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TITLE: An Open-Label Trial of Venetoclax with Ibrutinib in Relapsed or *Refractory* Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia
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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  
| coutre@stanford.edu                                                                        |                                                                                                                  |
|--------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|
| Investigators at other Sites:                                                              |                                                                                                                  |
| Steven Rosen, MD City of Hope National Medical Center 1500 East Duarte Rd Duarte, CA 91010 | Tanya Siddiqi, MD City of Hope National Medical Center 1500 East Duarte Rd Duarte, CA 91010 tanyasiddiqi@coh.org |
| srosen@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

| Table of Contents                                                                                                                                        |                                                                                                                                                  |                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|
| OBJECTIVES, ENDPOINTS, AND OUTCOMES .................................................................17                                                  |                                                                                                                                                  |                                                                                                                                                    |
| 1                                                                                                                                                        | 1.1                                                                                                                                              | Objectives                                                                                                                                         |
| Primary Objectives ..............................................................................................................................17      |                                                                                                                                                  |                                                                                                                                                    |
| 1.1.1                                                                                                                                                    |                                                                                                                                                  |                                                                                                                                                    |
| 1.1.2                                                                                                                                                    | Secondary Objectives .........................................................................................................................17 |                                                                                                                                                    |
| 1.1.3                                                                                                                                                    | Exploratory Objectives .....................................................................................................................17   |                                                                                                                                                    |
| Endpoints (summary) ..................................................................................................................................17 |                                                                                                                                                  |                                                                                                                                                    |
| 1.2                                                                                                                                                      |                                                                                                                                                  |                                                                                                                                                    |
| 1.2.1                                                                                                                                                    | Primary Endpoint(s)                                                                                                                              |                                                                                                                                                    |
| 1.2.2                                                                                                                                                    | Secondary Endpoint(s)                                                                                                                            |                                                                                                                                                    |
| Study Design .                                                                                                                                           |                                                                                                                                                  |                                                                                                                                                    |
| 1.3                                                                                                                                                      |                                                                                                                                                  |                                                                                                                                                    |
| 1.3.1                                                                                                                                                    | Overview .                                                                                                                                       |                                                                                                                                                    |
| 1.3.2                                                                                                                                                    | RANDOMIZATION                                                                                                                                    |                                                                                                                                                    |
| Number of Participants                                                                                                                                   |                                                                                                                                                  |                                                                                                                                                    |
| 1.3.3                                                                                                                                                    |                                                                                                                                                  |                                                                                                                                                    |
| 1.4                                                                                                                                                      | ClinicalTrials.gov Registration, Outcomes, and Results                                                                                           |                                                                                                                                                    |
| 1.4.1                                                                                                                                                    | Interventional model .                                                                                                                           |                                                                                                                                                    |
| Masking                                                                                                                                                  |                                                                                                                                                  |                                                                                                                                                    |
| 1.4.2                                                                                                                                                    | Type of Primary Objective / Outcome .......................................................................................18                    |                                                                                                                                                    |
| 1.4.3                                                                                                                                                    |                                                                                                                                                  |                                                                                                                                                    |
| 1.4.4                                                                                                                                                    | Outcomes Measures for ClinicalTrials.gov Results Reporting ...................................18                                                 |                                                                                                                                                    |
| Regulatory Status of Study Agents ......................................................................................................19               |                                                                                                                                                  |                                                                                                                                                    |
| 1.5                                                                                                                                                      |                                                                                                                                                  |                                                                                                                                                    |
| 1.5.1                                                                                                                                                    | Venetoclax                                                                                                                                       |                                                                                                                                                    |
| 1.5.2                                                                                                                                                    | Ibrutinib                                                                                                                                        |                                                                                                                                                    |
| BACKGROUND .                                                                                                                                             |                                                                                                                                                  |                                                                                                                                                    |
| 2                                                                                                                                                        | 2.1                                                                                                                                              | Study Disease ..................................................................................................................................20 |
| 2.1.1                                                                                                                                                    | Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma...............................20                                                         |                                                                                                                                                    |
| Treatment Options                                                                                                                                        |                                                                                                                                                  |                                                                                                                                                    |
| 2.1.2                                                                                                                                                    |                                                                                                                                                  |                                                                                                                                                    |
| 2.1.3                                                                                                                                                    | Role of BTK and Bcl-2 Family Proteins in CLL/SLL ......................................................21                                        |                                                                                                                                                    |
| 2.2                                                                                                                                                      | Study Drugs                                                                                                                                      |                                                                                                                                                    |
| 2.2.1                                                                                                                                                    | Venetoclax                                                                                                                                       |                                                                                                                                                    |
| 2.2.2                                                                                                                                                    | Ibrutinib.                                                                                                                                       |                                                                                                                                                    |
| 2.3                                                                                                                                                      | Rationale                                                                                                                                        |                                                                                                                                                    |
| Primary Purpose of the Study ......................................................................................................23                    |                                                                                                                                                  |                                                                                                                                                    |
| 2.3.1                                                                                                                                                    |                                                                                                                                                  |                                                                                                                                                    |
| 3                                                                                                                                                        | PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ..................................24                                                             |                                                                                                                                                    |
| __                                                                                                                                                       |                                                                                                                                                  |                                                                                                                                                    |
| Page 2 of 111                                                                                                                                            |                                                                                                                                                  |                                                                                                                                                    |  
| IRB-36705 Steven E Coutre, MD   | Protocol 10691 dated 27 AUG 2020                                    |
|---------------------------------|---------------------------------------------------------------------|
| 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 44Page 3 of 111 23 June 2017             |  
| Steven E Coutre, MD                                                                                                                               | Protocol 10691 dated 27 AUG  2020                                                                                                                  |                                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| Safety Profile ......................................................................................................................45           |                                                                                                                                                    |                                                                                                                                                 |
| 5.1.9                                                                                                                                             |                                                                                                                                                    |                                                                                                                                                 |
| 5.1.10                                                                                                                                            | Rationale for the Starting Dose and Regimen Selected .............................................47                                               |                                                                                                                                                 |
| 5.1.11                                                                                                                                            | Maximum Allowable Dose/ Overdose .............................................................................47                                   |                                                                                                                                                 |
| T Treatment Duration                                                                                                                              |                                                                                                                                                    |                                                                                                                                                 |
| 5.1.12                                                                                                                                            |                                                                                                                                                    |                                                                                                                                                 |
| 5.2                                                                                                                                               | Study Drug Ibrutinib                                                                                                                               |                                                                                                                                                 |
| 5.2.1                                                                                                                                             | Names ...............................................................................................................................48            |                                                                                                                                                 |
| 5.2.2                                                                                                                                             | Formulation ...................................................................................................................48                  |                                                                                                                                                 |
| 5.2.3                                                                                                                                             | Study Cohorts                                                                                                                                      |                                                                                                                                                 |
| 5.2.4                                                                                                                                             | Mechanism of Action ........................................................................................................48                     |                                                                                                                                                 |
| Non-Clinical and Clinical Pharmacokinetics ...............................................................48                                      |                                                                                                                                                    |                                                                                                                                                 |
| 5.2.5                                                                                                                                             |                                                                                                                                                    |                                                                                                                                                 |
| 5.2.6                                                                                                                                             | Summaries of Non-Clinical Pharmacology and Toxicology Studies ......................49                                                             |                                                                                                                                                 |
| 5.2.7                                                                                                                                             | Summaries of Clinical Studies                                                                                                                      |                                                                                                                                                 |
| Major Route of Elimination ..............................................................................................................50       |                                                                                                                                                    |                                                                                                                                                 |
| 5.2.8                                                                                                                                             |                                                                                                                                                    |                                                                                                                                                 |
| 5.2.9                                                                                                                                             | Safety Profile .                                                                                                                                   |                                                                                                                                                 |
| 5.2.9.11 Hypertension                                                                                                                             |                                                                                                                                                    |                                                                                                                                                 |
| 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                                                                                                                      |                                                                                                                                                    |                                                                                                                                                 |
| Study Drug Supply                                                                                                                                 |                                                                                                                                                    |                                                                                                                                                 |
| 5.3                                                                                                                                               |                                                                                                                                                    |                                                                                                                                                 |
| 5.3.1                                                                                                                                             | Venetoclax Drug Supply .                                                                                                                           |                                                                                                                                                 |
| 5.3.2                                                                                                                                             | Ibrutinib Drug Supply                                                                                                                              |                                                                                                                                                 |
| Venetoclax and Ibrutinib Accountability                                                                                                           |                                                                                                                                                    |                                                                                                                                                 |
| 5.4                                                                                                                                               | DOSE MODIFICATIONS AND DISCONTINUATION .                                                                                                           |                                                                                                                                                 |
| 6                                                                                                                                                 | 6.1                                                                                                                                                | Venetoclax Dose Modification .                                                                                                                  |
| Ibrutinib Dose Modification ...................................................................................................................56 |                                                                                                                                                    |                                                                                                                                                 |
| 6.2                                                                                                                                               |                                                                                                                                                    |                                                                                                                                                 |
| 6.3                                                                                                                                               | Dose Modification for Both Venetoclax and Ibrutinib                                                                                                |                                                                                                                                                 |
| 6.4                                                                                                                                               | T Treatment Discontinuation                                                                                                                        |                                                                                                                                                 |
| ADVERSE EVENTS AND REPORTING PROCEDURES .......................................................59                                                 |                                                                                                                                                    |                                                                                                                                                 |
| 7                                                                                                                                                 | 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                             |                                                                                                                                                 |
| time the content of the                                                                                                                           |                                                                                                                                                    |                                                                                                                                                 |
| Page 4 of 111                                                                                                                                     |                                                                                                                                                    |                                                                                                                                                 |  
| Steven E Coutre, MD                                                                                                                                     | Protocol 10691 dated 27 AUG  2020                                                                                                                     |                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|
| Second Malignancy vs Secondary Malignancy .............................................................62                                               |                                                                                                                                                       |                                                                                                                  |
| 7.4.1                                                                                                                                                   |                                                                                                                                                       |                                                                                                                  |
| 7.4.2                                                                                                                                                   | Other Adverse Events of Special Considerations ..........................................................63                                           |                                                                                                                  |
| 7.5                                                                                                                                                     | Case Report Forms (CRFs) for Adverse Event Reporting ...............................................64                                                |                                                                                                                  |
| CORRELATIVE / SPECIAL STUDIES ...................................................................................................65                     |                                                                                                                                                       |                                                                                                                  |
| 8                                                                                                                                                       | 8.1                                                                                                                                                   | Pharmacokinetics Assessments: Collected at Stanford Cancer Institute Site ONLY 65                                |
| 8.2                                                                                                                                                     | Biomarker Assessments                                                                                                                                 |                                                                                                                  |
| 9                                                                                                                                                       | TREATMENT ASSESSMENTS AND STUDY CALENDAR ...................................................66                                                        |                                                                                                                  |
| 9.1                                                                                                                                                     | Study Treatment Schedule                                                                                                                              |                                                                                                                  |
| 9.1.1                                                                                                                                                   | Screening Phase                                                                                                                                       |                                                                                                                  |
| T Treatment Phase                                                                                                                                       |                                                                                                                                                       |                                                                                                                  |
| 9.1.2                                                                                                                                                   |                                                                                                                                                       |                                                                                                                  |
| 9.2                                                                                                                                                     | Study Procedures and Assessments .....................................................................................67                              |                                                                                                                  |
| 9.2.1                                                                                                                                                   | Study Assessments                                                                                                                                     |                                                                                                                  |
| Efficacy Evaluations ................................................................................................................68                 |                                                                                                                                                       |                                                                                                                  |
| 9.2.2                                                                                                                                                   |                                                                                                                                                       |                                                                                                                  |
| 9.2.3                                                                                                                                                   | Study Diagnostics / Procedures ...........................................................................................69                          |                                                                                                                  |
| 9.3                                                                                                                                                     | Table of Assessments / Study Calendar .......................................................................................73                       |                                                                                                                  |
| End-of-Study ........................................................................................................................................76 |                                                                                                                                                       |                                                                                                                  |
| 9.4                                                                                                                                                     | Study Discontinuation                                                                                                                                 |                                                                                                                  |
| 9.4.1                                                                                                                                                   |                                                                                                                                                       |                                                                                                                  |
| 9.4.2                                                                                                                                                   | Publication of Study Results                                                                                                                          |                                                                                                                  |
| Follow-up                                                                                                                                               |                                                                                                                                                       |                                                                                                                  |
| 9.5                                                                                                                                                     | REGULATORY CONSIDERATIONS ........................................................................................................77                  |                                                                                                                  |
| 10                                                                                                                                                      | 10.1                                                                                                                                                  | Institutional Review Board (IRB) Approval of Protocol ........................................................77 |
| Protocol Compliance and Deviations ...........................................................................................77                        |                                                                                                                                                       |                                                                                                                  |
| 10.2                                                                                                                                                    | Compliance with the Protocol ........................................................................................................77               |                                                                                                                  |
| 10.2.1                                                                                                                                                  |                                                                                                                                                       |                                                                                                                  |
| 10.2.2                                                                                                                                                  | Protocol Deviations ...............................................................................................................................77 |                                                                                                                  |
| Protected Subject Health Information Authorization                                                                                                      |                                                                                                                                                       |                                                                                                                  |
| 10.2.3                                                                                                                                                  |                                                                                                                                                       |                                                                                                                  |
| 10.3   Data and Safety Monitoring Plan..............................................................................................78                  |                                                                                                                                                       |                                                                                                                  |
| 10.3.1                                                                                                                                                  | Data Management Plan                                                                                                                                  |                                                                                                                  |
| Investigator Responsibilities                                                                                                                           |                                                                                                                                                       |                                                                                                                  |
| 10.4                                                                                                                                                    |                                                                                                                                                       |                                                                                                                  |
| 10.5                                                                                                                                                    | Protocol Amendments ...........................................................................................................................79     |                                                                                                                  |
| 10.6                                                                                                                                                    | Publication of Study Results..........................................................................................................79              |                                                                                                                  |
| STATISTICAL CONSIDERATIONS                                                                                                                              |                                                                                                                                                       |                                                                                                                  |
| 11                                                                                                                                                      | 11.1                                                                                                                                                  | Statistical Design                                                                                               |
| 11.1.1                                                                                                                                                  | Treatment Assignment ..............................................................................................................80                 |                                                                                                                  |
| __                                                                                                                                                      | __                                                                                                                                                    |                                                                                                                  |
| Page 5 of 111                                                                                                                                           |                                                                                                                                                       |                                                                                                                  |  
E  
| Steven E Coutre, MD                                                                            | Protocol 10691 dated 27 AUG 2020                                                                                                 |
|------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|
| 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 |                                                                                                                                  |  
| 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.Page 7 of 111 23 June 2017                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
E  
| Steven E Coutre, MD                                                                                  | Protocol 10691 dated 27 AUG 2020                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Secondary                                                                                            | For the combination of venetoclax and ibrutinib:                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                   |
| Endpoint(s)                                                                                          | -                                                                                                                                                                                                                                                                                                                             | 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                                                                                                                        |                                                                                                                                                                                                                                                                                                   |
| -                                                                                                    | Time to next CLL treatment (TNT)                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                   |
| Exploratory  Objectives                                                                              | -                                                                                                                                                                                                                                                                                                                             | 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                                                                                           | Inclusion Criteria                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                   |
| Eligibility 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 Page 8 of 111 23 June 2017 |                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                   |  
E  
| Steven E Coutre, MD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Protocol 10691 dated 27 AUG 2020                                                                                                                                                                                                                                                                                                                                   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 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)Page 9 of 111 23 June 2017 |                                                                                                                                                                                                                                                                                                                                                                    |  
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 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 Page 10 of 111 23 June 2017 |                                                |  
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| Steven E Coutre, MD                                                                                                                                                                                         | Protocol 10691 dated 27 AUG 2020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 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. All efficacy analyses will be performed using the intent-to-treat (ITT)                                                |
| Statistical  Considerations                                                                                                                                                                                 | 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.Page 11 of 111 23 June 2017                                                                                                                                                                                                                 |
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secondary efficacy analysis overall response

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.
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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.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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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   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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.
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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
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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 Page 13 of 111 23 June 2017   |
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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. |  
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:  
  
| 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 | International Workshop on Chronic            |
| NCI-WG                                           | 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                               | PFS   | Progression-free survival                    |
| Adverse Events                                   |                                                               |       |                                              |
| 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                          | SRC   | Scientific Review Committee                  |
| Mental Disorders (4th edition)                   |                                                               |       |                                              |
| 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                                   | USP   | United States Pharmacopeia                   |
| Harmonization                                    |                                                               |       |                                              |
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1 objectives endpoints and outcomes

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.
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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.
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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.
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1.2 endpoints (summary)

Endpoints for this study are presented in greater detail in Section 11.2 Endpoints.
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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.  
| Week     | Venetoclax   | Ibrutinib   |
|----------|--------------|-------------|
| (mg/day) | (mg/day)     |             |
| 1        | 0            | 420         |
| 9        | 20           | 420         |
| 10       | 50           | 420         |
| 11       | 100          | 420         |
| 12       | 200          | 420         |
| 13-117   | 400          | 420         |
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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.
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1.4 clinicaltrials.gov registration outcomes and

The intervention model of this study is a single group study.
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1.4.3 type of primary objective

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).
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1.4.4 outcomes measures for clinicaltrials.gov

- **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).  
- **Time Frame**: The time frame for assessment of the primary outcome / primary endpoint is 62 weeks.
- **Safety Issue**: Does not assess a safety issue.
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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
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1.5 regulatory status of study

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.
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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.
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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

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.
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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

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.
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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.
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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.
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2.3.1 primary purpose of the

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

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.
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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
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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.  
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.
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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
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3.5 study timeline 3.5.1 completion

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.
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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

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.
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4.2 toxicity management

Adverse event management and dose modifications are outlined in Section 6 Dose Modifications.
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4.3 general concomitant medication and

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.  
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.  
| Risk Categories for   | TLS Risk Category Criteria                                                                                                                                 |
|-----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Developing TLS 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 Any measurable lymph node with the largest diameter ≥ 10 cm, |
| High                  | OR ALC ≥ 25 × 109 /L AND any measurable lymph node with the  largest diameter ≥ 5 cm but < 10 cm                                                           |
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4.3.1.1 first dose of venetoclax

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
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:
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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.
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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).  
- 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.
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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
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.
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4.3.1.2 dose escalation of venetoclax

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
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:
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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.
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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
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.
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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.
E
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.
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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.
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4.3.3 concomitant medications to be

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.  
| Patient                                                                                                                 | Co-administered Drug                                                                                                                                                                                                                                                                                                                                                                                                                     | Recommended Ibrutinib Dose      |
|-------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|
| Population                                                                                                              | for the Duration of the Inhibitor  Usea                                                                                                                                                                                                                                                                                                                                                                                                  |                                 |
| B-Cell                                                                                                                  | Mild CYP3A inhibitors                                                                                                                                                                                                                                                                                                                                                                                                                    | 420 mg or 560 mg once daily per |
| Malignancies                                                                                                            | 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. 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  Other strong CYP3A inhibitors Posaconazole at higher  dosesb                                                                                                                                                                                                                                                                     |                                 |  
Table . Ibrutinib Dose Modification Guidance for Co-Administration with CYP3A 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

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.
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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.