for gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. 
Medical evaluation should be made to rule out other etiologies such as Clostridium difficile or 
other infectious agents. Should symptoms be severe or prolonged, follow the protocol dose 
modification guidelines. 
5.2.9.5  Infections 
Infections (sepsis, bacterial, viral, or fungal infections) were observed in subjects treated with 
ibrutinib therapy.  Some of these infections have been associated with hospitalization and 
death.  Consider prophylaxis according to standard of care in subjects who are at risk for 
opportunistic infections.  Although causality has not been established, cases of progressive 
multifocal leukoencephalopathy (PML) and hepatitis B reactivation have occurred in subjects 
treated with ibrutinib.  Subjects should be monitored for signs and symptoms (fever, chills, 
weakness, confusion, vomiting and jaundice) and appropriate therapy should be instituted as 
indicated.  
5.2.9.6  Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor subjects 
for the appearance of non-melanoma skin cancer. 
5.2.9.7  Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity.  Isolated cases 
of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) 
have been reported in subjects treated with ibrutinib.  Subjects should be closely monitored for 
signs and symptoms suggestive of SCAR including SJS.  Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 


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agent as appropriate.  In addition, hypersensitivity-related events including erythema; urticaria; 
and angioedema have been reported. 
5.2.9.8  Lymphocytosis and Leukostasis 
5.2.9.1.1 Lymphocytosis  
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% 
increase from baseline and an absolute count > 5000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL/ 
small lymphocytic lymphoma (SLL) treated with ibrutinib.  This effect has also been 
observed in some subjects with MCL treated with ibrutinib.  This observed 
lymphocytosis (increase in the number of circulating lymphocytes eg, > 400,000/µL) is a 
pharmacodynamic effect and should not be considered progressive disease in the 
absence of other clinical findings.  In both disease types, lymphocytosis typically occurs 
during the first few weeks of ibrutinib therapy (median time 1.1 weeks) and typically 
resolves within a median of 8.0 weeks in subjects with MCL and 14 weeks in subjects 
with CLL/SLL (range 0.1 to 104 weeks).   
When ibrutinib was administered in combination with BR or with obinutuzumab in 
subjects with CLL/SLL, lymphocytosis was infrequent (7% with ibrutinib + BR versus 6% 
with placebo + BR and 7% with ibrutinib + obinutuzumab versus 1% with chlorambucil + 
obinutuzumab).  
Lymphocytosis was not observed with WM treated with ibrutinib.   
5.2.9.1.2 Leukostasis  
There were isolated cases of leukostasis reported in subjects treated with ibrutinib.  A high 
number of circulating lymphocytes (> 400,000/µL) may confer increased risk. Consider 
temporarily withholding ibrutinib. Subjects should be closely monitored. Administer supportive 
care including hydration and/or cytoreduction as indicated.  For subject and ibrutinib 
management guidance, refer to Section 6.2.1.2. 
5.2.9.9  Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
5.2.9.10  Interstitial Lung Disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib.  
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 
ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines (see Section 6).  
5.2.9.11  Hypertension  
Hypertension has occurred in subjects treated with ibrutinib.  Regularly monitor blood pressure 
in subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout 
treatment with ibrutinib as appropriate.  


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Cerebrovascular Accidents 
Although causality has not been established, cases of cerebrovascular accident, 
transient ischemic attack, and ischemic stroke including fatalities have been reported 
with the use of ibrutinib in the post-marketing setting, with and without concomitant atrial 
fibrillation and/or hypertension. Regular monitoring and appropriate treatment of 
conditions that can contribute to the occurrence of these events is recommended.  
Long-term safety 
The long-term safety data over 5 years from 1,178 subjects (treatment-naїve CLL/SLL n 
= 162, relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated 
with ibrutinib were analyzed. The median duration of treatment for CLL/SLL was 51 
months (range, 0.2 to 98 months) with 70% and 52% of subjects receiving treatment for 
more than 2 years and 4 years, respectively. The median duration of treatment for MCL 
was 11 months (range, 0 to 87 months) with 31% and 17% of subjects receiving 
treatment for more than 2 years and 4 years, respectively. The overall known safety 
profile of ibrutinib-exposed subjects remained consistent, other than an increasing 
prevalence of hypertension, with no new safety concerns identified. The prevalence for 
Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2 – 3), 9% 
(year 3- 4), and 9% (year 4-5). The incidence for the 5-year period was 11%.  
5.2.9.12  Rationale for the Starting Dose and Regimen Selected  
This study uses the FDA approved dose of ibrutinib 420 mg PO daily for CLL/SLL.  Dose 
reduction of ibrutinib is allowed for attributable toxicity as specified in Section 6.2. 
5.2.9.13  Maximum Allowable Dose / Overdose 
There are limited data on the effects of ibrutinib overdose.  No maximum tolerated dose (MTD) 
was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day 
(1400 mg/day).  In a separate study, 1 healthy subject who received a dose of 1680 mg 
experienced reversible Grade 4 hepatic enzyme increases (AST and ALT). There is no specific 
antidote to ibrutinib. Subjects who ingest more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment. 
Refer to Section 7 for further information regarding AE reporting. 
5.2.9.14  Treatment Duration 
All study participants will receive ibrutinib daily starting at Week 1 Day 1 and be dosed 
continuously throughout the study until completion of 2 years combined therapy with venetoclax, 
disease progression, development of intolerable side effects, need to initiate prohibited 
therapies, or participant withdrawal. Upon completion of ibrutinib + venetoclax combination 
treatment at Week 117, participants will have completed the trial and may transition off-study to 
receive commercial ibrutinib at the discretion of the investigator. 


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5.3 Study Drug Supply  
5.3.1 Venetoclax Drug Supply  
Venetoclax will be supplied by Abbvie.  
5.3.1.1 Venetoclax Ordering 
The investigational pharmacist will request drug supply using the form in Appendix H.   
The form should be sent to supplies.team@abbvie.com.  
5.3.2 Ibrutinib Drug Supply  
Ibrutinib will be supplied by Pharmacyclics.   
5.3.2.1 Ibrutinib Ordering 
The investigational pharmacist will request drug supply using the form in Appendix I. 
The form should be sent to ist.ctep@pcyc.com.   
5.4 Venetoclax and Ibrutinib Accountability 
All clinical supplies must be maintained under adequate security and stored under conditions 
specified on the label.  The venetoclax tablets must be stored at 15° to 25°C (59° to 77°F). 
Ibrutinib must be kept in a locked limited access room.  The study drug must not be used 
outside the context of the protocol.  Under no circumstances should the Investigator or other site 
personnel supply ibrutinib or venetoclax to other Investigators, subjects, or clinics or allow 
supplies to be used other than as directed by this protocol.  An Investigational Drug 
Accountability Log must be used for drug accountability.  For accurate accountability, the 
following information must be noted when drug supplies are used during the study: 
1. Study identification number  
2. Subject identification number  
3. Lot number(s) of ibrutinib or venetoclax dispensed for that subject  
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject  
6 DOSE MODIFICATIONS AND DISCONTINUATION 
6.1 Venetoclax Dose Modification  
If one or more electrolyte changes (from the pre-dose value) suggestive of tumor lysis syndrome 
(TLS) occurs within 24 hours of venetoclax initiation (20 mg dose) or dose escalation (50, 100, 
200, 400 mg doses) and is confirmed by a repeat laboratory test within 1 to 2 hours, 
no additional venetoclax doses will be administered until resolution (within normal range) of 
those laboratory abnormalities.  Upon resolution of laboratory abnormalities, the subject will 
remain at the current dose level of venetoclax (eg, if receiving 20 mg, will remain at 20 mg) 
through 7 doses. 


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The additional Warnings in the Package Insert are administration of live attenuated vaccines 
prior to, during, or after venetoclax treatment (prohibited in this protocol) and embryo-fetal 
toxicity.   
See also Section 6.3 Dose Modification for Both Venetoclax and Ibrutinib.  
6.2 Ibrutinib Dose Modification  
The dose of ibrutinib should be modified according to the dose modification guidelines in 
Table 4 if any of the following toxicities attributable to ibrutinib occur: 
• 
Grade 3 or greater non-hematological toxicities.  
• 
Grade 3 or greater neutropenia with infection or fever 
• 
Grade 3 thrombocytopenia (< 50,000/µL) in the presence of clinically-significant 
bleeding events. 
• 
Grade 4 hematological toxicities, including thrombocytopenia < 20,000/µL. 
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the 
thromboprophylaxis of atrial fibrillation (Section 4.3.3.4). 
Recommended dose modifications are described in Table 4 below.  
Table 4.  Ibrutinib Dose Modifications 
Occurrence Action to be Taken  
First 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level (420 mg/day) 
Second 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at 
≤ 280 mg/day  
Third 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at 
≤ 140 mg/day  
Fourth 
Discontinue ibrutinib 
A high number of circulating malignant cells (> 400,000/uL) may confer increased risk of 
leukostasis; these subjects should be closely monitored.  Administer supportive care such as 
hydration and/or leukapheresis as indicated.  Ibrutinib may be temporarily held.  
6.2.1.1 Dose Modification for Hepatic-Impaired Subjects 
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section Error! Reference 
source not found.. Ibrutinib is metabolized in the liver. In the population PK analysis (1,202 
subjects), 179 subjects (14.9%) had mild hepatic impairment according to National Cancer 
Institute criteria and 12 subjects (1.0%) had moderate hepatic impairment. These subjects did 
not show a significantly higher ibrutinib exposure compared with subjects with normal hepatic 
function. In a hepatic impairment study, data showed an increase in ibrutinib exposure. For 
subjects with mild liver impairment (Child-Pugh class A), the recommended dose is 280mg 


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daily. For subjects with moderate liver impairment (Child-Pugh class B), the recommended dose 
is 140mg daily. Monitor subjects for signs of ibrutinib toxicity and follow dose modification 
guidance as needed. It is not recommended to administer ibrutinib to subjects with severe 
hepatic impairment Subjects with clinically significant chronic hepatic impairment at the time of 
Screening (Child- Pugh class C) are excluded from study participation. Concomitant use of 
strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment. Refer to 
Appendix D for Child-Pugh classification. Please refer to table below for dose modifications due 
to hepatic impairment.  
Table .  Dose Modification Guidance for Hepatic Impaired Subjects 
 
Child Pugh class A 
(Mild hepatic 
impairment)* 
Child Pugh Class B 
(Moderate hepatic 
impairment)** 
Child Pugh class 
C 
(Severe hepatic 
impairment) 
 
Ongoing at 
time of 
enrollment 
Develops 
during 
study 
Ongoing at time 
of enrollment 
Develops 
during study 
Develops during 
study 
Ibrutinib 
Dose 
(daily) 
280 mg 
280mg 
140 mg 
140 mg 
Hold until 
improves to 
moderate [Class 
B] or better) 
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In 
the event that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity 
until resolution. 
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until 
resolution.  
6.2.1.2 Leukocytosis / Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating white blood cells (>400,000/µL) may confer increased risk of leukostasis;  
these subjects should be closely monitored.  Administer supportive care such as hydration 
and/or leukapheresis as indicated.  Consider temporarily withholding ibrutinib, and medical 
monitor should be contacted.  
6.3 Dose Modification for Both Venetoclax and Ibrutinib  
If the events below occur, no additional venetoclax doses will be administered until resolution of 
those laboratory abnormalities (≤ Grade 1), and ibrutinib dosing should continue or be 
discontinued per Table 4.   
• 
Grade 4 ANC (< 500/µL) for more than 7 days.  See Section 4.3.2 for instructions 
regarding the use of growth factor support.  
• 
Any other Grade 4 toxicity, or unmanageable Grade 3 toxicity. 


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6.4 Treatment Discontinuation  
Study treatment with venetoclax and ibrutinib will be permanently discontinued for any subject if 
any of the following occur.  
• Grade 4 treatment-related (ie, possibly-, probably-, or definitely-related) non-hematologic 
toxicity.  
• Grade 4 neutropenia lasting > 21 days  
• Grade 4 thrombocytopenia lasting > 21 days or associated with clinically-significant 
bleeding (requiring > 3 units of packed red blood cells within 24 hours to replace loss 
OR bleeding from a site which in the Investigator’s opinion is a potential life-threatening 
source irrespective of blood loss) 


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7 ADVERSE EVENTS AND REPORTING PROCEDURES 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. 
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study.  All adverse events (AE) and serious adverse 
events (SAE) whether volunteered by the subject, discovered by study personnel during 
questioning, detected through physical examination, clinically significant laboratory test, or other 
means, will be recorded.  Each recorded adverse event or serious adverse event will be 
described by its duration (ie, start and end dates), severity, regulatory seriousness criteria (if 
applicable), suspected relationship to the investigational product, and any actions taken. 
The Protocol Director or designee will assess each AE to determine whether it is unexpected 
according to the Investigator’s Brochure; Protocol; and Informed Consent, and whether it is 
related to the investigation (eg, study procedures) and/or the investigational agent.  All SAEs will 
be tracked until resolution, or until at least 30 days after the last dose of the study treatment.   
7.1 Adverse Events Definition 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an adverse event term.  As an 
example, "worsening of underlying disease" or the clinical diagnosis that is associated with 
disease progression should be reported. 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms provided by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the subject through the completion of final study procedures. 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease 
that were not present before the AE reporting period  
• 
Complications that occur due to protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• 
Pre-existing condition:  A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 


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• 
Diagnostic Testing and Procedures:  Testing and procedures should not to be 
reported as AEs or SAEs, but rather the cause for the test or procedure should be 
reported. 
• 
Asymptomatic Treatment-related Lymphocytosis:  This event should also not be 
considered an AE.  Subjects with treatment-related lymphocytosis should remain on 
study treatment and continue with all study-related procedures. 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation.   
7.1.1 Serious Adverse Events Definition 
For this investigational drug study, AEs will be determined to be Serious Adverse Events (SAEs) 
per 21CFR§312.32(a) and ICH GCP E6r1 (revision 1).  An adverse event is considered 
"serious" if, in the opinion of the Protocol Director;  investigator;  or sponsor, it results in any of 
the following. 
• 
Death 
• 
Life-threatening, ie, immediate risk of death  
(NOTE:  Life-threatening does NOT include laboratory values that are “Grade 4 
Life-threatening” per CTCAE v4.03, unless there is an immediate risk of death) 
• 
Requires, results in, or prolongs inpatient hospitalization  
• 
Is a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Is a congenital anomaly/birth defect in the offspring of a study participant 
• 
Jeopardizes the subject, in the opinion of the Protocol Director;  investigator;  or sponsor 
• 
Requires medical or surgical intervention to prevent one of the outcomes listed in this 
definition, in the opinion of the Protocol Director; investigator; or sponsor 
The following are NOT considered SAEs: 
• 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs. 
7.2 Adverse Event Reporting 
Adverse events (AEs) will be graded according to CTCAE v4.03, except as noted below.  The 
CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each 


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referenced AE.  Should a subject experience any AE not listed in the CTCAE v4.03 the following 
grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be 
in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
All treatment-emergent AEs will be captured from the first dose of study drug.  SAEs will be 
reported to the Sponsor from the time of ICF signing.  Both serious and non-serious AEs will be 
recorded in the eCRF from the first dose of study drug until 30 days after the last dose of study 
drug. 
Serious adverse events reported after 30 days following the last dose of study drug should also 
be reported if considered related to study drug.  Resolution information after 30 days should be 
provided. 
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document.  All records will need to 
capture the details of the duration and the severity of each episode, the action taken with 
respect to the study drug, investigator’s evaluation of its relationship to the study drug, and the 
event outcome.  Whenever possible, diagnoses should be given when signs and symptoms are 
due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection").  Investigators must record in the eCRF their 
opinion concerning the relationship of the adverse event to study therapy 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  If a death occurs within 30 days after the 
last dose of study drug, the death must be reported as a serious adverse event. 
All serious adverse events (SAEs) and AESIs (initial and follow-up information) will be reported 
to the FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB 
Reporting Form and sent via email (AEintakeCT@pcyc) or fax (408-215-3500) to Pharmacyclics 
Drug Safety, or designee, within 15 days of the event.  Pharmacyclics may request follow-up 
and other additional information from the Sponsor Investigator. 
All serious adverse events (SAEs) CTCAE Grade 3 and above, and all subsequent follow-up 
reports will be reported to the Stanford Cancer Institute (SCI) Data and Safety Monitoring 
Committee (DSMC) using the study-specific CRF regardless of the event’s relatedness to the 
investigation.  Following review by the DSMC, events meeting the IRB definition of 


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“Unanticipated Problem” will be reported to the IRB using eProtocol within 10 working days of 
DSMC review, or within 5 working days for deaths or life-threatening experiences 
AEs, serious or otherwise, will be attributed to study treatment as follows: 
• 
Definite:   
The AE is clearly related to the study treatment. 
• 
Probable:   
The AE is likely related to the study treatment. 
• 
Possible:   
The AE may be related to the study treatment. 
• 
Unlikely:   
The AE is doubtfully related to the study treatment. 
• 
Unrelated:   
The AE is clearly NOT related to the study treatment. 
All serious adverse events (SAEs) will be followed until the SAE(s) is(are) resolved, stabilized, 
returned to baseline, attributed to agents other than the study drugs or to factors unrelated to 
study conduct, or until additional information cannot be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of due 
diligence with follow-up efforts), whichever is longer.   
Adverse events that are serious and unexpected suspected adverse reactions, ie, are possibly, 
probably, or definitely related to the study drugs venetoclax and ibrutinib, will be reported to the 
FDA via IND Safety Report [21CFR§312.32] within 14 calendar days, or within 7 calendar days 
if the event is an unexpected fatal or life-threatening suspected adverse reaction.   
7.3 Safety Monitoring 
This study is monitored by the Stanford Data and Safety Monitoring Committee (DSMC).  SAEs 
will be reported by the study team to Stanford DSMC per the current Stanford SOP.  SAEs that 
meet the definition of an “Unanticipated Problem” per the Stanford DSMC will be reported to the 
Stanford IRB using eProtocol within 10 working days of the Stanford DSMC’s report to the 
Protocol Director regarding the event (within 5 working days for deaths or life-threatening 
events).  See also Section 10.3 Data and Safety Monitoring Plan.  
All serious adverse events (SAEs) that are CTCAE Grade 3 and above, and all subsequent 
follow-up reports will be reported to the Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC) using the study specific CRF regardless of the event’s relatedness to the 
investigation.   
All SAEs will be reported will be reporting to the IRB in the annual Continuing Review, or the 
Final Report, that is submitted to the IRB. 
7.4 Adverse Events of Special Consideration 
7.4.1 Second Malignancy vs Secondary Malignancy 
7.4.1.1   Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  All new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies will be reported as SAEs per the current Stanford 
SOP, for the duration of study treatment and during any protocol-specified follow-up periods 
including post-progression follow-up for overall survival. 


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7.4.1.2   Secondary Malignancy 
In the context of a clinical study, a secondary malignancy is a cancer caused by the 
investigational agent/intervention, radiation, or chemotherapy.  A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  All secondary malignancies will be reported as 
SAEs per the current Stanford SOP.  Three options/examples are available to describe the 
event:   
• 
Leukemia secondary to oncology chemotherapy [eg, acute myeloid leukemia (AML)]  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
By definition, secondary malignancies are serious and related adverse events, and require 
expedited reporting. 
7.4.2 Other Adverse Events of Special Considerations  
7.4.2.1   Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities.  In addition to normal reporting, these events (regardless of seriousness) 
will be reported on the Serious Adverse Event Report Form and sent via email or fax to 
Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E), or designee within 
15 days of awareness. 
• 
Major Hemorrhage, as defined by any of the following: 
o Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher. *  
o Any treatment-emergent serious adverse events of bleeding of any grade. 
o Any treatment-emergent central nervous system hemorrhage/hematoma of any 
grade. 
* All hemorrhagic events requiring transfusion of red blood cells should be reported as 
Grade 3 or higher AE per CTCAE v4.03.  
7.4.2.2   Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported in the CRF.  
7.4.2.3   Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days 
old will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of study drug.  A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months 
after the last dose of study drug.  Any female subjects receiving study drug(s) who become 


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pregnant must immediately discontinue study drug.  The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
Men should be advised not to father a child or donate sperm while receiving ibrutinib, 
and for 3 months following completion of treatment. 
 
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented.  Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported.  Any occurrence of pregnancy 
must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines.  All 
pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus.  Pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old by completing will need to be reported to 
Pharmacyclics per SAE reporting timelines.  Any congenital anomaly/birth defect noted in the 
infant must be reported as a serious adverse event. 
7.5 Case Report Forms (CRFs) for Adverse Event Reporting 
Both SAEs and non-serious AEs will be clearly described in source documentation and listed on 
study-specific Case Report Forms (CRFs or eCRFs).  


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8 CORRELATIVE / SPECIAL STUDIES  
8.1 Pharmacokinetics Assessments: Collected at Stanford Cancer 
Institute Site ONLY 
Ibrutinib: 
Pharmacokinetic samples for ibrutinib will be collected pre-dose (window: 30 to 60 minutes 
before dose), then 1 hour (window: 45 to 75 minutes); 2 hours (window: 1.5 to 2.5 hours); 
4 hours (window: 3.5 to 4.5 hours); and 6 hours (window 5.5 to 6.5 hours) post-ibrutinib 
administration on the first day of ibrutinib dosing (Week 1 Day 1) and each day when dosed in 
combination with newly-escalated dose of venetoclax in all subjects enrolled in the study.   
Venetoclax: 
Pharmacokinetic samples for venetoclax will be collected at 0, 8, 24 hours with each 
dose-escalation of venetoclax. 
8.2 Biomarker Assessments 
Blood for CLL FISH 
Approximately 4 mL of blood will be collected by venipuncture into a heparin vacutainer from 
subjects at the following time point: 
• 
Screening or Week 1 Day 1 pre-dose 
Blood for Mutation Profiling 
Approximately 10 mL of blood will be collected by venipuncture into ACD vacutainers from 
all subjects at the following time points: 
• 
Week 1 Day 1 pre-dose 
• 
Final Visit/Time of Relapse 
Blood/Bone Marrow for ClonoSEQ Sequencing 
Approximately 10 mL of blood will be collected by venipuncture into EDTA tube from all subjects 
at the following time points: 
Blood: 
• 
Week 1 Day 1 pre-dose or anytime between screening and start of treatment 
• 
Within 1 month of completion of therapy at Week 117 
Bone Marrow: 
• 
Week 62 


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9 TREATMENT ASSESSMENTS AND STUDY CALENDAR 
9.1 Study Treatment Schedule 
9.1.1 Screening Phase 
Subjects will undergo screening procedures as described within Section 3 and Section 9.2.1 
within 28 days prior to first study drug administration.  Signed informed consent will be obtained 
from the subject or the subject's legally acceptable representative before any study-specific 
procedures are undertaken or before any prohibited medications are withheld from the subject 
to participate in this study.  After signing the informed consent form, screening and meeting 
inclusion/exclusion criteria for trial enrollment, Stanford will assign subjects a unique 
consecutive subject number. 
9.1.2 Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects are 
enrolled.  Enrollment should occur as close to the time of the expected first dose as possible.  
During the treatment and follow-up periods, AE and assessment will occur on an ongoing basis.  
Local labs will be used to guide all dosing-related decisions. 
Treatment will initiate on Week 1 Day 1 with ibrutinib 420 mg PO daily.  For tumor lysis 
prophylaxis, all subjects will be classified into 3 risk categories based on the risk for developing 
TLS prior to venetoclax administration (ie, after 8 weeks of ibrutinib administration) as detailed 
in Section 4.3.1.   
Subjects in low category and medium risk category with CrCl ≥ 80 mL/min and low tumor 
burden will begin treatment with venetoclax in the outpatient setting with an initial dose of 20 mg 
venetoclax on Week 9 Day 1.  If no significant findings suggestive of clinical or lab TLS occur 
within 24 hours, the same dose will be continued until Day 7 in the outpatient setting.  Subjects 
with no laboratory abnormalities suggestive of LTLS will escalate to a dose of 50 mg venetoclax 
on Week 10 Day 1 in the outpatient setting. 
Medium risk subjects with CrCl < 80 mL/min and higher tumor burden may be admitted to the 
hospital at the investigator discretion to begin venetoclax with an initial dose of 20 mg on 
Week 9 Day 1.  If no significant findings suggestive of clinical or lab TLS occur within 24 hours, 
the same dose will be continued until Day 7 in the outpatient setting.  Subjects may be 
hospitalized prior to the first dose increment if they continue to have Cr Cl < 80 mL/min and 
higher tumor burden at the investigator's discretion.  Subjects with no laboratory abnormalities 
suggestive of LTLS will escalate to a dose of 50 mg venetoclax on Week 10 Day 1 in the 
outpatient setting. 
All high-risk subjects will be admitted to the hospital and begin treatment with venetoclax with an 
initial dose of 20 mg on Week 9 Day 1.  If no significant findings suggestive of clinical or lab TLS 
occur within 24 hours, the same dose will be continued until Day 7 in the outpatient setting.  
Each subject's risk status will be reassessed prior to subsequent dose increments to determine 
the need for hospitalization. 
If no significant findings occur within 24 hours at dose escalation, the study drug will be 
continued at the same dose from Days 2 through 7.  If there is indication of lab or clinical TLS 


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the study drug dose will be held till resolution of all findings.  TLS management will be 
implemented as appropriate. 
A lower starting dose to the lead-in regimen may be implemented for individual subject(s) at 
particularly high-risk for TLS. 
9.2 Study Procedures and Assessments 
All study procedures are discussed in detail in this section except for adverse event information 
(discussed in Section 7).  Procedures performed at Screening will serve as baseline unless 
repeated prior to dosing in which case the latest prior to dosing will serve as baseline. 
9.2.1 Study Assessments 
Medical and Oncologic History 
Screening Visit assessment will include: 
• 
Complete medical history, including documentation of any clinically significant medical 
condition 
• 
History of tobacco and alcohol use 
• 
Detailed oncology history including: 
o Histology 
o Cytogenetics 
o Date of CLL diagnosis 
o Stage at diagnosis 
o Any surgical procedures 
o Treatments administered (including dates, type of modality, response to 
treatment and reason for treatment discontinuation) 
• 
Detailed prior and concomitant medication usage including dates of usage and dosing 
information for all medications and supplements taken 
Week 1 Day 1:  Any changes observed from the Screening assessments (prior to dosing) will be 
recorded in the subject's medical history. 
Adverse Event and Concomitant Medication Assessment 
Medication (prescription or over-the-counter, including vitamins and herbal supplements) will be 
recorded beginning with the Screening Visit through the end of the study.  At each visit, 
including the Final Visit and the 30-Day Safety Follow-Up Visit, the subject's medical history will 
be reviewed and any changes from baseline will be recorded. 
Vital Signs, Physical Examination, ECOG Performance Status 
Body temperature (oral or tympanic), weight, blood pressure and heart rate, evaluation of 
ECOG performance status (see Appendix B) as well as a complete physical examination 
including evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal and neurologic systems will be performed at 
screening, Week 1 Day 1, Week 5 Day 1, Weekly from Week 9 Day 1 through Week 14 Day 1, 
every 4 weeks from Week 18 Day 1 through Week 30 Day 1, and every 12 weeks starting on 


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Week 38 day 1.  ECOG status, vital signs and a complete physical exam should be performed 
at the Final Visit and 30-Day Safety Follow-Up Visit. 
Subject Calendars/Diaries 
Subject calendars/diaries will be provided.  Subjects will be instructed to bring their 
calendars/diaries for review at: 
• 
Week 1 Day 1 
• 
Week 5 Day 1 
• 
Week 9-14 Day 1 
• 
Week 18 Day 1 
• 
Week 22 Day 1 
• 
Week 26 Day 1 
• 
Week 30 Day 1  
• 
Week 38 Day 1 and every 12 weeks thereafter through Week 117 
Subjects will be instructed to record the date and time each dose of study drug is taken, 
(indicating if any doses of study drug are missed) and the timing of each dose relative to the 
subject’s first meal of the day.  Subjects will also be instructed to record adverse events and 
concomitant medications. 
The calendars/diaries are to be reviewed at each visit and relevant pages are to be photocopied 
by study staff.  At the end of the subject's participation in the study, the calendars/diaries are to 
be returned to the site and appropriately filed with the subject's source documents for this study. 
9.2.2 Efficacy Evaluations 
Response will be assessed by the investigator based on analysis of clinical laboratory tests, 
complete physical examination, and CT scan of involved anatomic regions (or MRI if CT is 
medically contraindicated) as well as bone marrow aspirate and biopsy with MRD assessment.  
Subjects will be evaluated with documentation of response (CR/PR/SD/progressive disease) per 
2008 Modified IWCLL NCI-WG Criteria for Tumor Response (Appendix D).  
• 
Week 9 Day 1 
• 
Week 14 Day 1, and every 4 weeks through Week 30 Day 1 
• 
starting Week 38 Day 1, every 12 weeks thereafter 
CT scans (or MRI) will be obtained 
• 
Week 9 Day 1 
• 
Week 38 Day 1 
• 
Week 62 Day 1 
• 
Within 1 month of completion of therapy 
Bone marrow aspirate and biopsy will be obtained Week 62 and within 1 month of completion of 
therapy 


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Minimal Residual Disease (MRD) Assessment 
Subjects will have MRD assessed in a bone marrow aspirate sample using sensitive flow 
cytometry as well as ClonoSEQ. 
Survival Assessment(s) 
Survival information will not be collected. 
9.2.3 Study Diagnostics / Procedures 
Clinical Laboratory Tests 
Pregnancy Test 
For female subjects of childbearing potential, pregnancy testing must be performed as follows: 
• 
Screening – quantitative beta-human chorionic gonadotropin (β-hCG) serum pregnancy 
test. 
• 
Week 1 Day 1:  Urine test, if it has been > 7 days since obtaining the Screening serum 
pregnancy test results. 
Pregnancy test results must be reviewed and determined to be negative prior to dosing. 
Subjects considered not of childbearing potential must be documented as being surgically 
sterile or postmenopausal for at least ≥ 1 year. 
Hematology and Chemistry 
Chemistry and hematology samples will be collected at the following time points (refer to 
Table 5 for specific tests): 
• 
Screening 
• 
Week 1 Day 1 
• 
Week 5 Day 1 
• 
For Weeks 9-13 refer to Section 4.3.1 Prophylaxis and Management of Tumor Lysis 
Syndrome and Appendix E Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS) for monitoring during 
intra-patient dose escalation of venetoclax 
• 
Week 14 Day 1 
• 
Week 18 Day 1 
• 
Week 22 Day 1 
• 
Week 26 Day 1 
• 
Week 30 Day 1 
• 
Week 38 Day 1and every 12 weeks thereafter 
• 
Final Visit 
• 
30-Day Safety Follow-Up Visit 
• 
As needed throughout study 


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Coagulation Panel 
PT/aPTT samples will be collected at the following time points: 
• 
Screening 
• 
Week 9 Day 1 
Note:  Coagulation panel may be collected within 72 hours prior to the scheduled visit. 
Urinalysis 
Urinalysis samples will be collected at: 
• 
Screening 
Note:  Urinalysis may be collected within 72 hours prior to the scheduled visit. 
Viral Serologies 
A sample for viral serologies to identify Hepatitis B (HBsAg, anti-HBs, total anti-HBc, IgM 
anti-HBc), Hepatitis C (HCV) antibody or RNA, cytomegalovirus, varicella zoster virus, herpes 
simplex virus, and Epstein-Barr virus will be collected at the following time points: 
• 
Screening 
• 
As needed for suspicion of viral infection 
Table 5.  Clinical Laboratory Tests 
Hematology  
Hematocrit 
Hemoglobin 
Red Blood Cell (RBC) count 
White Blood Cell (WBC) count 
Neutrophils 
Bands 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
Platelet count (estimate not acceptable) 
Mean platelet volume (MPV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Clinical Chemistry 
Blood Urea Nitrogen (BUN) 
Creatinine 
Total bilirubin 
Serum glutamic-pyruvic transaminase 
(SGPT/ALT) 
Serum glutamic-oxaloacetic transaminase 
(SGOT/AST) 
Alkaline phosphatase 
Sodium 
Potassium 
Calcium 
Inorganic phosphorus 
Uric acid 
Total protein 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Magnesium 
Chloride 
Bicarbonate 
G6PD assay (prior to rasburicase only) 


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Urinalysis 
Specific gravity 
Ketones 
pH 
Protein 
Blood 
Glucose 
Coagulation 
Prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
Note for samples from patients treated with rasburicase:  rasburicase causes enzymatic degradation of the uric acid 
in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings.  The following 
special sample handling procedure must be followed to avoid ex vivo uric acid degradation.  Uric acid must be 
analyzed in plasma.  Blood must be collected into pre-chilled tubes containing heparin anticoagulant.  Immediately 
immerse plasma samples for uric acid measurement in an ice water bath.  Plasma samples must be prepared 
by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be maintained in an ice water bath and 
analyzed for uric acid within four hours of collection. 
Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) 
A CT scan with contrast (unless medically contraindicated) must be performed within 28 days 
prior to study drug administration.  A CT scan without contrast or a MRI may be substituted 
when clinically warranted.  Subjects should have the same imaging test performed through the 
study for accurate comparison. 
A CT scan will also be performed at the completion of Week 8, 37 and 61 and should be 
performed within 1 week of the Week 38 and Week 62 scheduled visits and within 1 month of 
the completion of therapy. 
If a subject exhibits clinical signs of disease progression (increased lymphadenopathy, 
hepatosplenomegaly) without meeting laboratory criteria for progression, a CT scan will be 
performed within 2 weeks to confirm or rule out progressive disease as described in Appendix D 
according to the Modified IWCLL Criteria for Tumor Response. 
Bone Marrow Aspirate and Biopsy 
A bone marrow aspirate and biopsy will be done at Screening (within 28 days prior to the first 
dose of study drug).  The bone marrow aspirate and biopsy should be performed after all other 
eligibility criteria have been met, unless otherwise obtained through standard of care.  Bone 
marrow aspirates and biopsies, immunohistochemical analysis and cytogenetics performed as 
standard of care throughout the study should also be documented. 
If the subject meets clinical/laboratory criteria and a confirmatory CT scan meets criteria for a 
CR, a bone marrow aspirate and biopsy should be repeated. 
The order of collections from the bone marrow aspirate and biopsy should be 1) MRD 
assessment and 2) clinical assessment.  
12-Lead Electrocardiogram 
A 12-lead resting ECG will be obtained at the following: 
• 
Screening 
• 
As clinically indicated 
The ECG results will be used by the investigator for subject safety assessments, including 
adverse event determination and management and termination of subjects from the study. 
- 
ECG results will be summarized as follows: 


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- 
Normal ECG 
- 
Abnormal ECG – not clinically significant 
- 
Abnormal ECG – clinically significant 
- 
Unable to evaluate 
The QT interval measurement will be documented only if a "prolonged QT" is observed.  
Correction by the Fridericia formula (QTcF) is preferred.  The original ECG tracing will be 
retained in the subject's records at the study site.  


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9.3 Table of Assessments / Study Calendar 
Table 6:  Schedule of Assessments  
Study Visits 
Screenin
g Phase 
Treatment Phase 
Week 
1 D1 
Week 5 
D1 
Weeks 9-13 
Week 14, 
18, 22, 26, 
30 
Day 1 
Week 38 
Day 1- 
Week 61 
Q12 weeks 
Wk 62
- Wk 
117  
Final 
visit 
Day 1 
Day 
2 
Study Visit Windows 
-28 days 
 
 
exact 
± 7 days 
+ 30 
days 
 
Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Confirm eligibility and enroll 
 
X 
 
 
 
 
 
 
 
 
Cumulative Illness Rating Scale 
(CIRS) 
 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Adverse events b 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Study drug compliance review c 
 
 
X 
X 
 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Physical exam, vital signs, weight, 
ECOG 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Disease assessment: 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan 
X j 
 
 
X f 
 
 
X f 
 
X f   
Bone marrow biopsy/aspirate h 
X 
 
 
 
 
 
 
 
X 
 
Disease-related symptoms i 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Overall response assessment 
 
 
 
X 
 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Creatinine clearance 
(Cockcroft-Gault) 
X 
 
 
X 
 
 
 
 
 
 
Cytogenetic, CLL FISH panel 
X 
 
 
 
 
 
 
 
 
 
Hepatitis serologies 
X 
 
 
 
 
 
 
 
 
 
Coagulation panel 
X 
 
 
X l 
 
 
 
 
 
 
12-lead ECG k 
X 
 
Any new anticancer therapy 
 
 
 
 
 
 
 
 
 


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Protocol 10691 dated 27 AUG  2020 
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Study Visits 
Screenin
g Phase 
Treatment Phase 
Week 
1 D1 
Week 5 
D1 
Weeks 9-13 
Week 14, 
18, 22, 26, 
30 
Day 1 
Week 38 
Day 1- 
Week 61 
Q12 weeks 
Wk 62
- Wk 
117  
Final 
visit 
Day 1 
Day 
2 
PK sample collection 
 
X d 
 
X d 
 
 
 
 
 
Mutational profiling  
 
X a 
 
 
 
 
 
 
 
MRD assessment m  
X 
 
 
 
 
 
 
 
X 
 
 
Study Visits 
Screenin
g Phase 
Treatment Phase 
 
 
 
Study Drug Administration and Dispensation 
 
Venetoclax 
 
 
Continuous daily dosing 
Dispensed weekly during dose ramp-up and every specified 
study visit thereafter through Week 117 
 
Intra-patient dose 
ramp-up  
400 mg daily 
 
Ibrutinib 420 mg PO 
 
Continuous daily dosing g 
Dispensed every 4 weeks from Week 1 through Week 30 and every 
specified study visit thereafter through Week 117 
 
D = day; Term = treatment termination; d/c = discontinuation; PD = progressive disease; FU = follow-up; (x) = not all visits or all subjects 
a To be collected pre-dose 
b AEs are reported from the time the patient signs the Informed Consent Form until 30 days following last dose of study drug.  In addition to all routine AE reporting, all 
new malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events for the duration of the study 
treatment and during any protocol-specified follow-up periods including post-progression follow-up for overall survival. 
c Includes patient instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration 
d At SCI only:  Ibrutinib: Pre-dose (window:  30 to 60 minutes before dose), then 1 hour (window:  45 to 75 minutes), 2 hours (window:  1.5 to 2.5 hours), 4 hours 
(window:  3.5 to 4.5 hours), and 6 hours (window:  5.5 to 6.5 hours) post-dose on the first day of ibrutinib dose administration (Week 1 Day 1) and each day when 
dosed in combination with new dose of venetoclax.  Venetoclax:  0 hour, then 8 hour and 24 hour post-dose with each Day 1 dose increase of venetoclax  
f Between Week 8 Day 1 and prior to Week 9 Day 1; Week 38 Day 1 +/- 7 days; Week 62 Day 1 +/- 7 days; within 1 month after completion of therapy; within 2 weeks 
of suspected disease progression 
g Day 1 dose of Cycle 1 and each PK day should be administered at the investigational site.  Subsequent daily doses may be self-administered at home. 
h Bone marrow biopsy and/or aspirate should be performed at Screening within 28 days before the first dose of study drug, Week 62, and within 1 month of completion 
of therapy.  Marrow collected to confirm CR should have minimal residual disease (MRD) assessed by flow cytometry and ClonoSEQ on the aspirate  
i Disease-related symptoms include weight loss, fatigue, fever, night sweats, abdominal pain/discomfort due to splenomegaly including early satiety, and anorexia. 
j Baseline CT scan can be performed within 28 days prior to study drug administration 
k ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea 
l Coagulation test to be done Week 9, Day1 only 


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m Bone marrow aspirate for ClonoSEQ between Screening and start of therapy, at Week 62, and within 1 month of completion of therapy at Week 117. Bone marrow 
aspirate for MRD flow assessment at Week 62 and within 1 month of completion of therapy at Week 117. 
 


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9.4 End-of-Study 
The study will end after the last subject completes therapy.  This is expected to be up to 4 years total, 
depending on the accrual rate.  
9.4.1 Study Discontinuation 
Per the IST Agreement, the Investigator reserves the right to terminate the study at any time.  Should 
this be necessary, both the Investigator will arrange discontinuation procedures in partnership with 
Pharmacyclics.  In terminating the study, the Investigator will assure that adequate consideration is 
given to the protection of the subjects’ interests.  Pharmacyclics may terminate the study for reasons 
including, but not limited to:  evidence that the PI or an involved investigator is unqualified to conduct 
research or fulfill sponsor responsibilities (eg, is listed on a debarment or ineligible investigator list); 
failure to meet timelines or achieve agreed upon milestones; a known or perceived risk to patient 
well-being is identified; or breach of contract.  Additional grounds for termination are outlined in the IST 
Agreement. 
9.4.2 Publication of Study Results 
Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a copy of a planned 
publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for 
publication or disclosure.  Pharmacyclics may provide scientific comments and suggestions 
understanding that the Investigator has sole editorial responsibility,and retains the authority to make the 
final determination on whether or not to incorporate Pharmacyclics comments or requests for additional 
information. 
9.5 Follow-up 
For subjects who complete or discontinue therapy, follow up assessments will not be performed, except 
to assess resolution of therapy-related toxicities that led to discontinuation of therapy. 


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10 REGULATORY CONSIDERATIONS 
10.1 Institutional Review Board (IRB) Approval of Protocol 
This clinical study was designed and will be implemented in accordance with the protocol, the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations 
(including US Code of Federal Regulations [CFR] Title 21 and European Directive 2001/20/EC), and 
with the ethical principles laid down in the Declaration of Helsinki.  This protocol; the proposed informed 
consent; and all forms of information related to the study that will be provided to the subjects (eg, 
questionnaires, handouts, written instructions, diaries, advertisements used to recruit participants, etc) 
will be submitted to and reviewed and approved by the Stanford IRB and Stanford Cancer Institute 
Scientific Review Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol Director will 
disseminate the protocol amendment information to all participating investigators.  The IRB must 
comply with current United States (US) regulations (§21 CFR 56) as well as country-specific national 
regulations and/or local laws.   
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form must be sent to 
Pharmacyclics for review and approval prior to submission to the IRB.  Written verification of IRB 
approval will be obtained before any amendment is implemented.  The following documents must be 
provided to Pharmacyclics or its authorized representative before entering subjects in this study:  
(1) a copy of the IRB letter that grants formal approval; and  (2) a copy of the IRB-approved ICF.  
10.2 Protocol Compliance and Deviations  
10.2.1 Compliance with the Protocol  
No deviation or changes from the procedures and process described by the IRB-approved protocol, 
except those necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) 
involves only logistical or administrative aspects of the trial [eg, change in study monitor(s), change of 
telephone number(s)], will be knowingly permitted without review and approval by the IRB. 
10.2.2 Protocol Deviations  
Any deviation from the IRB-approved protocol, including those that eliminate an immediate hazard or 
are administrative nature, will be documented and explained in the study site file.   
In addition, any deviation from the approved protocol that meets the reporting requirements defined in 
the Stanford University HRPP Policy Guidance “Events and Information that Require Prompt Reporting 
to the IRB” GUI-P13 with be reported to the IRB within the defined timeframes.   
10.2.3 Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national subject 
privacy regulations must be provided to each subject as part of the informed consent process, either as 
part of the ICF or as a separate signed document (for example, in the US, a site-specific HIPAA 
consent may be used).  The Investigator or designee must explain to each subject that for the 
evaluation of study results, the subject’s protected health information obtained during the study may be 
shared with Pharmacyclics and its designees, regulatory agencies, and IRBs.  As the study Sponsor, 


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Pharmacyclics will not use the subject’s protected health information or disclose it to a third party 
without applicable subject authorization.  It is the Investigator’s or designee’s responsibility to obtain 
written permission to use protected health information from each subject.  If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be collected from 
the subject.  Any data collected on the subject before withdrawal will be used in the analysis of study 
results.  During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
10.3 Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring 
entity for this study.  The DSMC will audit study-related activities to determine whether the study has 
been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, 
and Good Clinical Practice (GCP).  This may include review of the following types of documents 
participating in the study:  regulatory binders; case report forms; eligibility checklists; and source 
documents.  In addition, the DSMC will regularly review serious adverse events and protocol deviations 
associated with the research to ensure the protection of human subjects.  Results of the DSMC audit 
will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing 
review, or in an expedited fashion, as needed. 
10.3.1 Data Management Plan 
CRFs will be used to collect the clinical study data and must be completed for each enrolled subject 
with all required study data accurately recorded such that the information matches the data contained in 
medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other study-specific source 
documents).  Authorized study site personnel (ie, listed on the Delegation of Authority log) will complete 
CRFs designed for this study according to the completion guidelines that will be provided.  The 
Investigator will ensure that the CRFs are accurate, complete, legible, and completed within a 
reasonable time.  At all times, the Investigator has final responsibility for the accuracy and authenticity 
of all clinical data.  Study staff will be appropriately trained in the use of CRFs before the start of the 
study.  After database lock, the Investigator will receive a copy of the subject data (eg, paper; CD; or 
other appropriate media) for archiving at the study site. 
10.3.1.1 
Record Retention 
The Investigator must keep a record that lists all subjects considered for enrollment (including those 
who did not undergo screening) in the study.  For those subjects subsequently excluded from 
enrollment, the reason(s) for exclusion is to be recorded.  The Investigator/study staff must maintain 
adequate and accurate records to enable the conduct of the study to be fully documented and the study 
data to be subsequently verified.   
Essential documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB approval letters (dated), signed Form FDA 1572 and Financial Disclosures, signed ICFs (including 
subject confidentiality information), drug dispensing and accountability records, shipping records of 
investigational product and study-related materials, signed, dated and completed CRFs, and 
documentation of CRF corrections, SAE forms and notification of SAEs and related reports, source 
documentation, normal laboratory values, curricula vitae for study staff, and all relevant 
correspondence and other documents pertaining to the conduct of the study.   


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The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics before 
destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at any time.  
Should an Investigator wish to assign the study records to another party or move them to another 
location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will inform the 
Investigator of the date that study records may be destroyed or returned to Pharmacyclics.  
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator wishes to 
move study records to another location or assign responsibility for record retention to another party.  If 
the Investigator cannot guarantee the archiving requirements set forth herein at his or her study site for 
all such documents, special arrangements must be made between the Investigator and Pharmacyclics 
to store such documents in sealed containers away from the study site so that they can be returned 
sealed to the Investigator for audit purposes. 
10.4 Investigator Responsibilities 
A complete list of Investigator responsibilities is outlined in the clinical trial research agreement and the 
Statement of Investigator Form FDA 1572, both of which are signed by the Investigator before 
commencement of the study.  In summary, the Investigator will conduct the study according to the 
current protocol; will read and understand the IB; will obtain IRB approval to conduct the study; will 
obtain informed consent from each study participant; will maintain and supply to, auditors and 
regulatory agencies adequate and accurate records of study activity and drug accountability for 
study-related monitoring, audits, IRB reviews and regulatory inspections; will report SAEs to 
Pharmacyclics and IRB according to the specifics outlined in this protocol; will personally conduct or 
supervise the study; and will ensure that colleagues participating in the study are informed about their 
obligations in meeting the above commitments. 
10.5 Protocol Amendments 
Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol must be 
sent to Pharmacyclics for review and approval prior to submission to the IRB.  Written verification of 
IRB approval will be obtained before any amendment is implemented.  
10.6 Publication of Study Results 
Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a copy of a planned 
publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for 
publication or disclosure.  Pharmacyclics may provide scientific comments and suggestions 
understanding that the Investigator has sole editorial responsibility, and retains the authority to make 
the final determination on whether or not to incorporate Pharmacyclics comments or requests for 
additional information.  


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11 STATISTICAL CONSIDERATIONS 
11.1 Statistical Design 
This study uses the FDA approved dose of ibrutinib 420 mg PO daily for CLL/SLL and intra-patient 
dose-escalation of venetoclax to establish the efficacy, safety, and tolerability of venetoclax when 
combined with ibrutinib in patients with relapsed and refractory CLL/SLL.  A description of the statistical 
methods to be used to analyze the efficacy and safety data is outlined below.   
11.1.1 Treatment Assignment 
Not applicable for this single-arm study. 
11.2 Endpoints 
All endpoints will be assessed during treatment period only.  
11.2.1 Primary Endpoint 
Complete response rate (CRR)  
11.2.1.1 
Measurement Time Points 
The time frame for assessment of the primary endpoint is 62 weeks. 
11.2.2 Secondary Endpoint(s) 
Secondary Endpoints include: 
• 
Overall response rate (ORR) 
• 
Duration of response (DOR) 
• 
Time-to-progression (TTP) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Rate of minimal residual disease (MRD) negativity in the bone marrow 
• 
Safety 
Efficacy analyses will be performed on the intent-to-treat population but will also detail the response 
rates for evaluable patients (those who receive at least one dose of venetoclax). 
11.2.2.1.1 
Assessment Methods 
Laboratory and clinical assessments gathered as directed in the Study Treatment Schedule (Section 9).  
11.2.2.2 
Overall Response Rate 
The proportion of subjects with an overall response (per investigator assessment) will be calculated for 
all subjects based on IWCLL criteria.   


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11.2.2.3 
Duration of Response 
Duration of response will be defined as the number of days from the date of first response per 
investigator assessment to the earliest recurrence or progressive disease per investigator assessment.  
If a subject is still responding then the subject's data will be censored at the date of the subject's last 
available clinical disease assessment.  For subjects who never experienced response, the subject's 
data will be censored on the date of enrollment. 
11.2.2.4 
Time-to-progression 
Time-to-progression will be defined as the number of days from the date of first dose (date of 
enrollment if not dosed) to the date of earliest disease progression (per the investigator assessment).  
All disease progression will be included regardless whether the event occurred while the subject was 
taking study drug or had previously discontinued study drug.  If the subject does not experience 
disease progression, then the data will be censored at the date of the last available disease 
assessment. 
11.2.2.5 
Progression-free Survival (PFS)  
Progression-free Survival will be defined as the number of days from the date of first dose to the date of 
earliest disease progression (per the investigator assessment) or death.  All disease progression will be 
included regardless whether the event occurred while the subject was taking study drug or had 
previously discontinued study drug.  If the subject does not experience disease progression or death, 
then the data will be censored at the date of the last disease assessment.   
11.2.2.6 
Overall Survival (OS) 
Overall survival will be defined as the number of days from the date of first dose to the date of death for 
all dosed subjects.  For subjects who did not die, their data will be censored at the date of last study 
visit or the last known date to be alive, whichever is later.  
11.2.2.7 
Rate of Minimal Residual Disease (MRD) Negativity in the Bone Marrow 
MRD negativity will be defined as less than one CLL cell per 10,000 leukocytes (or below 10-4) on bone 
marrow-based flow cytometry.  Rate of MRD negativity will be defined as the proportion of subjects who 
achieve MRD negativity status.   
11.2.3 Exploratory Endpoint(s) 
Time to Next Anti-CLL Treatment (TTNT) 
Time to next anti-CLL treatment will be defined as the number of days from the date of the first dose of 
ibrutinib to the date of first dose of new non-protocol anti-leukemia therapy (NPT) or death from any 
cause.  For subjects who did not take NPT, the data will be censored at the last known date to be free 
of NPT.   
11.3 Interim analyses 
No interim analysis for efficacy is planned. 


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11.4 Primary Analysis  
11.4.1 Primary Analysis Population 
All enrolled subjects who receive at least one dose of ibrutinib will be included in the safety and 
response-evaluable populations. 
11.4.2 Sample Size 
The total number of patients needed for this Phase 2 intra-patient dose escalation study is estimated to 
be 22, to accommodate 1 early withdrawal, and simultaneous screening of 2 eligible subjects for the 
last accrual slot.  Accrual of 1 to 2 patients a month is anticipated.  The historical rate of complete 
response (CR) in this setting is on the order of 7 to 8%.36 8% will be taken as a null hypothesis for an 
informal power calculation to describe the precision furnished by this study.  With a minimum of 
20 patients evaluable for CR, there is 80% power to reject a CR rate of 8% with a one-sided 
significance level of 5%, if the true CR rate is 32% or better.  
Efficacy Analysis  
Efficacy analysis will be performed on the intent-to-treat population but will also detail the response 
rates for evaluable patients (those who receive at least one dose of venetoclax). 
Overall Response Rate 
A 95% confidence interval based on binomial distribution will be constructed for the calculated 
ORR.  
Duration of Response 
Duration of response will be analyzed by Kaplan-Meier methodology using data for all enrolled 
subjects.  Median duration of response will be calculated and the corresponding 95% confidence 
interval will be presented. 
Time-to-progression (TTP)  
TTP will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects.  Median 
time TTP will be calculated and 95% confidence interval for median time TTP will be presented. 
Progression-Free Survival 
PFS will be analyzed by Kaplan Meier methodology using data for all dosed subjects.  Median PFS 
time will be calculated and 95% confidence interval for median PFS time will be presented. 
Overall Survival 
OS will be analyzed by Kaplan-Meier methodology using data from all dosed subjects.  Median 
time survival will be calculated and 95% confidence interval for the median time survival will be 
presented. 
Rate of Minimal Residual Disease (MRD) Negativity in the Bone Marrow 
Ninety-five percent (95%) confidence intervals based on the binomial distribution will be provided. 
Time-to-Next Anti-CLL Treatment (TTNT) 
TTNT will be analyzed by Kaplan-Meier methodology using data for all dosed subjects.  Median 
TTNT time will be calculated. 


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11.4.3 Accrual estimates 
It is anticipated that 1-2 patients a month will accrue.   
11.4.4 Safety Analysis 
Safety Endpoints:  
• 
Frequency, severity, and relatedness of AEs 
• 
Frequency, severity and management of TLS 
• 
Frequency of AEs requiring discontinuation of study drug or dose reductions, or leading to death 
All patient safety information collected will be summarized using descriptive statistics (number of 
non-missing values, mean, median, standard deviation, minimum and maximum) for continuous 
variables and counts and percentages for categorical variables, where applicable.  All safety outcome 
information reported will be presented in data listings. 
11.4.5 Pharmacokinetic Analysis 
Values for the pharmacokinetic parameters for ibrutinib and venetoclax including the maximum 
observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area under the plasma 
concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) and 
AUC over a 24-hour dose interval (AUC0-24) will be determined using non-compartmental methods.  
Additional analyses may be performed if useful in the interpretation of the data. 


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12 REFERENCES 
1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS.  Lymphoma incidence 
patterns by WHO subtype in the United States, 1992–2001.  Blood.  2006; 107: 265–76. 
2. Zwiebel JA, Cheson BD.  Chronic lymphocytic leukemia:  staging and prognostic factors.  
Semin Oncol.  1998;25(1):42-59. 
3. American Cancer Society:  Cancer Facts and Figures 2013.  Atlanta, GA:  American Cancer 
Society, 2013. 
4. Sant M, Allemani C, Tereanu C, et al.  Incidence of hematologic malignancies in Europe by 
morphologic subtype:  results of the HAEMACARE project.  Blood.  2010;116(19);3724-34.  
Erratum in:  Blood.  2011;117(12):3477. 
5. Jemal A, Clegg LX, Ward E, et al.  Annual report to the nation on the status of cancer, 1975-2001, 
with a special feature regarding survival.  Cancer.  2004;101(1):3-27. 
6. Dighiero G, Maloum K, Desablens B, et al.  Chlorambucil in indolent chronic lymphocytic leukemia. 
French Cooperative Group on Chronic Lymphocytic Leukemia.  N Engl J Med.  1998;338:1506-14. 
7. Rai KR, Peterson BL, Appelbaum FR, et al.  Fludarabine compared with chlorambucil as primary 
therapy for chronic lymphocytic leukemia.  N Engl J Med.  2000;343:1750-7. 
8. Byrd JC, Rai K, Peterson BL, et al.  Addition of rituximab to fludarabine may prolong 
progression-free survival and overall survival in patients with previously untreated chronic 
lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 
9011.  Blood.  2005;105:49-53. 
9. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and 
rituximab regimen as initial therapy of chronic lymphocytic leukemia.  Blood.  2008;112:975-80. 
10. Hallek M, Fischer K, Fingerle-Rowson G, et al.  Addition of rituximab to fludarabine and 
cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, 
phase 3 trial.  Lancet.  2010;376:1164-74. 
11. Bishop GA, Haxhinasto SA, Stunz LL, et al.  Antigen-specific B-lymphocyte activation.  
Crit Rev Immunol.  2003;23:165–197.   
12. Shaffer AL, Rosenwald A, Staudt LM.  Lymphoid malignancies: The dark side of B-cell 
differentiation.  Nat Rev Immunol.  2002;2:920–932.  
13. Afar DE, Park H, Howell BW, Rawlings DJ, Cooper J, Witte ON.  Regulation of BTK by Src family 
tyrosine kinases.  Mol Cell Biol.  1996;16:3465-71. 
14. Cheng G, Ye ZS, Baltimore D.  Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a 
Src homology 3 domain-mediated interaction.  Proc Natl Acad Sci USA.  1994;91:8152-5. 
15. Humphries LA, Dangelmaier C, Sommer K, et al.  Tec kinases mediate sustained calcium influx via 
site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 
3 linker.  J Biol Chem.  2004;279:37651-61. 
16. Kuppers R.  Mechanisms of B-cell lymphoma pathogenesis.  Nat Rev Cancer.  2005;5:251-62. 
17. Meeker T, Lowder J, Cleary ML, et al.  Emergence of idiotype variants during treatment of B-cell 
lymphoma with anti-idiotype antibodies.  N Engl J Med.  1985;312:1658-65. 
18. Gururajan M, Jennings CD, Bondada S.  Cutting edge: constitutive B cell receptor signaling is 
critical for basal growth of B lymphoma.  J Immunol.  2006;176:5715-9. 


IRB-36705 
 
 
Steven E Coutre, MD  
 
Protocol 10691 dated 27 AUG  2020 
Page 85 of 111  
 
19. Satterthwaite AB, Witte ON.  The role of Bruton's tyrosine kinase in B cell development and 
function: a genetic perspective.  Immunol Rev.  2000;175:120-127. 
20. Willis S, Day CL, Hinds MG, et al.  The Bcl-2-regulated apoptotic pathway.  J Cell Sci.  
2003;116(20):4053-6. 
21. Cory S, Adams JM.  The Bcl-2 family:  regulators of the cellular life-or-death switch.  
Nature Rev Cancer.  2002;2(9):647-56. 
22. Borner C.  The Bcl-2 protein family:  sensors and checkpoints for life-or-death decisions.  
Mol Immunol.  2003;39(11):615-47. 
23. Cory S, Huang DC, Adams JM.  The Bcl-2 family:  roles in cell survival and oncogenesis.  
Oncogene.  2003;22(53):8590-607. 
24. Cimmino A, Calin GA, Fabbri M, et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2.  
Proc Natl Acad Sci USA.  2005;102(39):13944-9. 
25. Calin GA, Cimmino A, Fabbri M, et al.  MiR-15a and miR-16-1 cluster functions in human leukemia.  
Proc Natl Acad Sci USA.  2008;105(13):5166-71. 
26. Souers AJ, Leverson JD, Boghaert ER, et al.  Venetoclax, a potent and selective BCL-2 inhibitor, 
achieves antitumor activity while sparing platelets.  Nat Med.  2013;19(2):202-208. 
27. Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations for the use of 
white blood cell growth factors:  an evidence-based clinical practice guideline.  J Clin Oncol.  
2006;24(19):3187-205 
28. Yamamura K, Kamada S, Ito S, et al.  Accelerated disappearance of melanocytes in bcl-2-deficient 
mice.  Cancer Res.  1996;56(15):3546-50. 
29. Wilson H, O'Connor A, Czuczman S, et al.  Phase 1/2a study of navitoclax (ABT-263) in relapsed or 
refractory lymphoid malignancies.  Haematologica.  2010;95 Suppl 2:116-7.  Abstract 0292. 
30. Yan W, Huang JX, Lax AS, et al.  Overexpression of Bcl-W in the testis disrupts spermatogenesis:  
revelation of a role of BCL-W in male germ cell cycle control.  Mol Endocrinol.  2003;17(9):1868-79. 
31. Sugiyama N, Obinata M, Matsui Y.  Bcl-2 inhibits apoptosis of spermatogonia and growth of 
spermatogonial stem cells in a cell-intrinsic manner.  Mol Reprod Dev.  2001;58(1):30-8. 
32. Oldereid NB, Angelis PD, Wiger R, et al.  Expression of Bcl-2 family proteins and spontaneous 
apoptosis in normal human testis.  Mol Hum Reprod.  2001;7(5):403-8. 
33. Seymour JF, Davids MS, Pagel JM, et al.  Bcl-2 inhibitor venetoclax (GDC-0199) monotherapy 
shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) 
chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).  Presented at:  
55th annual ASH Meeting; December 7-10, 2013; New Orleans, LA.  Abstract 872. 
34. Pan Z, Scheerens H, Li SJ, et al.  Discovery of selective irreversible inhibitors for Bruton's tyrosine 
kinase.  ChemMedChem.  2007;2:58-61. 
35. Herman SE, Gordon AL, Hertlein E, et al.  Bruton tyrosine kinase represents a promising 
therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by 
PCI-32765.  Blood.  2011;117:6287-96. 
36. Byrd JC, Furman RR, Coutre SE, et al.  Three-year follow-up of treatment-naïve and previously 
treated patients with CLL and SLL receiving single-agent ibrutinib.  Blood.  2015;125:2497-506. 
 


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13 APPENDICES 
13.1 Appendix A.  Participant Eligibility Checklist 
The following Participant Eligibility Checklist will be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist will be retained in the patient’s study file, and 
the study’s Regulatory Binder.   
The Study Coordinator, treating Physician and an Independent Reviewer will verify that the participant’s 
eligibility is accurate, complete, and legible in source records.  A description of the eligibility verification 
process will be included in the EPIC or other Electronic Medical Record progress note.  
I. 
Protocol Information  
Protocol Title: An Open Label Phase 1-2 Trial of Venetoclax with Ibrutinib in Relapsed 
and Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic 
Leukemia 
eProtocol Number: IRB-36705  
Principal Investigator: Steven E Coutre, MD 
II. 
Subject Information  
Subject name / Study ID:   
Gender                    Male  
                       Female  
 
III. 
Study Information  
SRC-Approved  
 
IRB-Approved  
 
Contract signed  
 
IV. 
Inclusion / Exclusion Criteria 
Inclusion Criteria 
(From IRB-approved protocol 3.1) 
Yes 
No 
Supporting Documentation* 
1. Voluntarily sign and date an informed consent 
form (ICF) with authorization to use protected 
health information (in accordance with national and 
local subject privacy regulations) and approved by 
the Institutional Review Board (IRB) prior to 
initiation of any study specific procedures 
 
 
 
2. Diagnosis of chronic lymphocytic leukemia CLL) or 
small lymphocytic leukemia (SLL) meeting 
IWCLL/NCI-WG criteria, and relapsed after or 
refractory to at least 1 prior treatment  
 
 
 


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Inclusion Criteria 
(From IRB-approved protocol 3.1) 
Yes 
No 
Supporting Documentation* 
3. Measurable nodal disease by computed 
tomography (CT) 
 
 
 
4. Adequate hematologic function independent of 
transfusion and growth factor support for at least 
7 days prior to screening [except for pegylated 
G-CSF (pegfilgrastim) and darbepoetin which 
require at least 14 days prior to screening] defined 
as the following.  
• Absolute neutrophil count > 750 cells/mm3 
(0.75 x 109/L) 
• Platelet count > 30,000 cells/mm3 (30 x 109/L) 
without transfusion support; evidence of mucosal 
bleeding; a known bleeding episode within 
3 months of screening; or a history of a 
bleeding disorder  
• Hemoglobin > 8.0 g/dL 
If the bone marrow evaluation shows heavy 
infiltration with underlying disease, growth factor 
support may be administered after screening and 
prior to the first dose of therapy. 
 
 
 
5. Adequate hepatic and renal function defined as: 
• Serum aspartate transaminase (AST) or alanine 
transaminase (ALT) ≤ 2.5 x upper limit of normal 
(ULN) 
• Estimated Creatinine Clearance ≥ 30 mL/min 
(Cockcroft-Gault) 
• Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due 
to Gilbert’s syndrome or of non-hepatic origin) 
 
 
 
6. PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN 
 
 
 
7. Men and women ≥ 18 years of age 
 
 
 
8. Eastern Cooperative Oncology Group (ECOG) 
performance status of 0, 1, or 2 
 
 
 
9. Female subjects who are of non-reproductive 
potential (ie, post-menopausal by history - no 
menses for ≥ 1 year; OR history of hysterectomy; 
OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy).   
OR 
Female subjects of childbearing potential must 
have a negative serum pregnancy test upon study 
entry. 
 
 
 


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Protocol 10691 dated 27 AUG  2020 
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Inclusion Criteria 
(From IRB-approved protocol 3.1) 
Yes 
No 
Supporting Documentation* 
10. Male and female subjects who agree to use highly 
effective methods of birth control (eg, condoms, 
implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs], sexual 
abstinence, or sterilized partner) during the period 
of therapy and for 90 days after the last dose of 
study drug. 
 
 
 
 
Exclusion Criteria 
(From IRB-approved protocol 3.2) 
Yes 
No 
Supporting Documentation* 
1. Prior treatment with either venetoclax or ibrutinib. 
 
 
 
2. Vaccinated with live, attenuated vaccine(s) within 
28 days prior to first dose of study drug. 
 
 
 
3. Received an allogeneic stem cell transplant in the 
past 1 year and must not have active cGVHD if 
over 1 year post allogeneic transplant. 
 
 
 
4. Richter’s transformation confirmed by biopsy. 
 
 
 
5. Active uncontrolled autoimmune cytopenias  
 
 
 
6. Chemotherapy ≤ 21 days prior to first 
administration of study treatment and/or 
monoclonal antibody ≤ 4 weeks prior to first 
administration of study treatment. 
 
 
 
7. History of other malignancies, except: 
• Malignancy treated with curative intent and with 
no known active disease present for ≥ 3 years 
before the first dose of study drug and felt to be 
at low risk for recurrence by treating physician. 
• Adequately treated non-melanoma skin cancer or 
lentigo maligna without evidence of disease. 
• Adequately treated carcinoma in situ without 
evidence of disease. 
 
 
 
8. Concurrent systemic immunosuppressant therapy 
(eg, cyclosporine A, tacrolimus, etc, or chronic 
administration [> 14 days] of > 20 mg/day of 
prednisone) within 28 days of the first dose of study 
drug. 
 
 
 
9. Recent infection requiring systemic treatment that 
was completed ≤ 14 days before the first dose of 
study drug. 
 
 
 


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Protocol 10691 dated 27 AUG  2020 
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Exclusion Criteria 
(From IRB-approved protocol 3.2) 
Yes 
No 
Supporting Documentation* 
10. Unresolved toxicities from prior anti-cancer therapy, 
defined as having not resolved to Common 
Terminology Criteria for Adverse Event (CTCAE, 
version 4.03), Grade ≤ 1, or to the levels dictated in 
the inclusion/exclusion criteria except for alopecia. 
 
 
 
11. Known bleeding disorders (eg, von Willebrand’s 
disease) or hemophilia 
 
 
 
12. History of stroke or intracranial hemorrhage within 
6 months prior to first dose of study drug. 
 
 
 
13. Known history of human immunodeficiency virus 
(HIV) or active with hepatitis C virus (HCV) or 
hepatitis B virus (HBV).  
Subjects who are positive for hepatitis B core 
antibody or hepatitis B surface antigen must have a 
negative polymerase chain reaction (PCR) result 
before enrollment.  Those who are PCR-positive 
will be excluded. 
 
 
 
14. Any uncontrolled active systemic infection. 
 
 
 
15. Major surgery within 4 weeks of first dose of study 
drug 
 
 
 
16. Any life-threatening illness, medical condition, or 
organ system dysfunction that, in the investigator’s 
opinion, could compromise the subject’s safety or 
put the study outcomes at undue risk. 
 
 
 
17. Currently active, clinically significant cardiovascular 
disease, such as uncontrolled arrhythmia or Class 
3 or 4 congestive heart failure as defined by the 
New York Heart Association Functional 
Classification; or a history of myocardial infarction, 
unstable angina, or acute coronary syndrome 
within 6 months screening. 
 
 
 
18. Unable to swallow capsules; malabsorption 
syndrome;  disease significantly affecting 
gastrointestinal function;  resection of the stomach 
or small bowel;  symptomatic inflammatory bowel 
disease or ulcerative colitis;  or partial or complete 
bowel obstruction 
 
 
 
19. Concomitant use of warfarin or other Vitamin K 
antagonists 
 
 
 
20. Received a strong cytochrome P450 (CYP) 3A 
inhibitor or inducer within 7 days prior to the first 
dose of ibrutinib, OR subjects who require 
continuous treatment with a strong 
cytochrome P450 CYP3A inhibitor or inducer 
(see Appendix C)  
 
 
 


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Exclusion Criteria 
(From IRB-approved protocol 3.2) 
Yes 
No 
Supporting Documentation* 
21. Lactating or pregnant. 
 
 
 
22. Unwilling or unable to participate in all required 
study evaluations and procedures. 
 
 
 
23. Unable to understand the purpose and risks of the 
study  
 
 
 
24. Subjects with chronic liver disease with hepatic 
impairment Child-Pugh class B or C 
 
 
 
* All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject 
self-report, and medical record review.   
By signing this form of this trial I verify that this subject is:  
 eligible / 
 ineligible for participation in 
the study.  This study is approved by the Stanford Cancer Institute Scientific Review Committee, the 
Stanford IRB, and has finalized financial and contractual agreements as required by Stanford School of 
Medicine’s Research Management Group.   
Treating Physician Signature: 
Date:   
Printed name: 
 
Secondary Reviewer Signature: 
Date:   
Printed name: 
 
Study Coordinator Signature: 
Date:   
Printed name: 


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13.2 Appendix B.  ECOG Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
**Oken,MM, Creech RH, Tormey DC, et al.  Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group.  Am J Clin Oncol.  1982;5:649-655. 
Available at:  http://www.ecog.org/general/perf_stat.html.  Accessed 4 January 2008. 
13.3 Appendix C.  Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A are defined as follows.   
Note that this is not an exhaustive list.  Further information can be found at the following websites: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ and   
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm080499.htm 
Refer to Section 4.3.3.1 on instructions for concomitant use of CYP3A inhibitors and inducers with 
ibrutinib and venetoclax. 
 
CYP3A inhibitors: 
Strong 
Moderate  
Weak 
boceprevir 
aprepitant 
alprazolam 
clarithromycin 
amprenavir 
amiodarone 
cobicistat 
atazanavir 
amlodipine 
conivaptan 
ciprofloxacin 
atorvastatin 
indinavir 
crizotinib 
bicalutamide 
itraconazole 
darunavir/ritonavir 
cilostazol 
ketoconazole 
dronedarone 
cimetidine 
lopinavir 
erythromycin 
cyclosporine 
mibefradil 
diltiazem  
fluvoxamine 
nefazodone 
fluconazole 
fluoxetine 


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CYP3A inhibitors: 
Strong 
Moderate  
Weak 
nelfinavir 
fosamprenavir 
ginkgo 
posaconazole 
imatinib 
goldenseal 
ritonavir 
verapamil 
isoniazid 
saquinavir 
 
nilotinib 
telaprevir 
 
oral contraceptives 
telithromycin 
 
pazopanib 
troleandomycin 
 
ranitidine 
voriconazole* 
 
ranolazine 
 
 
suboxone 
 
 
tipranavir/ritonavir 
 
 
ticagrelor 
 
 
zileuton 
 
CYP3A inducers: 
Strong 
Moderate  
Weak 
avasimibe 
bosentan 
amprenavir 
carbamazepine 
efavirenz 
aprepitant, 
phenobarbital 
etravirine 
armodafinil 
phenytoin 
modafinil 
clobazamechinacea 
rifabutin 
nafcillin 
glucocorticoids (eg, prednisone) 
rifampin 
oxcarbazepine 
nevirapine 
St John’s Wort 
troglitazone 
pioglitazone 
 
 
rufinamide 
 
 
vemurafenib 
 
Substrates of P-gp 
aliskiren 
fexofenadine 
saxagliptin 
ambrisentan 
lapatinib 
sirolimus 
colchicines 
loperamide 
sitagliptin 
dabigatran etexilate 
maraviroc 
talinolol 
digoxin 
nilotinib 
tolvaptan 
everolimus 
ranolazine 
topotecan 
 
Inhibitors of P-gp (Venetoclax) 
amiodarone 
cyclosporine 
quinidine 
azithromycin 
dronedarone 
ranolazine 
captopril 
felodipine 
ticagrelor 
carvedilol 
quercetin 
 
 


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BCRP (Venetoclax only) 
Substrates  
Inhibitors  
methotrexate 
cyclosporine 
mitoxantrone 
geftinib 
irrinotecan 
 
lapatinib 
 
rosuvastatin 
 
sulfasalazine 
 
topotecan 
 
 
OATP1B1/B3 (Venetoclax only) 
Substrates  
Inhibitors  
atrasentan 
gemfibrozil 
atorvastatin 
eltrombopag 
ezetimibe 
cyclosporine 
fluvastatin 
tipranavir 
glyburide 
 
olmesartan 
 
rosuvastatin 
 
simvastatin acid 
 
pitavastatin 
 
pravastatin 
 
repaglinide 
 
telmisartan 
 
valsartan 
 
* Allowed to dose with 140 mg ibrutinib based on clinical data 
Note that this is not an exhaustive list.  Further information can be found at the following websites: 
• http://medicine.iupui.edu/clinpharm/ddis/main-table/ and  
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08 0499.htm.  
In addition to the medications listed in this table, subjects receiving venetoclax should not consume grapefruit, 
grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruits. 


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13.4 Appendix D.  Modified 2008 IWCLL Criteria for Tumor Response 
 


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13.5 Appendix E.  Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS) 
Section 1:  First Dose of Venetoclax or Dose Escalation 
• 
Within the first 24 hours after either the first dose or dose escalation, if any laboratory criteria below 
are met, the patient should be hospitalized for monitoring and the investigator notified.  No 


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additional venetoclax doses should be administered until resolution.  A rapidly rising serum 
potassium is a medical emergency. 
• 
Nephrology (or other acute dialysis service) must be consulted/contacted (per institutional 
standards to ensure emergency dialysis is available) upon admission for any subject hospitalized 
prophylactically or in response to laboratory changes. 
• 
IV fluids (eg, D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr rounded to the 
nearest 10 mL (target 150 to 200 mL/hr;  not < 50 mL/hr).  Modification of fluid rate should also be 
considered for individuals with specific medical needs. 
• 
Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, vomiting, diarrhea, 
diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status changes, 
confusion and seizures).  If any clinical features are observed, recheck potassium, phosphorus, 
uric acid, calcium and creatinine within 1 hour STAT. 
• 
Vital signs should be taken at time of all blood draws or any intervention. 
• 
The management recommendations below focus on the minimum initial responses required.  If a 
diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary management 
will be per institutional protocols. 
In addition to the recommendations below, for patients receiving the first dose of venetoclax: 
• 
For potassium increase ≥ 0.5 mmol/L from baseline, or any value > 5.0 mmol/L, recheck potassium, 
phosphorus, uric acid, calcium and creatinine within 1 hour STAT and follow first guideline. 
• 
For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT. 
If Potassium ≥ 0.5 mmol/L increase from prior value (even if potassium within normal limits [WNL]) 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT.   
If further ≥ 0.2 mmol/L increase in potassium, but still < upper limit of normal (ULN), manage as per 
potassium ≥ ULN.   
Otherwise recheck in 1 hour.  Resume per protocol testing if change in potassium is < 0.2 mmol/L, 
and potassium < ULN, and no other evidence of tumor lysis.   
At the discretion of the investigator, may recheck prior to hospitalization.  If stable or decreased, 
and still WNL, hospitalization is at the discretion of the investigator.  Potassium, phosphorus, 
uric acid, calcium and creatinine must be rechecked within 24 hours. 
If Potassium > upper limit of normal  
Perform STAT ECG and commence telemetry. 
Nephrology (or other acute dialysis service) notification with consideration of initiating dialysis. 
Administer Kayexalate 60 g (or Resonium A 60 g). 
Administer furosemide 20 mg IV × 1. 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is ECG/telemetry evidence of life 
threatening arrhythmias. 


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Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. 
If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 
1, 2 and 4 hours, if no other evidence of tumor lysis. 
If Potassium ≥ 6.0 mmol/L(6.0 mEq/L) and/or symptomatic (eg, muscle cramps, weakness, 
paresthesias, nausea, vomiting, diarrhea) 
Perform STAT ECG and commence telemetry. 
Nephrology (or other acute dialysis service) assessment with consideration of initiating dialysis. 
Administer Kayexalate 60 g (or Resonium A 60 g). 
Administer furosemide 20 mg IV × 1. 
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. 
Administer sodium bicarbonate 1 to 2 mEq/kg IV push. 
If sodium bicarbonate is used, rasburicase should not be used as this may exacerbate calcium 
phosphate precipitation. 
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life threatening arrhythmias.  Do not administer in same IV line as 
sodium bicarbonate. 
Recheck potassium, phosphorus, uric acid, calcium and creatinine every hour STAT. 
If Uric acid ≥ 8.0 mg/dL (476 μmol/L) 
Consider rasburicase (dose based on local guidelines and/or institutional standards). 
If rasburicase is used, sodium bicarbonate should not be used as this may exacerbate calcium 
phosphate precipitation. 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. 
If Uric acid ≥ 10 mg/dL (595 μmol/L) OR Uric acid ≥ 8.0 mg/dL(476 μmol/L) with 25% increase and 
creatinine increase ≥ 0.3 mg/dL (≥ 0.027 mmol/L) from pre-dose level 
Administer rasburicase (dose based on local guidelines and/or institutional standards). 
When rasburicase is used, sodium bicarbonate should not be used as this may exacerbate calcium 
phosphate precipitation. 
Notify nephrology (or other acute dialysis service). 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. 
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours, later, if no other evidence of tumor lysis. 
If Calcium ≤ 7.0 mg/dL (1.75 mmol/L) AND Patient symptomatic  
(eg, muscle cramps, hypotension, tetany, cardiac arrhythmias) 
Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG monitoring. 
Telemetry. 


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Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. 
If calcium normalized 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 
2 and 4 hours, later, if no other evidence of tumor lysis. 
Calculate corrected calcium and check ionized calcium if albumin low. 
If Phosphorus ≥ 5.0 mg/dL (1.615 mmol/L) with≥ 0.5 mg/dL (0.16 mmol/L) increase 
Administer a phosphate binder (eg, aluminum hydroxide, calcium carbonate, sevelamer hydroxide, 
or lanthanum carbonate). 
Nephrology (or other acute dialysis service) notification (dialysis required for phosphorus 
≥ 10 mg/dL). 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. 
If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours, later, if no other evidence of tumor lysis. 
If Creatinine Increase ≥ 25% from baseline 
Start or increase rate of IV fluids. 
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 to 2 hours STAT. 
Section 2:  Ongoing Dosing of Venetoclax 
Management of electrolyte changes from last value at intervals > 24 hours after either the first dose or 
dose escalation (eg, 48 or 72 hours) are as below. 
Note:  If the patient is hospitalized, no additional venetoclax doses should be administered until 
resolution. 
• 
For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level > upper limit of 
normal. 
o Refer to the management guidelines for electrolyte changes observed within the first 24 hours 
after either the first dose or dose escalation (see prior section). 
• 
If a smaller potassium increase is observed that does not meet the criteria for admission above, 
recheck potassium, phosphorus, uric acid, calcium and creatinine in 24 hours and confirm no 
evidence of tumor lysis prior to further venetoclax dosing. 
• 
For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines for 
electrolyte changes observed within the first 24 hours after either the first dose or dose escalation 
(see prior table). 


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13.6 Appendix F.  Clinical and Laboratory Definition of Tumor Lysis 
Syndrome 
 


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13.7 Appendix G.  Template for Protocol Amendments 
Protocol Amendment < Arabic number> to Stanford IRB-< number>  
< Date>  
Retain this template for your files.   
Please provide a list of changes from the previous IRB-approved version of the protocol.  The list shall 
identify by page and section each change made to a protocol document with hyperlinks to the section in 
the protocol document.  All changes shall be described in a point-by-point format (ie, Page 3, section 
1.2, replace ‘xyz’ and insert ‘abc’).  When appropriate, a brief justification for the change should be 
included. 
 
Item 
Section 
Page(s) 
Change 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
5. 
 
 
 
 


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13.8 Appendix H.  Drug Order Form for Venetoclax 


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13.9 Appendix I.  Drug Order Form for Ibrutinib 


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13.10 Appendix J.  Drug Diary for Ibrutinib 
PATIENT DRUG DIARY INSTRUCTIONS 
Instructions:   The bottles with the study drug, ibrutinib, should be stored at room temperature 
and should not be stored in the bathroom.  Please do not freeze or refrigerate the study drug.  
You will take 420 mg of study drug (3 x 140-mg capsules) by mouth once a day with 8 ounces 
(240 mL) of water (do not take with grapefruit juice or Seville orange juice).  The capsules 
should be swallowed intact.  Do not open capsules or dissolve them in water.   
Each dose (all 3 capsules) should be taken at least 30 minutes before eating and at least 
2 hours after a meal, at around the same time each day.  If a dose is missed, it can be taken 
up to 6 hours after the scheduled time with a return to the normal schedule the following day.  
If it has been more than 6 hours, the dose should be skipped and you must take the next dose 
at the scheduled time the next day.  The missed dose will not be made up and all the capsules 
from the missed dose must be returned to the clinic or hospital at the next visit.   
Please complete the form attached when a dose is missed or reduced. The purpose of this 
form is to help you keep track and remember when/why a dose was missed or reduced.  For 
each day a dose is missed or reduced, complete the date it was missed or reduced and 
specify the reason for the missed or reduced dose.  If you experience any abnormal 
symptoms while taking the study drug, you can also record them on the attached form.  It is 
mandatory that you return this form and your bottles of the study drug to the study staff at each 
visit to the clinic or hospital.  


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PATIENT DRUG DIARY - IBRUTINIB 
Site # 
 
Patient #: 
 
Date Dispensed 
 
Date 
Returned 
 
PI Name 
 
Initial here to confirm that the drug has been maintained at room temperature.                      
Initial here to confirm that no doses of the study drug were missed or reduced.  
Initial here to confirm that no extra doses of the study drug were taken by mistake.     
   
DIARY FOR MISSED OR REDUCED DOSES OF IBRUTINIB 
Date Dose is 
Missed or 
Reduced 
Number of 
capsules taken if 
Missed or 
Reduced 
Reason for Missed or 
Reduced Dose 
Abnormal  Symptoms  
 (if applicable) 
Example: 10/1/2016 
0 
Not feeling well 
Nauseous 
Example: 10/1/2016 
2 
Forgot to take all 3 capsules 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient’s Signature 
 
 
Date 


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13.11 Appendix K.  Drug Diary for Venetoclax 
Subject Calendar/Diary Venetoclax 
Subject Number: 
Date Calendar dispensed: 
Week  
  Day 1 
Venetoclax Study Drug Dosing Instructions 
1. Take 1 dose of Study Drug, by mouth every day, within 30 minutes after 
completion of breakfast or your first meal of the day. 
a. Drink 1 glass of water (approximately 8 oz or 240 mL) when you take your 
Study Drug. 
b. Do NOT chew or crush the Study Drug tablets;  tablets must be swallowed whole. 
c. Use all medication within a bottle before opening another bottle of the same dose 
strength.  Bottle may contain more tablets than are needed.  Return all bottles (including 
empty and partially full) to the clinic.  
2. Record the doses you take in the Daily Calendar: 
a. 
Record dose information daily: 
1) Record Week of treatment. 
2) Record the Date (Month/Day/Year). 
3) Record your current dose. 
4) Record the time that you took your dose. 
5) Record whether your dose was taken within 30 minutes after completion of 
breakfast or your first meal of the day. 
Note:  Store study drug supplies as listed on the label.  Keep out of the reach of children. 


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Subject Number: 
 
WEEK_____DOSING DETAILS 
WEEK_____DOSING DETAILS
WEEK_____DOSING DETAILS 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:______:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 


IRB-36705 
 
 
Steven E Coutre, MD  
 
Protocol 10691 dated 27 AUG  2020 
Page 109 of 111  
 
Subject Number: 
WEEK_____DOSING DETAILS 
WEEK_____DOSING DETAILS
WEEK_____DOSING DETAILS
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:______:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 


IRB-36705 
 
 
Steven E Coutre, MD  
 
Protocol 10691 dated 27 AUG  2020 
Page 110 of 111  
 
Subject Number: 
WEEK_____DOSING DETAILS 
WEEK_____DOSING DETAILS
WEEK_____DOSING DETAILS
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:______:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 


IRB-36705 
 
 
Steven E Coutre, MD  
 
Protocol 10691 dated 27 AUG  2020 
Page 111 of 111  
 
Subject Number: 
WEEK_____DOSING DETAILS 
WEEK_____DOSING DETAILS
WEEK_____DOSING DETAILS
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:______:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Date:___/___/_____ 
Dose:______mg 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Time of dose:_____:_____  am   pm 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
Dose within 30 min of first meal?   Yes   No 
 

ICF_000.pdf: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 1 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Are you participating in any other research studies?   _____ Yes   _____No 
INTRODUCTION TO RESEARCH STUDIES 
You are invited to voluntarily participate in a research study of venetoclax (Venclexta or 
ABT-199, formerly GDC-0199) and ibrutinib (Imbruvica, also known as PCI-32765), an 
experimental (“investigational”) combination treatment for leukemia, being conducted by 
Steven E. Coutre, MD, at the Stanford Cancer Center.  You were selected as a 
possible participant in this study because you have either chronic lymphocytic 
leukemia (CLL) or small lymphocytic leukemia (SLL), and your leukemia is relapsed or 
refractory to currently available treatments.  
This document is to be used as a guide for a discussion between you and your 
Study Doctor and the study team.  This form, called an informed consent document, 
was designed to help you understand why this study is being done; what part of the 
study is “research” or “experimental;”  what will be asked of you if you choose to 
participate; possible risks; any inconveniences or discomforts you may experience; and 
other important information.  This form may also be helpful as a reference if you choose 
to participate, as a reminder of what your role in the study is, and who to contact if you 
have questions at any time during your participation.  You are urged to discuss any and 
all questions you have about this study with members of the study team.  If you wish, 
you can also discuss this study and your role with your family doctor or 
medical provider. 
PURPOSE OF RESEARCH 
The proposed study investigates the use of venetoclax in combination with a standard 
dose of ibrutinib, as a treatment for CLL or SLL.   
The proposed study is called a “Phase 2” study.  The study team hopes to learn if the 
combination of venetoclax and ibrutinib is safe and effective to treat CLL or SLL.  
Venetoclax, as Venclexta, has been approved by FDA for the treatment of patients with 
CLL who have a genetic mutation called “17p deletion;” after at least one prior therapy.  
Ibrutinib, as Imbruvica, has been approved by FDA for the treatment of CLL regardless 
of the presence or absence of the 17p deletion, and also to treat mantle cell lymphoma 
(MCL) after one prior therapy;  relapsed or refractory marginal zone lymphoma (MZL);  
chronic graft-vs-host disease (GvHD);  or Waldenström’s macroglobulinemia (WM).  
Both drugs are being studied in other various disease settings.  
The combination of venetoclax + ibrutinib is being used in this study under a study 
protocol submitted to FDA, in an Investigational New Drug application (IND).  Although 
both drugs are approved by FDA, the drugs continue to be studied in several cancer 
settings, including both CLL and SLL.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 2 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Your normal medical care, or the “Standard of Care,” for CLL or SLL could include 
ibrutinib alone, or venetoclax if you have the 17p deletion, as well as allogeneic stem 
cell transplantation, chemotherapeutic agents; and/or monoclonal antibodies, as well as 
allogeneic hematopoietic cell transplantation (eg, bone marrow transplant).  Some of 
these alternatives may not be right for you.  Your doctor will discuss the specifics of 
your case with you.  Your normal medical care would also include medical exams and 
blood tests, and medical scans to check the status of your cancer such as computed 
tomography (CT) or magnetic resonance imaging MRI scans.  
The use of venetoclax in this research study is investigational (“experimental”).  The 
word “investigational” means that venetoclax is not approved by the FDA for use in the 
United States to treat CLL that does not have the 17p deletion, or to treat SLL.  This 
study is being conducted under an application submitted to FDA, called an 
“Investigational New Drug Application” or “IND.”  
Venetoclax will be provided by the drug manufacturer AbbVie Inc. Ibrutinib will be 
provided by the drug manufacturer Pharmacyclics LLC.  
The other parts of this study that are research (not part of your regular care) are the  
 The collection of blood samples for determinations of drug levels in the blood  
 Blood collection for genetic testing before treatment at Week 1 Day 1, and at the 
Final Study Visit or time of relapse. 
If you decide to terminate your participation in this study, you should notify Dr Coutre at 
650-823-0828.   
This research study is looking for 20 people with CLL or SLL.  The study is being done 
at 2 research sites, Stanford University and City of Hope in Duarte, CA.  Stanford 
University expects to enroll and treat about 15 research study participants.  
This study is being paid for by Pharmacyclics LLC.  Study drugs are being provided by 
Pharmacyclics and AbbVie, Inc.  
VOLUNTARY PARTICIPATION  
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 
You will be informed of any significant new information about this study or the 
study drugs venetoclax and ibrutinib that might affect your willingness to participate in 
this research study. 
You will be told the results of tests that are part of your medical care, but you may not 
be told the results of the research tests, including any future research tests.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 3 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
DURATION OF STUDY INVOLVEMENT  
Your treatment in this research study is initially expected to take up to about 117 weeks, 
followed by continued treatment with ibrutinib alone if you are benefitting.  
After 117 weeks, you may be able to continue treatment with ibrutinib only until you 
withdraw from the study, your cancer gets worse (disease progression), or death.  
Your treatment in this study can continue until one of the following occurs:   
 You withdraw your agreement to continue to take part in this research study  
 You become “lost-to-follow-up”  
 Your cancer becomes worse (disease or tumor progression)  
 You need a treatment that is not allowed in this study  
 You have a different illness that prevents further administration of study drugs  
 You or your doctor decide that the side effects are too severe  
 You are a woman and have become pregnant  
 The study is terminated or  
 You are removed from the research study for any of the following reasons:  
o You do not follow the study team’s instructions for the study.  
o Your Study Doctor determines it is in your best interest. 
o Other unanticipated; appropriate; and/or administrative reasons as 
determined by your doctor or the study sponsor. 
When your participation in this study ends, you may be asked to return for a final visit to 
have some end-of-study evaluations or tests, or to allow medical information to be 
collected about your health after the trial treatment is stopped.  After you finish the 
study, or stop taking the study drug for any other reason, you may continue to be 
checked regularly (physical exams; blood tests; tumor measurements; X-rays; 
other scans, etc) if you continue to have significant side effects from the treatment.  This 
is called follow-up.  Your Study Doctor will follow your progress, in accordance with 
good medical care, for as long as it is felt to be necessary by both you and the doctor, 
unless you ask otherwise.  Many, if not all, of these procedures will be part of your 
regular continued medical care.   
PROCEDURES 
It may be harmful to enter this study while receiving some medications, therefore, you 
may need to stop taking certain medications.  Your Study Doctor will review your 
medications and provide you with specific instructions. 
Before you begin the study, you will need to have certain medical examinations, tests, 
or procedures to find out if you can be in the study.  This is called “screening.”  Some of 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 4 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
these examinations, tests, or procedures may be part of your regular medical care, 
and/or and may be done even if you do not join the study.  If you have had some of 
them recently, they may not need to be repeated.  
Before you join this study, the Protocol Director Steven E. Coutre, MD and/or the 
research study staff will review this document with you, and ask you to sign this 
informed consent document.  After you have signed this document, and received a 
signed copy, the study will begin with a screening visit.   
Screening Visit 
If you choose to participate, the first activity will be Screening.  During the Screening Visit, 
you will be asked to have the following tests and activities or assessments.  These 
evaluations need to be conducted within 28 days of the 1st day of treatment on this study.  
General information:  Information about you, such as date of birth; gender (sex); and 
ethnic origin (“demographic information”).  
Medical history:  Your complete medical history will be reviewed, including: 
 Review of all medicines and/or supplements you are taking or have been taking 
 Questions about any symptoms you are having 
 Surgery and cancer history  
 Tobacco and alcohol use 
 Reproductive status 
Physical examination:  A complete physical exam will be performed, including: 
 Your vital signs, including blood pressure; heart rate; temperature; breathing rate; 
height; weight; and other measurements 
 General examination of your body systems, such as heart and lungs; ear, nose, 
and throat; skin; muscles and joints; stomach and gastrointestinal tract; and 
nervous system 
 You will be asked how well you are able to perform normal daily living activities 
(such as bathing, driving, shopping, working, etc), according to the Eastern 
Cooperative Oncology Group (ECOG) performance evaluation 
 You will be asked about your symptoms  
Blood collection:  Blood collection will typically be from a vein in your arm, using a 
blood collection needle.  This is called venipuncture.  If you have an implanted venous 
access port, this may be used for blood collection.  Standard aseptic (clean) techniques 
will be used.  A total of about 2 tablespoons (30 mL) of blood will be collected for: 
 Complete blood count (CBC) with differential, including red blood cells (RBC, 
oxygen-carrying cells):  white blood cells (WBC, infection-fighting cells); platelets; 
and other blood components. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 5 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Serum chemistry, consisting of tests for blood chemicals that indicate how well 
your body and organs are working, and if you have any significant diseases.  
NOTE:  You may be asked to not drink or eat anything (“fast”) for several hours 
before the test.  
 Coagulation tests to determine how well your blood clots.  
 CLL Blood test, if your 17p deletion status is not known.  A little less than 
1 teaspoon (4 mL) of blood will be collected.  If not collected at Screening, this 
sample will be collected before treatment on the 1st day of treatment.  
 Serum pregnancy test (if you are a woman who can become pregnant.  A urine 
pregnancy test may also be required.  The pregnancy test(s) must be negative 
within 7 days before the 1st dose of the Study Drug.  
 Blood test for certain types of viral infections, including hepatitis viruses.  
These tests are required to participate in this study.  
o Notice pursuant to California Senate Bill 699 (April 2006):  Health care 
providers and laboratories such as those involved in this study are required 
to confidentially report positive HIV or hepatitis B or C test results by 
patient name to the San Mateo County Dept of Public Health and to the 
California Dept of Health Services.  You have the right to refuse the test for 
these viruses, but you will not be able to be in this study.  Additional 
important information is provided below. 
 There are numerous treatment options available to the patient who 
tests positive. 
 There is a risk of false negatives (a false negative is a test result that 
indicates a person does not have a condition, but they really do). 
 There is a need for routine testing. 
 For more information, see California Health and Safety 
Code 120990. 
Electrocardiogram (ECG):  This non-radiation test measures and records the electrical 
activity of your heart.  The procedure is called a 12-lead ECG because 12 wires will be 
attached to your chest near your heart, and at your wrists/arms and ankles/legs with 
adhesive pads.  You will be asked to lie still during the procedure.  A computer will 
make a recording of your heart’s electrical activity, which will tell doctors information 
about how well your heart is working.  
Bone marrow biopsy, consisting of a standard collection of a sample of the marrow 
from within a large bone, typically the hip (pelvis).  The complete tissue sample, called a 
“biopsy,” usually has a small piece of bone and a sample of the pulpy marrow material 
from within the bone, called the “aspirate.”  The doctor will give you a local painkiller, 
and make an incision over the bone to be sampled, and a large needle will be used to 
collect the sample.  Tell the doctor if you think this will make you very uncomfortable.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 6 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
The biopsy will be used for a type of microscopic evaluation called “cytogenetics” and 
other testing to determine or confirm your diagnosis. 
Disease Status / Cancer Assessment:  The extent and severity of your tumor will be 
assessed during the physical exam above, and by a radiologic evaluation (an “X-ray”) 
within 28 days of starting study treatment.  These scans look at the blood flow and the 
extent and activity of your cancer, and are a part of your regular medical care 
(Standard-of-Care, SOC).  The radiologic evaluation may be computed 
tomography (CT) scan; or a magnetic resonance imaging (MRI); or an alternate scan as 
medically necessary.  Regardless of which scan will be conducted, these scans are part 
of your regular medical care.  These procedures are described below: 
CT scan (an “X-ray”) with or without contrast may be performed according to standard 
practice.  The CT scan will be used to look at the blood flow and the extent and activity 
of your cancer.  This scan is part of your normal medical care.  You may be asked to 
not drink or eat anything (“fast”) for several hours before the scan.  The scan will take 
about 30 to 60 minutes.  You will need to remove all jewelry, piercings, and other 
metal items.  A tourniquet will be applied to your arm or leg to help find a vein, and a 
contrast agent will be injected into a vein.  For some patients, the contrast agent may be 
given orally.  The entire scan procedure will take about 30 to 60 minutes.  You will be 
asked to lie still on a long narrow bench, or scanner bed, for up to 45 minutes.  You will 
be asked not to move during the scan and to relax and breathe normally.  A strap and/or 
pillows may be placed across your body to prevent movement.  You may experience 
some discomfort or anxiety from being in the confined space.  If this bothers you too 
much, the study team may provide you with a medication to help you stay calm.  During 
the CT scan procedure, the scanner will rotate around you, and make clicking sounds, 
which is normal.  Tell the CT technician immediately if you have any breathing 
difficulties; sweating; numbness; or heart palpitations.   
IT IS VERY IMPORTANT THAT YOU IMMEDIATELY TELL THE INVESTIGATOR 
AND THE CT TECHNICIAN if any of the following apply to you:  
 You are or could be pregnant. 
 You have, or previously had, kidney problems. 
 You are taking Glucophage (metformin).  
 You have any allergies to medications, contrast agents, iodine, or shellfish, or 
have a history or severe allergies. 
 You have recently taken or received barium (“barium study”) or bismuth, or have 
recently taken Pepto-Bismol; Kaopectate; Maalox; Bismatrol; or other digestive 
aids. 
 You have a cardiac pacemaker or any other biomedical device, such as 
surgical clips, pins; screws; or metal plates in or on your body. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 7 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 You have any body piercings in or near the area of the scan;  
 In some cases, these could mean you should not have a CT scan performed. 
Magnetic Resonance Imaging (MRI):  An MRI, which does not require radiation 
exposure, may be used in place of a CT “X-ray” scan.  The MRI will be performed 
according to standard practice, and will take about 30 to 60 minutes.  MRI machines 
use a powerful magnet and radiofrequency fields to make images of the body interior, 
and to evaluate blood flow and the extent of the cancer.  An MRI scanner is a large, 
tunnel-shaped machine, and uses a strong magnet and radiofrequency magnetic fields 
to make images of the body interior.  This magnet is very strong, and will attract or pull 
on some metals and affect some electronic devices, including magnetic access cards, 
and the magnetic strip on credit / debit /ID cards.  Do not bring any metal objects into 
the magnet room.  Any metal objects that you are carrying or have in your body could 
be a hazard to you or others.  Watches; hearing aids or other removable medical 
devices; jewelry / rings; credit / debit / ID /access cards should be removed.  You will be 
provided a way to secure these items.  Because the magnetic field is so strong, tell the 
study team now, and also tell the MRI operator before entering the MRI room, if any of 
the following apply to you. 
IT IS VERY IMPORTANT THAT YOU IMMEDIATELY TELL THE INVESTIGATOR 
AND THE MRI OPERATOR if you have a cardiac pacemaker or any other biomedical 
device in or on your body. 
 You have any other metal objects in or on your body, such as: 
 Metal plates; pins; screws; surgical clips 
 Medical devices, including hearing aids 
 Other implants 
 Metal fragments in your body, such as bullet fragments or shrapnel fragments 
 Piercings 
 You have ever had a head or eye injury involving metal fragments 
 You have ever worked in a metal or fabrication shop  
 You have a history of severe allergies, or have previously had a reaction to a 
Gadolinium-based contrast agents  
 You have, or previously had, kidney problems 
 You are or could be pregnant 
 In some cases, these could mean you should not have an MRI scan performed 
The scanning procedure is very much like an X-ray, but uses a strong magnetic field 
instead of X-rays.  You will not be able to feel the magnetic field.  You will be asked to 
lie on a long narrow bench for up to 45 minutes while the machine performs the scan.  
You will be asked not to move during the scan and to relax and breathe normally.  During 
this time, you will not be exposed to X-rays, but rather the magnetic field.  During the 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 8 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
scan, the bench you are lying on will move into a narrow space in the scanner.  
Many steps have been taken to make the procedure comfortable, but you may still 
experience some discomfort or anxiety ("claustrophobia”) from being in this 
confined space.  If this bothers you too much, the study team may provide you with a 
medication to help you stay calm.  The scanner will make repetitive tapping noises, 
which can seem very loud inside the scanner.  You may be provided with earplugs or 
headphones to wear.   
IF YOU FEEL DISCOMFORT AT ANY TIME, NOTIFY THE OPERATOR AND YOU 
CAN DISCONTINUE THE EXAM AT ANY TIME. 
Women of Childbearing Potential 
If you are pregnant or currently breast-feeding, you may not participate in this study.  It 
is not known whether the Study Drug is safe for fetuses or breast-fed babies.  A 
pregnancy test, as described above, will be conducted.  
Location:  The location of the Screening Visit will be in the Stanford Cancer Center 
Clinics at 875 Blake Wilbur Dr, or as otherwise directed by study staff. 
Medical imaging may be performed at the following clinic locations.  The Study Team will 
let you know which locations you need to go to:  
Stanford Hospital 
Stanford Cancer Center,  
MRI department, ground floor  
Blake Wilbur Building 
300 Pasteur Dr  
Radiology, ground floor  
Stanford, CA  94305 
900 Blake Wilbur Dr  
Phone (650) 723-6855 
Palo Alto, CA  94306 
  
Phone (650) 723-6855 
Stanford Medicine Outpatient Center 
Stanford Medicine Imaging Center 
Pavilion B 
451 Sherman Ave 
450 Broadway St 
Palo Alto, CA  94306 
Redwood City, CA  94063 
Phone (650) 723-6855 
Phone (650) 723-6855 
Study Treatment  
All participants in this study will receive the anti-cancer study drugs ibrutinib and 
venetoclax.  You may know ibrutinib by the tradename Imbruvica, and venetoclax by the 
tradename Venclexta.  This study tests whether adding venetoclax to ibrutinib therapy 
improves the overall anti-cancer effect for people with CLL or SLL, independent of 
mutation status. 
All participants will receive ibrutinib 420 mg PO daily, or until your CLL / SLL gets worse 
(disease progression).  Venetoclax treatment will start at Week 9 at 20 mg/day, 
increasing each week to 50 mg/day; 100 mg/day; 200 mg/day; and finally 400 mg/day, 
as shown in the following table.    


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 9 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Your Study Doctor will give you a prescription for a medication such as allopurinol to 
reduce your blood levels of uric acid before beginning treatment with venetoclax.  This 
is to help minimize the occurrence of a specific type of adverse reaction 
(tumor lysis syndrome, TLS, discussed later in this document).  Treatment with 
allopurinol or similar may need to be continued for up to 5 weeks.  
Week 
Venetoclax (mg/day) 
Ibrutinib (mg/day) 
1 
0 
420 
9 
20 
420 
10 
50 
420 
11 
100 
420 
12 
200 
420 
13 
400 
420 
14 to 61 
MTD dose 
420 
62+ 
0 
420 
This dose escalation is the same way venetoclax is normally used, except venetoclax 
and ibrutinib are not normally used together.  On Weeks 14 to 117 of treatment, 
participants will take either 400 mg/day venetoclax, or the highest dose they could take 
without having serious side effects.   
You will receive the study drugs venetoclax and ibrutinib in childproof bottles.  Tell the 
study team if childproof bottles are a difficulty for you.   
Study Treatment Period Evaluations 
During the treatment period, you will take the study treatments ibrutinib and venetoclax, 
provided as daily tablets or capsules.  Your Study Doctor will provide the 
study treatments and instructions for days in-between scheduled Study Visits.  You will 
receive a study diary to help you keep track of each study treatment and any adverse 
effects that you experience.  You will also need to record any information related to any 
symptoms/side effects that you experience while taking the study treatments.  You will 
need to bring this diary back to the clinic for review by the study personnel at every 
clinic visit.  The study team will provide instructions for the completion of the study diary.  
Study Visits will be on Treatment Day 1; then Week 5; then weekly for Weeks 9 to 13 
(this is when you will be receiving venetoclax); on Weeks 14; 18; 22; 26; 30; 38; 50; and 
62, and then every 12 weeks thereafter.  The Study Team will tell you how flexible the 
Study Visit Days are.  You will also have to come into the study clinic to provide blood 
samples ONLY on the day after (ie, 24 hours) your first treatment with venetoclax at 
Week 9, and on the day after you start a higher dose of venetoclax, ie, Day 2 of 
Weeks 10, 11, 12, and 13.  You will also be asked to come in for a Study Visit if the 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 10 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
doctor suspects that your cancer has returned (relapsed).  The following tests and 
evaluations will be conducted.  
Medical history:  Your medical information as described above will be reviewed and 
updated, including any side effects that you have experienced since the previous visit.  
Physical examination:  A physical exam with vital signs and ECOG performance 
status, as described above, will be conducted.  
Blood collection:  Blood will be collected as described above.  Except for the samples 
to test for blood levels of the study drugs and for cancer mutation testing, the amount of 
blood collected will be about 1 tablespoon (15 mL).  
 CBC with differential (hematology) 
 Serum chemistry  
 CLL blood test, as described above, if not collected during Screening.   
 Blood for tumor burden testing (ClonoSEQ).  Less than 1 tablespoon (10 mL) of 
blood will be collected to evaluate the extent of your cancer.  These samples will 
be collected on Study Day 1 before your first treatment.  
 Blood for cancer mutation testing.  About 2 tablespoons (30 mL) of blood will be 
collected to evaluate your cancer for genetic mutations.  These samples will be 
collected on Study Day 1 before your first treatment, and at the Final Study Visit or 
time or relapse.  More information about this type of testing is provided below 
under “Your Genetic Data / Tissue Sampling for Research and Genetic Testing.” 
 Blood to test for study drug levels in your blood (pharmacokinetics, pK).  pK 
samples will be collected on Treatment Day 1, and at study Weeks 9 to 13, and at 
Weeks 14; 18; 22; 26; and 30.  On Treatment Day 1, and Day 1 of Weeks 9 to 13, 
blood samples will be collected before study treatment, and at about 1 hour; 
2 hours; 4 hours; 6 hours; and 8 hours after study treatment (about 2 tablespoons 
(30 mL will be collected).  On Day 2 of Weeks 9 to 13, you will also have to come 
into the study clinic for a blood sample collection [about 1 teaspoon (5 mL)].  For 
Weeks 14; 18; 22; 26; and 30, only a single sample [about 1 teaspoon (5 mL)] will 
be collected before study treatment for that week.   
Electrocardiogram (ECG):  As described above, if the Study Doctor feels it is 
necessary to evaluate your current medical condition. 
Bone marrow biopsy:  As described above, if / when the Study Doctor suspects that 
your cancer may have gotten worse (disease progression). 
Disease Status / Cancer Assessment:  As described above.  These assessments will 
occur at the Study Visit that you start venetoclax (Week 9) and continue weekly through 
Week 14, and then at Weeks 18; 22; 26; 30; 38; 50; and 62, and then every 12 weeks 
thereafter.  This will include a CT or MRI scan, as described above, at about Week 9; 
Week 37; and Week 61, and then every 12 weeks thereafter.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 11 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Adverse event monitoring:  During the treatment period, the Study Doctors will 
monitor you for any potential side effects.  If the side effects are severe, the 
Study Doctors may temporarily stop study medication; change the dosage of your study 
medication; or withdraw your medication completely.  
Treatment Discontinuation 
At the time that it is decided you should conclude treatment in this study, you will have a 
final study visit, and the following tests and procedures/assessments will be performed: 
Medical history:  as described above.  
Physical examination:  as described above.  
Blood collection:  Blood will be collected as described above, for hematology; CLL 
blood test; and cancer mutation testing.  About 1 tablespoon (15 mL) will be collected.  
Disease Status / Cancer Assessment:  As described above, with CT or MRI scan.  
Electrocardiogram (ECG):  As described above, if the Study Doctor feels it is 
necessary to evaluate your current medical condition. 
Adverse event monitoring:  as described above.  
Location:  The location of the Study Visits will be at the Study Clinic and the Stanford 
medical imaging locations, as described above.  
End-of-Treatment (about 30 days after last dose) 
When you are finished taking the Study Drugs, you will have the following tests and 
procedures/assessments. 
Medical history:  as described above.  
Physical examination:  as described above.  
Blood collection:  Blood will be collected as described above, for hematology; blood 
chemistry; and cancer mutation testing.  About 3 tablespoons (45 mL) will be collected.  
Electrocardiogram (ECG):  As described above, if the Study Doctor feels it is 
necessary to evaluate your current medical condition. 
Location:  The location of the End-of-Treatment Visit will be at Study Clinic and the 
Stanford medical imaging locations, as described above.  
Study Follow-Up Procedures 
As part of your regular medical care, the study team would like to follow-up with you 
about every 3 months after you finish study treatment.  The following tests and 
procedures/assessments will be conducted. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 12 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Medical history:  as described above.  
Physical examination:  as described above.  
Blood collection:  Blood will be collected as described above, for hematology; blood 
chemistry; and cancer mutation testing.  About 3 tablespoons (45 mL) will be collected.  
Adverse event monitoring:  as described above.  
Disease Status / Cancer Assessment:  As described above, but without CT or MRI 
scan or bone marrow biopsy unless medically justified.  
If necessary, the study team may ask you to return to the center for additional 
study tests (“follow-up tests”) to clarify or confirm data already generated in the study.  
Throughout the study, you will be told the results of tests that are part of your clinical 
care, but you may not be told the results of the tests for research purposes only, 
including the genetic tests and any future research tests.   
Location:  The location of the Study Follow-Up Visit will be at the Study Clinic and the 
Stanford medical imaging locations, as described above.  
Long-term Survival Follow-Up Procedures 
Long-term, the study team may follow-up with you to obtain medical history information, 
as described above.  
Your Genetic Data / Tissue Sampling for Research and Genetic Testing  
Research using tissues, such as from your research blood sample for cancer mutation 
testing, is an important way to try to understand human disease.  Sometimes, research 
may include the testing and study of genes, also known as DNA, and related materials 
called proteins.  This type of testing is also called “genetic analysis” or called 
“pharmacogenomic research.”  You are being given this information because the 
investigators want to include your blood sample in a research project and because they 
want to save the samples for future research.   
There are several things you should know before participating in this study and allowing 
your blood to be studied in this way.  This subject is complicated, and there are 
many considerations.  Ask for more information if you do not understand any part of this 
information.  
Genes are in every cell of your body.  Your genes were inherited from your 
biological parents and carry instructions for the body to grow, develop, and survive.  
Genes are made of a substance called DNA.  Most genes and DNA are identical among 
human beings, but there are small variations between different people.  These small 
genetic differences are why people have their own unique characteristics, such 
hair color, eye color, height, and other characteristics.  Some traits affected by genetics 
are not visible, such as why different people have different responses, including 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 13 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
side effects, to the same drug.  The proteins in your body were determined by 
your genes, and control how your body works.  Differences in genes and therefore 
proteins can affect the way a disease develops, the way drugs act against the disease, 
or the way your body uses the drugs.   
The purpose of this type of research is to understand the cause of disease or the 
bodily response to the treatments (such as safety findings or drug level patterns).  
In this study, the genetic research is being done to see if the treatment reduces the 
detectable levels of genetic material associated with your kind of cancer. 
Agreeing to provide this blood sample is required to participate in this study.  
The data from your sample for this genetic research project will be used for research 
purposes only.  This genetic research sample may be used for additional research 
including:  additional studies of CLL or other types of cancer; as a comparison sample 
(“control sample”) in other cancer studies or in a group of other patients’ samples to 
determine the natural difference in genes and proteins in groups of people with cancer; 
or to develop new gene research techniques.  The sample and/or data generated from 
them will be held by the study team; Stanford; and/or Pharmacyclics LLC (and its 
affiliates and collaborators, eg, Janssen Biotech, Inc.) for many years.  These samples 
and data generated from them may be used for any purpose including research, which 
may lead to the development of medical products such as devices, or new drugs or 
patentable processes and procedures; shared with other researchers; or entered into 
databases, provided confidentiality is upheld.  The information in these databases may 
be kept forever, however, information that could directly identify you will not be included 
in these databases.  
Although you will be told the results of study tests that are part of your regular 
medical care, the genetic testing described here will not be used for decisions about 
your medical care, and there may be no results from this genetic research for 
many years, therefore the results of the genetic testing may not be given to you, your 
doctor, or any other staff at the study center.  
Providing genetic information to others 
Sometimes patients have been required to furnish information from genetic testing for 
health insurance, life insurance, and/or a job.  A Federal law, the Genetic Information 
Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance 
companies, group health plans, and employers with 15 or more employees to 
discriminate against you based on your genetic information.  
Be aware that that GINA 2008 does not specifically protect you against 
genetic discrimination by companies that sell life insurance; disability insurance; or 
long-term care insurance.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 14 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
PARTICIPANT RESPONSIBILITIES  
As a participant, your responsibilities include:    
 Follow the instructions of the Protocol Director and study staff.   
 Drinks lots of water while receiving treatment, especially when taking venetoclax, 
to help reduce the chance of a specific type of adverse event (tumor lysis 
syndrome, TLS, discussed later in this document). 
 Be sure to tell the study staff all your present and past diseases, allergies and any 
drugs or medications you are taking.  This is for your safety.  Other drugs or 
medications includes all prescription drugs; over-the-counter (OTC) drugs; herbal 
preparations; and nutritional supplements.  These may interact with the 
study drugs.  If any other medical provider prescribes new medications for you 
while you are on this study, please contact the study staff before taking the 
new medicine, or have that medical provider contact the study staff before 
prescribing it to you.  You should not take any new non-prescription medicine 
while you are on this study unless you first check with the study staff.  See the 
following precautions.  The Study Team will give you more information.  
Venetoclax should not be taken with 
CYP3A inhibitors or potent CYP3A 
inducers such as warfarin or rifampin.  
Venetoclax should be taken with caution when 
using weak or moderate CYP3A inducers, or 
CYP2C8 and CYP2C9 substrates.  
Also, do not eat grapefruit or grapefruit products;  Seville oranges or 
products such as marmalade containing Seville oranges;  or 
star fruit from 3 days before your first dose of venetoclax through 
the last day of venetoclax treatment, completed due to possible 
metabolic interactions between the fruit and venetoclax .   
 Come to the Study Visits as scheduled.  
 Take the Study Drugs as instructed. 
 Maintain control of the Study Drugs, and keep them in a safe place where children 
cannot access them.  Follow any additional storage instructions that you are 
provided with.  
 Ask questions as you think of them. 
 Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Protocol Director or research study staff to reschedule as soon as you 
know you will miss the appointment. 
 Tell the Protocol Director or study team if you change your mind about staying in 
the study.  
 Tell the Protocol Director or study team about any side effects, doctor visits, or 
hospitalizations that you may have. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 15 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Tell the Protocol Director or study team if you believe you might be pregnant or 
gotten your partner pregnant. 
 Do not breast-feed an infant.  Because many drugs are excreted in human milk 
and because of the potential for serious adverse reactions in nursing infants from 
ibrutinib, breast-feeding should be discontinued during ibrutinib treatment.  
 You must use a medically-approved method of birth control, preferably a 
barrier method, for the duration of the treatment period and for at least 1 month 
after the last day you receive the Study Drug. 
 Keep, complete, and return your study diaries as instructed. 
About Pregnancy  
To participate in this study, you must agree to avoid sexual intercourse or use a 
highly-effective birth-control method(s).  Acceptable methods of birth control are listed 
below.  If you do not use the required birth-control method(s), you may be discontinued 
from this study.  Please ask the Study Doctor or study team if you have any questions.  
 Abstinence  
 Not able to have children / sterilization (eg, tubal ligation / hysterectomy or 
vasectomy for the participant or the partner of a monogamous participant)  
 Hormonal contraceptive, such as birth control pills (must have 2 hormones) or 
approved injected or implanted hormonal methods of contraception  
o Hormonal contraceptive must only be used in combination with a barrier 
method of contraception (eg, condoms or diaphragm)  
 Some IUDs (intrauterine devices) or an intrauterine system (IUS)  
Any or both methods must be judged by the investigator to be effective, and to not 
interfere with the study.  In particular, use of a hormonal contraception must be 
approved by the Study Doctor before you begin taking the Study Drug.  There is a risk 
that pregnancy could still result despite the responsible use of a reliable method of birth 
control.  You agree to notify the investigator as soon as possible of any failure of proper 
use of your birth control method, or if you become pregnant, either of which may result 
in your being withdrawn from the study.   
Women of Childbearing Potential:  If you are a woman capable of having children and 
choose to have sex, it is expected that you will use an effective method of birth control 
to prevent exposing a fetus to a potentially dangerous agent with unknown risk, for 
12 weeks after your last dose of study drug.  The only certain way to be 100% certain 
you will not get pregnant is to not have sex.  You understand that if you are pregnant, if 
you become pregnant, or if you are breast-feeding during this study, you; the fetus 
(unborn child); or the child may be exposed to unknown risks.  To confirm that you are 
not pregnant, you agree to have a pregnancy test done before beginning this research 
study.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 16 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
During the study, if you become pregnant, or you think you may be, you must 
immediately stop taking the Study Drug and tell your Study Doctor.  If you become 
pregnant during the study, the Study Drug may involve unforeseeable risks to the 
unborn baby, and your pregnancy will be followed to determine the outcome.  The 
Information about you;  your pregnancy;  and the birth of your child will continue to be 
collected even after study treatment is stopped. 
Men:  Venetoclax treatment may reduce the ability of a man to produce sperm.  In dogs,  
this effect was not reversible after 4 weeks of dosing.  If you are a male and may wish to 
have children, you should consider sperm banking before treatment with venetoclax.  
The study team can provide you with more information.  
If you are a man, while you are on study treatment and for 12 weeks after your last dose 
of study drug, you must:  
 Prevent pregnancy in your female partners  
 Prevent the possible exposure of a pregnant female to the Study Drug from your 
semen  
 You should inform your female partners of the potential for harm to her or a fetus.  
They should know that if pregnancy occurs, they should promptly notify their 
doctors  
 Not donate sperm  
 If your partner becomes pregnant, you need to tell both the Study Team and her 
physician immediately 
Your doctor will discuss with you whether your preference for birth control is considered 
adequate. 
WITHDRAWAL FROM THE STUDY 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your decision will 
not affect your ability to receive medical care for your disease and you will not lose 
any benefits to which you would otherwise be entitled.   
If you decide to withdraw your consent to participate in this study, you should notify 
Steven E Coutre, MD at 650-823-0828.  To help you safely finish your participation in 
the study, the Study Doctors may ask you to have more tests and you will be asked to 
come into the clinic for an End-of-Treatment Visit after stopping the Study Drug.  The 
Study Doctor will discuss your treatment options with you at this time.  If your 
participation in the study is ended, you must return all study-related supplies, including 
unused Study Drug. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 17 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
If you withdraw from the study, or the study medication is stopped for any reason,  
 Your cancer may get worse.   
 To help you leave the study safely, the Study Doctors may ask you to have more 
tests.   
 The Study Doctors may also ask if you wish to take part in the follow-up portion of 
the study.  If you agree to continue with the follow-up portion of the study, 
information about your health will continue to be collected as described above in 
the Follow-up Procedures section.   
 The Study Doctor will discuss with you the different withdrawal decisions, including 
your options for continued treatment.   
 If your participation in the study ends, you must return all study-related supplies, 
including unused Study Drug. 
 Data and information from your participation may not be removed from the 
research study database and may continue to be used to complete the research 
analysis.  This is discussed in more detail under the heading “Authorization To 
Use Your Health Information For Research Purposes” on the following pages.   
The Protocol Director may also withdraw you from the study and the study medications 
may be stopped, without your consent for one or more of the following reasons: 
 Failure to follow the instructions of the Protocol Director and study staff. 
 The Protocol Director decides that continuing your participation could be harmful 
to you. 
 If your tumor worsens (tumor progression).  
 If you have serious side effects during treatment with Study Drug.  
 You have become pregnant.  
 You need treatment not allowed in the study. 
 The study is stopped by the drug manufacturer; the Study Doctor; the Stanford 
Institutional Review Board (the IRB, a group of people who review the research to 
protect your rights), or by a regulatory agency such as the US FDA. 
 Other administrative reasons. 
 Unanticipated circumstances. 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
There are risks, discomforts, and inconveniences associated with any research study.  
This section describes the reasonably foreseeable risks; discomforts; and 
inconveniences that you may experience.  In addition, because this is a research study, 
there may be risks that are not yet known (“unforeseeable”), including a risk of death 
due to unknown risks.  These deserve careful thought.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 18 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
You should talk with the Study Doctor if you have any questions.  If you do not 
understand what any of the words in this section or elsewhere mean, please ask the 
Study Doctor or study staff to explain these terms to you.  
You must tell the Study Doctor or Study Team about all side effects that you have.  If 
you experience serious problems, you may be asked to return to the study center for 
more tests.  Furthermore, due to the risk of side effects resulting from different 
combinations of drugs (called drug-drug interactions), you must inform the Study Team 
of any medications you are taking, including over-the-counter medicines or 
herbal remedies, during the course of the study, and you must also notify the 
Study Doctor of any other medical treatments or procedures that may be necessary for 
you to undergo.  If you are not honest about your side effects and other medications 
and procedures, it may not be safe for you to stay in the study.  All patients in the study 
will be monitored for side effects.  Your Study Doctor may give you medications or stop 
the study drug(s) for a short time or reduce their dose to try to help lessen some of the 
side effects.   
Each person’s reaction to the study drug may be different.  You may experience a side 
effect that could not be predicted by the Study Doctor.  Please review the side effects 
known to be related to the study drug being evaluated in this study.  You may 
experience many, some, or none of the side effects described below.  Side effects may 
be mild, moderate, or severe, and although they usually subside, they could also be 
permanent.  It is possible that a side effect could be fatal.  
If you experience serious problems, you may be asked to return to the study center for 
more tests.  If you experience the following symptoms of an allergic reaction, contact 
the Study Doctor or the Study Team immediately.  If you are in distress, CALL 911 
immediately.  
 Allergic reaction, including rash, hives and/or itching of the skin, or blisters; 
increased heart rate (a fast pulse or tachycardia); and/or abnormal or increased 
sweating  
 Swelling of the face, mouth, lips, gums, tongue and/or neck 
 Wheezing; shortness of breath; or difficulty breathing  
 Dizziness; confusion; feeling light-headed; pounding or racing heart; and/or 
fainting  
 Fever; chills; weakness; confusion; body aches; cold or flu symptoms; and/or 
feeling tired 
 Easy bruising and/or bleeding 
 Sudden severe headaches; weakness in the arms or legs; difficulty speaking or 
understanding speech; and/or loss of balance 
 Yellowing of the eyes and skin (jaundice), dark-colored urine; and/or gray- or 
clay-colored bowel movement (stools);  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 19 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Upset stomach (nausea),  loss of appetite; tiredness (fatigue); and/r diarrhea 
 Severe skin reactions and/or rash with blisters and peeling skin or spreads quickly, 
which may include open ulcers or sores in the mouth and other areas of the body  
Venetoclax has been administered to at least 567 people with cancer.  The following 
side effects (adverse events) were reported to be related to treatment with venetoclax. 
Most Common Side Effects of the Study Drug Venetoclax [these side effects  
occurred in more than 1 in 10 people taking venetoclax (more than 10%)]   
 Decreased levels of neutrophils in the blood (cells that help fight infection, 
neutropenia 
 Decreased levels of red blood cells and/or hemoglobin (anemia)  
 Decreased levels of platelets in the blood (thrombocytopenia).  May cause bruises 
or even bleeding 
 Upset stomach (nausea)  
 Diarrhea  
 Upper respiratory tract infection (URI)  
Less-likely Side Effects of the Study Drug Venetoclax [these side effects occurred 
in more than 1 in 100 people taking venetoclax (1% to 10%)]  
 Low white blood cell count (WBC, blood cells that help fight infection) with fever 
(febrile neutropenia)  
 Persistent cough with lung inflammation (bronchitis)  
 Lung infection (pneumonia or similar)  
 Respiratory tract infection  
 Viral upper respiratory tract infection  
 Lower respiratory tract infection  
 Flu (influenza)  
 Common cold (nasopharyngitis) 
 Herpes infection (Herpes zoster) 
 Oral herpes  
 Yeast infection of mouth (oral candidiasis) 
 Other Candida infection (candidiasis) 
 Urinary tract infection (UTI) 
 Bacterial skin infection, may become serious (cellulitis) 
 Bacterial infection of the blood (sepsis), a serious condition 
 Reduced levels of calcium in the blood (hypocalcaemia)  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 20 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Increased levels of phosphate in the blood (hyperphosphatemia  
 Increased levels of potassium in the blood (hyperkalemia)  
 Increased levels of uric acid in the blood (hyperuricemia)  
 Tumor lysis syndrome (additional information below) 
Following are specific safety warnings and precautions when taking venetoclax.  
Food Effects  
When you eat your meals relative to when you take your venetoclax can change the 
effects, or the amount of the effect, of venetoclax.  Follow the directions of the study 
team, and try to eat and take your venetoclax at the same time every day.   
Tumor Lysis Syndrome (TLS) 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells 
has occurred with venetoclax treatment, most often right after starting treatment, or if 
the patient has a large or extensive cancer.  The levels of breakdown products in your 
blood may cause changes in kidney function, abnormal heartbeat, or seizures.  This is 
called tumor lysis syndrome (TLS).  Your Study Doctor will give you a medication to 
reduce the chance of TLS, but may still do blood tests to check for TLS.   
Reduced blood levels of infection-fighting cells (neutropenia)  
Venetoclax treatment may reduce your blood levels of a certain type of white blood 
cell (WBC), called neutrophils (neutropenia), or in general (leukopenia) in your blood.  
These types of cells help fight infections, and reduced numbers may mean a greater 
risk of infection.  There may be an increased risk of infection, which can be serious.  
You may receive an additional medication to help boost the levels of these type of cells.   
Other Blood Effects 
Venetoclax treatment may reduce your levels of red blood cells (RBC), which is called 
anemia.  This may make you feel weak or tired, or worsen how weak or tired you feel 
due to other causes.  
Venetoclax treatment may reduce your blood levels of platelets.  This may cause 
bruises or even bleeding, or worsen how easily you bruise or bleed due to other causes.  
Reproductive Effects 
Venetoclax treatment may reduce the ability of a man to produce sperm.  In dogs, this 
effect was not reversible after 4 weeks of dosing.  If you are a male and may want to 
have children, you should consider sperm banking before treatment with venetoclax.  
The study team can provide you with more information.  
Second Cancer 
At least 10 people receiving venetoclax have developed a second, new cancer (a 
different cancer not the same as the first disease).  This number does not include 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 21 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
instances of skin cancer that was not melanoma.  Most patients had one or more other 
risk factors, such as being elderly or having received multiple prior therapies.  No 
pattern was apparent, and no instances of 2nd cancer were considered to be related to 
venetoclax.  
Use with Other Medications, including Vaccines 
There may be risks if venetoclax is used with other medications.  Consult your 
Study Team before taking any additional medications during this study.  Talk with your 
doctor before getting any vaccines during this study.  Use of venetoclax may raise the 
chances of an infection or make the vaccine not work as well. 
Ibrutinib.  The following side effects (adverse events) were reported in people receiving 
ibrutinib. 
Most Common Side Effects of the Study Drug Ibrutinib (these side effects 
occurred in at least 1 in every 5 people taking ibrutinib, 20% or more)   
 Muscle and joint pain (musculoskeletal pain) 
 Low white blood cell count (WBC, blood cells that help fight infection) 
(neutropenia) 
 Bruises  
 Rash  
 Upset stomach (nausea)  
 Increase in frequency of diarrhea (loose or watery stools) 
Less-likely Side Effects (these side effects occurred in at least 1 in every 10 
people taking ibrutinib; 10% or more)  
 Common cold (upper respiratory tract infection)  
 Lung infection (pneumonia)  
 Sores in the mouth (stomatitis)  
 Sinus infection (sinusitis) 
 Skin infection  
 Fever (pyrexia) 
 Low platelet count (cells that help blood to clot) (thrombocytopenia)  
 High blood pressure (hypertension)  
 Headache  
 Joint aches (arthralgia) 
 Vomiting  
 Constipation  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 22 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Swelling of the hands or feet (peripheral edema)  
 Muscle spasms  
Unlikely Side Effects (these side effects occurred in at least 1 in every 100 people 
taking ibrutinib; 1% or more)  
 Non-melanoma skin cancer, such as basal cell carcinoma (BCC) or 
squamous cell carcinoma 
 Severe infection throughout the body (sepsis)  
 Inflammation within the lungs that may lead to permanent damage 
(Interstitial lung disease) 
 Abnormal heart rhythm (atrial fibrillation)  
 Urinary tract infection (UTI)  
 Increased level of uric acid in the blood (hyperuricemia) 
 Dizziness 
 Nose bleed (epistaxis) 
 Small red or purple spots caused by bleeding under the skin (petechiae) 
 Low white blood cell count (WBC, blood cells that help fight infection) with fever 
(febrile neutropenia)  
 Increase in WBC counts (leukocytosis) 
 Increase in lymphocyte (a type of WBC) count (lymphocytosis) 
 Blurry vision 
 Skin redness (erythema)  
 Fingernails or toenails breaking (onychoclasis) 
Rare Side Effects (these side effects occurred in less than 1 in every 100 people 
taking ibrutinib; less than 1%)  
 High levels of cancer cell breakdown products, which may lead to changes in 
kidney function, abnormal heartbeat, or seizures (tumor lysis syndrome) 
 Bleeding around the brain (subdural hematoma) 
 Liver failure (hepatic failure)  
 High WBC count with abnormal clumping that can lead to bleeding 
(leukostasis syndrome) 
 Inflammation of the fatty tissue underneath the skin (panniculitis)  
 Severe rash with blisters and peeling skin, particularly around the mouth, nose, 
eyes and genitals (Stevens-Johnson syndrome)  
 Swollen face, lip, mouth, tongue or throat (angioedema) 
 Itchy rash (urticaria)  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 23 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Abnormal rapid and/or irregular heart rhythm that starts from the lower chambers 
(ventricles) of the heart (Ventricular tachyarrhythmia)  
Serious Side Effects of Ibrutinib – Contact your Study Doctor IMMEDIATELY.  
Most of these side effects listed above have been mild to moderate in severity;  
however severe side effects have occurred.  Some side effects have been severe 
enough to lead to study drug discontinuation, dose modification or reduction, 
hospitalization, disability, and sometimes death.  If any of the events below happen, 
contact your Study Doctor immediately to help prevent the event from getting worse.  If 
the event gets worse or you are in distress, CALL 911.  Your study doctor may also 
choose to stop ibrutinib for a short time or reduce its dose to allow you to recover from 
any side effects.  
Effects on the heart 
Abnormal heartbeats (atrial fibrillation;  atrial flutter;  and/or ventricular tachyarrhythmia) 
) have been reported in patients treated with ibrutinib especially when they also have 
had heart conditions; increased blood pressure; infections; or an abnormal heartbeat in 
the past.  The heartbeat may be fast or irregular causing symptoms such as a pounding 
or racing heart;  chest discomfort;  shortness of breath;  dizziness;  fainting;  
feeling light-headed;  and/or weakness.  You should seek medical attention and notify 
your Study Doctor immediately if you develop any of these symptoms while receiving 
the study drug. 
Interstitial lung disease (ILD)  
Interstitial lung disease is a group of lung disorders in which the tissues become 
inflamed and may become damaged.  Interstitial lung disease is not associated with 
infections (eg, bacteria, viruses, fungi) and has been reported in patients treated with 
ibrutinib.  You should report to your physician if you have cough; or any signs of new or 
worsening respiratory symptoms, such as shortness of breath or difficulty breathing.  
Notify your Study Doctor immediately, as these symptoms could also be due to other 
events, such as heart problems (see above). 
Tumor Lysis Syndrome (TLS) 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells 
have happened during treatment of cancer and sometimes even without treatment.  
This may lead to changes in kidney function, abnormal heartbeat, or seizures.  Your 
study doctor may do blood tests to check for TLS. 
Non-Melanoma Skin Cancer and Other Cancers 
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the 
skin) have been reported with more frequency and may be related to the use of 
ibrutinib.  Other cancers have been reported such as solid tumors and blood cancers, 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 24 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
but their relationship to the use of ibrutinib is unknown.  You should tell your study 
doctor if you develop a new cancer while in the study.  
Hypertension 
Hypertension is also called high blood pressure, and has been commonly reported in 
subjects treated with ibrutinib.  Sometimes, people with high blood pressure may have 
headaches, dizziness, nervousness, sweating, difficulty in sleeping, facial flushing or 
nosebleeds, but in some cases, there may be no symptoms and it may go undetected.  
After starting ibrutinib, your doctor may measure your blood pressure regularly.  You 
should let your study doctor know if you have any of the symptoms of high blood 
pressure which may mean that you have developed hypertension or that your 
hypertension is getting worse.  Your study doctor may adjust existing anti-hypertensive 
medications and/or initiate anti-hypertensive treatment as appropriate. 
Infections 
You may experience viral, bacterial, or fungal infections during treatment with ibrutinib.  
Some of these infections have been associated with hospitalization and death.  Contact 
your Study Doctor immediately if you have fever;  chills;  weakness;  confusion;  
body aches;  cold or flu symptoms;  vomiting;  jaundice;  feel tired;  or feel short of 
breath.  These could be signs of a serious infection.  Your study doctor may start or 
continue medication to help prevent or treat an infection.  
A rare and usually fatal viral disease in the brain, progressive multifocal 
leukoencephalopathy (PML), has been reported in patients treated with ibrutinib in 
combination with rituximab and in patients who were previously treated with rituximab.  
If you experience symptoms such as weakness, paralysis, vision loss and/or 
impaired speech, you should seek medical attention immediately and also tell your 
Study Doctor. 
Bleeding effects  
You may experience bruising or bleeding during treatment with ibrutinib.  Rarely, 
serious or fatal internal bleeding may occur, such as bleeding in your stomach, in your 
intestine, or in or around your brain, sometimes resulting in death.  If you take other 
medicines or supplements that increase your risk of bleeding (such as aspirin, 
non-steroidal anti-inflammatory drugs (NSAIDs) or medicines used to prevent or treat 
blood clots or stroke) ibrutinib may increase this risk.  Blood thinners such as warfarin or 
other vitamin K antagonists should not be taken together with ibrutinib.  Supplements 
such as fish oil and vitamin E preparations should be avoided while taking ibrutinib.  
Seek medical attention immediately and also call your Study Doctor if you have signs 
or symptoms of severe bleeding in or around the brain such as sudden 
severe headaches; weakness in the arms or legs; difficulty speaking or 
understanding speech; or loss of balance.  You should also seek medical attention 
immediately and notify your Study Doctor if you have signs or symptoms of serious 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 25 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
bleeding, such as blood in your stools or urine or bleeding that lasts for a long time or 
that you cannot control. 
Lymphocytosis and leukostasis 
You may experience an increase in the number of lymphocytes, which is a type of white 
blood cell, in your blood (lymphocytosis).  This may occur in the first few weeks of 
treatment and you should not assume that this increase in white blood cells means that 
your disease is worsening.  This increase may last for several weeks to months.  
Increased number of white blood cells in your bloodstream may change the blood flow, 
resulting in bleeding or clotting (leukostasis).  Isolated cases of these events have been 
reported in patients treated with ibrutinib.  Your Study Doctor will monitor your blood 
counts and may administer additional therapy as needed.  Talk to your Study Doctor 
about what your test results mean.  
Decreased blood counts  
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia, 
anemia, and thrombocytopenia) were reported in subjects treated with ibrutinib.  If you 
experience symptoms such as fever; weakness; or easy bruising and/or bleeding; you 
should tell your Study Doctor immediately and seek medical attention.  
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib.  
Symptoms of liver failure include yellowing of the eyes and skin (jaundice), itching of the 
skin, dark-colored urine; gray- or clay-colored bowel movement (stools); confusion; 
upset stomach (nausea),  loss of appetite; tiredness (fatigue); or diarrhea.  You should 
tell your Study Doctor immediately if you have any of these symptoms which may 
suggest liver disease.  Your Study Doctor may be able to diagnose and provide you 
required medical care.  
Allergic reactions  
Sometimes people have allergic reactions to drugs.  Serious allergic reactions can be 
life-threatening.  If you have an allergic reaction to the study drugs, you might develop a 
rash; difficulty breathing; wheezing when you breathe; sudden low blood pressure with 
light-headedness; swelling around the mouth, throat or eyes; a racing heartbeat; and/or 
abnormal or increased sweating.  Before starting the study drug, you must tell your 
Study Doctor about any drug allergies.  You should tell the Study Doctor immediately if 
you have any allergy symptoms listed above.  
Rash 
A maculopapular rash (flat, red areas on the skin with small bumps) has been 
commonly reported in patients treated with ibrutinib alone or in combination with other 
drugs.  Most rashes are mild to moderate in severity and begin 2 to 3 weeks or longer 
after starting ibrutinib.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 26 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
There have been rare reports of severe skin reactions (known as severe cutaneous 
adverse reaction or “SCAR,” involving more than 50% of the body), and/or rash with 
blisters and peeling skin, which may include open ulcers or sores in the mouth and 
other areas of the body (Stevens-Johnson Syndrome).  These skin rashes could be 
life-threatening.  You should notify your Study Doctor immediately if you develop a rash 
that spreads quickly, or if you notice peeling of your skin, with or without ulcers or sores 
in your mouth. 
Interference with other drugs  
Some juices or foods like grapefruit and Seville oranges, as well as some medications, 
may interfere with the way your body processes ibrutinib.  This interference could cause 
the amount of ibrutinib in your body to be higher or lower than expected.  It is also 
possible that taking the study drug with your regular medications or supplements, 
including fish oil, Vitamin E, or other vitamins, may change how your regular 
medications, or your regular supplements, work.  It is very important that you avoid 
grapefruit juice and Seville oranges and tell the Study Doctor about all medications, 
supplements, or herbal medicine like St John’s wort that you are taking during the study.  
You should notify your Study Doctor immediately about any side effects to avoid 
possible harm.  
Other Serious Side Effects of Ibrutinib  
Lymphocytosis and leukostasis (increases in WBC) 
You may experience an increase in the number of lymphocytes, which is a type of white 
blood cell, in your blood (lymphocytosis).  This may occur in the first few weeks of 
treatment and you should not assume that this increase in white blood cells means that 
your disease is worsening.  This increase may last for several weeks to months.  
Increased number of white blood cells in your bloodstream may change the blood flow 
resulting in bleeding or clotting (leukostasis).  Isolated cases of these events have been 
reported in patients treated with ibrutinib.  It is not clear whether ibrutinib will increase 
the number of total white blood cells in the blood, not just the lymphocytes.  This is 
something the Study Team will be looking out for.  Your Study Doctor will monitor your 
blood counts and may administer additional therapy as needed.  Talk to your 
Study Doctor about what your test results mean.  
Tumor Lysis Syndrome (TLS) 
Tumor lysis syndrome (TLS), discussed above, may occur with ibrutinib treatment, and 
may cause changes in kidney function, abnormal heartbeat, or seizures.  Your 
Study Doctor may do blood tests to check for TLS.  
High blood pressure (hypertension)  
High blood pressure, also called hypertension, has been commonly-reported in subjects 
treated with ibrutinib.  Sometimes people with high blood pressure may have 
headaches; dizziness; nervousness; sweating; difficulty in sleeping; facial flushing or 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 27 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
nosebleeds; but in some cases, there may be no symptoms and it may go undetected.  
After starting ibrutinib, your doctor may measure your blood pressure regularly.  You 
should let your Study Doctor know if you have any of the symptoms of high blood 
pressure, which may mean that you have developed hypertension or that your 
hypertension is getting worse.  Your Study Doctor may adjust existing anti-hypertensive 
medications and/or start anti-hypertensive therapy as appropriate.  
Non-Melanoma Skin Cancer and Other Cancers 
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the 
skin) have been reported with more frequency and maybe related to the use of ibrutinib.  
Other cancers have been reported such as solid tumors and blood cancers, the 
relationship to the use of ibrutinib is unknown.  You should tell your Study Doctor if you 
develop a new cancer while in the study.  
Drug interruption for any surgical procedures  
Ibrutinib may increase the risk of bleeding with any surgical procedure.  Ibrutinib should 
be held at least 3 to 7 days before and after surgery depending upon the type of surgery 
and the risk of bleeding.  For emergency surgical procedures, ibrutinib should be 
discontinued (stopped) after the procedure until the surgical site is reasonably healed 
(not oozing fluid).  
Please contact your Study Doctor if you have any surgical procedures and your 
Study Doctor will tell you when to stop ibrutinib and when to restart it following a surgical 
procedure.  
Use with Other Medications, including Vaccines 
There may be risks if ibrutinib is used with other medications.  Consult your Study Team 
before taking any additional medications during this study.  Talk with your doctor before 
getting any vaccines during this study.  Use of ibrutinib may raise the chances of an 
infection or make the vaccine not work as well. 
Risks of Ibrutinib during the Maintenance Phase  
The effects and safety of ibrutinib as maintenance therapy is unknown.  
You may have all, some, or none of the listed side effects of ibrutinib.  Please tell the 
Study Doctor or study staff right away if you have any side effects.  Please tell them if 
you have any other problems with your health or the way you feel during the study, 
whether or not you think they are related to the study drug.  Your Study Doctors and 
nurses will check you closely for side effects.  You may receive medicines or other 
treatments to prevent or reduce some of these effects.  In addition to the risks listed 
above, there could be unknown or unexpected side effects associated with the use of 
ibrutinib.  You will be told in a timely manner, verbally and in writing, of any new 
information, findings, or changes to the way the research will be done that might 
influence your willingness to continue your participation in this study.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 28 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
You should get medical help and contact the Study Doctor or study staff if you have any 
of these or any other side effects during the study.  
In addition, there are other risks and possible discomforts you might experience from 
the study procedures.  The following discusses procedure risks related only to the 
research, and does not include risks of procedures that should be discussed as part of 
your regular medical care.  
 Blood draws:  A blood draw may cause fainting; inflammation of the vein; stinging, 
discomfort, or pain; bruising; discomfort; redness; burning; or bleeding at the site 
where the needle is placed to draw the blood.  There is a slight chance of 
infection.  You may feel dizzy or you may faint.  If you feel faint, you should 
immediately lie down to avoid falling 
 ECG:  Risks from an ECG can include skin irritation and/or a rash from the gel, or 
from wearing or removing the patches. 
 MRI:  The very strong magnetic fields of the MRI machine do not cause generally 
cause harmful effects at the levels used in the machine.  However, there are some 
important considerations.  The magnet will attract or even move some metals and 
affect or damage some electronic devices.  Exposure of the following to MRI 
magnetic fields may cause harm to you or others.   
o Artificial heart valve; a pacemaker; or any other biomedical device in or on 
your body.  These devices could malfunction when exposed to the very 
strong magnetic field.  
o Metal plate; pin; screws; surgical clips; metallic fragments; or any other 
metallic implant in your body.  These pieces of metal could move while in 
your body, causing possible serious injury or death.  
In addition, when you are in the MRI scanner, you may experience discomfort or anxiety 
due to the small amount of space inside the machine, or from the loud noises the MRI 
scanner makes.  You may receive a medication to calm you if you need help with this.  
If you have a history of severe allergies (eg, bee-sting reaction, food, shellfish, or nut 
reactions), or have previously had a reaction to medications or contrast agents, 
in particular, Gadolinium-based contrast agents, you may be at risk of a serious 
reaction, which can be severe and/or life-threatening, including breathing difficulty; 
sweating; numbness; or heart palpitations.  Tell the study team or technician 
immediately if you experience these.  
 Radiologic imaging:  X-ray / CT scans.  A CT scan exposes you to radiation 
(discussed below).  When you are in the scanner, you may experience discomfort 
or anxiety due to be in the small amount of space inside the machine, or from the 
loud noises the scanner makes.  If you become anxious or concerned in tight 
spaces, or from loud noises, tell the study team or technician before the scan.  
You may receive a medication to calm you if you need help with this. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 29 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Bone marrow biopsy:  The most common side effects, which are usually minor, 
include pain; discomfort; bleeding; swelling; scarring; bruising; infection; and fever.  
In extremely rare cases, an allergic reaction to the local anesthetic used to numb 
the biopsy site can occur.  This is a routine procedure, and established institutional 
procedures will be followed.  
 Pregnancy / Reproductive Risk:  There may be known or unknown risks to a fetus 
(unborn child) or the pregnant woman, even if it is the man participating in this 
study.  The effects of ibrutinib on a developing fetus or a child are also unknown; 
therefore women who are pregnant or nursing are not allowed to be in this study.  
Nobody knows what these risks are right now.  Some of these drugs cause women 
to have premature (early) delivery, or to have a child with birth defects.  There is a 
risk that pregnancy could still result despite the responsible use of reliable method 
of birth control.  Detailed information about preventing pregnancy is given 
elsewhere in this document.  
 Women of childbearing potential:  If you believe you might be pregnant, or even if 
you experience a menses cycle (“have your period”), you must inform the 
Protocol Director or study team immediately.   
 Breast-feeding:  It is not known whether ibrutinib or its metabolites are excreted in 
human milk.  Nobody knows what these risks are right now.  Because many drugs 
are excreted in human milk and because of the potential for serious adverse 
reactions in nursing infants from ibrutinib, breast-feeding should be discontinued 
during ibrutinib treatment.  
 Genetic research risks:  This research involves genetic studies and information.  
Procedures have been put into place that are designed to make it very difficult for 
the results from genetic research to be linked to you.  However, even without your 
name or other identifiers, your genetic information is unique to you, and there is a 
remote possibility that someone could trace the information in a central database 
back, and identify you.  There is a remote possibility information from your 
participation in this study could adversely affect you or your family in some way if a 
genetic disorder were discovered.  
 Personal anxiety:  Following are some common concerns that research subjects 
may have. 
o You may be asked sensitive or private questions which you normally do not 
discuss.  It may be necessary to answer some of these questions related to 
your health and medical status. 
o You may feel embarrassed during the physical exam.  You may request 
that the physical exam be done by a clinician of the same gender.  
o You may be concerned about your personal information being revealed.  
Although the Study Team; the IRB; and FDA do their best to protect your 
personal information, this cannot be absolutely guaranteed.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 30 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 Other risks:  Since venetoclax and ibrutinib are investigational when taken in 
combination, there may be other risks that are unknown (“unforeseeable”) at this 
time.   
 You may experience some inconvenience due to the schedule and length of 
Study Visits.  Your doctor may require that you remain in the clinic until very late in 
the day or that you even stay overnight in order to comply with the requested 
blood sampling schedule on some of the pharmacokinetic (PK) days.  
It is important that you report all symptoms and side effects that you experience 
as soon as they occur, whether or not you think they are caused by the 
Study Drug.  Contact the Study Team at (650) 725-4041 or via the Nurse 
Coordinators at (650) 498-6000 (24 hour number).  If you are unable to reach anyone 
at the number(s) listed above, and you feel you may need medical attention, call 911 or 
go to the nearest emergency room.  
POTENTIAL BENEFITS  
It is possible that your condition or health may improve because of your participation in 
this study.  The use of the study treatment, venetoclax plus ibrutinib may help to treat 
your disease.  However, there is no guarantee that you will benefit in this or 
any other way.  
Although you may not directly benefit from participation in this study, information 
learned from this study may help other people in the future, including other people with 
cancer.  
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
ALTERNATIVES 
You do not have to be in this study to receive treatment for your CLL or SLL.  Possible 
alternative treatments and side effects of these treatments depend on the 
characteristics and stage of your cancer.  The effectiveness and side effects of other 
treatments may be different for different people.  Instead of taking part in this study, you 
may choose to:  
 Receive treatment with other chemotherapy drugs, including those approved for 
use in the US, including fludarabine; bendamustine; rituximab; cyclophosphamide; 
and others, alone or in combination.  There are numerous treatments that may or 
may not be suitable for the specifics of your cancer.  
 Participate in another research study with a different study drug or procedure  
 While your type of cancer may be treatable with currently approved and available 
medications and procedures, another alternative is to receive only comfort care, 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 31 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
also called “palliative care,” like painkillers.  These types of treatments do not treat 
your cancer (ie, are not curative), and only make you comfortable (symptom relief).  
If you think you might prefer comfort care, please discuss this with your family, 
friends, and doctor.  NOTE: The Study Doctors do not recommend this decision for 
you at this time, although it is and will remain your decision.  
The Study Doctors will discuss with you the risks and benefits of these alternatives, 
including which other treatments might be suitable for you. 
If you decide that you do not wish to take part in this study and wish to pursue any of 
these, or other alternatives, this will not change your regular medical care or the other 
treatment choices in any way.  
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell the 
Study Director.  You can also tell any other member of the study staff. 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your condition or your willingness to continue 
participation in this study.  After you hear about this information, you have the right to 
withdraw from the program. 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by US Law.  This web site will not include information that can identify you.  
At most, the web site will include a summary of the results.  You can search this 
web site at any time. 
The description of this clinical trial is at https://clinicaltrials.gov/ct2/show/NCT03045328.  
CONFIDENTIALITY 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information will 
not be disclosed except as authorized by you or as required by law.  However, there is 
always some risk that even de-identified information might be re-identified.   
Your research records may be disclosed outside of Stanford, but in this case, you will 
be identified only by a unique code number.  Information about the code will be kept in a 
secure location and access limited to research study personnel.   


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 32 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Patient information may be provided to Federal and other regulatory agencies 
as required.  The US FDA, for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction. 
The purpose of this research study is to obtain data or information on the safety and 
effectiveness of venetoclax and ibrutinib.  The results will be provided to the drug 
manufacturers AbbVie Inc. and Pharmacyclics, LLC;  their affiliates and collaborators 
(eg, Janssen Biotech, Inc.);  the Food and Drug Administration (FDA);  and other federal 
and regulatory agencies as required. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 33 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Authorization To Use Your Health Information  
For Research Purposes 
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law.  Please read it carefully before signing it.   
What is the purpose of this research study and how will my health 
information be utilized in the study? 
This study may help the drug manufacturers and FDA determine if 
development of venetoclax plus ibrutinib as a combination treatment should 
continue.  Information from this study will be submitted to the companies 
supporting this study (AbbVie Inc and Pharmacyclics LLC,  and their 
affiliates and collaborators, eg, Janssen Biotech, Inc.) and international 
regulatory agencies including the FDA.  The results from this 
research study are expected to be presented at scientific or 
medical meetings or published in scientific journals.  You will not be 
personally identified in the publications, although representatives of 
the sponsor and FDA and other international regulatory agencies may 
need to know who you are.   
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study, including receiving any 
research-related treatment.   
Signing the form is not a condition for receiving any medical care outside 
the study.  
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 34 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
the study, except to the extent that the law allows us to continue using your 
information (eg, necessary to maintain integrity of research).  If you wish to 
revoke your authorization for the research use or disclosure of your health 
information in this study, you must write to:  
Steven E. Coutre, MD 
875 Blake Wilbur Dr, MC 5821 
Stanford, CA  94305 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to identifiers 
such as your name and initials; address including ZIP code; 
phone numbers; dates including date of birth; age; sex; race; ethnicity; 
Medicare ID number; medical record number (MRN); and other numbers or 
codes such as your study ID number that might identify you.  During the 
study, researchers will also obtain information about your health status, 
life-style choices, medical history, and medical diagnoses, including family 
medical history and allergies; your current and past medications or 
therapies; your physical examination results including height and weight, 
blood pressure readings, heart rate, breathing rate and temperature; your 
laboratory test results including blood, urine, and pregnancy tests; results 
of procedures, such as cancer assessments, medical scans including MRI 
and CT scans, bone marrow aspiration/biopsy; results of genetic 
and biomarker testing; and medical reports, such as the discharge 
summary and radiology, post-operative, and pathology reports.  The 
researchers will also get information from your medical record 
(including hospital records from the Stanford Healthcare and your 
referring physician’s records).  
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
 The Protocol Director Steven E. Coutre, MD  
 Research Staff 
 The Stanford University Administrative Panel on Human Subjects in 
Medical Research; the Stanford Data and Safety Monitoring 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 35 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
Committee (DSMC); and/or any other unit of Stanford University as 
necessary 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
 Pharmacyclics LLC (and its affiliates, eg, Janssen Biotech Inc.), and 
AbbVie, Inc., or their representatives  
 The Food and Drug Administration (FDA) and/or other state or 
international regulatory authorities 
 The Office for Human Research Protections (OHRP) in the 
US Department of Health and Human Services (DHHS) 
 The US Centers for Medicare & Medicaid Services (CMS), the agency 
responsible for administration of the Medicare program  
 Government agencies to whom certain diseases (like HIV, hepatitis, 
and STDs) must be reported 
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on 31 December 2066 or when the research project ends, 
whichever is earlier.  
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to 
any health information developed as part of this study until it is completed.  
At that point, you would have access to such health information if it was 
used to make a medical or billing decision about you (eg, if included in your 
official medical record).  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 36 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
 
 
___________________________________________ 
____________  
Signature of Adult Participant  
 
 Date 
 
 
___________________________________________ 
Printed Name of Adult Participant  
 
 
 
___________________________________________ 
 
If needed:   Signature of Legally Authorized Representative (LAR)  
 
 
___________________________________________ 
____________  
Printed Name of LAR 
 
Date 
 
 
___________________________________________ 
LAR’s Authority to Act for Participant  
(e.g., parent, guardian, or conservator) 
 
NOTE:  If using the Short Form Consent process for informed consent in 
another language pursuant to an "Alteration of HIPAA Authorization," neither 
the participant nor their LAR should sign the HIPAA “Authorization To Use 
Your Health Information For Research Purposes” above. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 37 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
FINANCIAL CONSIDERATIONS 
Payments 
You will not be paid to participate in this research study.  There is no reimbursement 
offered for any expenses related to your participation in this study.  
This study includes the collection of research samples.  Any of your samples which are 
used in research may result in new products; tests; or discoveries.  In some instances, 
these products may have commercial value, and may be developed and owned by the 
study team; Stanford University; Pharmacyclics LLC (and its affiliates and collaborators, 
eg, Janssen Biotech, Inc.) and/or others.  However, donors of samples do not retain any 
property rights to the samples or data derived from them.  Therefore, you would not 
share in any financial benefits from these products, tests or discoveries. 
Costs 
If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with this study that are not a part of your routine 
medical care.  However, there may be additional costs to you.  These include basic 
expenses like transportation and the personal time it will take to come to the 
Study Visits.   
You and/or your health insurance must pay for services, supplies, procedures, and care 
that are required during this study for routine medical care.  You will also be 
responsible for any co-payments and/or deductibles as required by your 
insurance.  Participation in this study is not a substitute for health insurance.   
Some insurance companies or other 3rd-party payers may not pay for standard-of-care 
procedures or laboratory tests, including hospitalization, when they are done as part of 
a research study.  You should consult with your health benefit plan to determine 
whether your medical costs associated with your care during this study are covered.  
Funding Source  
Pharmacyclics LLC is providing financial support and/or materials (ie, study drugs) for 
this study.  AbbVie, Inc is providing materials (ie, study drugs) for this study.  
Consultative or Financial Relationships   
Dr. Coutre receives no direct compensation from Pharmacyclics and/or AbbVie for the 
conduct of this study. 
COMPENSATION for Research-Related Injury 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 38 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
medical complications from participating in this study.  If such complications arise, the 
Protocol Director and the research study team will assist you in obtaining appropriate 
medical treatment.  In the event that you have an injury or illness that is directly caused 
by your participation in this study, reimbursement for all related costs of care first will be 
sought from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance. 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director and/or the research study staff will 
assist you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
You do not waive any liability rights for personal injury by signing this form. 
CONTACT INFORMATION  
Questions, Concerns, Complaints, or to Report an Injury or Side Effect:  If you 
have any questions, concerns or complaints about this research study, its procedures, 
risks and benefits, or alternative courses of treatment, you should ask the 
Protocol Director, Steven E. Coutre, MD, at (650) 823-0828.  You should also contact 
him at any time if you feel you have been hurt by being a part of this study.  
If you are unable to reach anyone at the number(s) listed above, and you fell you may 
need medical attention, call or go to the nearest emergency room.  
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board (IRB) 
to speak to someone independent of the research team at (650) 723-5244 or toll-free at 
1-866-680-2906.  You can also write to the Stanford IRB, Stanford University, 
3000 El Camino Real, Five Palo Alto Square, 4th Floor, Palo Alto, CA 94306. 
Alternate Contact:  If you cannot reach the Protocol Director, or if you need to change 
your appointment, please contact the Study Team at (650) 725-4041. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 39 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
 
Be informed of the nature and purpose of the experiment;  
 
Be given an explanation of the procedures to be followed in the 
medical experiment, and any drug or device to be utilized;  
 
Be given a description of any attendant discomforts and risks reasonably 
expected;  
 
Be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
 
Be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
 
Be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
 
Be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
 
Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
 
Be given a copy of the signed and dated consent form; and  
 
Be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Steven E. Coutre, MD 
Protocol Title:  An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed and Refractory Chronic 
Lymphocytic Leukemia and Small Lymphocytic Leukemia 
 
 
 
Page 40 of 40 
 
Participant ID: 
IRB Use Only 
Approval Date:   November 14, 2018 
Expiration Date: November 14, 2019 
May we contact you about future studies that may be of interest to you? ___Yes ___No  
Signing your name means you agree to be in this study and that you will receive a copy 
of this signed and dated consent form.  
_______________________________________________ 
Printed Name of Adult Participant 
  
_______________________________________________ 
____________  
Signature of Adult Participant 
 Date 
_______________________________________________ 
If needed: Printed Name of Legally Authorized Representative (LAR) 
  
_______________________________________________ 
____________  
Signature of LAR 
 Date 
_______________________________________________ 
LAR’s Authority to Act for Participant (eg, parent, guardian, or conservator) 
_______________________________________________ 
Printed Name of Person Obtaining Consent (POC) 
 
_______________________________________________ 
____________  
Signature of POC 
 Date  
 
The following witness line is to be signed only if the consent is provided as a summary form and accompanied by a 
short-form foreign language informed consent document. 
_______________________________________________ 
Printed name of witness 
_______________________________________________ 
____________  
Signature of witness 
 Date 
(eg, staff, translator/interpreter, family member, or other person who speaks both English and the 
participant’s language)  
The translated short form must be signed and dated by BOTH the participant (or their LAR) AND the witness.  
The English consent form (“referred to as the "Summary Form" in the regulations”):  
 
Must be signed by BOTH the witness AND the Person Obtaining Consent (POC).  
 
The non-English speaking participant / LAR does NOT sign the English consent.  
 
The non-English speaking participant / LAR should NOT sign the HIPAA participant line.  
 
If the participant / LAR is non-English speaking, the POC must ensure that:  
1) The LAR's Description of Authority is completed, and  
2)  Any questions or options presented by the consent form are documented and initialed by the POC on the 
Summary Form, per the participant's wishes, as they are understood during the consent process. .