Conditions: Follicular Lymphoma Lymphoma, Large B-Cell, Diffuse
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will evaluate the safety, efficacy, and pharmacokinetics of obinutuzumab in combination with idasanutlin and venetoclax in participants with R/R FL and obinutuzumab or rituximab in combination with idasanutlin and venetoclax in participants with R/R DLBCL. The study will include an initial dose-escalation phase followed by an expansion phase. The dose-escalation phase is designed to determine the recommended phase II doses (RP2Ds) and regimen for idasanutlin and venetoclax in combination with obinutuzumab for FL participants and in combination with rituximab for DLBCL participants.

Detailed description:

Arms:
arm 1: Induction Treatment: Participants will receive either Regimen A or Regimen B. Regimen A: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Regimen B (in bridging cohort): Participants will receive obinutuzumab alone in Cycle 1 and obinutuzumab with idasanutlin and venetoclax (both at maximum tolerated dose \[MTD\] established from Regimen A) in Cycles 2 to 6. Post-Induction Treatment (Maintenance Treatment): Participants will receive obinutuzumab every 2 months for 24 months; idasanutlin and venetoclax for 6 months. arm 2: Induction Treatment: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. In bridging cohort, participants will receive rituximab on Day 1 of Cycles 1 to 6 and idasanutlin and venetoclax (both at MTD) in Cycles 1 to 6. Post-Induction Treatment (Consolidation Treatment): Participants will receive obinutuzumab or rituximab (according to study treatment received in the induction) every 2 months for 6 months; idasanutlin and venetoclax for 6 months. arm 3: Induction Treatment: Participants will receive idasanutlin and venetoclax at the RP2D of the selected regimen (Regimen A or B) identified during the dose-escalation phase in combination with obinutuzumab. Regimen A: Participants will receive either obinutuzumab on Days 1, 8, 15 of Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin and venetoclax on Days 1 to 5 of Cycles 1 to 6 or obinutuzumab on Days 1, 8, 15 on Cycle 1 and then on Day 1 of Cycles 2 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Regimen B (in bridging cohort): Participants will receive obinutuzumab alone in Cycle 1 and obinutuzumab with idasanutlin and venetoclax in Cycles 2 to 6. Post-Induction Treatment (Maintenance Treatment): Participants will receive obinutuzumab every 2 months for 24 months; idasanutlin and venetoclax for 6 months. arm 4: Induction Treatment: Participants will receive rituximab on Day 1 of Cycles 1 to 6; idasanutlin and venetoclax (both at RP2D) on Days 1 to 5 of Cycles 1 to 6 or rituximab on Day 1 of Cycles 1 to 6; idasanutlin on Days 1 to 5 and venetoclax on Days 1 to 10 of Cycles 1 to 6. Post-Induction Treatment (Consolidation Treatment): Participants will receive rituximab every 2 months for 6 months; idasanutlin and venetoclax for 6 months.

Interventions: intervention 1: Idasanutlin intervention 2: Obinutuzumab intervention 3: Venetoclax intervention 4: Rituximab
Intervention descriptions: intervention 1: Induction Treatment: Idasanutlin tablets will be administered orally once daily at escalated doses (starting dose 100 milligrams \[mg\], maximum 600 mg). Post-Induction Treatment: The dose and regimen will be determined by the Sponsor after review of all relevant data. The dose for maintenance/consolidation will not exceed the dose the participant received during induction. intervention 2: Participants will receive a fixed dose of obinutuzumab, 1000 mg by intravenous (IV) infusion on Days 1, 8 and 15 of Cycle 1 and on Day 1 of each subsequent cycle (Cycles 2 to 6) (each cycle = 28 days) during induction treatment, and on Day 1 of every other month during maintenance treatment (eligible participants with FL only) or during consolidation treatment (eligible participants with DLBCL only). intervention 3: Induction Treatment: Venetoclax tablets will be administered orally once daily at escalated doses (starting dose 200 mg, maximum 800 mg). Post-Induction Treatment: The dose and regimen will be determined by the Sponsor after review of all relevant data. The dose for maintenance/consolidation will not exceed the dose the participant received during induction. intervention 4: Rituximab will be administered by IV infusion at a dose of 375 milligrams per square meter (mg/m\^2) on Day 1 of Cycles 1-6 during induction treatment and on Day 1 of every other month during consolidation treatment.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase Ib/II Study Evaluating the Safety and Efficacy of 
Obinutuzumab in Combination With Idasanutlin and Venetoclax in 
Patients With Relapsed or Refractory Follicular Lymphoma and 
Obinutuzumab or Rituximab in Combination With Idasanutlin and 
Venetoclax in Patients With Relapsed or Refractory Diffuse Large B-
Cell Lymphoma 
NCT Number: 
NCT03135262 
Document Date: 
Protocol Version 4: 13-June-2018 
 
 
 


 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd 
Protocol BH39147, Version 4 
PROTOCOL 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH IDASANUTLIN AND 
VENETOCLAX IN PATIENTS WITH RELAPSED OR 
REFRACTORY FOLLICULAR LYMPHOMA AND 
OBINUTUZUMAB OR RITUXIMAB IN COMBINATION 
WITH IDASANUTLIN AND VENETOCLAX IN 
PATIENTS WITH RELAPSED OR REFRACTORY 
DIFFUSE LARGE B-CELL LYMPHOMA 
PROTOCOL 
NUMBER: 
BH39147   
VERSION NUMBER: 
4 
EUDRACT NUMBER: 2016-002480-34 
IND NUMBER: 
127311 
TEST PRODUCTS: 
Obinutuzumab (RO5072759) 
Rituximab (RO0452294) 
Idasanutlin (RO5503781) 
Venetoclax (RO5537382) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 2:  17 January 2017  
DATES AMENDED: 
Version 3:  1 March 2017 
Version 4:  See electronic date stamp below. 
 
13-Jun-2018 07:09:19
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
2/Protocol BH39147, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE OF CHANGES FROM VERSION 3 TO 4
Changes to Protocol BH39147, along with a rationale for each change, are 
summarized below.

The option to delay, suspend, or terminate enrollment within a given arm has been 
added to the protocol (Section 3.1.1) to allow flexibility in trial management, 
balancing safety and efficacy, due to the nature of the Phase Ib/II study.

Granulocyte colony-stimulating factor (G-CSF) use is now allowed in Cycles 1 and 2 
(dose-limiting toxicity [DLT] observation window) to treat Grade 3 neutropenia in 
the dose-escalation phase to optimize benefit/risk.  The definition for DLT has been 
updated accordingly in Sections 3.1.2.1 and 4.4.1.  Table 17 has been also updated 
to align guidelines for G-CSF use.

The option to open the bridging cohorts upon Sponsor decision based on clinical 
judgment has been added to the protocol (Section 3.1.2.2) to allow flexibility in trial 
management, balancing safety and efficacy, due to the nature of the Phase Ib/II
study.

The option to collect visible manifestation or lymphoma involvement or toxicities has
been added (Section 4.5.3) to allow collection of such data upon additional consent.

Footnote "gg" related to positron emission tomography (PET)-computed tomography 
(CT) at end of induction in Appendix 2 was referenced by mistake.  A new footnote 
"oo" has been added. 

New safety language regarding collection of special situation cases has been
included in the protocol as a corrective measure to address a self-identified process 
gap related to the collection of overdose, medication errors, drug abuse, and drug 
misuse from interventional clinical trials (Sections 4.3.2, 5.4, and 5.4.4).

The duration of male contraception period in Sections 4.1.1, 5.1.4.5, and 5.4.3.2 has
been corrected from 6 months to 3 months based on requirements for each 
treatment drug (no requirement for venetoclax, 3 months each for idasanutlin, 
obinutuzumab, and rituximab).

The duration of female contraception period in Sections 4.1.1 and 5.4.3.1 has been 
clarified based on requirements for each treatment drug (obinutuzumab vs. 
rituximab).  In addition, text has been added to Section 4.1.1 to specify when 
women must refrain from donating eggs.

Instructions about patient withdrawal from the Research Biosample Repository 
(RBR) after site closure have been modified to indicate that the investigator must 
inform the Sponsor of patient withdrawal by emailing the study number and patient 
number to global_rcr-withdrawal@roche.com (see Section 4.5.9.6).
Substantive new information appears in italics.  Additional minor changes have been 
made to improve clarity and consistency and to provide updated language regarding 
safety reporting.  This amendment represents cumulative changes to the original 
protocol.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
3/Protocol BH39147, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Non-Hodgkin’s Lymphoma ........................... 27
1.1.1
Follicular Lymphoma ............................................................. 27
1.1.2
Diffuse Large B-Cell Lymphoma............................................ 27
1.2
Background on Obinutuzumab .............................................. 29
1.2.1
Nonclinical Studies with Obinutuzumab................................. 29
1.2.2
Clinical Studies with Obinutuzumab ...................................... 29
1.2.2.1
Clinical Efficacy of Obinutuzumab in Patients with 
Non-Hodgkin’s Lymphoma .................................................... 30
1.2.2.2
Clinical Safety of Obinutuzumab............................................ 31
1.2.2.3
Clinical Pharmacokinetics of Obinutuzumab.......................... 31
1.3
Background on Idasanutlin .................................................... 32
1.3.1
Quality Development ............................................................. 33
1.3.2
Clinical Studies with RO5045337 and Idasanutlin ................. 34
1.3.2.1
Clinical Pharmacology ........................................................... 37
1.3.2.2
Clinical Safety of Idasanutlin.................................................. 38
1.4
Background on Venetoclax.................................................... 40
1.4.1
Nonclinical Studies with Venetoclax ...................................... 40
1.4.2
Clinical Studies with Venetoclax............................................ 41
1.4.2.1
Clinical Results in Non-Hodgkin’s Lymphoma ....................... 41
1.4.2.2
Clinical Pharmacokinetics and 
Pharmacodynamics ............................................................... 42
1.5
Study Rationale and Benefit-Risk Assessment...................... 43
2.
OBJECTIVES AND ENDPOINTS ............................................................... 46
2.1
Safety Objectives................................................................... 46
2.2
Efficacy Objectives ................................................................ 47
2.2.1
Primary Efficacy Objective..................................................... 47
2.2.2
Secondary Efficacy Objective................................................ 47


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2.2.3
Exploratory Efficacy Objective............................................... 48
2.3
Pharmacokinetic Objectives .................................................. 48
2.4
Biomarker Objective .............................................................. 49
3.
STUDY DESIGN......................................................................................... 49
3.1
Description of Study .............................................................. 49
3.1.1
Overview of Study ................................................................. 49
3.1.2
Dose-Escalation Phase ......................................................... 51
3.1.2.1
Definition of Dose-Limiting Toxicity........................................ 52
3.1.2.2
Treatment Regimens and Dose-Escalation Rules................. 53
3.1.2.3
Use of Modified Continual Reassessment Model 
for Dose and MTD Determination.......................................... 58
3.1.3
Expansion Phase................................................................... 62
3.1.4
Internal Monitoring Committee............................................... 65
3.1.5
Independent Review Committee............................................ 66
3.1.6
Post-Treatment Follow-Up and Survival Follow-
Up.......................................................................................... 66
3.2
End of Study and Length of Study......................................... 66
3.3
Rationale for Study Design.................................................... 66
3.3.1
Rationale for Treatment Combination.................................... 66
3.3.2
Rationale for Dosing Regimen............................................... 72
3.3.2.1
Rationale for Obinutuzumab and Rituximab 
Dosing Regimen.................................................................... 72
3.3.2.2
Rationale for Idasanutlin Dosing Regimen............................. 73
3.3.2.3
Rationale for Venetoclax Dosing Regimen ............................ 74
3.3.2.4
Rationale for Treatment Duration .......................................... 75
3.3.3
Rationale for PET-CT-Based Complete 
Response as the Primary Efficacy Endpoint.......................... 75
3.3.4
Rationale for Biomarker Assessments................................... 76
3.3.4.1
Rationale for Analysis of DLBCL Subtype, BCL2, 
and MYC................................................................................ 76
3.3.4.2
Rationale for p53 and Pharmacodynamic Marker 
Assessments ......................................................................... 77
3.3.4.3
Rationale for Assessment of 
Minimal Residual Disease ..................................................... 78


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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4.
MATERIALS AND METHODS .................................................................... 79
4.1
Patients.................................................................................. 79
4.1.1
Inclusion Criteria.................................................................... 79
4.1.2
Exclusion Criteria................................................................... 80
4.2
Method of Treatment Assignment.......................................... 84
4.3
Study Treatment.................................................................... 84
4.3.1
Formulation, Packaging, and Handling.................................. 84
4.3.1.1
Obinutuzumab ....................................................................... 84
4.3.1.2
Rituximab............................................................................... 85
4.3.1.3
Idasanutlin ............................................................................. 85
4.3.1.4
Venetoclax............................................................................. 85
4.3.2
Dosage, Administration, and Compliance.............................. 85
4.3.2.1
Obinutuzumab ....................................................................... 85
4.3.2.2
Rituximab............................................................................... 89
4.3.2.3
Idasanutlin ............................................................................. 90
4.3.2.4
Venetoclax............................................................................. 91
4.3.2.5
Premedication........................................................................ 91
4.3.3
Investigational Medicinal Product Accountability ................... 96
4.3.4
Post-Trial Access to Obinutuzumab, Rituximab, 
Idasanutlin, and Venetoclax................................................... 96
4.4
Concomitant Therapy ............................................................ 96
4.4.1
Permitted Therapy................................................................. 96
4.4.2
Prohibited and Cautionary Therapy....................................... 97
4.4.3
Additional Restrictions ......................................................... 102
4.5
Study Assessments ............................................................. 102
4.5.1
Informed Consent Forms and Screening Log...................... 102
4.5.2
Medical History and Demographic Data .............................. 103
4.5.3
Physical Examinations......................................................... 103
4.5.4
Vital Signs............................................................................ 104
4.5.5
Tumor and Response Evaluations....................................... 104
4.5.5.1
Radiographic Assessments ................................................. 104
4.5.5.2
Bone Marrow Assessments................................................. 105
4.5.6
Laboratory, Biomarker, and Other 
Biological Samples .............................................................. 105


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4.5.7
Electrocardiograms.............................................................. 108
4.5.8
Multigated Acquisition Scan or Echocardiogram ................. 109
4.5.9
Samples for Research Biosample Repository ..................... 109
4.5.9.1
Overview of the Research Biosample Repository................ 109
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 109
4.5.9.3
Sample Collection................................................................ 110
4.5.9.4
Confidentiality...................................................................... 110
4.5.9.5
Consent to Participate in the Research 
Biosample Repository.......................................................... 111
4.5.9.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 111
4.5.9.7
Monitoring and Oversight..................................................... 112
4.6
Patient, Treatment, Study, and 
Site Discontinuation............................................................. 112
4.6.1
Patient Discontinuation........................................................ 112
4.6.2
Study Treatment Discontinuation......................................... 112
4.6.3
Study and Site Discontinuation............................................ 113
5.
ASSESSMENT OF SAFETY..................................................................... 114
5.1
Safety Plan .......................................................................... 114
5.1.1
Risks Associated with Obinutuzumab.................................. 114
5.1.1.1
Infusion-Related Reactions.................................................. 114
5.1.1.2
Tumor Lysis Syndrome........................................................ 115
5.1.1.3
Neutropenia......................................................................... 115
5.1.1.4
Thrombocytopenia............................................................... 115
5.1.1.5
Infections ............................................................................. 116
5.1.1.6
Immunizations ..................................................................... 116
5.1.1.7
Worsening of Preexisting Cardiac Condition ....................... 116
5.1.1.8
Gastrointestinal Perforation ................................................. 117
5.1.2
Risks Associated with Rituximab......................................... 117
5.1.2.1
Infusion-Related Reactions.................................................. 117
5.1.2.2
Infections (Including Serious Infections) .............................. 117
5.1.2.3
Hepatitis B Reactivation....................................................... 117
5.1.2.4
Progressive Multifocal Leukoencephalopathy...................... 118


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5.1.2.5
Neutropenia (Including Prolonged Neutropenia).................. 118
5.1.2.6
Tumor Lysis Syndrome........................................................ 118
5.1.2.7
Impaired Immunization Response ....................................... 118
5.1.2.8
Stevens Johnson Syndrome and Toxic 
Epidermal Necrolysis........................................................... 119
5.1.2.9
Gastrointestinal Perforation ................................................. 119
5.1.3
Risks Associated with Idasanutlin........................................ 119
5.1.3.1
Gastrointestinal Disorders ................................................... 119
5.1.3.2
Myelosuppression................................................................ 120
5.1.3.3
Infections ............................................................................. 120
5.1.3.4
Tumor Lysis Syndrome........................................................ 121
5.1.3.5
Electrolyte Disorders ........................................................... 121
5.1.3.6
Other Adverse Events.......................................................... 121
5.1.4
Risks Associated with Venetoclax ....................................... 121
5.1.4.1
Tumor Lysis Syndrome........................................................ 121
5.1.4.2
Cytopenia ............................................................................ 122
5.1.4.3
Infectious Complications...................................................... 122
5.1.4.4
Effects on Cardiac Function................................................. 122
5.1.4.5
Effects on Fertility ................................................................ 122
5.1.5
Risk of Overlapping Toxicities ............................................. 122
5.1.5.1
Thrombocytopenia............................................................... 124
5.1.5.2
Neutropenia and Febrile Neutropenia.................................. 125
5.1.5.3
Infectious Complications...................................................... 125
5.1.5.4
Gastrointestinal Disorders ................................................... 126
5.1.5.5
Tumor Lysis Syndrome........................................................ 126
5.1.6
Prophylaxis and Monitoring for Tumor Lysis 
Syndrome ............................................................................ 126
5.1.7
Prophylaxis and Monitoring for All Patients ......................... 127
5.1.7.1
Guidelines for Hospitalization of Patients at Risk 
for Tumor Lysis Syndrome................................................... 127
5.1.7.2
Hospitalization Procedures.................................................. 128
5.1.8
Management of Patients Who Experience 
Specific Adverse Events...................................................... 129
5.1.8.1
Toxicities during Induction Treatment.................................. 130


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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5.1.8.2
Toxicities during Maintenance or 
Consolidation Treatment...................................................... 137
5.2
Safety Parameters and Definitions ...................................... 137
5.2.1
Adverse Events ................................................................... 138
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 138
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 139
5.2.4
Selected Adverse Events..................................................... 139
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 140
5.3.1
Adverse Event Reporting Period ......................................... 140
5.3.2
Eliciting Adverse Event Information..................................... 141
5.3.3
Assessment of Severity of Adverse Events ......................... 141
5.3.4
Assessment of Causality of Adverse Events ....................... 141
5.3.5
Procedures for Recording Adverse Events.......................... 142
5.3.5.1
Infusion-Related Reactions.................................................. 142
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 142
5.3.5.3
Adverse Events That Are Secondary to 
Other Events........................................................................ 143
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 143
5.3.5.5
Abnormal Laboratory Values ............................................... 144
5.3.5.6
Abnormal Vital Sign Values ................................................. 144
5.3.5.7
Abnormal Liver Function Tests............................................ 145
5.3.5.8
Deaths ................................................................................. 145
5.3.5.9
Preexisting Medical Conditions............................................ 146
5.3.5.10
Lack of Efficacy or Worsening of Lymphoma....................... 146
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 146
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Treatment Administration........................................ 147
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 147
5.4.1
Emergency Medical Contacts.............................................. 148
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 148


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 148
5.4.2.2
Events That Occur after Study 
Treatment Initiation.............................................................. 149
5.4.3
Reporting Requirements for Pregnancies............................ 149
5.4.3.1
Pregnancies in Female Patients.......................................... 149
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 150
5.4.3.3
Abortions ............................................................................. 150
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 150
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ................... 150
5.5
Follow-Up of Patients after Adverse Events ........................ 152
5.5.1
Investigator Follow-Up......................................................... 152
5.5.2
Sponsor Follow-Up .............................................................. 153
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ......................................... 153
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 153
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 154
6.1
Determination of Sample Size ............................................. 154
6.1.1
Dose Escalation................................................................... 154
6.1.2
Expansion Cohorts .............................................................. 154
6.2
Summaries of Conduct of Study.......................................... 155
6.3
Summaries of Demographic and 
Baseline Characteristics ...................................................... 155
6.4
Safety Analyses................................................................... 155
6.5
Efficacy Analyses ................................................................ 156
6.5.1
Primary Efficacy Endpoint.................................................... 156
6.5.2
Secondary Efficacy Endpoints............................................. 156
6.5.3
Exploratory Efficacy Endpoints............................................ 157
6.6
Pharmacokinetic Analyses................................................... 158
6.7
Biomarker Analyses............................................................. 158
6.8
Interim Analyses .................................................................. 158


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7.
DATA COLLECTION AND MANAGEMENT ............................................. 159
7.1
Data Quality Assurance....................................................... 159
7.2
Electronic Case Report Forms............................................. 159
7.3
Source Data Documentation................................................ 160
7.4
Use of Computerized Systems ............................................ 160
7.5
Retention of Records........................................................... 160
8.
ETHICAL CONSIDERATIONS.................................................................. 161
8.1
Compliance with Laws and Regulations .............................. 161
8.2
Informed Consent................................................................ 161
8.3
Institutional Review Board or Ethics Committee.................. 162
8.4
Confidentiality...................................................................... 163
8.5
Financial Disclosure ............................................................ 163
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 163
9.1
Study Documentation .......................................................... 163
9.2
Protocol Deviations.............................................................. 164
9.3
Site Inspections ................................................................... 164
9.4
Administrative Structure....................................................... 164
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 164
9.6
Protocol Amendments ......................................................... 165
10. REFERENCES ......................................................................................... 166


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Induction Treatment during the Dose-Escalation Phase for 
Patients with Follicular Lymphoma and DLBCL .......................... 57
Table 2
Post-Induction Treatment during the Dose-Escalation Phase..... 58
Table 3
Prior Elicitation............................................................................ 60
Table 4
Induction Treatment for the Expansion Phase ............................ 64
Table 5
Post-Induction Treatment for the Expansion Phase.................... 65
Table 6
Administration of First and Subsequent Infusions of 
Rituximab.................................................................................... 90
Table 7
Premedication............................................................................. 92
Table 8
Prohibited CYP2C8 Substrates................................................... 98
Table 9
Examples of Strong and Moderate CYP3A Inhibitors and 
Inducers ...................................................................................... 99
Table 10
Prohibited OATP1B1/3 Substrates............................................ 100
Table 11
Cautionary Medications for Venetoclax..................................... 101
Table 12
Proposed Non-Inherited Biomarkers for Exploratory Analysis .. 107
Table 13
Overlapping Toxicities:  Obinutuzumab, Idasanutlin, 
and Venetoclax ......................................................................... 123
Table 14
Overlapping Toxicities:  Rituximab, Idasanutlin, 
and Venetoclax ......................................................................... 124
Table 15
Idasanutlin Dose-Reduction Steps............................................ 130
Table 16
Guidelines for Management of Hematologic Toxicities That 
Occur during Induction Treatment (Except on Days 8 and 15 
of Cycle 1)................................................................................. 131
Table 17
Guidelines for Management of Hematologic Toxicities That 
Occur on Days 8 and 15 of Cycle 1 .......................................... 132
Table 18
Guidelines for Management of Non-Hematologic Toxicities...... 133
Table 19
Guidelines for Management of Toxicities That Occur during 
Maintenance or Consolidation Treatment ................................. 137
Table 20
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 141
Table 21
Potential 90% CI for the True Probability of Achieving a PET-
CT−Defined Complete Response at End of Induction for 
n 40........................................................................................ 155
LIST OF FIGURES
Figure 1
Regulation of p53 Stability and Activity by MDM2....................... 33
Figure 2
Study Schema............................................................................. 50
Figure 3
Dose-Escalation Schema (Regimen A)....................................... 54
Figure 4
Dose-Escalation Schema in Bridging Cohorts ............................ 56
Figure 5
Margins for Venetoclax and Idasanutlin...................................... 61
Figure 6
Marginal Priors for Venetoclax and Idasanutlin........................... 62
Figure 7
DOHH-2 DLBCL Xenograft Model:  Tumor Volume Analysis...... 68


 
Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd 
12/Protocol BH39147, Version 4 
Figure 8 
Z-138 MCL Xenograft Model:  Tumor Growth 
Inhibition Analysis ....................................................................... 69 
Figure 9 
WSU-DLCL2 Xenograft Model:  Tumor Volume Analysis ........... 70 
Figure 10 
Z-138 Xenograft Model:  Time-to-Event Analysis ........................ 71 
Figure 11 
Guidelines for Obinutuzumab Infusions:  First Infusion ............... 87 
Figure 12 
Guidelines for Obinutuzumab Infusions:  Second and 
Subsequent Infusions ................................................................. 88 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities for Patients with Follicular Lymphoma:   
Dose-Escalation and Expansion Phases .................................. 173 
Appendix 2 
Schedule of Activities for Patients with Diffuse Large B-Cell 
Lymphoma:  Dose-Escalation and Expansion Phases .............. 182 
Appendix 3 
Pharmacokinetic and Biomarker Sampling Schedule ............... 192 
Appendix 4 
Lugano Response Criteria for Malignant Lymphoma ................ 203 
Appendix 5 
Classification of Tumor Lysis Syndrome Based on 
Howard Definition ...................................................................... 208 
Appendix 6 
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with 
Overdose Control ...................................................................... 209 
Appendix 7 
ECOG Performance Status Scale ............................................. 223 
Appendix 8 
Ann Arbor Staging ..................................................................... 224 
Appendix 9 
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index ................................................... 225 
Appendix 10 Anaphylaxis Precautions ........................................................... 228 
Appendix 11 Calculation of Creatinine Clearance Using the modified 
Cockcroft-Gault Formula ........................................................... 229 
Appendix 12 Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax ....................................... 230 
Appendix 13 Safety Overview in Solid Tumor Study NP27872, Including 
3 Patients with NHL .................................................................. 235 


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
13/Protocol BH39147, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF OBINUTUZUMAB IN 
COMBINATION WITH IDASANUTLIN AND 
VENETOCLAX IN PATIENTS WITH RELAPSED OR 
REFRACTORY FOLLICULAR LYMPHOMA AND 
OBINUTUZUMAB OR RITUXIMAB IN 
COMBINATION WITH IDASANUTLIN AND 
VENETOCLAX IN PATIENTS WITH RELAPSED OR 
REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA
PROTOCOL NUMBER:
BH39147
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-002480-34
IND NUMBER:
127311
TEST PRODUCTS:
Obinutuzumab (RO5072759)
Rituximab (RO0452294)
Idasanutlin (RO5503781)
Venetoclax (RO5537382)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a 
copy as instructed by your local study monitor at Covance.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
14/Protocol BH39147, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF OBINUTUZUMAB IN COMBINATION WITH 
IDASANUTLIN AND VENETOCLAX IN PATIENTS WITH 
RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA AND 
OBINUTUZUMAB OR RITUXIMAB IN COMBINATION WITH 
IDASANUTLIN AND VENETOCLAX IN PATIENTS WITH 
RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL 
LYMPHOMA
PROTOCOL NUMBER:
BH39147
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-002480-34
IND NUMBER:
127311
TEST PRODUCTS:
Obinutuzumab (RO5072759)
Rituximab (RO0452294)
Idasanutlin (RO5503781)
Venetoclax (RO5537382)
PHASE:
Phase Ib/II
INDICATION:
Relapsed or refractory follicular lymphoma or diffuse large 
B-cell lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, efficacy, and pharmacokinetics (PK) of obinutuzumab in 
combination with idasanutlin and venetoclax in patients with relapsed or refractory (R/R) 
follicular lymphoma (FL) and rituximab in combination idasanutlin and venetoclax in 
patients with R/R diffuse large B-cell lymphoma (DLBCL), with safety being the primary 
objective for the dose-escalation phase and the expansion phase of the study and efficacy 
being the primary objective for the expansion phase.  PK objectives are secondary and 
exploratory.  Specific objectives and corresponding endpoints for the study are outlined 
below.
Safety Objective
The safety objectives for this study are as follows:

To determine the recommended Phase II doses (RP2Ds) for idasanutlin and venetoclax 
when given in combination with a fixed dose of obinutuzumab or rituximab during the 
dose-escalation phase on the basis of the following endpoint:
–
Incidence of dose-limiting toxicities (DLTs) during the first two cycles of study 
treatment

To evaluate the safety and tolerability of obinutuzumab or rituximab in combination with 
idasanutlin and venetoclax, during dose-escalation and expansion phases, on the basis 
of the following endpoints:
–
Nature, frequency, severity, and timing of adverse events, including DLTs


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
15/Protocol BH39147, Version 4
–
Changes in vital signs, ECGs, and clinical laboratory results during and following 
study treatment administration
Efficacy Objectives
Response will be determined on the basis of positron emission tomography and computed 
tomography (PET-CT) scans or CT scans alone, using Revised Lugano Response Criteria 
for Malignant Lymphoma, hereinafter referred to as the modified Lugano 2014 criteria.  
Response will be determined by an independent review committee (IRC) and by the 
investigator.
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of obinutuzumab in 
combination with idasanutlin and venetoclax in R/R FL and rituximab in combination with 
idasanutlin and venetoclax in R/R DLBCL on the basis of the following endpoint:

Complete response (CR) at the end of induction (EOI), as determined by the IRC on the 
basis of PET-CT scans 
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of obinutuzumab 
in combination with idasanutlin and venetoclax in R/R FL and rituximab in combination with 
idasanutlin and venetoclax in R/R DLBCL on the basis of the following endpoints within 
each disease cohort:

CR at the EOI, as determined by the investigator on the basis of PET-CT scans

CR at the EOI, as determined by the IRC and by the investigator on the basis of 
CT scans alone

Objective response (defined as a CR or partial response [PR]) at the EOI, as 
determined by the IRC and by the investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at the EOI, as determined by the IRC and 
by the investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on the 
basis of CT scans alone
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
obinutuzumab or rituximab in combination with idasanutlin and venetoclax on the basis of 
the following endpoints:

For patients who have positive PET scans at the EOI:  
–
CR at 12 months, as determined by the IRC and by the investigator on the basis of 
PET-CT scans, in patients with FL
–
CR at end of consolidation (EOC), as determined by the IRC and by the investigator 
on the basis of PET-CT scans, in patients with DLBCL

Progression-free survival, defined as the time from initiation of study treatment to first 
occurrence of disease progression or relapse, as determined by the investigator on the 
basis of CT scans alone, or death from any cause

Event-free survival, defined as the time from initiation of study treatment to any 
treatment failure, including disease progression or relapse, as determined by the 
investigator on the basis of CT scans alone, initiation of new anti-lymphoma therapy, or 
death from any cause, whichever occurs first

Disease-free survival, defined, among patients achieving a CR, as the time from the first 
occurrence of a documented CR to relapse, as determined by the investigator on the 
basis of CT scans alone, or death from any cause, whichever occurs first

Overall survival, defined as the time from initiation of study treatment to death from any 
cause


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
16/Protocol BH39147, Version 4

Additional descriptive analysis based on TP53 status will be performed on the following 
endpoint:
–
CR at the EOI, as determined by the IRC on the basis of PET-CT scans
Pharmacokinetic Objectives
The PK objectives for this study are as follows:
Secondary PK Objectives

To characterize the PK profiles of obinutuzumab or rituximab, idasanutlin (and its 
metabolites, if appropriate) and venetoclax to support dose escalation

To assess potential PK interactions between idasanutlin, venetoclax, and obinutuzumab
or rituximab
Exploratory PK Objective

To explore PK exposure-effect (including pharmacodynamic, efficacy, and adverse 
event) relationships 
Biomarker Objective
The exploratory biomarker objective for this study is to identify non-inherited biomarkers 
that are associated with response to study treatment (i.e., that could serve to inform 
precision healthcare approaches with predictive and/or prognostic potential), are 
associated with acquired resistance to study treatment, are associated with susceptibility to 
developing adverse events, can provide evidence of study treatment activity, can increase 
the knowledge and understanding of lymphoma biology or study treatment mechanism of 
action, or can contribute to improvement of diagnostic assays, on the basis of the following

Association between non-inherited biomarkers and efficacy, safety, and PK endpoints
Study Design
Description of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, and pharmacokinetics of obinutuzumab in combination with 
idasanutlin and venetoclax in patients with R/R FL and rituximab in combination with 
idasanutlin and venetoclax in patients with R/R DLBCL.  The study will include an initial 
dose-escalation phase followed by an expansion phase.  The dose-escalation phase is
designed to determine the RP2Ds and regimen for idasanutlin and venetoclax in
combination with obinutuzumab for FL patients and in combination with rituximab for 
DLBCL patients.  Dose escalation starts with idasanutlin and venetoclax in combination 
with obinutuzumab in all patients (FL and DLBCL) until the MTD (Regimen A) or until 
Sponsor decision based on clinical judgment, followed by:

Dose confirmation and potential dose escalation in patients with DLBCL for idasanutlin 
and venetoclax in combination with rituximab to determine the RP2Ds for this 
combination 

Dose confirmation and potential dose escalation in patients with FL with a different 
regimen (Regimen B, obinutuzumab given alone in Cycle 1 followed by idasanutlin, 
venetoclax, and obinutuzumab in combination in Cycles 26) to determine the RP2Ds 
for this regimen  
The RP2Ds and regimen for FL and RP2Ds for DLBCL will be decided at the end of dose-
escalation phase. Different RP2Ds and/or regimens may apply for FL and DLBCL, 
respectively.
In the expansion phase, patients with FL will receive idasanutlin and venetoclax at the 
RP2Ds of the selected regimen (Regimen A or B) in combination with obinutuzumab, and 
patients with DLBCL will receive idasanutlin and venetoclax at the RP2Ds in combination 
with rituximab. 
Patients with R/R FL enrolled in the dose-escalation and expansion phases may be eligible 
to receive post-induction treatment (referred to as maintenance) with obinutuzumab, 
venetoclax, and idasanutlin.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
17/Protocol BH39147, Version 4
Patients with R/R DLBCL enrolled in the dose-escalation and expansion phases may be 
eligible to receive post-induction treatment (referred to as consolidation) with 
obinutuzumab or rituximab, venetoclax, and idasanutlin.  Patients who receive 
obinutuzumab during induction will continue to receive obinutuzumab in consolidation, and 
patients who receive rituximab during induction will continue to receive rituximab in 
consolidation.
Number of Patients
Approximately 140 patients with R/R FL and DLBCL are expected to be enrolled in this 
study at approximately 25 investigational sites worldwide.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ages 18 years

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

B-cell lymphoma classified as either of the following:
R/R FL after treatment with at least one prior chemoimmunotherapy regimen that 
included an anti-CD20 monoclonal antibody 
–
Relapsed or refractory DLBCL after treatment with at least one prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in 
patients who are not eligible for second-line combination chemotherapy and 
autologous stem-cell transplantation, have failed second-line combination 
chemotherapy, or experienced disease progression following autologous stem-cell 
transplantation

Histologically documented CD20-positive lymphoma, as determined by a 
local laboratory

Fluorodeoxyglucose-avid lymphoma (i.e., PET-positive lymphoma)

At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by CT 
scan or magnetic resonance imaging)

Availability of a representative tumor specimen and the corresponding pathology report 
for retrospective central confirmation of the diagnosis of FL or DLBCL
–
If the archival tissue is unavailable or unacceptable, a pretreatment core-needle, 
excisional or incisional tumor biopsy is required.  Cytological or fine-needle 
aspiration samples are not acceptable.
–
If a patient received anti-lymphoma treatment between the time of the most recent 
available biopsy and initiation of study treatment, a core-needle biopsy is strongly 
recommended.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
–
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for at least 18 months after the last 
dose of study treatment for those treated with obinutuzumab, idasanutlin, and 
venetoclax; and for at least 12 months after the last dose of study treatment for 
those treated with rituximab, idasanutlin, and venetoclax.  Women must refrain 
from donating eggs during this same period.
–
A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
18/Protocol BH39147, Version 4
–
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
–
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below:
–
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of 1% per year during the treatment period and for at least 3 months after the last 
dose of study treatment.  Men must refrain from donating sperm during this same 
period.
–
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 3 months after the last dose of study treatment 
to avoid exposing the embryo.
–
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known CD20-negative status at relapse or progression

Prior allogeneic SCT

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1

Prior standard or investigational anti-cancer therapy as specified below:
–
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
–
Monoclonal antibody or antibody–drug conjugate therapy within 4 weeks prior to 
Day 1 of Cycle 1
–
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy 
within 2 weeks prior to Day 1 of Cycle 1

Clinically significant toxicity (other than alopecia) from prior therapy that has not 
resolved to Grade 2 (according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 [NCI CTCAE v4.0]) prior to Day 1 of Cycle 1

Grade 3b FL

History of transformation of indolent disease to DLBCL (expansion-phase only) 
–
History of transformation of indolent disease is allowed in the dose escalation phase.

Central nervous system lymphoma or leptomeningeal infiltration

Treatment with systemic corticosteroids 20 mg/day, prednisone or equivalent
–
Patients receiving corticosteroids 20 mg/day, prednisone or equivalent, must be 
documented to be on a stable dose for at least 4 weeks prior to Day 1 of Cycle 1. 
–
If corticosteroid treatment is urgently required for lymphoma symptom control prior to 
the start of study treatment, 100 mg of prednisone or equivalent can be given for a 
maximum of 5 days, but all tumor assessments must be completed prior to start of 
corticosteroid treatment.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
19/Protocol BH39147, Version 4

Clinical conditions requiring treatment with oral or parenteral anticoagulants or 
antiplatelet agents (e.g., chronic daily treatment with aspirin 325 mg/day, clopidogrel, 
warfarin, systemic low-molecular-weight heparin) unless treatment can be discontinued 
7 days (or 5 half-lives) prior to initiation of study treatment (except used as flushes for 
indwelling catheters)

Refusal of blood products and/or sensitivity to blood products

History of severe allergic or anaphylactic reaction to humanized or murine monoclonal 
antibodies

Known hypersensitivity or allergy to murine products or any component of the 
obinutuzumab, rituximab, idasanutlin, or venetoclax formulation

Infection considered by the investigator to be clinically uncontrolled or poses an 
unacceptable risk to the patient upon the induction of neutropenia, that is, patients who 
are or should be on antimicrobial agents for the treatment of active infection such as the 
following: 
–
Fungal infection with visceral involvement, other than mucosal candidiasis, with 2 
weeks of appropriate systemic antifungal therapy
–
Bacterial infection with positive cultures within 7 days prior to initiation of study 
treatment
–
Patients who have received 5 days of appropriate therapeutic antibiotic therapy for 
an identified infection
–
Neutropenic fever considered infection related within 72 hours prior to initiation of 
study treatment
–
History of symptomatic C. difficile infection that required treatment within 1 month 
prior to dosing 
Upon clinical response to C. difficile treatment, the stool consistency and 
frequency must have returned to normal.
In all cases, the patient should be afebrile and hemodynamically stable for at least 
72 hours at the time of study treatment initiation.

Caution should be exercised when considering the use of obinutuzumab or rituximab in 
patients with a history of recurring or chronic infections.

Treatment with the following agents within 7 days prior to the first dose of venetoclax
and idasanutlin:
–
Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and 
clarithromycin
–
Moderate CYP3A inducers such as bosetan
–
CYP2C8 substrates such as repaglinide
–
UGT1A3 inhibitors such as gemfibrozil
–
OATP1B1/3 substrates such as statin drugs

Treatment with the following agents within 14 days prior to the first dose of venetoclax 
and idasanutlin:
–
Strong CYP3A inducers such as rifampin (also a CYP2C8 inducer) and 
carbamazepine

Chronic use of CYP2C8 or OATP1B1/3 substrates

Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade 
that contains Seville oranges), or star fruit within 3 days prior to the first dose of 
venetoclax

Clinically significant history of liver disease, including viral or other hepatitis, current 
alcohol abuse, or cirrhosis (e.g., Child-Pugh class B and C)


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
20/Protocol BH39147, Version 4

Current or history of hepatitis B virus or hepatitis C virus (HCV) infection:  positive for 
hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or HCV
antibody at screening
–
Patients are eligible if both HBsAg and HBcAb are negative but tested positive for 
hepatitis B surface antibody after vaccination.

Known history of HIV-positive status
–
For patients with unknown HIV status, HIV testing must be performed at screening if 
not in contradiction with local regulations.

History of progressive multifocal leukoencephalopathy 

Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1

History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following:
–
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma 
in situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or 
low-grade, early-stage localized prostate cancer
–
Any previously treated malignancy that has been in remission without treatment 
for 2 years prior to enrollment

Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 
unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm), or uncontrolled irritable bowel disease (i.e., Crohn 
disease, ulcerative colitis, diverticulosis-associated colitis, and Behçet disease)

Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by study treatment, such as severe hereditary coagulation disorders or 
insulin-dependent diabetes mellitus that is not optimally controlled with medical 
management (e.g., presence of ketoacidosis)

Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle
1, or anticipation of a major surgical procedure during the study

Inadequate hematologic function (unless due to underlying lymphoma), defined as 
follows:
–
Hemoglobin 9 g/dL
–
ANC 1.5 109 cells/L 
–
Platelet count 75 109 cells/L 

Any of the following abnormal laboratory values (unless due to underlying lymphoma):
–
Calculated creatinine clearance 50 mL/min using the modified Cockcroft-Gault
–
Patients with clinically significant persistent electrolyte abnormalities, such as 
hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and 
hypermagnesemia of Grade 1 according to NCI CTCAE, v4.0
–
Treatment for correction of above electrolyte imbalances is permitted during 
screening to meet eligibility criteria.
–
AST or ALT 2.5 upper limit of normal (ULN)
–
Serum total bilirubin 1.5 ULN (or 3 ULN for patients with Gilbert syndrome)
–
INR or PT 1.5 ULN in the absence of therapeutic anticoagulation
–
PTT or aPTT 1.5 ULN in the absence of a lupus anticoagulant

Pregnancy or lactation, or plans to become pregnant during the study

Women of childbearing potential must have a negative serum pregnancy test result within 7 
days prior to Day 1 of Cycle 1.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
21/Protocol BH39147, Version 4

Life expectancy 3 months

Inability to comply with the study protocol, in the investigator’s judgment
End of Study
The end of this study is defined as the time when both of the following conditions are met:

All enrolled patients with FL have completed or discontinued study treatment (including 
induction and maintenance, as applicable), and

All enrolled patients with DLBCL have been followed for at least 1 year after they have 
completed or discontinued study treatment (including induction and consolidation, as 
applicable).
Length of Study
The total length of the study is expected to be approximately 48 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Study treatment will be administered in 28-day cycles.
Obinutuzumab will be administered by intravenous infusion at an absolute (flat) dose of 
1000 mg on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during
induction treatment, and on Day 1 of every other month (i.e., every 2 months) for 24 months 
during maintenance treatment (eligible patients with FL only) or for 6 months during 
consolidation treatment (eligible patients with DLBCL only).
Rituximab will be administered by intravenous infusion at a dose of 375 mg/m2 on Day 1 of 
Cycles 16 during induction treatment and on Day 1 of every other month (i.e., every 2 months) 
for 6 months during consolidation treatment (eligible patients with DLBCL only).
Idasanutlin tablets will be taken once daily by mouth, approximately 15 minutes after eating a 
meal and with water, on Days 15 of Cycles 16 (or Cycles 26 for the bridging cohorts in FL 
patients and in the expansion phase if this regimen is chosen), followed by 6 months of post-
induction treatment.  The starting dose will be 100 mg during the dose-escalation phase.  The 
RP2D with the selected regimen will be administered during the expansion phase.  The dose 
and regimen for post-induction treatment will be determined by the Sponsor after review of all 
relevant data.  
Each once-daily dose of venetoclax will be taken orally with approximately 240 mL of water 
within approximately 30 minutes after the completion of breakfast or the first meal of the day.  
For Cycles 16 (induction; or Cycles 26 for the bridging cohorts in FL patients and in the 
expansion phase if this regimen is chosen) and for 6 months thereafter (post-induction), 
venetoclax will be given once-daily on Days 15 or Days 110 depending on tolerability.  The 
selection of the venetoclax dose schedule will be determined according to the dose-escalation 
plan.  The starting dose will be 200 mg during the dose-escalation phase.  The RP2D with the 
selected regimen will be administered during the expansion phase.  The dose and regimen for 
post-induction treatment will be determined by the Sponsor after review of all relevant data.  
Statistical Methods
Primary Analysis
Safety
The safety analysis population will include all patients who have received at least one dose of 
any component of the combination, whether patients are prematurely withdrawn from the study 
or not.  All safety parameters will be summarized and presented in tables based on this safety 
population.  
All adverse events occurring on or after the first dose of study treatment will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  All serious adverse 
events, adverse events of special interest, and selected adverse events will be summarized and 
listed.  
Deaths reported during the treatment period and during post-treatment follow-up will be listed.
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, and blood pressure) 
data will be displayed by time, with Grade 3 and 4 values identified as appropriate.


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Efficacy
The primary efficacy analysis will include all patients enrolled in the expansion phase who 
receive at least one dose of any component of the combination.  Data from patients who were 
dosed at the RP2D and selected regimen during the dose-escalation phase may be pooled with 
the corresponding arm of the expansion phase, depending on their indication.
The primary efficacy analysis will be estimation of the proportion of patients achieving a CR at 
EOI, as determined by the IRC through use of the PET-CTbased modified Lugano 2014 
criteria.  Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact confidence intervals (CIs), for the proportion of patients who achieve a 
CR at the EOI.  Patients without a post-baseline tumor assessment will be considered 
non-responders.
Determination of Sample Size
The primary efficacy analysis for the expansion phase will be estimation of the true proportion of 
patients expected to obtain a PET-defined CR at EOI.  A sample size of 40 patients is deemed 
sufficient to provide adequate precision for the point estimate and for the lower end of the 90% 
CI to rule out a clinically uninteresting probability of response of 40% in FL, and 40% in 
DLBCL assuming an observed PET-defined CR rate of 55%.
Interim Analyses
During the expansion phase, predictive probabilities may be used to guide early stopping for 
futility by comparing the observed proportion of patients who achieve a PET-CTdefined CR at 
the EOI with that in historical controls.  The design is based on Lee and Liu (2008), with the 
modification that the uncertainty in historical control data is fully taken into account by utilizing a 
distribution on the control response rate.  Interim analysis decision rules will be based on the 
predictive probability that this trial will have a positive outcome if carried out to completion and 
will use the historical control data available at the time of analysis.
It is anticipated that at least one interim analysis per disease indication will be conducted during 
the expansion phase of the study, with the earliest interim analysis taking place when at least 
15 patients treated have been evaluated for a PET-CTdefined CR at EOI.  If, at any interim 
analysis, a low predictive probability suggests that the proportion of patients achieving a PET-
CT–defined CR at EOI is lower than desired, the IMC will review the data and decide whether to 
recommend an early decision to stop enrollment.
Additional review of safety and/or efficacy data by the IMC may be requested by and carried out 
at the discretion of the Medical Monitor.  Further details regarding the rules and guidelines of 
data will be provided in an IMC charter.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABC
activated B cell–like (subgroup)
ADCC
antibody-dependent cellular cytotoxicity 
ADCP
antibody-dependent cellular phagocytosis
ALT
alanine aminotransferase
AML
acute myeloid leukemia
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentrationtime curve
BID
twice daily
BR
bendamustine and rituximab
BSA
body surface area
CDC
complement-dependent cytotoxicity
CI
confidence interval
CHOP
cyclophosphamide, doxorubicin, vincristine, 
and prednisolone or prednisone
CLL
chronic lymphocytic leukemia
Cmax
maximum serum concentration
CML
chronic myelogenous leukemia
CR
complete response
CRi
complete remission with incomplete blood count 
recovery
CRp
complete remission with incomplete platelet count 
recovery
CSR
Clinical Study Report
CT
computed tomography
CVP
cyclophosphamide, vincristine, and prednisone
CYP
cytochrome P450
DDI
drugdrug interaction
DFS
disease-free survival
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture


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Abbreviation
Definition
EFS
event-free survival
EOC
end of consolidation
EOI
end of induction
EORTC
European Organization for Research and Treatment 
of Cancer
ESMO
European Society for Medical Oncology
FCBL
fold change from baseline
FDA
(U.S.) Food and Drug Administration
FDG
fluorodeoxyglucose
FFPE
formalin-fixed, paraffin-embedded
FL
follicular lymphoma
FLIPI, FLIPI2
Follicular Lymphoma International Prognostic Index,
Follicular Lymphoma International Prognostic Index 2
G
obinutuzumab (GA101)
GB
obinutuzumab plus bendamustine 
GCB
germinal-center B cell–like (subgroup)
G-CHOP
obinutuzumab plus CHOP
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HI
hematologic improvement
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
ICH
International Council for Harmonisation
Ig
immunoglobulin
IHC
immunohistochemistry
IMC
internal monitoring committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee


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Abbreviation
Definition
IRR
infusion-related reaction
IV
intravenous
IxRS
interactive voice or Web-based response system
JC
John Cunningham (virus)
LMWH
low-molecular-weight heparin
MBP
microprecipitated bulk
MCL
mantle-cell lymphoma
mCRM
modified Continual Reassessment Model
MDM2
murine double minute 2
MIC-1
macrophage inhibitory cytokine1
MLFS
morphologic leukemia-free state
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition (scan)
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
NHL
non-Hodgkin’s lymphoma
NK
natural killer
OATP
organic anion-transporting polypeptide
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PML
progressive multifocal leukoencephalopathy
PO
orally (by mouth)
PR
partial response
QD
once a day
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
R-CHOP
rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisolone or 
prednisone
RP2D
recommended Phase II dose
R/R
relapsed or refractory
SCID
severely compromised immunodeficient


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Abbreviation
Definition
SCT
stem-cell transplantation
SD
stable disease
SDP
spray-dried powder
SLL
small lymphocytic lymphoma
SOC
System Organ Class
SPD
sum of the product of the diameters
TGI
tumor growth inhibition
TLS
tumor lysis syndrome
ULN
upper limit of normal
WM
Waldenström’s macroglobulinemia


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1.
BACKGROUND
1.1
BACKGROUND ON NON-HODGKIN’S LYMPHOMA
Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignancy in adults.  
In 2013, there were an estimated 69,740 new cases and 19,020 deaths due to the 
disease in the United States (Siegel et al. 2013).  In Europe, there were an estimated 
93,400 new cases and 37,900 deaths in 2012 (Ferlay et al. 2013).  NHL is most often of 
B-cell origin, including a wide range of different subtypes of B-cell lymphoma, broadly 
divided into indolent and aggressive lymphomas, each with unique characteristics.
1.1.1
Follicular Lymphoma
Indolent B-cell lymphomas are a heterogeneous group of malignant lymphomas and 
account for approximately one-third of all NHLs.  Follicular lymphoma (FL) is the most 
common subtype of indolent B-cell lymphoma, accounting for about 22% of all newly 
diagnosed cases of NHL (Armitage and Weisenburger 1998).  Approximately 90% of the 
cases have a t(14;18) translocation, which juxtaposes BCL2 with the IgH locus and 
results in overexpression of the anti-apoptotic protein, Bcl-2. 
FL remains an incurable disease with the currently available therapies.  The addition of 
rituximab, an anti-CD20 monoclonal antibody, to commonly used induction 
chemotherapy, including CHOP (cyclophosphamide, doxorubicin, vincristine, and 
prednisone), CVP (cyclophosphamide, vincristine, and prednisone), fludarabine, or 
bendamustine (Dreyling et al. 2014; Zelenetz et al. 2014) followed by rituximab 
maintenance therapy led to prolonged remission and improved patient outcomes.  
Updated results from Study MO18264 confirmed the benefit of 2-year rituximab 
maintenance in patients responding to first-line immunotherapy, with a 6-year 
progression-free survival (PFS) of 59.2% compared with 42.7% in the observation arm 
(p0.0001) (Salles et al. 2013). 
Despite significant therapeutic progress with the use of chemoimmunotherapy as 
first-line treatment, most patients will eventually experience disease relapse.  Relapses 
are characterized by increasing refractoriness and decreasing duration of response to 
subsequent lines of therapy.  Thus, new treatments are needed to improve the outcome 
for these patients.
1.1.2
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL, 
accounting for approximately 30% of all NHLs diagnosed annually (Armitage and 
Weisenburger 1998).  The use of immunochemotherapy, most commonly R-CHOP 
(rituximab plus CHOP), for newly diagnosed DLBCL led to a significant improvement in 
survival in patients of all age groups.  In older patients (60 years), R-CHOP was 
associated with a 2-year event-free survival (EFS) rate of 57% and a 10-year survival 
rate of 43.5% (Coiffier et al. 2010).  In younger patients (1860 years old) with favorable 
prognostic features, R-CHOP demonstrated a 3-year EFS rate of 79% and a survival 


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rate at 3 and 6 years of 93% and 74.3%, respectively (Pfreundschuh et al. 2011).  
However, nearly 40% of patients with DLBCL will eventually die of relapsed disease or 
disease that is refractory to first-line treatment.  Patients with a high-risk International 
Prognostic Index (IPI) have a 5-year PFS rate of 40% following treatment with R-CHOP 
(Zhou et al. 2014).
Second-line treatments consist of high-dose chemotherapy regimens such as R-ICE 
(rituximab plus ifosfamide, carboplatin, and etoposide) or R-DHAP (rituximab plus 
dexamethasone, cytosine arabinoside, and cisplatin) followed by autologous stem-cell 
transplantation (SCT).  Approximately half of the patients do not achieve a complete 
remission after salvage treatment (Gisselbrecht et al. 2010).  Moreover, elderly patients 
or patients with comorbidities are often deemed ineligible for such aggressive therapy.
Specific molecular subsets of DLBCL are associated with an inferior outcome following 
R-CHOP therapy.  Patients with germinal center B celllike (GCB) DLBCL had a better 
prognosis than patients with activated (non-germinal) B celllike (ABC) DLBCL, with a 
3-year survival rate of 84% versus 56%, respectively (p0.001) (Lenz et al. 2008).  
Several genetic abnormalities associated with poor prognoses have been identified in 
DLBCL, including MYC rearrangement, BCL2 and BCL6 overexpression, and TP53
mutations.  Rearrangement in MYC (MYC-positive DLBCL) has been reported in 9%17% 
of DLBCL cases and often correlates with the GCB DLBCL phenotype (Savage et al. 
2009; Barrans et al. 2010).  DLBCL treated with R-CHOP has a markedly worse 5-year 
survival rate in patients with MYC-positive DLBCL compared with MYC-negative DLBCL 
(33% vs. 72%) (Savage et al. 2009).  Concurrent MYC and IGH-BCL2 rearrangement 
(“double-hit" DLBCL), observed in 2%11% of DLBCL patients, represents a DLBCL 
subset with an inferior outcome (5-year PFS of 18%; 5-year survival of 27%) (Savage 
et al. 2009; Dunleavy et al. 2014).  Mutations in TP53 have been described in 
approximately 20% of patients with DLBCL and are strong predictors of poor overall 
survival (Young et al. 2008; Xu-Monette et al. 2012).
Bcl-2 is an anti-apoptotic molecule overexpressed in many hematologic malignancies, 
including many DLBCLs, through translocation of the BCL-2 gene in juxtaposition with 
the IGH gene t(14;18), through gene amplification, or by other mechanisms (Gascoyne 
et al. 1997; Davis et al. 2001). Bcl-2 protein inhibits death of lymphoma cells in 
response to chemotherapy and other anti-neoplastic agents, including rituximab.  
Overexpression of Bcl-2 has been shown to be associated with inferior outcomes in
DLBCL with standard treatment (Iqbal et al. 2011; Hu et al. 2013; Visco et al. 2013).  
The frequent overexpression of Bcl-2 combined with its contribution to therapy
resistance makes Bcl-2 inhibition an attractive therapeutic target in DLBCL.
DLBCL remains a disease with a high unmet medical need.  Novel targeted therapies 
are needed to move treatment options beyond R-CHOP.


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1.2
BACKGROUND ON OBINUTUZUMAB
Obinutuzumab (also known as GA101) is a novel glycoengineered type II anti-CD20 
antibody.  Compared with rituximab, obinutuzumab is characterized by more potent 
direct B-cell death induction and increased affinity for FcRIII receptors expressed on 
natural killer (NK) cells, macrophages, and monocytes, resulting in enhanced 
antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular 
phagocytosis (ADCP) (Beers et al. 2010; Mössner et al. 2010; Herter et al. 2014).  
Together, these characteristics confer obinutuzumab with enhanced immune effector 
functions and B celldepleting activity compared with rituximab. 
Obinutuzumab is approved for the treatment of patients with relapsed or refractory (R/R) 
FL and is approved for use in combination with chlorambucil for the treatment of patients 
with previously untreated chronic lymphocytic leukemia (CLL). Obinutuzumab is also 
approved for use in combination with bendamustine followed by obinutuzumab 
maintenance for the treatment of patients with FL who did not respond to or who 
progressed during or after treatment with rituximab or a rituximab-containing regimen.
Obinutuzumab continues to be investigated in a large clinical program.
Background on rituximab can be found in Sections 1.1 and 1.5.
1.2.1
Nonclinical Studies with Obinutuzumab
In nonclinical studies, obinutuzumab demonstrated superior depletion of normal B cells 
(measured as CD19+ depletion) from the blood of healthy volunteers (Mössner et al. 
2010), as well as malignant B cells from the blood of patients with CLL (Patz et al. 2011).  
Nonclinical xenograft experiments performed with obinutuzumab as monotherapy and in 
combination with chemotherapy have consistently shown that obinutuzumab has 
promising anti-tumor activity (Mössner et al. 2010; Dalle et al. 2011) and have 
demonstrated the superiority of obinutuzumab over rituximab (Mössner et al. 2010; 
Herting et al. 2014).
For more detailed nonclinical information on obinutuzumab, refer to the Obinutuzumab 
Investigator’s Brochure.
1.2.2
Clinical Studies with Obinutuzumab
As of 4 July 2016, clinical data from Roche-sponsored studies on obinutuzumab are 
available from 13 clinical studies: 8 Phase I or II studies (BO20999, BO21003, JO21900, 
BO21000, GAO4915g, GAO4779g, YP25623, and GAO4768g) and 5 Phase III/IIIb 
studies (BO21004/CLL11, GAO4753g, MO28543, BO21223, and BO21005).  Available 
efficacy results from the NHL cohorts in these studies and available safety results from 
all patients are summarized below.  Efficacy data from a Phase III study (GAO4753g) of 
obinutuzumab are also presented.  Studies BO21223 (in previously untreated patients 
with indolent NHL) and BO21005 (in previously untreated patients with DLBCL) have 
passed futility analyses on efficacy, are ongoing, and remain blinded.  


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For more detailed clinical information on obinutuzumab, including results in the CLL 
cohorts of the clinical studies and clinical pharmacology data, refer to the Obinutuzumab 
Investigator’s Brochure.
1.2.2.1
Clinical Efficacy of Obinutuzumab in Patients with Non-
Hodgkin’s Lymphoma
In studies of obinutuzumab monotherapy in patients with R/R NHL (Studies BO20999, 
BO21003, and JO21900), the proportion of patients who had a response (a complete 
response [CR] or partial response [PR]) at the end of treatment (as determined on the 
basis of computed tomography [CT] scans alone) ranged from 28% to 58%.  The CR 
rate ranged from 0% to 19%.
In early studies of obinutuzumab in combination with chemotherapy (e.g., CHOP or 
bendamustine) in patients with previously untreated or R/R NHL (Studies BO21000, 
GAO4915g, and GAO4753g), the proportion of patients with a CR or PR at the end of 
induction (EOI) treatment ranged from 69% to 96%.  The CR rate was higher with 
combination therapy (35%39% in patients with previously untreated FL, 39%50% in 
patients with R/R FL, and 55% in patients with previously untreated DLBCL) than with 
monotherapy (see Obinutuzumab Investigator’s Brochure).
A Phase III study, GAO4753g, investigated obinutuzumab plus bendamustine (GB) 
compared with bendamustine alone in patients with R/R indolent NHL (n396).  Patients 
in the GB group who had not experienced disease progression at the EOI received 
obinutuzumab monotherapy every 2 months for up to 2 years.  PFS was significantly 
longer in the GB arm, with a median PFS of 29 versus 14 months (hazard ratio [HR]: 
0.48; 95% CI: 0.35, 0.67; p 0.0001) (Sehn 2015; Trněný et al. 2016). Obinutuzumab 
was granted approval for use in patients with FL who did not respond to or who 
progressed during or after treatment with rituximab or a rituximab-containing regimen 
(see Section 1.2). 
A Phase III study, BO21223, investigated obinutuzumab plus chemotherapy (G-benda, 
G-CVP, obinutuzumab plus CHOP [G-CHOP]) compared with rituximab plus 
chemotherapy followed by obinutuzumab or rituximab maintenance in patients with 
previously untreated indolent NHL (FL cohort, n1202).  On the basis of positive results 
that demonstrated significant improvement in PFS in the obinutuzumab plus
chemotherapy arm, the independent Data Monitoring Committee recommended that the 
study be unblinded to the Sponsor at a pre-planned interim analysis.
A Phase III study, BO21005, investigated G-CHOP compared with R-CHOP in patients 
with previously untreated DLBCL. The study did not meet its primary endpoint of PFS 
difference at final analysis. Based upon the BO21005 efficacy results, this study 
protocol has been amended (Version 3) to cease evaluating obinutuzumab in patients 
with R/R DLBCL in the expansion phase. Patients with DLBCL enrolled after the 
identification of idasanutlin and venetoclax maximum tolerated dose (MTD) in 


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combination with obinutuzumab will instead receive idasanutlin and venetoclax in 
combination with rituximab.
1.2.2.2
Clinical Safety of Obinutuzumab
As of 4 July 2016, an estimated 4454 patients with NHL (including DLBCL, indolent B-
cell lymphoma, and CLL) have been treated with obinutuzumab given as monotherapy 
or in combination with CHOP, bendamustine, fludarabine plus cyclophosphamide, or 
chlorambucil, at doses ranging from 50 mg to 2000 mg.  Overall, the safety of 
obinutuzumab monotherapy and obinutuzumab combination therapy was manageable.
The most frequent causes of death were disease progression and adverse events 
associated with infectious diseases.  This is consistent with the study population and the 
disease under treatment.  The incidence of fatal adverse events was similar across all 
ongoing trials.  In Study GAO4768g (obinutuzumab 1000 mg vs. 2000 mg), the 
incidence of deaths did not increase with increased obinutuzumab dose (7.5% and 2.6%, 
respectively).
Of particular interest, a high incidence of infusion-related reactions (IRRs) was observed 
consistently in all obinutuzumab trials.  The reported incidence of IRRs varied across 
studies.  In the CLL population, the incidence ranged from 66% in previously untreated 
patients receiving obinutuzumab plus chlorambucil (Study BO21004) to 100% in patients 
with R/R disease receiving obinutuzumab monotherapy (pooled data from Studies 
BO21003 and BO20999).
In the NHL population, the incidence of IRRs in studies of obinutuzumab monotherapy 
was 75.1% (pooled data from Study BO21003 and from the high-dose NHL cohorts from 
Study BO20999).  In studies of obinutuzumab in combination with either CHOP 
(Study GAO4915g) or bendamustine (Study BO21000), the incidence of IRRs, 
regardless of the relationship with obinutuzumab, was 70%78%.  IRRs mainly occurred
during Cycle 1, with a higher frequency reported on the first day of treatment.
Other important risks associated or potentially associated with obinutuzumab are tumor 
lysis syndrome (TLS), neutropenia, prolonged B-cell depletion, thrombocytopenia 
(including acute thrombocytopenia), infections (including progressive multifocal 
leukoencephalopathy [PML] and hepatitis B virus [HBV] reactivation), impaired 
immunization response, worsening of preexisting cardiac conditions, gastrointestinal (GI) 
perforation, immunogenicity, and second malignancies.  The important identified risks 
associated with obinutuzumab are presented in detail in Section 5.1.1 and in the 
Obinutuzumab Investigator’s Brochure.
1.2.2.3
Clinical Pharmacokinetics of Obinutuzumab
On the basis of available pharmacokinetic (PK) data, a two-compartment PK model 
comprising both a linear clearance pathway and a nonlinear time-varying clearance 
pathway adequately describes serum obinutuzumab concentration data.  The initial 


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clearance of obinutuzumab is approximately 2.8 times higher than the steady-state 
clearance, consistent with a decrease in the time-varying clearance component, which is 
high at the start of treatment and declines with repeated cycles of obinutuzumab 
treatment.  The time-varying clearance pathway is consistent with target-mediated drug 
disposition, such that at the start of treatment, there is a large quantity of CD20-positive 
cells that rapidly bind to obinutuzumab.  Repeated dosing of obinutuzumab saturates the 
pool of CD20-positive cells, hence reducing clearance via this pathway.  The linear 
clearance pathway is consistent with catabolism of immunoglobulin (Ig) G antibodies and 
is therefore independent of CD20-positive cells.  Refer to the Obinutuzumab 
Investigator’s Brochure for additional details.
1.3
BACKGROUND ON IDASANUTLIN
The tumor suppressor p53 plays a pivotal role in protection from cancer development.  
p53 is a transcription factor that is activated following stress and regulates multiple 
downstream genes implicated in cell-cycle control, apoptosis, DNA repair, and 
senescence in non-stressed cells (Ray-Coquard et al. 2012); the level of p53 is 
controlled tightly by murine double minute 2 (MDM2).  MDM2 regulates p53 through a 
negative feedback loop, and when the nuclear p53 level is elevated, it activates 
transcription of the MDM2 gene.  In turn, MDM2 binds to p53 and blocks its 
transactivation domain.  MDM2 also serves as a p53 ubiquitin ligase that targets p53 for 
ubiquitin-dependent degradation in the proteasome.  Both p53 and MDM2 have a short 
half-life and their nuclear concentrations are kept very low as a result of the functioning 
of the regulatory circuit.  However, in cancer cells overexpressing MDM2, this feedback 
loop is dysregulated.  Stress-induced p53 activation mechanisms in these tumors are 
believed to be inadequate, leading to inefficient growth arrest and/or apoptosis.
Therefore, blocking the p53MDM2 interaction is expected to overcome the oncogenic 
consequences of MDM2 overproduction, leading to enhanced p53 stabilization and 
function (Ray-Coquard et al. 2012).  Treatment of cancer cells expressing functional p53 
with MDM2 antagonists should result in the concurrent transcriptional activation of p53 
downstream genes, cell-cycle arrest, and apoptosis.
A class of imidazoline compounds was identified as potent and selective inhibitors of the 
p53MDM2 interaction (Vassilev et al. 2004).  These molecules, part of the family of 
nutlins, interact specifically with the p53-binding pocket of MDM2 and, thus, free p53 
from negative feedback mechanisms.  Treatment of cancer cells with nutlins activates 
the p53 pathway leading to activation of P53 target genes, cell-cycle arrest, apoptosis, 
and/or senescence (Tovar et al. 2006; Vassilev et al. 2007).
The imadazoline RO5045337 was the first member of the nutlin family of MDM2 
antagonists tested in humans and is the predecessor of the pyrrolidine idasanutlin 
(RO5503781), the compound that will be investigated in this study.  Both compounds 
bind selectively to the p53 binding site on the surface of the MDM2 molecule in vitro with
high affinity.  The compound has good oral bioavailability and has shown tumor growth 


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inhibition (TGI) in four mouse xenograft models of human cancer, including two NHL 
models tested at doses that did not cause noteworthy toxicity.
In cell-free assays, idasanutlin has been shown to bind to the MDM2 protein with high 
affinity (Kd5.7 nM) and to inhibit MDM2−p53 binding with an IC50 of 6.61.0 nM.  
Exposure of tumor cells, including lymphoma cells to the compound, leads to a dose-
dependent accumulation of p53 protein and activation of its transcriptional targets and 
the p53 pathway.  As a result, cancer cells undergo a cell-cycle block during G1 and G2 
phases followed by apoptosis in vitro and in vivo (see Figure 1) (Ding et al. 2013).
Figure 1
Regulation of p53 Stability and Activity by MDM2
BAX BCL-2associated X protein; BCL-2 B-cell lymphoma 2 protein; CDKs cyclin-dependent
kinases; Cyto C cytochrome C; G1 Growth 1/Gap 1 phase; G2 Growth 2/Gap 2 phase;
Mmitosis; MDM2 murine double minute 2; NOXA phorbol-12-myristate-13-acetateinduced
protein 1, p21 cyclin-dependent kinase inhibitor 1A (CDKN1A, CIP1); PUMA p53 upregulated
modulator of apoptosis; S synthesis phase.
1.3.1
Quality Development
Two oral compounds of the drug family of nutlins binding to an identical binding site have 
been investigated in clinical studies:  RO5045337, the predecessor molecule with lower 
affinity was evaluated in 350 patients in total, and an improved selective MDM2 inhibitor 
with increased target affinity and pharmacokinetic properties, idasanutlin, which is used 
in all ongoing and planned studies.  Tablets manufactured with the amorphous 
compound were originally developed with a microprecipitated bulk powder (MBP) 
formulation and used to treat 209 patients in early clinical studies.  Using an alternative 


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approach to stabilize the amorphous state of the drug substance, a spray-dried powder 
(SDP) formulation was developed. PK results from a relative bioavailability study 
(NP28902, Part 2) demonstrated that the SDP formulation has an increased maximum 
concentration (Cmax) observed and exposure (area under the concentrationtime curve 
[AUC]) compared with the MBP formulation and similar patient variability in exposure.
Based on these positive results, as well as the reduced formation of a genotoxic impurity, 
the SDP formulation is planned for use in all future clinical development.  Subsequently, 
an optimized SDP formulation (filler and film-coat color change) has been developed for 
use in the proposed Phase Ib/II study.  Similar systemic exposures, safety, and efficacy 
can be achieved with a reduced dose of the SDP formulation (300 mg twice daily [BID]) 
compared with the MBP formulation (600 mg BID).  As of 13 September 2016, 
357 patients have been treated with idasanutlin (both formulations: 191 patients with
acute myeloid leukemia (AML) and 166 patients with solid tumors or NHL.
1.3.2
Clinical Studies with RO5045337 and Idasanutlin
Initial proof of mechanism for MDM2 inhibition leading to p53 activation was 
demonstrated in solid tumors with RO50405337; however, the best response observed 
in patients with relapsed solid tumors was stable disease (SD) (RO5045337 
Investigator’s Brochure).
In the RO5045337 leukemia study (NO21279), 96 patients whose disease was R/R to 
available standard-of-care regimens were treated in Stratum A (AML, acute lymphocytic 
leukemia [ALL], and chronic myelogenous leukemia [CML]) and 20 patients in Stratum B 
(CLL) during dose escalation.  The doses ranged from 20 mg/m2 to 1920 mg/m2.  One 
patient achieved a PR (and continued to receive 25 cycles; the patient had a history of 
Richter syndrome), and 15 patients showed SD with this early formulation of the MDM2 
inhibitor.  
Six patients experienced at least one Grade 4 adverse event.  Grade 4 adverse events 
in patients with CLL included pneumonia, hypophosphatemia, febrile neutropenia, and 
hemorrhagic stroke (reported in 1 patient each), and anemia and thrombocytopenia (in 
2 patients each).  The events were considered by the investigator to be study treatment 
related.  Patients received treatment for the adverse event and continued study 
treatment without dose adjustments.  No dose-limiting toxicities (DLTs) were reported in 
the 20 patients with CLL.  
As of 13 September 2016, idasanutlin had been studied in 298 patients in the Phase I/Ib 
program, including 131 patients with AML (and 1 patient with CML), 160 patients in the 
solid tumor setting, and 6 patients with NHL.  
The idasanutlin solid tumor study (NP27872; n99) tested different doses and 
schedules using the MBP formulation.  The study was an entry-into-human, multiple-
ascending dose-escalation study with two dosing schedules (weekly3 [Schedule A] vs. 


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daily [5 or 3; Schedule B], each administered on a 28-day cycle duration) escalating 
independently.  Each schedule started with a single-patient dose escalation at a dose of 
100 mg.  The five most common tumor types were leiomyosarcoma (8 of 99 patients 
[8.1%]), liposarcoma (7 of 99 [7.1%]), and adenocarcinoma of the colon, rectal 
adenocarcinoma, and transitional cell carcinoma (5 of 99 patients [5.1%] each).  The 
MTD for weekly dosing (Schedule A) was determined as 1600 mg BID, with DLTs of 
nausea (Grade 3), vomiting (Grade 3), and thrombocytopenia (Grade 4).  For daily5 
dosing (Schedule B), the MTD was determined to be 500 mg once a day (QD), with 
DLTs of thrombocytopenia (Grade 4; including the preferred term “platelet count 
decreased”), neutropenia (Grade 4), febrile neutropenia (Grades 3 and 4), leukopenia 
(Grade 4), and diarrhea (Grade 3).  For daily 3 dosing (Schedule B), the MTD was 
determined to be 500 mg BID, with DLTs of pancytopenia (Grade 4), thrombocytopenia 
(Grades 3 and 4), febrile neutropenia (Grade 3), and neutropenia (Grade 4) reported.  
Eight of 34 patients treated QD5 days had a best response of SD.
Three patients with NHL were treated in this study (2 patients at 500 mg BID3 days 
and 1 patient at 400 mg BID5 days with the MBP formulation), and no differences in 
safety profile of patients with lymphoma compared with that of patients with solid tumors 
could be detected.  One patient with anaplastic lymphoma had a Grade 3 adverse event 
of neutropenic sepsis (reported as being unrelated to study drug) and prolonged Grade 4 
thrombocytopenia for 55 days (related to study drug).  One patient with DLBCL had a 
Grade 3 serious adverse event of febrile neutropenia and Grade 4 thrombocytopenia 
(both related to study drug) and discontinued treatment.
One patient with DLBCL also had GI toxicity presenting as Grade 3 diarrhea and 
Grade 3 nausea, as well as hematologic toxicity in terms of concurrent Grade 4 
thrombocytopenia, Grade 4 neutropenia, and Grade 3 anemia, which were all mitigated 
by blood transfusions and growth factors.
In the Phase I/Ib AML study, NP28679, 46 patients were treated with monotherapy and 
76 patients were treated with combination therapy with cytarabine. 
As of the clinical cutoff date (15 April 2016), of the 17 (of 20) response-evaluable 
patients treated with idasanutlin monotherapy during the dose-escalation period in Part 1, 
the best hematologic malignancy responses during treatment were as follows:  
2 patients achieved a CR (1 patient had received no prior cancer therapies and 
continued to have a CR for 1 year from initiation of therapy, and the other patient had 
prior therapy for myelofibrosis and was relapse free for 9 months), 3 patients achieved 
complete remission with incomplete blood count recovery (CRi)/morphologic leukemia-
free state (MLFS), 3 patients achieved a PR, and 4 patients experienced hematologic 
improvement (HI).  HI was defined as decreased percentage of peripheral blasts, 
decreased frequency of transfusions, and improvement in peripheral cell counts
(Martinelli et al. 2016).


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Eight of 9 patients were evaluable for response in the Part 1 extension.  Response 
assessments indicated 2 patients each with CR/CRp or CRi/MLFS (1 patient bridged to 
an allogeneic transplant and 1 patient discontinued on Day 737), and 2 patients with HI.
In the Part 2 (idasanutlin plus cytarabine) dose escalation in 22 response-evaluable 
patients, there were 6 patients with a best response of CR/CRp, 1 with CRi/MLFS, and 2 
patients each with a PR and HI.  In the Part 2 extension phase of the study, 17 patients 
received idasanutlin monotherapy and 21 patients received combination therapy with 
cytarabine.  More patients treated with idasanutlin plus cytarabine achieved CR/CRp 
than those treated with idasanutlin alone in the Part 2 extension phase. A total of 5 of 16 
response-evaluable patients achieved a CR/CRp following treatment with idasanutlin 
plus cytarabine; all 5 patients had a CR, with 1 patient bridged to transplant prior to 
confirmation but remained as having a CR following transplant.  Only 1 of the 17 
response-evaluable patients in the Part 2 extension treated with idasanutlin alone had a 
CR/CRp.
Initial analysis of the number of prior regimens for antecedent hematologic disease or 
antecedent malignancy, number of prior therapies for AML, exposure, and best response 
in the study for patients treated with idasanutlin in combination with cytarabine (Part 2, 
Part 2 extension, and Part 4) demonstrated activity in patients who received prior 
cytarabine-containing regimens and had R/R disease.  One patient with AML treated 
with idasanutlin plus cytarabine in Study NP28679 achieved a CR despite harboring a 
TP53 mutation.
In Part 4 of the study, 10 of 31 response-evaluable patients who were treated with the 
SDP formulation of idasanutlin in combination with cytarabine achieved a CR/CRp 
(9 CRs and 1 CRp) and 3 patients achieved a CRi/MLFS (1 CRi and 2 MLFS) (cutoff, 
15 April 2016; enrollment is complete).
In a Phase Ib/II study, GH29914, 10 patients have received combination therapy with 
venetoclax and the SDP formulation of idasanutlin until the cutoff date of 13 September 
2016.  Three dosing cohorts have been evaluated to date: 3 patients received 
400 mg/200 mg (venetoclax/idasanutlin), 3 patients received 400 mg/400 mg, and 
4 patients received 600 mg/200 mg.
In a Phase Ib/II NHL study, BH29812, 6 patients were treated with two different 
idasanutlin dose levels as of 13 September 2016. Three patients each were treated with 
100 mg of idasanutlin plus 1000 mg of obinutuzumab or 150 mg of idasanutlin plus 1000 
mg of obinutuzumab, respectively.  All 6 patients cleared the DLT period and 5 were 
safely treated in Cycle 2. One patient discontinued after Cycle 1 due to disease 
progression.


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1.3.2.1
Clinical Pharmacology 
Clinical Pharmacokinetics
Clinical pharmacokinetics obtained from studies in patients with solid tumors 
(Studies NP27872 and NP28902) or AML (Study NP28679) treated with idasanutlin at
daily doses ranging from 100 to 3200 mg or weekly doses of 400 or 800 mg are 
summarized as follows:

Half-life was approximately 1 day; the half-life was the same on the weekly schedule 
as on Day 3 or Day 5 of the daily schedules.

For AUC values, intrapatient variability was 30% and interpatient variability was
approximately 50%.

East-Asian ethnicity, age, sex, and concomitant cytarabine treatment did not have
an apparent effect on PK exposure.

The SDP formulation was tested in Studies NP28679 and NP28902 and appears to 
be twice more bioavailable than the MBP formulation.

No major effect of low-fat and high-fat meals was observed on pharmacokinetics of 
the SDP formulation to be used in the current study.

Idasanutlin is 99.99% protein bound; bone marrow exposure is approximately 70% 
of its plasma level at steady state. Idasanutlin and its metabolites are mainly 
excreted via the hepatic route through bile, with minimal (1%) renal elimination.
Clinical Pharmacodynamics
Serum levels of macrophage inhibitory cytokine1 (MIC-1), a secreted protein that is 
transcriptionally induced by p53 (with the promotor containing two p53 response 
elements), have been used to assess pharmacodynamic (PD) effects in all clinical 
studies.  Following a single dose, an increase in MIC-1 levels by fold change from 
baseline (FCBL) was observed.  Such correlations between MDM2-antagonist 
therapeutic level exposure and MIC-1 increase, as measured by FCBL, was identified in 
early studies of RO5045337 in liposarcoma (Ray-Coquard et al. 2012) and have been 
further validated as a biomarker tracking with therapeutic exposure of the current 
MDM2-antagonist idasanutlin in AML.
No correlation was apparent between idasanutlin plasma concentration and QT interval 
corrected using Fridericia’s formula (QTcF).  
Drug-Drug Interactions
Idasanutlin is a cytochrome P450 (CYP) 2C8 inhibitor that could affect concomitant 
CYP2C8 substrates at therapeutic exposure levels.  Its M4 metabolite is an organic 
anion-transporting polypeptide (OATP)-1B1/3 transporter inhibitor that has been shown 
to inhibit OATP1B1 and OATP1B3 in vitro, and thus concomitant use of OATP1B1 and 
OATP1B3 substrates, including statins, is to be avoided.  These are the basis for the 
prohibited therapy list for idasanutlin in this study (see Section 4.4.2).  However, 
idasanutlin is not expected to interact with substrates of deaminases such as cytarabine 
(no interaction observed with cytarabine in Study NP28679).  Analysis of this potential 


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interaction will continue in the ongoing Phase I/Ib study NP28679 in AML, which is 
expected to be completed in December of 2016.
Only one metabolite, RO6802287 (M4) (~25% of parent exposure), which is inactive, 
was identified.  This metabolite was generated by CYP3A4 and CYP2C8 at an 
approximate 50:50 ratio.  A strong CYP3A4 inhibitor, posaconazole, had no effect on 
idasanutlin Cmax but increased AUC values by 32%, which suggests a minimal (not 
clinically significant) drugdrug interaction (DDI) potential with use of a single strong or 
moderate CYP3A4 or CYP2C8 inhibitor (assuming the same minimal effect, as the two 
isozymes have the metabolic pathway for idasanutlin).  UGT1A3 may be a major 
clearing enzyme for idasanutlin; its strong inhibitor gemfibrozil will be excluded from use 
in the current study.
As idasanutlin is a substrate for both CYP3A4 and CYP2C8, the known strong and 
moderate inducers of CYP3A4 or CYP2C8 (only one, i.e., rifampicin, which is also a 
CYP3A4 inducer) will only be allowed after washing out with sufficient duration during 
the post-DLT window to prevent potential loss of exposure for idasanutlin and/or 
venetoclax.  The known inducers of CYP3A4 will be prohibited during the first 2 cycles of 
induction, and guidance is provided for their use in the remainder of the study 
(Section 4.4.2, Table 10).
See the Idasanutlin Investigator’s Brochure for additional details on nonclinical and 
clinical studies.
1.3.2.2
Clinical Safety of Idasanutlin
Solid Tumors:  Studies NP27872 and NP28902
A total of 160 patients with advanced malignancies (excluding leukemia) received 
idasanutlin in Study NP27872 (study now completed; cutoff date for safety data, 
2 September 2014; 99 patients) and Study NP28902 (study now completed; data cutoff 
date, 5 May 2015; 61 patients).  All 99 patients in Study NP27872 experienced at least 
one adverse event, with diarrhea, nausea, vomiting, decreased appetite, and 
thrombocytopenia being the most common adverse events. Grade 3 adverse events 
were reported for 63.6% of patients with solid tumors treated with idasanutlin in Study 
NP27872, most commonly from the Blood and Lymphatic System Disorders, GI 
Disorders, and Metabolism and Nutritional Disorders System Organ Classes (SOCs).  
In Study NP28902, 85%100% of patients in each cohort experienced at least one 
adverse event. The most common adverse events were diarrhea, nausea, decreased 
platelet count, vomiting, fatigue, constipation, and decreased appetite. GI events were 
the most common study drugrelated adverse events across all treatment groups and 
occurred during the days of treatment. The events were reversible and manageable with 
anti-emetic and antidiarrheal treatments for subsequent cycles.


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Serious adverse events were reported for 32 of 99 patients in Study NP27872, most 
commonly thrombocytopenia, febrile neutropenia, neutropenia, anemia, and leukopenia, 
and for 16 of 61 patients in Study NP28902, most commonly pyrexia, cellulitis, and 
dehydration.  Overall, seven deaths in Study NP27872 and three deaths in Study 
NP28902 were reported.  Of the seven deaths reported in Study NP27872, five were 
attributed to disease progression, one was attributed to intra-abdominal hemorrhage with 
pulmonary embolism (unrelated), and one was due to pulmonary embolism (Phase I 
category:  remotely related).  In Study NP28902, the cause of death for 2 patients was 
attributed to disease progression and pneumonia aspiration, which was considered by 
the investigator to be unrelated to study drug.
Acute Myeloid Leukemia:  Studies NP28679 and GH29914
Overall, the current safety profile of Study NP28679 is consistent with findings from other 
studies in patients with R/R AML treated with cytarabine.
As of 15 April 2016, all patients in NP28679 (n122) had experienced at least one 
adverse event.  The most common adverse events across the study groups were from 
the GI Disorders SOC; in particular, patients experienced diarrhea and nausea, and to a 
lesser extent, vomiting.  These events were also the most common adverse events 
considered by investigators to be related to study treatment.  Serious adverse events 
occurred in 71 of 122 patients during the study; the most common were infectious and 
hematologic events.  Infectious adverse events were more common for patients with 
AML compared with patients with solid tumors (Studies NP27872 and NP28902).  Of the 
25 of the 71 serious adverse events that were considered by investigators to be related 
to study treatment, the most frequent events were sepsis and febrile neutropenia.
Overall, there were 27 deaths reported during the study, 16 of which were associated 
with or resulted from adverse events.  Of the eight deaths considered by investigators to 
be related to study treatment, the causes of death were identified as sepsis (3 patients), 
pneumonia (1 patient), Clostridium difficile infection (1 patient), Scedosporium infection 
(1 patient), neutropenic colitis (1 patient), and neutropenic sepsis (1 patient).
Although the MTD was not reached in a formal manner for the 56 patients with AML 
during dose escalation, the clinical experience for patients treated at 800 mg BID was 
evaluated by investigators as not tolerable for those patients, primarily due to GI adverse 
events (mainly diarrhea) and bone marrow failure (DLT), and further dose escalations 
were not recommended.  Although there are fewer patients treated with the SDP 
formulation than with the MBP formulation across all studies (solid tumor and AML), 
there do not appear to be differences in tolerability and/or collective safety parameters.
The adverse event profile of the SDP formulation of idasanutlin with cutoff date of 
25 February 2015 (Part 4) is similar to that of the MBP (see Appendix 13). 


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In a Phase Ib/II study (GH29914) in elderly patients with R/R AML, 10 patients have 
received combination therapy with venetoclax (daily dosing) and idasanutlin (Days 15)
till the cutoff date of 13 September 2016.  Three dosing cohorts have been evaluated to 
date: 3 patients received 400 mg/200 mg (venetoclax/idasanutlin), 3 patients received 
400 mg/400 mg, and 4 patients received 600 mg/200 mg.  Of the 10 patients enrolled, 9 
patients developed at least one adverse event.  Similar to other idasanutlin trials, the 
most common adverse events were reported from SOC infection and infestations and 
SOC GI disorders across all study groups. There were no fatal adverse events.  One 
case of a serious Grade 3 DLT of asthenia was reported in the 600 mg/200 mg group 
and was considered related to study treatment by the investigator.
1.4
BACKGROUND ON VENETOCLAX
Venetoclax (synonymous with ABT-199 and GDC-0199) is a highly selective, orally
available smallmolecule Bcl-2 family protein inhibitor that binds with high affinity
(dissociation constant [Ki] 0.10 nM) to Bcl-2 and with lower affinity to other Bcl-2 family
proteins Bcl-XL and Bcl-w (480- and 2000-fold lower affinity than to Bcl-2,
respectively). Overexpression of anti-apoptotic Bcl-2 family proteins is associated with
resistance to chemotherapy, and antagonism of the action of these proteins might
overcome resistance and enhance response to therapy. Anti-apoptotic Bcl-2 family
members are associated with tumor initiation, disease progression, and drug resistance,
making them compelling targets for anti-tumor therapy.
1.4.1
Nonclinical Studies with Venetoclax
In vitro, venetoclax demonstrated broad cell-killing activity against a panel of lymphoma
and leukemia cells, including B-cell FL, mantle-cell lymphoma (MCL), DLBCL, and AML. 
Venetoclax was especially potent against cell lines that expressed high levels of Bcl-2. 
Leukemia and lymphoma cell lines that bore the t(14;18) translocation were significantly 
more sensitive to venetoclax than wild-type cell lines.
Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines 
derived from ALL and NHL.
The PK profile of venetoclax was evaluated in multiple animal species. In mice, rats,
monkeys, and dogs, low plasma clearance and low volumes of distribution characterized
the venetoclax PK profile. Half-lives ranged from 2.2 hours in monkeys to 12 hours in
dogs. Food had a marked effect on the oral bioavailability in dogs.
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey plasma
proteins (99.9%). In rats, venetoclax was widely distributed in the liver, kidneys, spleen,
heart, lungs, small intestine, and white fat but was poorly distributed in the testes, brain,
muscle, and bone. Liver metabolism was the major route of elimination, with biliary
excretion of the parent drug playing a secondary role in rats. Venetoclax showed
moderate metabolic stability in in vitro hepatic systems across species tested, except for
low to moderate stability in dog hepatocytes.


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A more detailed discussion of the nonclinical activity of venetoclax, including
pharmacokinetic, toxicology, and metabolism, is provided in the current Venetoclax
Investigator’s Brochure.
1.4.2
Clinical Studies with Venetoclax
As of 28 November 2015, on the basis of data available in the AbbVie and
Genentech/Roche clinical databases, a total of 1662 patients have been exposed to at 
least one dose of venetoclax in the oncology and immunology development programs. 
A total of 1498 oncology patients had data available in AbbVie and Genentech/Roche 
studies as of 28 November 2015. Of the 1498 patients, 935 patients had CLL/small 
lymphocytic leukemia (SLL), 346 patients had NHL, 115 patients had MM, and 102 had 
AML. An additional 66 participants were healthy volunteers. A total of 564 oncology 
patients received the drug as monotherapy, 933 received the drug in combination with 
other therapies, and 1 patient received venetoclax as a single dose in a DDI study and 
did not re-enroll in a subsequent monotherapy study. Additionally, 98 patients had been
exposed to at least one dose of venetoclax in the AbbVie immunology study, M13-093, 
as of 28 November 2015.
Three ongoing Phase Ib/II studies, GP28331, GO28440, and GO27878, include the 
combination of obinutuzumab and venetoclax in CLL and NHL, respectively. In addition, 
Study BO25323, a Phase III randomized study evaluating the efficacy of obinutuzumab 
plus venetoclax compared with obinutuzumab plus chlorambucil in patients with 
previously untreated CLL, is ongoing.
For more detailed clinical information on venetoclax, including results in the CLL cohorts
of the clinical studies and clinical pharmacology data, refer to the Venetoclax
Investigator’s Brochure.
1.4.2.1
Clinical Results in Non-Hodgkin’s Lymphoma
Study M12-175, the first-in-human venetoclax monotherapy dose-escalation study, is
ongoing in patients with R/R CLL/SLL and NHL. Two DLTs have been reported in
patients with NHL who were treated with venetoclax in Study M12-175. Both DLTs
occurred at the 600-mg dose in Cohort 5 (which enrolled a total of 10 patients and had a
300-mg lead-in dose and 600-mg designated-cohort dose). One patient experienced a
DLT of serious Grade 3 febrile neutropenia, and the other patient experienced a DLT of
non-serious Grade 4 neutropenia. Dosing was interrupted, and patients were treated
with medication; the events resolved and patients restarted therapy at a reduced
venetoclax dose of 300 mg. No DLTs were reported in Cohorts 68, with the maximum
dose of 1200 mg studied.
The most common adverse events in the NHL cohort of Study M12-175 were nausea,
anemia, diarrhea, and fatigue, all occurring in 20% of patients. Grade 3 hematologic
toxicity was less common in patients with NHL than in patients with CLL. In Study


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M12-175, 13% of patients with NHL experienced Grade 3 neutropenia and 10%
experienced Grade 3 thrombocytopenia.
As of 15 September 2015, a total of 106 patients were enrolled in the R/R NHL arm of 
Study M12-175 (70 patients in the dose-escalation cohorts and 36 in the safety-
expansion cohort) and evaluated for objective response following the International 
Working Group criteria (patients with Waldenstrom’s macroglobulinemia [WM] were 
evaluated using the International Workshop [IW]-WM criteria). The investigator-
assessed objective response rate (ORR) for all FL patients and DLBCL patients (across 
dose-escalation and safety-expansion cohorts), excluding DLBCL-Richter’s 
transformation patients, was 37.9% and 17.6%, respectively; a CR was achieved by 4 
patients in each group (13.8% and 11.8%, respectively). 
Study M12-630 is evaluating venetoclax in combination with bendamustine and 
rituximab (BR) in patients with R/R NHL. Patients receive this regimen for six cycles. 
In Study M12-630, preliminary efficacy data are available for 48 patients with R/R NHL
as of 17 September 2015. Median time on study was 5.3 months (range: 0.1 to
38.1 months). The ORR was 67.4% (31 of 48 evaluable patients), with a CR in 13 
patients (28.3%) and a PR in 18 patients (39.1%). An additional 3 patients (6.5%) 
had SD. Hematologic toxicity in this study was not significantly greater than that 
expected with BR alone.  
Study GO27878 is a Phase Ib/II study evaluating venetoclax in combination with either 
obinutuzumab plus CHOP (G-CHOP) or R-CHOP in patients with NHL. Patients 
received CHOP for six cycles, obinutuzumab or rituximab for eight cycles, and 
venetoclax for eight cycles (Days 410 in Cycle 1 and Days 110 in subsequent cycles).
The recommended dose of venetoclax was found to be 800 mg in the R-CHOP arm and 
has yet to be identified in the G-CHOP arm, as dosing continues beyond 800 mg.
Venetoclax in combination with either R-CHOP or G-CHOP was well tolerated, and 
response rates were very promising (Zelenetz et al. 2016).
Additional details on the clinical activity and safety of venetoclax are provided in the
Venetoclax Investigator’s Brochure.
1.4.2.2
Clinical Pharmacokinetics and Pharmacodynamics
Venetoclax clinical pharmacology has been evaluated in several Phase I to III clinical 
trials, and preliminary data are available in the Investigator’s Brochure. 
The venetoclax formulation being used in clinical trials is a tablet formulation in strengths
of 10, 50, and 100 mg. After a single dose in patients with CLL/SLL, after a low-fat meal,
venetoclax plasma concentrations peaked at approximately 6 hours after dosing. The
mean harmonic terminal phase elimination half-life (t1/2) of venetoclax was approximately 
17 hours, and the mean oral clearance was approximately 13 L/hour. No accumulation 
was seen after repeated QD administration of venetoclax over the 100 to 800 mg QD 


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dose range in patients with CLL/SLL. Preliminary data from patients with CLL/SLL 
suggested that venetoclax AUC was approximately dose-proportional across the 150- to 
1200-mg dose levels at steady state. Preliminary data did not suggest apparent PK 
differences among patients with CLL/SLL, NHL, MM, or AML. Low-fat and high-fat 
meals increased the exposure compared with fasting in healthy volunteers by 
approximately 3.4- and 5.1-fold, respectively. Venetoclax should always be given after a 
low-fat meal.
Venetoclax is eliminated almost entirely through the hepatic route via metabolism by the
CYP3A enzyme system. Specific recommendations are provided for co-administration
of venetoclax with moderate and strong inhibitors and inducers of CYP3A. Venetoclax
does not appear to be a clinically significant inhibitor of CYP2C9.
Preliminary results from a dose- and exposure-response analysis based on
Study M12-175 data indicate that there is no relationship between venetoclax dose or
exposure and QT interval corrected using QTcF for doses up to 1200 mg (8 g/mL 
plasma concentrations) of venetoclax.
Venetoclax and its M27 metabolite are predominantly metabolized by cytochrome P450 
(CYP) 3A4 (CYP3A4) in vitro; UDP-glucuronosyltransferases (UGTs) are not involved in 
the metabolism of venetoclax. Venetoclax is also substrate for P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP) transporters. No active uptake of 
venetoclax was observed in cells overexpressing organic anion transporting polypeptide 
1B1 (OATP1B1) or OATP1B3. Based on in vitro results, venetoclax is a P-gp, BCRP, 
and OATP1B1 inhibitor. It is not a potent in vitro inhibitor of CYP3A4, CYP1A2, 
CYP2B6, or CYP2D6 (IC50 > 30 µM); and it does not induce CYP3A4 or CYP1A2 at 
concentrations up to 10 µM. Venetoclax is also not predicted to cause inhibition of 
CYP2C19, CYP2C8, CYP2C9, or UGT1A1 at clinically relevant concentrations. It is not 
an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7. 
Refer to the Venetoclax Investigator’s Brochure for additional details on nonclinical and 
clinical studies.
There is no clinically relevant DDI expected among the three combined drugs in the 
present study.  
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
FL remains an incurable disease with the currently available therapies (see
Section 1.1.1). Despite significant therapeutic progress with the use of
immunochemotherapy as first-line treatment, most patients will eventually experience
disease relapse. Relapses are characterized by increasing refractoriness and
decreasing duration of response to subsequent lines of therapy. Thus, new treatments
are needed to improve the outcome for patients.


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DLBCL is the most common aggressive NHL (see Section 1.1.2), accounting for
approximately 30% of all NHLs diagnosed annually. Despite significant therapeutic
progress with the addition of rituximab to chemotherapy in the first-line treatment of 
patients with B-cell NHL, FL and DLBCL remain an area of high medical need in which 
novel targeted therapies are required to improve patient outcome (see Section 1.1).
Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody 
with high-affinity binding to the CD20 antigen; high ADCC and ADCP; low complement-
dependent cytotoxicity (CDC) activity; and high direct cell death induction. Rituximab is 
a chimeric murine/human monoclonal antibody that binds to CD20 and eliminates CD20-
expressing B cells via a number of different mechanisms, including ADCC, CDC, and 
apoptosis. 
Although monotherapy studies with obinutuzumab or rituximab show good response, the 
limited CR rates indicate the potential need for a combination with a cytotoxic therapy, or 
at least one other targeted drug with independent but complementary mechanisms of 
action.
In a RO5045337 AML/CLL study (NO21279), 20 patients with CLL were treated with the
suboptimal version and formulation of the MDM2 inhibitor. The dose ranged from
20 mg/m2 to 1920 mg/m2. In total, 15 patients had SD and 1 patient with Richter 
syndrome achieved a PR and continued to receive 25 cycles. MDM2 inhibitor
single-dose therapy is safe but does not lead to relevant clinical responses in CLL, in
spite of PD biomarker activity. The idasanutlin MBP formulation was tested in a solid
tumor study in 95 patients at different doses and schedules, which led to different MTDs 
that were dependent on dose and schedule. Three patients with NHL tolerated the 
treatment well, but one DLT occurred as prolonged thrombocytopenia. No differences
were observed in the safety profile for patients treated with 400 and 500 mg on 
Days 15 BID (MBP formulation).
Venetoclax is a specific inhibitor of the Bcl-2 anti-apoptotic protein expressed in many
NHL cells. Bcl-2 is overexpressed in most FL and many DLBCLs as a consequence of
the t(14;18) chromosomal translocation or gene amplification and is associated with a
poor prognosis in multiple tumor types (Cory and Adams 2002; Cory et al. 2003; Reed 
2008; Iqbal et al. 2011). Bcl-2 has been shown to contribute to resistance of malignant 
cells to chemotherapies with varied mechanisms of action, consistent with its role as an 
inhibitor of the final common steps of apoptosis, and is likely to play a role in resistance 
to the pro-apoptotic activities of immunotherapy and chemotherapy. In solid and 
hematologic tumor models, antimitotic drugs (taxanes and auristatin) were shown to 
modulate Bcl-2 prosurvival proteins to induce cell death in vitro (Haldar et al. 1998;
Poruchynsky et al. 1998; Wertz et al. 2011).
MDM2 and Bcl-2 are important players in major common molecular pathways with 
regard to the control of cell survival or apoptosis induction.  Inhibition of both proteins is 


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likely to create a synergy of action at a cellular level, leading to a more efficient induction 
of cell death (Oren 2003; Harris and Levine 2005; Mahfoudhi et al. 2016; Valente et al. 
2016).  Moreover, idasanutlin may be able to downregulate Mcl-1 through inhibition of 
MDM2, a known resistance factor for venetoclax.  Therefore, the addition of venetoclax, 
a Bcl-2 inhibitor, to an MDM2 inhibitor may have the potential to significantly enhance 
the anti-lymphoma activity and to result in improved clinical outcomes.
Nonclinical data that support the triplet combination of obinutuzumab or rituximab with
idasanutlin and venetoclax include the following:

A DOHH-2 model in CB17 severely compromised immunodeficient (SCID) mice that 
demonstrated significantly improved anti-tumor activity of the triplet combination 
over the activity of any treatment regimen alone or doublet combination 
(obinutuzumab plus venetoclax or obinutuzumab plus idasanutlin; see Figure 7)

A Z-138 model in CB17 SCID mice that demonstrated significantly improved 
anti-tumor activity of the triplet combination over the activity of any treatment 
regimen alone or doublet combination (obinutuzumab plus venetoclax or 
obinutuzumab plus idasanutlin; see Figure 10)

A WSU-DLCL2 model in CB17 SCID mice that demonstrated significantly improved 
anti-tumor activity of the combination rituximab plus venetoclax (see Figure 9)
No nonclinical data with the combination of rituximab, idasanutlin, and venetoclax are
available. Based on the results from the combination of obinutuzumab, idasanutlin, and 
venetoclax and their complementary mechanisms of action (direct cell death mediated 
by the anti-CD20 antibody and apoptosis mediated by idasanutlin and venetoclax), it is 
expected that rituximab in combination with idasanutlin and venetoclax would show
superior anti-tumor activity compared with the single or doublet combination.
Although there is potential of overlapping toxicity with regard to bone marrow 
suppression (anemia, neutropenia, and thrombocytopenia) between obinutuzumab or 
rituximab, idasanutlin, and venetoclax, the Grade 3 adverse event rates of hematologic 
toxicities for obinutuzumab or rituximab are relatively low and range from 3% to 14% and 
1% to 4%, respectively.  These overlapping toxicities are readily manageable with 
growth factors, clinical monitoring, and supportive blood transfusions.  Clear guidance on 
dose reduction and dose delays is in place, despite the low starting dose for idasanutlin 
and venetoclax, to mitigate potential overlapping toxicities. 
In summary, Study BH39147 has been designed to explore different doses of idasanutlin 
and venetoclax in combination with a fixed dose of obinutuzumab or rituximab in patients 
with R/R FL and DLBCL, with the primary objective to determine the MTDs and 
recommended Phase II doses (RP2Ds) in combination with obinutuzumab or rituximab
during the dose-escalation phase and the response rates in addition to safety, 
pharmacokinetics, and exploratory PD parameters in the expansion phase.  The
chemotherapy-free regimen being used seeks to offer more options for patients with R/R 


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NHL and could be the first step to future triple combinations free of conventional 
cytotoxic drugs.
Available nonclinical and clinical data suggest that there is a strong rationale to expect 
an improved benefitrisk profile with the triplet combination of obinutuzumab or rituximab,
idasanutlin, and venetoclax.  Furthermore, synergistic activity is expected to allow for 
efficacy at lower doses than single agents.  This novel triplet regimen may have the 
potential to extend treatment-free remissions and decrease toxicity by improving on 
individual agents used as part of current standard of care.  With the risk-minimization 
measures in place (see Section 5.1), the benefitrisk assessment is considered 
acceptable for the use of idasanutlin and venetoclax in combination with obinutuzumab
or rituximab in this Phase Ib/II study.
This study will be conducted in parallel with the ongoing Phase Ib/II study BH29812, 
assessing the combination of obinutuzumab or rituximab and idasanutlin in a similar 
patient population.  These two studies will be linked and will share information regarding 
the safety, tolerability, as well as the efficacy of the combination on a regular basis.  As a 
safety measure, enrollment in Study BH39147 will start only after preliminary safety data 
from Study BH29812 become available.  Dose escalation of idasanutlin in this study will 
occur after the same or a higher dose has been tested in Study BH29812.  In addition, 
safety data from both Studies BH29812 and BH39147 will be integrated in a modified 
Continual Reassessment Model (mCRM) with overdose control (see Section 3.1.2.3) for 
selection of subsequent doses.  Any safety signals, tolerability data, or efficacy data 
reported in one study will be assessed and immediately put in context with available data 
in the second study.  
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, and pharmacokinetics of obinutuzumab in 
combination with idasanutlin and venetoclax in patients with R/R FL and rituximab in 
combination idasanutlin and venetoclax in patients with R/R DLBCL, with safety being 
the primary objective in the dose-escalation phase and the expansion phase of the study
and efficacy being the primary objective for the expansion phase. Specific objectives 
and corresponding endpoints for the study are outlined below. 
In this study, “study treatment” refers to the protocol-mandated treatments under study 
(i.e., obinutuzumab, rituximab, idasanutlin, and venetoclax).
2.1
SAFETY OBJECTIVES

To determine the RP2Ds for idasanutlin and venetoclax when given in combination 
with a fixed dose of obinutuzumab or rituximab during the dose-escalation phase on 
the basis of the following endpoint:
– Incidence of DLTs during the first two cycles of study treatment


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
To evaluate the safety and tolerability of obinutuzumab or rituximab in combination 
with idasanutlin and venetoclax during the dose-escalation and expansion phases
on the basis of the following endpoints:
– Nature, frequency, severity, and timing of adverse events, including DLTs
– Changes in vital signs, ECGs, and clinical laboratory results during and following 
study treatment administration
2.2
EFFICACY OBJECTIVES
Response will be determined on the basis of positron emission tomography and 
computed tomography (PET-CT) scans or CT scans alone, using Revised Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014; see Appendix 4), 
hereinafter referred to as the modified Lugano 2014 criteria. Response will be
determined by an independent review committee (IRC) and by the investigator.
2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of obinutuzumab 
in combination with idasanutlin and venetoclax in R/R FL and rituximab in combination 
with idasanutlin and venetoclax in R/R DLBCL on the basis of the following endpoint:

CR at the EOI, as determined by the IRC on the basis of PET-CT scans 
2.2.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of 
obinutuzumab in combination with idasanutlin and venetoclax in R/R FL and rituximab in 
combination with idasanutlin and venetoclax in R/R DLBCL on the basis of the following 
endpoints within each disease cohort:

CR at the EOI, as determined by the investigator on the basis of PET-CT scans

CR at the EOI, as determined by the IRC and by the investigator on the basis of 
CT scans alone

Objective response (defined as a CR or PR) at the EOI, as determined by the 
IRC and by the investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at the EOI, as determined by the 
IRC and by the investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone


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2.2.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the long-term efficacy of 
obinutuzumab or rituximab in combination with idasanutlin and venetoclax on the basis 
of the following endpoints:

For patients who have positive PET scans at EOI:  
CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans, in patients with FL 
CR at end of consolidation (EOC), as determined by the IRC and by the 
investigator on the basis of PET-CT scans, in patients with DLBCL

PFS, defined as the time from initiation of study treatment to first occurrence of 
disease progression or relapse, as determined by the investigator on the basis of 
CT scans alone, or death from any cause

EFS, defined as the time from initiation of study treatment to any treatment failure, 
including disease progression or relapse, as determined by the investigator on the 
basis of CT scans alone, initiation of new anti-lymphoma therapy, or death from any 
cause, whichever occurs first

Disease-free survival (DFS), defined, among patients achieving a CR, as the time 
from the first occurrence of a documented CR to relapse, as determined by the 
investigator on the basis of CT scans alone, or death from any cause, whichever 
occurs first

Overall survival (OS), defined as the time from initiation of study treatment to death 
from any cause

Additional descriptive analysis based on TP53 status will be performed on the 
following endpoint:
–
CR at the EOI, as determined by the IRC on the basis of PET-CT scans
2.3
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are as follows:
Secondary PK Objectives

To characterize the PK profiles of obinutuzumab or rituximab, idasanutlin (and its 
metabolites, if appropriate), and venetoclax to support dose escalation

To assess potential PK interactions between idasanutlin, venetoclax, 
and obinutuzumab or rituximab
Exploratory PK Objectives

To explore PK exposure-effect (including PD, efficacy, and adverse event) 
relationships 


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2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify non-inherited biomarkers 
that are associated with response to study treatment (i.e., that could serve to inform 
precision healthcare approaches with predictive and/or prognostic potential), are 
associated with acquired resistance to study treatment, are associated with susceptibility 
to developing adverse events, can provide evidence of study treatment activity, can 
increase the knowledge and understanding of lymphoma biology or study treatment 
mechanism of action, or can contribute to improvement of diagnostic assays, on the 
basis of the following:

Association between non-inherited biomarkers (listed in Section 4.5.6) and efficacy, 
safety, and PK endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study
This Phase Ib/II, open-label, multicenter, non-randomized, dose-escalation study will 
evaluate the safety, efficacy, and pharmacokinetics of obinutuzumab in combination with 
idasanutlin and venetoclax in patients with R/R FL and rituximab in combination with 
idasanutlin and venetoclax in patients with R/R DLBCL.  The study will include an initial 
dose-escalation phase followed by an expansion phase. The dose-escalation phase is
designed to determine the RP2Ds and regimen for idasanutlin and venetoclax in 
combination with obinutuzumab for FL patients and in combination with rituximab for 
DLBCL patients. Dose escalation starts with idasanutlin and venetoclax in combination 
with obinutuzumab in all patients (FL and DLBCL) until the MTD (Regimen A) or until 
Sponsor decision based on clinical judgment (see Section 3.1.2), followed by:

Dose confirmation and potential dose escalation in patients with DLBCL for 
idasanutlin and venetoclax in combination with rituximab to determine the RP2Ds for 
this combination

Dose confirmation and potential dose escalation in patients with FL with a different 
regimen (Regimen B, obinutuzumab given alone in Cycle 1 followed by idasanutlin, 
venetoclax, and obinutuzumab in combination in Cycles 26) to determine the 
RP2Ds for this regimen
The RP2Ds and regimen for FL and RP2Ds for DLBCL will be decided at the end of 
dose-escalation phase. Different RP2Ds and/or regimens may apply for FL and DLBCL,
respectively.
In the expansion phase, patients with FL will receive idasanutlin and venetoclax at the 
RP2Ds of the selected regimen (Regimen A or B) in combination with obinutuzumab,
and patients with DLBCL will receive idasanutlin and venetoclax at the RP2Ds in 
combination with rituximab (see Section 3.1.3).    


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Patients with R/R FL enrolled in the dose-escalation and expansion phases may be 
eligible to receive post-induction treatment (referred to as maintenance) with 
obinutuzumab, venetoclax, and idasanutlin (see Sections 3.1.2.2 and 3.1.3, respectively, 
for details on the treatment regimens).
Patients with R/R DLBCL enrolled in the dose-escalation and expansion phases may be 
eligible to receive post-induction treatment (referred to as consolidation) with 
obinutuzumab or rituximab, venetoclax, and idasanutlin (see Section 3.1.2.2 for details 
on treatment regimens).  Patients who receive obinutuzumab during induction will 
continue to receive obinutuzumab in consolidation, and patients who receive rituximab 
during induction will continue to receive rituximab in consolidation.
The study schema is presented in Figure 2. 
Figure 2
Study Schema
DLBCLdiffuse large B-cell lymphoma; EOIend of induction;  FLfollicular lymphoma; 
RP2Drecommended Phase II dose.
Approximately 140 patients with R/R FL and DLBCL are expected to be enrolled in this 
study at approximately 25 investigational sites worldwide.
All patients will be closely monitored for adverse events throughout the study and for at 
least 90 days after the last dose of study treatment (see Section 5.3.1).  Adverse events 
will be graded according to the National Cancer Institute Common Toxicity Criteria, 
Version 4.0 (NCI CTCAE v4.0).  An internal monitoring committee (IMC) will be 
established to monitor patient safety throughout the study (see Section 3.1.4).


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To characterize the PK properties of obinutuzumab or rituximab, idasanutlin, and
venetoclax when given in combination, blood samples will be taken at various timepoints 
before and during study treatment administration (see Appendix 3).
Response will be determined by the IRC (see Section 3.1.5) and the investigator using 
the modified Lugano 2014 criteria (see Appendix 4).  The primary efficacy endpoint will 
be based on IRC assessment of response.  Refer to Section 4.5.5 for details on tumor 
assessments.
The schedules of activities are provided in Appendix 1 and Appendix 2; the schedule for 
PK and biosample assessments is presented in Appendix 3.
The Sponsor may decide to delay, suspend, or terminate enrollment within a given arm.  
Experimental arms with insufficient clinical activity or unacceptable toxicity will not 
undergo expansion.  New experimental arms may be added during the study by 
amending the protocol.
3.1.2
Dose-Escalation Phase
The purpose of the dose-escalation phase is to identify the RP2Ds and regimen for 
idasanutlin and venetoclax when combined with a fixed dose of obinutuzumab in 
patients with R/R FL and the RP2D for idasanutlin and venetoclax when combined with 
375 mg/m2 of rituximab in patients with R/R DLBCL.  The RP2Ds will be based on the 
MTDs of idasanutlin and venetoclax when combined with a fixed dose of obinutuzumab
or with 375 mg/m2 of rituximab, but will also take into account all safety data during 
treatment. There could be two different RP2Ds and/or regimens dependent on the 
combination of idasanutlin, venetoclax plus obinutuzumab or idasanutlin, and venetoclax 
plus rituximab.
A minimum of 9 patients and a maximum of 60 patients will be enrolled during the 
dose-escalation phase.  Cohorts of 36 patients each will be treated at escalating doses 
of idasanutlin and venetoclax in accordance with the treatment regimens and
dose-escalation rules described in Section 3.1.2.2.
A Bayesian mCRM (see Section 3.1.2.3) is planned to guide the dose-escalation phase
to determine the MTD that achieves the efficacious exposure observed.  The principle 
underlying this trial design is the assessment of the dose-toxicity relationship in a safe 
and efficient manner, allowing for enrollment of patients at subsequent dose levels 
and/or defining the MTD with robust data, including data for patients from 
Study BH29812 (obinutuzumab or rituximab in combination with idasanutlin), when 
available. 
Patients will be closely monitored for adverse events during the DLT assessment 
window, defined as the first two treatment cycles. Adverse events meeting the criteria for 


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DLT, as defined in Section 3.1.2.1, will be reported to the Sponsor within 24 hours (see 
Section 5.4.2).
Patients experiencing a DLT during the DLT window (first two cycles of treatment) will 
permanently discontinue study treatment.
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and MTD assessments and will be replaced by an additional patient at that 
same dose level.  Patients who miss more than one dose of obinutuzumab or rituximab, 
idasanutlin, or venetoclax during the DLT assessment window for reasons other than a 
DLT will also be considered non-evaluable and will be replaced.  
Additional cohorts may be added following the Sponsor’s decision to explore 
idasanutlin’s therapeutic advantage as consolidation or maintenance treatment.  The 
decision for opening such cohorts will be based on long-term safety and tolerability data.  
3.1.2.1
Definition of Dose-Limiting Toxicity
In this study, a DLT is defined as at least one of the following events occurring during the 
first two cycles of treatment and assessed by the investigator as clearly not related to the 
patient’s underlying disease:

Any Grade 5 adverse event unless unequivocally due to the underlying malignancy 
or extraneous causes

Adverse event of any grade that leads to a delay of more than 14 days in the start of 
the next treatment cycle 

Hematologic adverse events that meet any of the following criteria: 
–
Grade 3 or 4 neutropenia in the presence of sustained fever of 38°C (lasting 
for 5 days) or a documented infection
–
Grade 4 neutropenia lasting for 7 days despite adequate supportive care 
measures.  G-CSF may be used to treat Grade 3 neutropenia but should not 
be used as prophylaxis in the DLT period.
–
Grade 3 or 4 thrombocytopenia if associated with grade ≥ 3 bleeding
–
Grade 4 thrombocytopenia lasting for 7 days 

Grade 3 or 4 non-hematologic adverse event, with the following exceptions: 
–
Grade 3 or 4 IRRs
Note that IRRs are not dose-dependent events. They may occur even after 
a small amount of drug has been administered.
–
Grade 3 laboratory TLS without manifestations of clinical TLS (see Appendix 5
for the Howard-based criteria for clinical and laboratory TLS)
–
Grade 3 AST or ALT increase lasting < 7 days
–
Grade 3 diarrhea that responds to adequate therapy within 48 hours 


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–
Grade 3 nausea or vomiting that occurs in the absence of premedication and 
responds to adequate therapy within 72 hours 
–
Grade 3 fatigue, asthenia, anorexia, or constipation that resolves to Grade 2 
in 7 days

Any increase in hepatic transaminase > 3 × baseline AND an increase in direct 
bilirubin > 2 × ULN, WITHOUT any findings of cholestasis or jaundice or signs of 
hepatic dysfunction AND in the absence of other contributory factors (e.g., 
worsening of metastatic disease or concomitant exposure to known hepatotoxic 
agent or of a documented infectious etiology) is suggestive of potential drug induced 
liver injury (DILI) (according to Hy’s Law) and will be considered a DLT.
Other toxicities that are considered clinically relevant and related to study treatment as 
determined by the investigator and the Medical Monitor may also be considered DLTs. 
3.1.2.2
Treatment Regimens and Dose-Escalation Rules
Patients with FL and DLBCL until the Bridging cohorts
During this first dose-escalation phase, patients will be enrolled according to the schema 
in Figure 3.  Three patients will initially be enrolled in each cohort, and up to 3 additional 
patients can be enrolled in a cohort at the Sponsor’s discretion.  The first patient in each 
cohort will be observed for safety for 1 week after Cycle 1 Day 1 before additional 
patients are enrolled in the same cohort.  A minimum of 3 patients enrolled in a cohort 
must complete at least the first two cycles (i.e., the DLT assessment window, until Cycle 
2, Day 28) before enrollment commences in the next cohort(s).  Intra-patient dose
escalation is not permitted in this study.
Enrollment will begin in a safety cohort in which patients will be treated at starting doses
of 100 mg QD on Days 15 of each cycle for idasanutlin and 200 mg QD on Days 15 of 
each cycle for venetoclax, given in combination with obinutuzumab at the standard dose
on Days 1, 8, and 15 of Cycle 1 and Day 1 of subsequent cycles (see Figure 3 for details 
on treatment regimens). If treatment in the safety cohort is well tolerated, treatment will 
be initiated in Cohort 1 at the same doses as the safety cohort, except that patients will 
receive venetoclax on Days 110 of each cycle (see Figure 3). This regimen is refered to
as Regimen A.
If the initial treatment regimen is not tolerated in the safety cohort, any subsequent 
cohorts will receive venetoclax on Days 15 of each cycle.
If safety and tolerability allow, the next two cohorts (Cohorts 2 and 3) will be enrolled 
concurrently.  Patients in Cohort 2 will receive an escalated dose of venetoclax, while 
patients in Cohort 3 will receive an escalated dose of idasanutlin.  Thus, only one drug 
will be escalated within each of the concurrent cohorts.  If safety and tolerability allow, 
patients in Cohort 4 will receive both venetoclax and idasanutlin at the escalated doses 
given in the previous two cohorts (see Figure 3).


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Figure 3
Dose-Escalation Schema (Regimen A)
Obinituzumab or rituximab are given at standard doses.
D15Days 15; D110Days 110; I=idasanutlin; QD once a day; Vvenetoclax.
If TLS is observed in the initial cohorts, venetoclax dosing may be modifed as follows:

Staggered dosing in which venetoclax may be initiated 2 or 3 days after the first 
idasanutlin dose during Cycle 1

Initiation of Cycle 1 treatment below the target dose for venetoclax, followed by 
incremental dose increases until the target dose is achieved
During this first dose-escalation phase, study treatment will be administered as outlined 
in Table 1). Patients with FL who achieve a CR or a PR at the EOI will also receive 
maintenance treatment with obinutuzumab, venetoclax, and idasanutlin. Patients with 
DLBCL who achieve a CR or a PR at the EOI will also receive consolidation treatment 
with obinutuzumab, venetoclax, and idasanutlin. Post-induction treatment should start 
8 weeks (1 week) after Day 1 of the final cycle of induction and will continue until 
disease progression or unacceptable toxicity for up to 2 years for maintenance treatment 
and 6 months for consolidation treatment (see Table 2).  Patients with DLBCL who 
achieve a CR based on modified Lugano 2014 criteria at the end of induction (defined as 
within 68 weeks after the start of the last cycle of study treatment) are allowed to 
proceed to hematopoietic stem cell transplantation if deemed appropriate by the 
investigator. Such patients will be followed for disease progression and survival.  The 
dose and regimen for venetoclax and idasanutlin will be determined by the Sponsor 
upon review of all available safety, PK, PD, and efficacy data. The dose for 
maintenance/consolidation will not exceed the dose the patient received during induction.  
The FL and DLBCL bridging cohorts may open at different times, and in this case, the 
venetoclax dosing regimen (5 vs. 10 days) may be explored independently.


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Combination of Rituximab, Idasanutlin, and Venetoclax in Patients with 
DLBCL in the Bridging Cohorts
Following the identification of the MTDs for idasanutlin and venetoclax in combination 
with obinutuzumab, or following Sponsor decision based on clinical judgment, a 
bridging cohort of patients with DLBCL will be opened to repeat the last dose tested in 
combination with rituximab instead of obinutuzumab (375 mg/m2 on Day 1 of each cycle; 
see Figure 4 and Table 1).
If safety and tolerability allow, idasanutlin and venetoclax dose escalations may be 
explored in combination with rituximab in patients with DLBCL until identification of new 
MTDs (see Figure 4).  
Combination of Obinutuzumab, Idasanutlin, and Venetoclax in Patients with 
FL in the Bridging Cohorts
Following the identification of the MTDs for idasanutlin and venetoclax in combination 
with obinutuzumab in Regimen A, or following Sponsor decision based on clinical 
judgment, a bridging cohort of patients with FL will be opened to repeat the last dose 
tested in a different regimen. Obinutuzumab will be given alone in Cycle 1 and in 
combination with idasanutlin and venetoclax from Cycle 2 to 6 (see Figure 4 and 
Table 1). This regimen is referred to as Regimen B.
If safety and tolerability allow, idasanutlin and venetoclax dose escalation may be 
explored with Regimen B in patients with FL until identification of new MTDs (see Figure 
4).  
After the last patient in each cohort has completed the two-cycle DLT observation period, 
the Sponsor, in consultation with the investigators, will evaluate the next dose 
recommended according to the mCRM (see Section 3.1.2.3) and agree on doses for the 
subsequent cohort(s), taking into account relevant demographic, adverse event, 
laboratory, dose administration, and PK (if available) data.  At each dose-escalation step, 
the dose may be escalated or de-escalated, or an additional cohort at the same dose 
level may be enrolled.
On the basis of review of real-time safety data from this study and all available data from 
Study BH29812, dose escalation may be halted or modified by the Sponsor as deemed 
appropriate.
Although the DLT assessment window is defined as the first two treatment cycles, 
cumulative toxicities occurring beyond the first two cycles may be considered when 
determining the MTDs for idasanutlin or venetoclax.


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Multiple MTDs may be identified, and the most appropriate RP2Ds will be chosen on the 
basis of safety, PK, and PD data. At the end of dose -escalation phase, RP2Ds (one for 
idasanutlin and one for venetoclax) in combination with obinutuzumab and one regimen 
will be decided for patients with FL. RP2Ds (one for idasanutlin and one for venetoclax) 
in combination with rituximab will be decided for patients with DLBCL. The RP2Ds of 
idasanutlin and venetoclax, as well as the treatment regimens for patients with FL and 
DLBCL, may be different.  
Figure 4
Dose-Escalation Schema in Bridging Cohorts
D15Days 15; I=idasanutlin; QDonce a day; MTDmaximum tolerated dose; Vvenetoclax.


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Table 1
Induction Treatment during the Dose-Escalation Phase for 
Patients with Follicular Lymphoma and DLBCL 
Cycle(s)
Safety Cohort (28-Day Cycles):
Regimen A
Cohort 1 (28-Day Cycles):
Regimen A
Cycle 1

Obinutuzumab 1000 mg IV on 
Days 1, 8, and 15

Idasanutlin 100 mg QD orally on 
Days 15

Venetoclax 200 mg QD orally on 
Days 15

Obinutuzumab 1000 mg IV on Days 1, 
8, and 15

Idasanutlin 100 mg QD orally on Days 
15

Venetoclax 200 mg QD orally on Days 
110
Cycles 26 
Obinutuzumab 1000 mg IV on 
Day 1

Idasanutlin 100 mg QD orally on
Days 15

Venetoclax 200 mg QD orally on 
Days 15

Obinutuzumab 1000 mg IV on 
Day 1

Idasanutlin 100 mg QD orally on Days 
15

Venetoclax 200 mg QD orally on Days 
110
Cohort 2 (28-Day Cycles):
Regimen A
Cohort 3 (28-Day Cycles):
Regimen A
Cycle 1

Obinutuzumab 1000 mg IV on 
Days 1, 8, and 15

Idasanutlin 100 mg QD orally on 
Days 15

Venetoclax TBD QD orally on 
Days 110

Obinutuzumab 1000 mg IV on Days 1, 
8, and 15

Idasanutlin TBD QD orally on Days 15

Venetoclax 200 mg QD orally on 
Days 110
Cycles 26 
Obinutuzumab 1000 mg IV on Day 1

Idasanutlin 100 mg QD orally on 
Days 15

Venetoclax TBD QD orally on 
Days 110

Obinutuzumab 1000 mg IV on Day 1

Idasanutlin TBD QD orally on 
Days 15

Venetoclax 200 mg QD orally on 
Days 110
Cohort 4 and Subsequent Cohorts (28-Day Cycles): Regimen A
Cycle 1

Obinutuzumab 1000 mg IV on Days 1, 8, and 15

Idasanutlin TBD QD orally on Days 15
Venetoclax TBD QD orally on Days 110
Cycles 26

Obinutuzumab 1000 mg IV on Day 1

Idasanutlin TBD QD orally on Days 15

Venetoclax TBD QD orally on Days 110
Bridging Cohorts, Patients with DLBCL Only
(28-Day Cycles)
Cycles 16
Rituximab 375 mg/m2 IV on Day 1
Idasanutlin, oral Days 15, starting dose MTD identified in combination with 
obinutuzumab and venetoclax, minimal clinically and pharmacologically feasible 
dose-escalation steps 50 mg
Venetoclax, oral, starting dose and regimen MTD identified in combination with 
obinutuzumab and idasanutlin, minimal clinically and pharmacologically feasible 
dose-escalation steps 100 mg


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Table 1
Induction Treatment during the Dose-Escalation Phase for 
Patients with Follicular Lymphoma and DLBCL (cont.)
Bridging Cohorts, Patients with Follicular Lymphoma Only
(28-Day Cycles): Regimen B
Cycle 1

Obinutuzumab 1000 mg IV on Days 1, 8, and 15
Cycle 26

Obinutuzumab 1000 mg IV on Day 1

Idasanutlin, oral Days 15, starting dose MTD identified in combination with 
obinutuzumab and venetoclax, minimal clinically and pharmacologically feasible 
dose-escalation steps 50 mg

Venetoclax, oral, starting dose and regimen MTD identified in combination with 
obinutuzumab and idasanutlin, minimal clinically and pharmacologically feasible 
dose-escalation steps 100 mg
DLBCLdiffuse large B-cell lymphoma; IVintravenous; MTDmaximum tolerated dose; 
QDonce a day; TBDto be determined.
Table 2
Post-Induction Treatment during the Dose-Escalation Phase
Post-Induction Treatment
Patients 
with FL
Maintenance treatment consisting of the following:
Obinutuzumab 1000 mg IV every 2 months for 24 months
Venetoclax for 6 months a
Idasanutlin for 6 months a
Patients 
with 
DLBCL
Consolidation treatment consisting of the following, administered for 6 months b:
Obinutuzumab 1000 mg IV every 2 months for 6 months
Or Rituximab 375 mg/m2 IV on Day 1 every 2 months for 6 months
Venetoclax for 6 months a
Idasanutlin for 6 months a
DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; IVintravenous.
a Dose and regimen to be determined by the Sponsor after review of all relevant data.  
The dose for maintenance/consolidation will not exceed the dose the patient received 
during induction.
b Patients will receive obinutuzumab or rituximab according to study treatment received in 
the induction.
3.1.2.3
Use of Modified Continual Reassessment Model for Dose and 
MTD Determination
The dose escalation will employ a mCRM with overdose control design in order to define 
the MTD and/or the recommended dose for subsequent cohorts.
The design is based on the primary safety variable, that is, the occurrence of a DLT. 
The MTD is defined as the dose that maximizes the probability of achieving a DLT rate 
of 16%33% (target toxicity interval) and results in a 35% probability of having a DLT 
rate of 33% (overdose control).


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The maximum allowable increments for idasanutlin from the highest dose already tested 
will not exceed 100 mg, with a minimum increase of 50 mg.  The maximum allowable 
increments for venetoclax from the highest dose already tested will not exceed 200 mg, 
with a minimum increase of 100 mg.
In addition, the dose of idasanutlin will not be escalated above 600 mg and the dose of 
venetoclax will not be escalated above 800 mg. The selection of the next dose will be 
subject to clinical judgment and mandated safety constraints that limit the size of the 
dose increments.  Clinical judgment will always override mCRM recommendations in the 
dose-selection process.
A detailed algorithm for the selection of the next recommended combination of doses in 
the dose-escalation procedure is described in Appendix 6. As stated above, only 
combinations of doses with a 35% probability of having a DLT rate of 33% will be 
allowed.
Dose escalation will stop when the maximum allowed sample size, 60 patients, has been 
reached or there is enough confidence in the prediction of the MTD (e.g., at least 
6 patients have been recruited at the MTD doses and there is a 40% probability of 
having a DLT rate of 16%33%).
The following two marginal models (two-parameter logistic regression), which describe 
the relationship between DLT and idasanutlin dose in the absence of venetoclax, and 
conversely, the relationship between DLT and venetoclax dose in the absence of 
idasanutlin, were considered:
 	
,
∗
 =  + ,
∗
      (1)
 	,
∗
 =  + ,
∗
    (2)
In the first model,  and  are model parameters and 
(,
∗
) is the probability of 
experiencing a DLT at a dose ,
∗
of idasanutlin, in the absence of venetoclax, 
with ,
∗
=
!"#$,%
!"#$
&'( being the normalized idasanutlin dose using the reference dose 

)* = 200 mg.  Similarly, in the second model, /0 and 10 are model parameters and
(,
∗
) is the probability of experiencing a DLT at a dose ,
∗
of venetoclax, in the 
absence of idasanutlin, with ,
∗
=
!2'3,%
!2'3
&'( being the normalized venetoclax dose 
using the reference dose 
)* = 400 mg.
In order to define the prior distributions (priors) for the parameters of the two marginal 
models, the Sponsor's clinical team went through a process of prior elicitation, based on 
expert knowledge and previous data (i.e., Study GO27878 for venetoclax and Study 
NP27872 for idasanutlin), to reach a consensus on the questions listed in Table 3.  


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Table 3
Prior Elicitation
Question
Idasanutlin with 
Obinutuzumab
Venetoclax with 
Obinutuzumab
1
What would be considered a negligible 
DLT rate?
16%
2
What would be considered a target DLT 
rate?
33%
3
What would be considered an 
unacceptable DLT rate?
60%
4
What is the highest dose known (i.e.,
almost certain) to have a negligible DLT 
rate (as per Question 1 above)?
100 mg
400 mg
5
What dose is thought to have an 
unacceptable DLT rate (as per 
Question 3 above)?
550 mg
900 mg
6
What is the smallest dose known (i.e., 
almost certain) to have a DLT rate above 
the target rate (as per Question 2 
above)?
800 mg
1000 mg
7
What dose is thought to have a target 
DLT rate (as per Question 2 above)?
300 mg
700 mg
Based on the answers from Table 3, the following priors were defined:
5

()6 ~8 5	 −2.0
0.916 , 	1.665
0.037
0.037
0.0026
5

()6 ~8 5	−3.905
1.685  , 	 1.47
0.0299
0.0299
0.003 6
A visual representation of the priors for the two marginal models is provided in Figure 5.


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Figure 5
Margins for Venetoclax and Idasanutlin
DLT dose-limiting toxicity.
Given the marginal models introduced in (1) and (2), the probability of DLT for a dose 
combination of idasanutlin and venetoclax in case of “no interaction” would be as follows:

B(
, ) = 
 +  −

The probability of DLT 
(
, , C) for a dose combination of idasanutlin and venetoclax is 
parameterized as follows:
D
1 −D =
DB
1 −DB ∙FG
(C ∙
∗
∙
∗
)
with the interaction between idasanutlin and venetoclax modeled through the interaction 
parameter C.
The interpretation of the interaction parameter C is the log of the ratio of the odds under 
interaction and no interaction, at the line where 
∗
∙
∗
= 1.  Hence, no interaction is 
attained with C = 0, synergy is attained with C > 0, and antagonism is attained with C < 0.  
A log-normal prior for C ( (C)~8(J = 0.4, K = 1.0)) was used to allow only for 
synergistic effect between the two drugs (see Figure 6).


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Figure 6
Marginal Priors for Venetoclax and Idasanutlin
The operating characteristics of the proposed mCRM were carefully evaluated through 
the use of simulations across different scenarios, and the results are reported in 
Appendix 6.  The general conclusion is that the current design provides, with an 
assumed sample size of 42 patients, overall good performances in selecting the correct 
MTD, while at the same time limiting the amount of overdosing across all scenarios.
During the study, DLT data will become available from the ongoing Phase Ib/II study 
BH29812, which is currently evaluating the safety and efficacy of obinutuzumab in 
combination with idasanutlin, and these data may be added to the BH39147 DLT data.
The above described mCRM algorithm will be first used for predicting the MTD in the 
combined FL/DLBCL dose-escalation cohorts where idasanutlin and venetoclax are 
given in combination with obinutuzumab. A similar mCRM will be then employed to 
support dose escalation in the DLBCL bridging cohorts where idasanutlin and venetoclax 
are given in combination with rituximab, if applicable, and in the FL bridging cohorts 
where idasanutlin and venetoclax are given in combination with obinutuzumab using a 
different regimen (Regimen B), if applicable.
In the event that more than one dose schedule for venetoclax will be explored during 
dose escalation (e.g., Days 15 and Days 110), independent mCRM models (with the 
same priors as described above) will be used for the different dose schedules. However 
a more complex mCRM, making use of all data (jointly modeling the different dose 
schedules) may be considered as well.
3.1.3
Expansion Phase
The expansion phase is designed to further assess the safety and efficacy of idasanutlin 
and venetoclax given in combination with obinutuzumab at their respective RP2Ds in 
patients with R/R FL and of rituximab in combination with idasanutlin and venetoclax at 
their respective RP2Ds in patients with R/R DLBCL.  Approximately 80 patients (40 
patients with FL and 40 patients with DLBCL) will be enrolled during the expansion 


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phase and treated as described below.  An interim futility analysis using a predictive 
probability design may be performed during the expansion phase. The start of the 
expansion phase may not happen simultaneously for the two indications.
All patients will receive induction treatment as outlined in Table 4.


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Table 4
Induction Treatment for the Expansion Phase
Triplet Dose: FL Cohort
(28-Day Cycles)
Regimen A a
Regimen B a
Cycle 1
Obinutuzumab 1000 mg IV on Days 1, 8, and 
15
Idasanutlin QD orally at the RP2D in 
combination with obinutuzumab on Days 15 a
Venetoclax QD orally at the RP2D in 
combination with obinutuzumab, with regimen 
determined in the dose-escalation phase (on 
Days 15 or Days 110) a
Cycle 1
Obinutuzumab 1000 mg IV on Days 1, 8, and 15
Cycles 
26
Obinutuzumab 1000 mg IV on Day 1
Idasanutlin QD orally at the RP2D in 
combination with obinutuzumab on Days 15
Venetoclax QD orally at the RP2D in 
combination with obinutuzumab, with regimen 
determined in the dose-escalation phase 
(Days 15 or Days 110)
Cycles 26
Obinutuzumab 1000 mg IV on Day 1
Idasanutlin QD orally at the RP2D in combination with 
obinutuzumab on Days 15
Venetoclax QD orally at the RP2D in combination with 
obinutuzumab, with regimen determined in the dose-
escalation phase (Days 15 or Days 110)
Triplet Dose:  DLBCL Cohort
(28-Day Cycles)
Cycles 
16

Rituximab 375 mg/m2 IV on Day 1

Idasanutlin QD orally at the RP2D in combination with rituximab on Days 15
Venetoclax QD orally at the RP2D in combination with rituximab, with regimen determined in the dose-escalation phase (on Days 
15 or Days 110)
DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; IVintravenous; QDonce a day; RP2Drecommended Phase II dose.
a The treatment regimen will be determined at the end of dose-escalation phase.


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Patients with FL who achieve a CR or a PR at the EOI will receive maintenance 
treatment with obinutuzumab, venetoclax, and idasanutlin.  Patients with DLBCL who 
achieve a CR or PR at the EOI will receive consolidation treatment with rituximab, 
venetoclax, and idasanutlin.  Post-induction treatment should start 8 weeks (1 week) 
after Day 1 of the final cycle of induction and will continue until disease progression or 
unacceptable toxicity for up to 2 years for maintenance treatment and 6 months for 
consolidation treatment (see Table 5). Patients with DLBCL who achieve a CR based 
on modified Lugano 2014 criteria at the end of induction (defined as within 68 weeks 
after the start of the last cycle of study treatment) are allowed to proceed to 
hematopoietic stem cell transplantation if deemed appropriate by the investigator.
Table 5
Post-Induction Treatment for the Expansion Phase
Post-Induction Treatment
Patients 
with FL
Maintenance treatment consisting of the following:
Obinutuzumab 1000 mg IV every 2 months for 24 months
Venetoclax for 6 months a
Idasanutlin for 6 months a
Patients 
with 
DLBCL
Consolidation treatment consisting of the following, administered 
for 6 months:
Rituximab 375 mg/m2 IV every 2 months for 6 months
Venetoclax for 6 months a
Idasanutlin for 6 months a
DLBCL diffuse large B-cell lymphoma; FLfollicular lymphoma; 
IVintravenous.
a Dose and regimen to be determined by the Sponsor after review of all 
relevant data. The dose for maintenance/consolidation will not exceed the 
dose the patient received during induction.
3.1.4
Internal Monitoring Committee 
An IMC will monitor patient safety throughout the study.  The IMC will include Sponsor 
representatives from Clinical Science, Drug Safety, Biostatistics, and Statistical 
Programming and Analysis.  In addition to the ongoing assessment of the incidence and 
nature of adverse events (particularly, Grade 3 events), serious adverse events, deaths, 
and laboratory abnormalities performed by the investigator and the Medical Monitor, the 
IMC will review all necessary cumulative data, including data required for determination 
of the RP2Ds, at regular intervals during the study and will also review results from the
interim analysis of efficacy data.  At the time of each review, the IMC will make 
appropriate recommendations (e.g., the study should continue as planned, additional 
analyses should be performed, enrollment should be held pending further safety 
evaluations).  Decisions will be made in consideration of the totality of the available data.  
Ad hoc meetings may be called in addition to scheduled meetings, as necessary, to 
provide recommendations on management of any potential new safety signals.  Specific 
operational details such as the committee’s composition, frequency and timing of 


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meetings, members’ roles and responsibilities, and data to be reviewed will be detailed 
in an IMC charter.
3.1.5
Independent Review Committee 
An IRC will assess all patients for response on the basis of imaging results, bone 
marrow biopsy results, and relevant clinical data.  The review will consist of two parts:  
a radiology review and an oncology review.  The IRC will consist of radiologists, nuclear 
medicine experts, and a board-certified oncologist with experience in malignant 
lymphoma.  Specific methodological and operational details will be specified in the 
IRC charter.
3.1.6
Post-Treatment Follow-Up and Survival Follow-Up
Patients who complete treatment or discontinue treatment for reasons other than 
disease progression will undergo assessments every 3 months during the post-treatment 
follow-up period, which will continue until disease progression, the start of new 
anti-lymphoma treatment, or the end of the study (as defined below), whichever occurs 
first.  Patients who experience disease progression will be evaluated for survival status 
and initiation of new anti-lymphoma treatment every 3 months until the end of the study.  
Details are provided in the schedules of activities (see Appendix 1 and Appendix 2).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the time when both of the following conditions are 
met:

All enrolled patients with FL have completed or discontinued study treatment
(including induction and maintenance, as applicable)

All enrolled patients with DLBCL have been followed for at least 1 year after they 
have completed or discontinued study treatment (including induction and 
consolidation, as applicable).
The total length of the study is expected to be approximately 48 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Treatment Combination
As discussed in Section 1.1.1, despite significant therapeutic progress with the use of
chemoimmunotherapy as first-line treatment, FL remains essentially an incurable
disease. Patients invariably relapse, and active and well-tolerated agents are needed
following relapse.  DLBCL can be cured in 50% of cases; however, up to one-third of
patients have refractory disease or relapse after treatment. Success rates with salvage
therapy and autologous transplantation are poor, which highlights the urgent need for
novel therapeutic approaches for these patients.
On the basis of a compelling biologic and clinical rationale, as presented in Section 1.5, 
the addition of venetoclax and idasanutlin to obinutuzumab or rituximab is a promising


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approach to increase the number of patients with R/R FL and DLBCL who achieve 
remission and to prolong the duration of response in these patients.
Obinutuzumab and rituximab are effective in the treatment of B-cell malignancies on the 
basis of their anti-CD20 mechanisms of action leading to direct cell death.  The majority 
of B-lymphoid malignancies, including NHL and CLL, also express wild-type p53 
(Imamura et al. 1994).  
MDM2 regulates p53 through a negative feedback loop. However, in cancer cells
overexpressing MDM2, this feedback loop is deregulated. Therefore, blocking the
p53MDM2 interaction is expected to overcome the oncogenic consequences of MDM2
overproduction and to restore p53 function (Ray-Coquard et al. 2012).
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway.  
The Bcl-2 oncogene was first identified in FL, where the t(14;18) chromosomal
translocation results in significant overexpression of the protein in B cells.  Bcl-2 
overexpression is a major contributor to the pathogenesis of many types of lymphoid 
malignancies and has been implicated as a cause of chemotherapy resistance.
The non-overlapping and complementary mechanisms of action of obinutuzumab or 
rituximab (direct tumor cell death) on one hand and idasanutlin and venetoclax 
(increased apoptosis) on the other may provide superior efficacy in treating B-lymphoid 
malignancies.  In addition, complementary mechanisms of action of venetoclax and 
idasanutlin may allow overcoming resistances that may develop during treatments with 
monotherapies.
In in vitro assays, both idasanutlin and venetoclax induced concentration-dependent 
apoptosis in a DLBCL cell line (DOHH-2) and in an MCL cell line (Z-138), and the 
combination with obinutuzumab or rituximab further enhanced cell-death induction.
Importantly, idasanutlin neither influenced obinutuzumab/rituximab–mediated ADCC 
activity nor B-cell depletion in healthy human whole blood at concentrations of up to 
1000 nM and did not affect obinutuzumab/rituximab–mediated NK cell activation (Herting 
et al. 2014; Herting et al.2016).  Similar experiments have been conducted with 
venetoclax with the same conclusions (Sampath et al. 2013).
In vivo single-agent and combination therapy, the efficacy (inhibition of tumor growth) of 
obinutuzumab, venetoclax, and idasanutlin was assessed in three NHL xenograft 
models.
In the in vivo study using the DOHH-2 DLBCL xenograft model, evaluating the triple 
combination versus respective monotherapies, the combination of obinutuzumab, 
venetoclax, and idasanutlin resulted in superior efficacy (115% TGI) and tumor 
regression (TGI 100%) (see Figure 7).


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Figure 7
DOHH-2 DLBCL Xenograft Model:  Tumor Volume Analysis
DLBCLdiffuse large B-cell lymphoma; IQR interquartile range.
In a Z-138 MCL xenograft study, tumor-bearing SCID beige mice received a suboptimal 
dose of 0.5 mg/kg obinutuzumab administered intraperitoneally QD with the idasanutlin 
MBP formulation given orally QD at 80 mg/kg dose (initially, 100 mg/kg for 3 days).  Mice 
were dosed with 100 mg/kg of venetoclax orally QD. Treatment with obinutuzumab, 
idasanutlin, and venetoclax monotherapy was significantly active resulting in TGI of 
47 %, 67%, and 53%, respectively.  The combination of obinutuzumab with idasanutlin 
or venetoclax resulted in 86% and 85% TGI, respectively. The combination groups of 
idasanutlin and venetoclax and also the triple combination with obinutuzumab showed 
superiority compared with monotherapy treatment, resulting in tumor regression of Z-138 
xenograft tumors (see Figure 8). 


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Figure 8
Z-138 MCL Xenograft Model:  Tumor Growth Inhibition Analysis
MCLmantle-cell lymphoma; PO by mouth; QDonce a day; QW once a week.
The efficacy of venetoclax (GDC-0199) in combination with rituximab was also evaluated 
in vivo in a WSU-DLCL2 xenograft model (DLBCL). When compared to treatment with 
rituximab, venetoclax as a single agent dosed orally and daily was less efficacious in the
WSU-DLCL2 xenograft model (see Figure 9). However, the combination of venetoclax 
with rituximab resulted in sustained in vivo efficacy and increased duration of response
(see Figure 9).




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Figure 10 Z-138 Xenograft Model:  Time-to-Event Analysis
Caution should be used when interpreting any mouse toxicology data. It is important to 
note that none of the mice experienced more than a 20% change in body weight, weight 
being the only useful toxicology parameter in a xenograft model, and no obvious 
potential drug-related adverse events were observed.
In summary, nonclinical in vitro and in vivo data strongly support the investigation of 
obinutuzumab or rituximab, venetoclax, and idasanutlin combination therapy in clinical 
studies.
Owing to the varying sensitivity of the respective cell lines in vivo (e.g., strong single-
agent activity of obinutuzumab in the Z-138 model) and the need to still be able to show 
a combination effect, tumor-bearing SCID beige mice received a suboptimal dose of 
0.5 mg/kg for obinutuzumab administered intraperitoneally QD with idasanutlin MBP 
formulation given orally (PO) QD at 80 mg/kg (initially, 100 mg/kg for 3 days) dose for 
the Z-138 model, whereas doses of 10 mg/kg obinutuzumab with idasanutlin at 30 mg/kg 
were chosen for the DOHH-2 model. Doses of 100 mg/kg of venetoclax PO QD were 
used for both models. 


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All compounds, given as a single agent, demonstrated significant anti-tumor efficacy. 
The triple combination showed superiority over monotherapy treatment, resulting in 
tumor regression of both xenograft tumors in a time-to-event analysis. To minimize the 
animal handling for multiple blood sampling, no direct pharmacokinetics for any of the 
three compounds were measured in the two NHL xenograft models studied.
Serum trough levels of obinutuzumab are projected to be approximately 5 and 60 g/mL, 
respectively, corresponding to weekly doses of 0.5 and 10 mg/kg (Obinutuzumab 
Investigator’s Brochure).  The obinutuzumab dose in the present clinical study is 1000 
mg, yielding mean serum trough concentration levels of obinutuzumab, ranging from 180
to 201 g/mL at steady state (Obinutuzumab Investigator’s Brochure), which can easily 
surpass the exposure in animal models.
The venetoclax exposure corresponded to an AUC 28.8 g hr/mL, and Cmax
2.74 g/mL was reached following a single dose of 25 mg/kg of venetoclax and to an 
AUC of 31.2 g hr/mL and a Cmax of 3.83 g/mL after 100 mg/kg of venetoclax, 
respectively (Venetoclax Investigator’s Brochure); no accumulation was observed in 
mice following repeated doses. In patients, following multiple oral administrations under 
fed conditions, venetoclax steady-state AUC increased proportionally over the dose 
range of 150800 mg. Under low-fat meal conditions, venetoclax mean steady-state 
Cmax was 2.1 g/mL and AUC0-24hr was 32.8 g hr/mL at the 400 mg QD dose. A 
significantly higher dose might be required to achieve the intended efficacy for 
venetoclax in the current clinical study.
Daily oral administration of idasanutlin at 30 mg/kg for 13 days in the DOHH-2 B-cell 
NHL mouse xenograft model corresponded to a cycle AUC of about 520 g hr/mL in 
combination with 100 mg/kg of venetoclax and obinutuzumab or 450 g hr/mL if given 
alone (SDP formulation).  
Daily oral administration of idasanutlin 30 mg/kg and 80 mg/kg in the Z-138 MCL
xenograft model corresponded to a cycle AUC of approximately 400 and 1200 g hr/mL
(MBP formulation), respectively, for a QD5-day dosing schedule. With the SDP 
formulation to be used in patients, these exposures can be achieved with 300 mg/day 
and 900 mg/day, respectively.
3.3.2
Rationale for Dosing Regimen
3.3.2.1
Rationale for Obinutuzumab and Rituximab Dosing Regimen
The dose and schedule of obinutuzumab in the induction regimen will be 1000 mg
administered to patients intravenously on Days 1, 8, and 15 of Cycle 1 and Day 1 of 
each subsequent 28-day cycle (Cycles 26). This is based on the recommended dose 
and schedule (six to eight cycles, depending on the trial) of obinutuzumab in the ongoing 
Phase III program in patients with NHL (Obinutuzumab Investigator’s Brochure). In this 
study, patients will be treated for six cycles during the induction phase.


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The dose and schedule of obinutuzumab in the maintenance regimen (FL) will be
1000 mg administered intravenously to patients every 2 months for up to 2 years. This 
dosing regimen is based on the obinutuzumab maintenance regimen that was 
administered in the Phase III study GAO4753g (Trněný et al. 2016).  The dose and 
schedule of obinutuzumab in the consolidation regimen (DLBCL) will be 1000 mg 
administered intravenously to patients every 2 months for up to 6 months.  The 
consolidation regimen is modeled after the FL maintenance regimen.  The rationale for 
treatment duration is provided in Section 3.3.2.4.
The study will start with obinutuzumab standard dosing in combination with idasanutlin
and venetoclax in Cycles 16 (Regimen A). For patients with FL, an alternative dosing 
regimen (Regimen B) with obinutuzumab given at Cycle 1 followed by obinutuzumab in 
combination with idasanutlin and venetoclax in Cycles 26 will be explored to investigate 
the possibility of alleviating hematological toxicities at Cycle 1. The rationale for 
exploring Regimen B in patients with FL is that obinutuzumab is given 3 times during 
Cycle 1 (Days 1, 8, and 15) compared to only at Day 1 in subsequent cycles. Those 3 
doses of obinutuzumab, when combined with idasanutlin and venetoclax at higher doses 
in the same treatment cycle, may induce more profound hematologic toxicities. 
Staggered idasanutlin and venetoclax dosing to start at Cycle 2 may mitigate toxicities 
and allow recovery before dosing with the combination.  Only one regimen will be 
chosen for the expansion phase.
For patients with DLBCL in the bridging cohort(s) and the expansion phase, the dose 
and schedule of rituximab in the induction regimen will be 375 mg/m2 on Day 1 of each 
28-day cycle (Cycles 16); and the dose and schedule in the maintenance or 
consolidation phase will be 375 mg/m2 every 2 months. This dose is the recommended 
dose in NHL population and is the standard of care. For patients receiving rituximab, no 
alternative regimen will be explored as rituximab is only given at Day 1 in each treatment 
cycle and the overlapping toxicities with idasanutlin are expected to be less pronounced.  
3.3.2.2
Rationale for Idasanutlin Dosing Regimen
Based on data from Studies NP27872 and NP28679 in solid tumors and AML, the first
PD signal was detected at an AUC24hr between 50 and 60 g hr/mL. For the QD5-day 
regimen, 55 g hr/mL (55000 ng hr/mL) corresponds to a daily dose of approximately 
100 mg of idasanutlin.
In addition, safety data are available for patients with solid tumors and NHL who
received idasanutlin.  For the 100-mg QD5-day schedule, no Grade 3 or 4 hematologic 
or related GI toxicities were observed.
Therefore, a daily dose of 100 mg of the idasanutlin SDP has been chosen as a safe 
starting dose with potential to activate p53 as determined by the MIC-1 PD marker in 
combination with obinutuzumab and venetoclax.


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Idasanutlin PK exposure, PD effects (e.g., MIC-1, a p53 activation marker), and 
target-mediated hematologic changes (platelet reduction, in particular) were evaluated to 
support the optimal dosing schedule. Weekly, 3-day, and 5-day schedules were tested,
with weekly higher doses not activating the PD marker MIC-1. The 3-day dosing did not 
achieve steady state and did not alleviate thrombocytopenia; therefore, a 5-day schedule 
was chosen.
Extended dosing of idasanutlin for up to 1 year in total with obinutuzumab or rituximab 
and venetoclax will allow exploration of whether additional activity is observed during the 
extended (post-induction) dosing period.
3.3.2.3
Rationale for Venetoclax Dosing Regimen
Venetoclax dosing for this study is based on experience from the Phase I study
(M12-175) with single-agent venetoclax in patients with R/R NHL and from the Phase Ib
study (M12-630) of venetoclax in combination with BR in patients with R/R NHL.  In NHL, 
all responses in patients with FL have occurred at doses 600 mg QD.  Although
nonclinical data exist for synergistic activity at a dose equivalent to 400 mg QD (Souers 
et al. 2013), it is desirable to give venetoclax at the higher doses at which single-agent 
activity has been observed.
The M12-175 study explored a step-up dosing schedule in order to safely administer
venetoclax by reducing the risk of TLS. The study showed safety of initial doses of up to 
400 mg without clinically significant TLS in patients with NHL. Patients with NHL have 
received single-agent target doses of 1200 mg without DLTs.  Single-agent target doses 
of up to 600 mg have been shown to be tolerable in patients with CLL. 
Furthermore, Study M12-630 has shown tolerability of starting doses of venetoclax of up
to 1200 mg in combination with chemoimmunotherapy without observation of clinically
significant TLS. 
The starting dose of venetoclax in this study will be 200 mg. Given that venetoclax will
be administered to patients in conjunction with obinutuzumab or rituximab and 
idasanutlin, which by themselves have a degree of myelosuppression, doses of 
venetoclax up to the MTD achieved when given as monotherapy may not be tolerable in 
this combination. Therefore, subsequent dose cohorts will be treated at progressively 
higher doses, up to a final daily dose of 800 mg if tolerated. The number of cycles of 
dosing (six 28-day cycles) is designed to provide treatment duration consistent with 
other therapies for NHL that have been shown to be sufficient to provide durable 
responses.
The duration of venetoclax dosing, Days 110, is designed to provide overlapping 
exposure with idasanutlin and obinutuzumab or rituximab as well as to reduce possible 
toxicity of the combination.  Furthermore, a safety cohort will be first evaluated with a 
shorter venetoclax treatment duration, Days 15, to ensure the safety and tolerability of 


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the combination before moving to a Days 110 regimen.  Extended dosing of venetoclax 
for up to 1 year in total with obinutuzumab or rituximab and idasanutlin will allow 
exploration of whether additional activity is observed during the extended (post-induction) 
dosing period.
3.3.2.4
Rationale for Treatment Duration
In this study, patients with R/R FL or DLBCL will receive six cycles of induction treatment 
followed by post-induction treatment, with the objective to improve the response to 
induction therapy, either by converting a PR to a CR, or by eradicating minimal residual 
disease (MRD) to achieve a molecular response in patients with a clinical CR after 
induction treatment, thus reducing the relapse risk for responders. In this study, MRD 
levels will be measured during the post-induction period as an additional means to 
evaluate the triple combination as post-induction treatment.
Despite recent improvements in therapy for FL, including demonstrated benefit from 
2-year rituximab maintenance in patients who responded to first-line 
immunochemotherapy (Study MO18264), FL is still not considered curable, with a 6-year 
PFS of 59.2% (Salles et al. 2013).  A Phase III study, GAO4753g, investigated GB 
compared with bendamustine alone in patients with R/R indolent NHL (n396).  Patients 
in the GB group who had not experienced disease progression at the EOI received 
obinutuzumab monotherapy every 2 months for up to 2 years. PFS was significantly 
longer in the GB arm, with a median PFS of 29 versus 14 months (HR: 0.48; 95% CI: 
0.35, 0.67; p 0.0001) (Trněný et al. 2016). The data support further investigation of 
obinutuzumab in combination with new targeted drugs in the setting of induction and 
maintenance treatment for patients with FL. 
Patients with R/R DLBCL who are not suitable for or do not benefit from consolidative 
autologous transplantation exhibit a poor prognosis. Responses obtained with different 
rituximab treatment regimens tested in clinical trials (e.g., rituximab in combination with 
bendamustine, with gemcitabine plus oxaliplatin, or with lenalidomide) have been of 
short duration, with the longest reported median PFS of approximately 7 months 
observed in one study of BR (Ohmachi et al. 2013).  Thus, 6 months of consolidation 
treatment, for a total treatment duration of approximately 12 months, is considered to be 
a reasonable exploratory therapeutic approach in patients with R/R DLBCL with an 
anticipated positive benefitrisk ratio. On the basis of the complementary mechanism of 
action between all three study drugs and considering the aggressiveness of R/R DLBCL, 
this study was designed to investigate the safety and efficacy of the triple combination in 
the consolidation setting.
3.3.3
Rationale for PET-CT-Based Complete Response as the 
Primary Efficacy Endpoint
In DLBCL, the prognostic value of the post-treatment fluorodeoxyglucose (FDG) PET-CT 
scan has been well documented (Thomas et al. 2010; Vitolo et al. 2010).  PET-CT scans 
have been incorporated in the Lugano 2014 criteria (Cheson et al. 2014) and are 


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commonly used to assess efficacy in medical practice and clinical trials in lymphoma.  
More recently, the value of post-induction PET-CT status has been investigated as a 
prognostic marker for long-term outcome in patients with FL.  In the first-line setting, 
results from a pooled analysis of 246 patients enrolled in three studies and having 
PET-CT scans available at the end of chemoimmunotherapy showedwith a median 
follow-up of 55 monthsa 4-year PFS in PET-CTpositive and PET-CTnegative 
patients of 23.2% (95% CI: 11.1%, 37.9%) versus 63.4% (95% CI: 55.9%, 70.0%; 
p0.001), respectively, and a 4-year survival rate of 87.2% (95% CI: 71.9%, 94.5%) 
versus 97.1% (95% CI: 93.2%, 98.8%; p0.0001), respectively (Trotman et al. 2014).  
In the relapsed FL setting, results from a preliminary analysis of the Phase II study 
BO21003 comparing obinutuzumab versus rituximab monotherapy demonstrated that 
the post-induction PET-CT status is strongly prognostic of PFS.  With a median follow-up 
of 32.1 months, the risk of disease progression was significantly reduced in 
PET-CTnegative patients compared with that for the PET-CTpositive patients, 
regardless of the assessment criteria, either International Harmonization Project criteria 
(HR, 0.25; 95% CI: 0.191, 0.807; p0.0083) or European Organization for Research and 
Treatment of Cancer (EORTC) criteria (HR, 0.39; 95% CI: 0.191, 0.807; p0.0083)
(Kostakoglu et al. 2014).
In response to developments involving PET-CT status, the 11th International Conference 
of Malignant Lymphoma Imaging Group provided updated guidance for the use of 
PET-CT scan results for lymphoma staging and response assessment (Lugano 2014 
criteria; Cheson et al. 2014).  
3.3.4
Rationale for Biomarker Assessments
3.3.4.1
Rationale for Analysis of DLBCL Subtype, BCL2, and MYC
DLBCL cell-of-origin prognostic subgroups (ABC and GCB), defined using gene 
expression profiling, have been associated with different clinical outcomes in patients 
receiving R-CHOP for DLBCL, with GCB subgroups demonstrating an improved 
prognosis than ABC groups (3-year survival rate of 84% vs. 56%, respectively; p0.001) 
(Lenz et al. 2008).
Bcl-2 overexpression has been shown to have prognostic value in DLBCL (Iqbal et al. 
2006).  Next-generation sequencing studies have also shown that BCL2 is the most 
mutated gene in patients with GCB DLBCL, observed in up to 35% of cases (Schuetz 
et al. 2012).  Approximately 9%17% of patients with newly diagnosed DLBCL harbor an 
underlying MYC rearrangement, and these patients are at high risk of treatment failure 
with R-CHOP (Savage et al. 2009).  A subset of patients with MYC-positive DLBCL also 
harbors an additional BCL2 rearrangement.  These "double-hit" lymphomas are 
associated with a very poor outcome (Savage et al. 2009; Dunleavy et al. 2014).  
Overexpression of Bcl-2 and Myc in DLBCL has also been observed in the absence of 
translocation.  This “double-positive” DLBCL status is also associated with poor
prognosis (Green et al. 2012; Johnson et al. 2012; Hu et al. 2013).


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Correlative investigations are essential to understand mechanisms of both sensitivity 
and resistance to therapy in patients with mutational profiles that may be predictive of
poor response to standard treatment.
3.3.4.2
Rationale for p53 and Pharmacodynamic Marker Assessments
The activity of idasanutlin is derived from the disruption of MDM2:p53 proteinprotein
interaction, thus reducing MDM2-mediated ubiquitination and subsequent degradation of
p53. This stabilization and accumulation of p53 confer enhanced function, including 
transcriptional activity. Therefore, defining cancer cells with respect to their ability to 
undergo p53 activation is important in achieving the desirable PD effects in vivo (i.e., 
inhibition of cancer cell growth and apoptosis). Furthermore, MDM2 status is important
with regard to the ability to activate p53 because MDM2 is overexpressed in a wide 
variety of hematologic malignancies, for instance, in approximately 50% of patients with 
AML (Fenaux et al. 1992; Hu et al. 1992; Wattel et al. 1994). This is believed to result in
decreased p53 levels and activity, and p53 function could be restored by MDM2
antagonists. Activated p53 induces or inhibits the expression of multiple genes, some of
which are secreted, and may be useful as PD indicators of clinical activity of idasanutlin.
Given as a single agent, idasanutlin demonstrated anti-tumor activity in cultured tumor
cells with wild-type tp53.  At the same concentrations, it is approximately 300-fold less
active in cultured cells with mutated tp53.  However, it is possible that not all tp53
mutations may disrupt p53 downstream activity. In NHL, the tp53 mutation rate is less
than that of solid tumors and is estimated to be approximately 18% in DLBCL (Ichikawa 
et al. 1997) and 21% in FL (Møller et al. 1999).
Lymphoma cells from patients will be tested for TP53 mutation, retrospectively, during 
this study. The data will be used to evaluate the role of TP53 mutation in lymphoma 
cells and response to treatment with idasanutlin, venetoclax, and obinutuzumab or 
rituximab. 
MDM2 mRNA expression in blood was found to be associated with clinical response in
the Phase I study NO21279 in patients with AML treated with RO5045337; however, the 
association is not sufficiently robust to use MDM2 alone for selection of responsive 
patients. Multigene transcripts expression algorithm(s) may provide a means of 
predicting patient response to MDM2 inhibitors. A signature of four genes (MDM2, 
BBC3/PUMA, XPC, and CDKN2A) has been shown to be associated with response to
the MDM2-antagonist RO5045337 in nonclinical experiments as well as in the clinical 
studies NO21279 (RO5045337) and NP28679 (idasanutlin) (Zhong et al. 2015). Further 
evaluation of this algorithm is ongoing in Phase I studies as well as an ongoing Phase III 
AML study of idasanutlin. Analysis of this four-gene algorithm in NHL-derived tumor 
tissue may be associated with patients who are likely to display propensity to have 
activatable p53.


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Additional information for patient-predicted efficacy may be gained from baseline protein
expression levels of genes such as, but not limited to, MDM2 and/or p53 from archival
material or fresh biopsied lymphoma tumor by immunohistochemistry (IHC) of
formalin-fixed, paraffin-embedded (FFPE)-derived tissue and digital pathology protein
expression assessment.  Indeed, baseline assessment of MDM2 protein expression 
specifically in malignant cells of interest, here AML leukemic blasts, in Study NP28679 
has shown that composite complete remission in AML patients treated with idasanutlin-
based therapy was associated with higher levels of MDM2 expression (Reis et al. 2016).
MIC-1, a secreted protein that is strongly induced by p53, can be detected in the blood 
of mice bearing human tumor xenografts after treatment with doxorubicin, a genotoxic 
p53 activator (Yang et al. 2003).  In Study NO21279 evaluating RO5045337, which 
included patients with AML and patients in the AML Phase I study NP28679 for 
idasanutlin, MIC-1 expression was shown to be a useful PD biomarker correlating with 
exposure.  Ongoing evaluation of PD biomarker activity in the aforementioned clinical 
studies demonstrated treatment-related increases in p53 activity, likely through the 
activation of P53 gene targets and induction of apoptosis (Kojima et al. 2005). On the 
basis of the results from these studies, additional analyses on tumor specimens may be 
performed as exploratory studies for biomarkers related to p53 and MDM2 activity and 
the activity of idasanutlin (Ray-Coquard et al. 2012).
3.3.4.3
Rationale for Assessment of Minimal Residual Disease
MRD measurement is an increasingly recognized tool for response assessment in B-cell 
malignancies.  Circulating lymphoma cells and tumor DNA can be detected and 
quantified at low levels as MRD to assess the degree of response and monitor patients 
for possible disease recurrence.  
In FL, MRD at the end of treatment is likely to be prognostic (Ladetto et al. 2013).  
In DLBCL, serum MRD was shown to be predictive of early and late progression after 
first-line treatment (Roschewski et al. 2014).  In addition, MRD assessment may 
complement the response assessment, particularly in immune treatmentbased 
regimens, and mitigate potential falsepositive PET-CT results caused by infiltration of 
metabolically active immune cells into the tumor.  
In this study, MRD will be quantified by circulating lymphoma cells and cell-free 
circulating-tumor DNA as an exploratory endpoint.  MRD assessments will be performed 
at the EOI to allow for an evaluation of the depth of response, and during post-induction
treatment to allow for an evaluation of long-term response or possible 
disease recurrence.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll patients with R/R FL or DLBCL who meet the eligibility criteria 
presented below.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(see Appendix 7)

B-cell lymphoma classified as either of the following:
– R/R FL after treatment with at least one prior chemoimmunotherapy regimen that 
included an anti-CD20 monoclonal antibody 
– Relapsed or refractory DLBCL after treatment with at least one prior 
chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody 
in patients who are not eligible for second line combination chemotherapy and 
autologous stem-cell transplantation, have failed second line combination 
chemotherapy, or experienced disease progression following autologous stem-
cell transplantation

Histologically documented CD20-positive lymphoma, as determined by a 
local laboratory

FDG-avid lymphoma (i.e., PET-positive lymphoma)

At least one bi-dimensionally measurable lesion (1.5 cm in its largest dimension by 
CT scan or magnetic resonance imaging [MRI])

Availability of a representative tumor specimen and the corresponding pathology 
report for retrospective central confirmation of the diagnosis of FL or DLBCL
– If the archival tissue is unavailable or unacceptable, a pretreatment core-needle, 
excisional or incisional tumor biopsy is required.  Cytological or fine-needle 
aspiration samples are not acceptable. Additional details are provided in 
Section 4.5.6.
– If a patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, a core-needle biopsy is 
strongly recommended.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
– Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for at least 18 months after the 
last dose of study treatment for those treated with obinutuzumab, idasanutlin, 


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and venetoclax; and for at least 12 months after the last dose of study treatment 
for those treated with rituximab, idasanutlin, and venetoclax 
(see Section 5.4.3.1).  Women must refrain from donating eggs during this 
same period.
– A woman is considered to be of childbearing potential if she is post-menarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
– Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
– The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
– With female partners of childbearing potential, men must remain abstinent or use 
a condom plus an additional contraceptive method that together result in a failure 
rate of 1% per year during the treatment period and for at least 3 months after 
the last dose of study treatment.  Men must refrain from donating sperm during 
this same period.
– With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 3 months after the last dose of study 
treatment to avoid exposing the embryo.
– The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known CD20-negative status at relapse or progression

Prior allogeneic SCT

Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1

Prior standard or investigational anti-cancer therapy as specified below:
–
Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
–
Monoclonal antibody or antibodydrug conjugate within 4 weeks prior to Day 1 
of Cycle 1


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–
Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule 
therapy within 2 weeks prior to Day 1 of Cycle 1

Clinically significant toxicity (other than alopecia) from prior therapy that has not 
resolved to Grade 2 (according to NCI CTCAE v4.0) prior to Day 1 of Cycle 1

Grade 3b FL

History of transformation of indolent disease to DLBCL (expansion-phase only) 
History of transformation of indolent disease is allowed in the dose escalation 
phase.

Central nervous system lymphoma or leptomeningeal infiltration

Treatment with systemic corticosteroids 20 mg/day, prednisone or equivalent
–
Patients receiving corticosteroids 20 mg/day, prednisone or equivalent, for 
reasons other than lymphoma must be documented to be on a stable dose for 
at least 4 weeks prior to Day 1 of Cycle 1. 
–
If corticosteroid treatment is urgently required for lymphoma symptom control 
prior to the start of study treatment, up to 100 mg/day of prednisone or 
equivalent may be given for a maximum of 5 days, but all tumor assessments 
must be completed prior to start of corticosteroid treatment.

Clinical conditions requiring treatment with oral or parenteral anticoagulants or 
antiplatelet agents (e.g., chronic daily treatment with aspirin 325 mg/day, 
clopidogrel, warfarin, systemic low-molecular-weight heparin [LMWH]) unless 
treatment can be discontinued 7 days (or 5 half-lives) prior to initiation of study 
treatment (except used as flushes for indwelling catheters)

Refusal of blood products and/or sensitivity to blood products

History of severe allergic or anaphylactic reaction to humanized or murine 
monoclonal antibodies

Known hypersensitivity or allergy to murine products or any component of the 
obinutuzumab, rituximab, idasanutlin, or venetoclax formulation

Infection considered by the investigator to be clinically uncontrolled or poses an 
unacceptable risk to the patient upon the induction of neutropenia, that is, patients 
who are or should be on antimicrobial agents for the treatment of active infection 
such as the following: 
–
Fungal infection with visceral involvement, other than mucosal candidiasis, with 
2 weeks of appropriate systemic antifungal therapy
–
Bacterial infection with positive cultures within 7 days prior to initiation of 
study treatment
–
Patients who have received 5 days of appropriate therapeutic antibiotic therapy 
for an identified infection
–
Neutropenic fever considered infection related within 72 hours prior to initiation 
of study treatment


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–
History of symptomatic C. difficile infection that required treatment within 
1 month prior to dosing 
Upon clinical response to C. difficile treatment, the stool consistency and 
frequency must have returned to normal.
In all cases, the patient should be afebrile and hemodynamically stable for at least 
72 hours at the time of study treatment initiation.
Caution should be exercised when considering the use of obinutuzumab or 
rituximab in patients with a history of recurring or chronic infections.

Treatment with the following agents within 7 days prior to the first dose of 
venetoclax and idasanutlin:
–
Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and
clarithromycin
–
Moderate CYP3A inducers such as bosentan
–
CYP2C8 substrates such as repaglinide
–
UGT1A3 inhibitor gemfibrozil
–
OATP1B1/3 substrates such as statin drugs

Treatment with the following agents within 14 days prior to the first doses of 
venetoclax and idasanutlin
–
Strong CYP3A inducers such as rifampin (also a CYP2C8 inducer) and 
carbamazepine

Chronic use of CYP2C8 or OATP1B1/3 substrates

Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade 
that contains Seville oranges), or star fruit within 3 days prior to the first dose of 
venetoclax

Clinically significant history of liver disease, including viral or other hepatitis, current
alcohol abuse, or cirrhosis (e.g., Child-Pugh class B and C)

Current or history of HBV or HCV infection:  positive for hepatitis B surface antigen 
(HBsAg), total hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody 
at screening
–
Patients are eligible if both HBsAg and HBcAb are negative but tested positive 
for hepatitis B surface antibody (HBsAb) after vaccination.

Known history of HIV-positive status
–
For patients with unknown HIV status, HIV testing must be performed at 
screening if not in contradiction with local regulations.

History of PML

Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1


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
History of other malignancy that could affect compliance with the protocol or 
interpretation of results, with the exception of the following:
– Curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer
– Any previously treated malignancy that has been in remission without treatment 
for 2 years prior to enrollment

Evidence of any significant, uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant 
cardiovascular disease (such as New York Heart Association Class III or IV cardiac 
disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or 
unstable angina) or significant pulmonary disease (such as obstructive pulmonary 
disease or history of bronchospasm), or uncontrolled irritable bowel disease (i.e., 
Crohn disease, ulcerative colitis, diverticulosis-associated colitis, and Behçet 
disease)

Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by study treatment, such as severe hereditary coagulation disorders or 
insulin-dependent diabetes mellitus that is not optimally controlled with medical 
management (e.g., presence of ketoacidosis)

Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of 
Cycle 1, or anticipation of a major surgical procedure during the study

Inadequate hematologic function (unless due to underlying lymphoma), defined 
as follows:
– Hemoglobin 9 g/dL
– ANC 1.5109 cells/L
– Platelet count 75109 cells/L

Any of the following abnormal laboratory values (unless due to underlying 
lymphoma):
–
Calculated creatinine clearance 50 mL/min using the modified Cockcroft-Gault 
(see Appendix 11) 
–
Patients with clinically significant persistent electrolyte abnormalities, such as 
hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, 
and hypermagnesemia of Grade 1 according to NCI CTCAE, v4.0
Treatment for correction of above electrolyte imbalances is permitted during 
screening to meet eligibility criteria.
–
AST or ALT 2.5 ULN
–
Serum total bilirubin 1.5ULN (or 3ULN for patients with Gilbert syndrome)
–
INR or PT 1.5ULN in the absence of therapeutic anticoagulation
–
PTT or aPTT 1.5ULN in the absence of a lupus anticoagulant


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
Pregnancy or lactation, or plans to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to Day 1 of Cycle 1.

Life expectancy 3 months

Inability to comply with the study protocol, in the investigator’s judgment
4.2
METHOD OF TREATMENT ASSIGNMENT
This is a Phase Ib/II, open-label, multicenter, non-randomized study of obinutuzumab in 
combination with idasanutlin and venetoclax in patients with R/R FL and obinutuzumab 
or rituximab in combination with idasanutlin and venetoclax in patients with R/R DLBCL.  
Following determination of the MTDs with idasanutlin and venetoclax in combination with 
obinutuzumab, cohort(s) of patients with DLBCL will be opened to confirm the MTDs of 
idasanutlin and venetoclax in combination with rituximab. Following determination of the 
MTDs of idasanutlin and venetoclax in combination with obinutuzumab, cohort(s) of 
patients with FL will be opened to explore a different regimen (Regimen B, 
obinutuzumab alone at Cycle 1 and obinutuzumab in combination with idasanutlin and 
venetoclax at Cycles 26). During the dose-escalation phase, patients will be assigned 
to dosing groups through use of an interactive voice or Web-based response system 
(IxRS).  During the expansion phase, all patients will be assigned to receive the RP2Ds
with the selected regimen via IxRS.  If eligible, patients will receive maintenance (FL 
patients) or consolidation (DLBCL patients) treatment (see Sections 3.1.2 and 3.1.3 for 
details).
Enrollment tracking will be performed through use of the IxRS.  Prior to initiation of 
screening, study site personnel should confirm through the appropriate communication 
channel that the planned dose-escalation or expansion cohort is open for enrollment.  
After written informed consent has been obtained and preliminary eligibility has been 
established, the study site will submit documentation supporting eligibility to the Sponsor 
and obtain the Sponsor’s approval to enroll the patient.  Once the Sponsor reviews and 
approves a patient for enrollment, a patient number will be assigned and the patient will 
be enrolled via the IxRS.  The Sponsor will communicate to the sites impending closure 
of screening for a particular disease cohort.
4.3
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are obinutuzumab, rituximab, 
idasanutlin, and venetoclax and will be supplied by the Sponsor.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Obinutuzumab 
Obinutuzumab will be provided as a single-dose, sterile liquid formulation in a 50-mL 
glass vial containing 1000 mg of obinutuzumab.  For information on the formulation and 
handling of obinutuzumab, see the Obinutuzumab Investigator’s Brochure and the 
pharmacy manual.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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4.3.1.2
Rituximab
Rituximab will be supplied by the Sponsor as an IMP.  Rituximab is packaged in 10-mL 
(100-mg) and 50-mL (500-mg) single-dose, pharmaceutical-grade glass vials at a 
concentration of 10 mg/mL of protein.  The antibody is formulated for IV injection as a 
sterile product in a solution of sodium chloride (pH 6.5) containing polysorbate 80 and 
sodium citrate. 
For information on the formulation and handling of rituximab, see the Rituximab IV 
Oncology Investigator's Brochure and the Rituximab Pharmacy Manual.
4.3.1.3
Idasanutlin
Idasanutlin will be supplied as film-coated tablets.  Four different dose strengths of 
50 mg (Ro 550-3781/F17), 200 mg (Ro 550-3781/F16), 300 mg (Ro 550-3781/F13), and 
400 mg (Ro 550-3781/F14) were developed and optimized for use in clinical studies.  
For information on the formulation and handling of idasanutlin, see the Idasanutlin
Investigator’s Brochure.
4.3.1.4
Venetoclax 
Venetoclax will be supplied as film-coated tablets.  Two different strengths of 50 mg and 
100 mg were developed and optimized for the use in clinical studies.  For information on 
the formulation and handling of venetoclax, see the Venetoclax Investigator’s Brochure.
4.3.2
Dosage, Administration, and Compliance
The treatment regimens are summarized in Table 1, Table 2, Table 5, and Table 5 (see 
Section 3.1).
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.4.4.
4.3.2.1
Obinutuzumab
Obinutuzumab will be administered by IV infusion at an absolute (flat) dose of 1000 mg 
on Days 1, 8, and 15 of the first cycle and on Day 1 of each subsequent cycle during 
induction treatment, and on Day 1 of every other month (i.e., every 2 months) during
maintenance treatment (eligible patients with FL only) or during consolidation treatment 
(eligible patients with DLBCL only).
Obinutuzumab should be administered as an IV infusion through a dedicated line in an 
environment in which full resuscitation facilities are immediately available and under the 
close supervision of an experienced physician.  Obinutuzumab infusions will be 
administered to patients according to the instructions outlined in Figure 11 and Figure 12.  
For patients with bulky lymphadenopathy, the infusion may be given extremely slowly 
over a longer period of time, or the dose may be split and given over more than 1 day. 


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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No dose modification for obinutuzumab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1.8.
Premedication with a corticosteroid, antihistamine, and analgesic or antipyretic
medication, as outlined in Section 4.3.2.5, is required to reduce the incidence and 
severity of IRRs.  For anaphylaxis precautions, see Appendix 10.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Figure 11 Guidelines for Obinutuzumab Infusions:  First Infusion
IRRinfusion-related reaction.
a All patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/anti-pyretic medication prior to the first 
obinutuzumab infusion.  Refer to Section 4.3.2.5 for details.
b Supportive treatment should include acetaminophen/paracetamol and an antihistamine such as diphenhydramine, if not administered within the 
previous 4 hours.  Intravenous saline may be indicated.  For bronchospasm, urticaria, or dyspnea, patients may require antihistamines, oxygen, 
corticosteroids (e.g., 100 mg oral prednisone or equivalent), and/or bronchodilators.  For anaphylaxis precautions, see Appendix 10.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Figure 12 Guidelines for Obinutuzumab Infusions:  Second and Subsequent Infusions
IRRinfusion-related reaction.
a Patients should receive full premedication with an oral corticosteroid, antihistamine, and oral analgesic/antipyretic medication prior to the 
obinutuzumab infusion.  Refer to Section 4.3.2.5 for details.  In the case of a recurrent Grade 3 IRR, obinutuzumab may be discontinued at the 
discretion of the investigator, following an individual benefitrisk assessment.
b Patients who experience wheezing, urticaria, or other symptoms of anaphylaxis must receive full premedication prior to all subsequent doses.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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4.3.2.2
Rituximab
Rituximab will be administered by IV infusion at a dose of 375 mg/m2 on Day 1 of 
Cycles 1−6 during induction treatment and on Day 1 of every other month (i.e., every 
2 months) during consolidation treatment.  
Body surface area (BSA) will be determined at screening and should be used to 
calculate the dose of rituximab throughout the study unless the patient’s weight 
increases or decreases by 10% from screening, in which case BSA should be 
recalculated and used for subsequent dosing.  In obese patients (defined as body mass 
index 30 kg/m2), there is no BSA cap and actual body weight, not adjusted weight, is 
recommended.  Empiric dose adjustment for obese patients may be implemented per 
institutional guidelines.
The infusion of rituximab may be split over 2 days if the patient is at increased risk for an 
IRR (high tumor burden or high peripheral lymphocyte count).  Administration of 
rituximab may be continued on the following day, if needed, for patients who experience 
an adverse event during the rituximab infusion. 
If a dose of rituximab is split over 2 days, both infusions must occur with appropriate 
premedication (see Section 4.3.2.5) and at the first infusion rate (see Table 6).
Rituximab infusions will be administered according to the instructions in Table 6.
During the treatment period, rituximab must be administered to patients in a setting 
where full emergency resuscitation facilities are immediately available.  Patients should 
be under close supervision of the investigator at all times. 
Rituximab should be administered as a slow IV infusion through a dedicated line.  After 
the end of the first infusion, the IV line or central venous catheter should remain in place 
for 2 hours in order to administer IV drugs, if necessary.  If no adverse events occur 
after 2 hours, the IV line may be removed or the central venous catheter may be 
de-accessed.  For subsequent infusions, the IV line or central venous catheter should 
remain in place for at least 1 hour after the end of the infusion.  If no adverse events 
occur after 1 hour, the IV line may be removed or the central venous catheter may be 
de-accessed.
If a patient tolerates the first cycle of study treatment without significant infusion 
reactions, rituximab may be administered as a rapid infusion (over 6090 minutes) in 
accordance with local institutional guidelines.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Table 6
Administration of First and Subsequent Infusions of Rituximab
First Infusion (Day 1 of Cycle 1)
Subsequent Infusions

Begin infusion at an initial rate of 
50 mg/hr.

If no infusion-related or 
hypersensitivity reaction occurs, 
increase the infusion rate in 50-
mg/hr increments every 
30 minutes to a maximum of 
400 mg/hr.

If a reaction develops, stop or 
slow the infusion.  Administer 
medications and supportive care 
in accordance with institutional 
guidelines.  If the reaction has 
resolved, resume the infusion at 
a 50% reduction in rate (i.e., 
50% of rate being used at the 
time when the reaction 
occurred).

If the patient experienced an infusion-
related or hypersensitivity reaction during 
the prior infusion, use full premedication, 
including 100 mg of 
prednisone/prednisolone or 80 mg of 
methylprednisolone or equivalent (until no 
further IRR occurs); begin infusion at an 
initial rate of 50 mg/hr; and follow 
instructions for first infusion.

If the patient tolerated the prior infusion 
well (defined by an absence of Grade 2 
reactions during a final infusion rate of 
100 mg/hr), begin infusion at a rate of 
100 mg/hr. If no reaction occurs, increase 
the infusion rate in 100-mg/hr increments 
every 30 minutes to a maximum of 
400 mg/hr.

If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction has 
resolved, resume the infusion at a 50% 
reduction in rate (i.e., 50% of rate being 
used at the time when the reaction 
occurred).
IRR infusion-related reaction.
No dose modification for rituximab is allowed.  Guidelines for treatment delays or 
discontinuation are provided in Section 5.1. 
Premedication with a corticosteroid, analgesic/antipyretic, and antihistamine, as outlined 
in Section 4.3.2.5, is required to reduce the incidence and severity of IRRs.  For 
anaphylaxis precautions, see Appendix 10.
4.3.2.3
Idasanutlin
Patients will self-administer idasanutlin tablets PO each day according the schedule of 
activities (see Appendix 1 and Appendix 2) approximately 15 minutes after eating a meal 
and with water.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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On days when idasanutlin, venetoclax, and obinutuzumab are all given, the order of 
study treatment administration will be idasanutlin followed by venetoclax and 
obinutuzumab.  Idasanutlin should always be given prior to venetoclax if both drugs are 
to be administered the same day.  If vomiting occurs within 15 minutes of taking 
idasanutlin, and all expelled tablets are still intact, another dose may be given and the 
second dose noted in the drug log.  Otherwise, no replacement dose is to be given.  In 
cases in which a QD dose of idasanutlin is missed or forgotten, the patient should take 
the dose as soon as possible, ensuring that the dose is taken within 8 hours of the 
missed dose with food and water.  Otherwise, the dose should not be taken.  On days 
when patients are scheduled to have blood samples collected for PK assessments, the 
time of each dose of idasanutlin will be recorded to the nearest minute.  
Idasanutlin must be stored according to labeled storage conditions.
4.3.2.4
Venetoclax
Each once-daily dose of venetoclax (per the dose schedule established during dose 
escalation) will be taken orally with approximately 240 mL of water within approximately 
30 minutes after the completion of breakfast or the first meal of the day. A meal 
containing approximately 30% of the total caloric content from fat is recommended to 
ensure adequate absorption of venetoclax. The Standard American Heart Association 
Healthy (Low-Fat) Breakfast includes 1 box cereal (30-40 g), skim milk (240 mL), 1 
boiled egg, 1 slice of toast, and margarine (10 g) for approximately 520 Kcal with 
approximately 17 grams of fat.
On days that venetoclax PK sampling is required, the patient’s first meal of the day (e.g., 
breakfast) should be consumed in the morning at the clinic, and venetoclax dosing 
should occur in the clinic after completion of the meal to facilitate PK sampling.
On days when idasanutlin, venetoclax, and obinutuzumab are all given, the order of 
study treatment administration will be idasanutlin followed by venetoclax and 
obinutuzumab. If vomiting occurs within 15 minutes after taking venetoclax and all 
expelled tablets are still intact, another dose may be given and the second dose noted in 
the drug log. If tablets are not identified, or if any are not intact, no replacement dose is 
to be given. In cases in which a dose of venetoclax is missed or forgotten, the patient 
should take the dose as soon as possible and ensure that the dose is taken with food
and water within 8 hours after the scheduled time of the missed dose. Otherwise, the 
missed dose should not be taken. On days when patients are scheduled to have blood 
samples collected for PK assessments, the time of each dose of venetoclax will be 
recorded to the nearest minute. 
Venetoclax must be stored according to labeled storage conditions.
4.3.2.5
Premedication
Patients must receive premedication as outlined in Table 7.


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Table 7
Premedication
Timepoint
Patients Requiring 
Premedication
Premedication
Administration
Cycle 1, 
Day 1
All patients
Oral corticosteroid a
Administer 1 hour prior to obinutuzumab or 
rituximab infusion.
All patients
Antihistamine drug b
Oral analgesic/anti-pyretic medication c
Administer 30 minutes prior to obinutuzumab 
or rituximab infusion.
Day 1 of the 
First cycle 
including 
venetoclax
All patients
Appropriate hydration d
Administer to 2448 hours prior to the start of 
venetoclax and continued for at least 24 hours 
after the first dose.
Administration of an oral agent to reduce 
uric acid, such as allopurinol 300 mg/day, 
or rasburicase IV, as judged appropriate 
by the investigator 
Rasburicase IV should be administered 
(unless medically contraindicated) for 
those patients with elevated uric acid 
levels e pretreatment
Administer starting 72 hours prior to the first 
venetoclax dose.  If serum uric acid is above 
ULN administer until normalization of serum 
uric acid and other laboratory evidence of TLS 
(e.g., elevated serum LDH levels). f
Patients considered at high risk 
of TLS (see Section 5.1.7.2)
Hospitalization is required for the initial 
venetoclax dose.
Refer to Section 5.1.7.2.


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Table 7
Premedication (cont.)
IRRinfusion-related reaction; TLStumor lysis syndrome; ULNupper limit of normal.
a Treat with 100 mg of prednisone or prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone.  Hydrocortisone should not be 
used, as it has not been effective in reducing rates of IRR.
b For example, 50 mg of diphenhydramine.
c For example, 1000 mg of acetaminophen/paracetamol.
d Fluid intake of approximately 23 L/day.  For patients for whom volume overload is considered a significant risk, hospitalization should be 
considered.
e Defined as a value above the local laboratory’s ULN, or above 476 mol/L (8 mg/dL) if no local laboratory ULN is available.
f
Laboratory results should be reviewed and electrolyte values should not demonstrate any clinically significant abnormalities prior to the first 
dose of venetoclax; otherwise, the patient should receive additional prophylactic treatment and hydration prior to the initiation of dosing.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Table 7
Premedication (cont.)
Timepoint
Patients Requiring 
Premedication
Premedication
Administration
Cycle 1, 
Days 8 and 15
(for patients 
receiving 
obinutuzumab); 
Cycles 2 and 
beyond,
Day 1
Patients with no IRR during the 
previous infusion
Oral analgesic/anti-pyretic medication c
Administer 30 minutes prior to obinutuzumab 
or rituximab infusion.  For patients receiving 
rituximab who do not experience any IRR with 
their previous infusion, premedication may be 
omitted at the investigator’s discretion.

Patients with Grade 1 or 2 
IRR during the previous 
infusion

Antihistamine drug b
Oral analgesic/anti-pyretic c
Administer 30 minutes prior to obinutuzumab 
or rituximab infusion.

Patients with Grade 3 IRR, 
wheezing, urticaria, or 
other symptoms of 
anaphylaxis during the 
previous infusion

Patients with bulky disease
Oral corticosteroid a
Administer 1 hour prior to obinutuzumab or 
rituximab infusion.
Antihistamine drug b
Oral analgesic/anti-pyretic medication c
Administer 30 minutes prior to obinutuzumab 
or rituximab infusion.
Patients at high risk of TLS 
(see Section 5.1.7.2)
Consider hospitalization if patient is still 
considered at high risk of TLS (see 
Section 5.1.7.2), refer to premedication 
as defined for Cycle 1.
Refer to Section 5.1.7.2.
Cycles 1 to 6
All patients receiving 
idasanutlin
Second-generation anti-emetic 
treatments, such as palonosetron, 
ondansetron, or granisetron
Administer per individual drug prescribing 
information.
Cycles 1 to 6
All patients
No premedication for diarrhea
Not applicable
Patients with previous episode 
of Grade 3 
Loperamide 4 mg orally 
Loading dose 30 minutes before first 
administration of study drug.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Table 7
Premedication (cont.)
IRRinfusion-related reaction; TLStumor lysis syndrome; ULNupper limit of normal.
a Treat with 100 mg of prednisone or prednisolone, 20 mg of dexamethasone, or 80 mg of methylprednisolone.  Hydrocortisone should not be 
used, as it has not been effective in reducing rates of IRR.
b For example, 50 mg of diphenhydramine.
c For example, 1000 mg of acetaminophen/paracetamol.
d Fluid intake of approximately 23 L/day.  For patients for whom volume overload is considered a significant risk, hospitalization should be 
considered.
e Defined as a value above the local laboratory’s ULN, or above 476 mol/L if no local laboratory ULN is available.
f
Laboratory results should be reviewed and electrolyte values should not demonstrate any clinically significant abnormalities prior to the first 
dose of venetoclax; otherwise, the patient should receive additional prophylactic treatment and hydration prior to the initiation of dosing. 


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (obinutuzumab, rituximab, idasanutlin, and 
venetoclax) will be provided by the Sponsor.  The study site will acknowledge receipt of 
IMPs using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded in the Drug Inventory Log.
4.3.4
Post-Trial Access to Obinutuzumab, Rituximab, Idasanutlin, 
and Venetoclax
Currently, the Sponsor does not have any plans to provide obinutuzumab, rituximab, 
idasanutlin, venetoclax, or any other study treatments or interventions to patients who 
have completed the study.  The Sponsor may evaluate whether to continue providing 
obinutuzumab, rituximab, idasanutlin, and venetoclax in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
14 days prior to the screening period to the visit at the EOI or at the end of 
post-induction treatment, whichever occurs later.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Premedication is permitted as described in Section 4.3.2.5.
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.
Hematopoietic growth factors are allowed in all study phases if clinically indicated and 
used in accordance with the prescribing information.  G-CSF may be used in the DLT 
period (Cycles 1 and 2) to treat Grade 3 neutropenia, but is not allowed as 
prophylaxis. Outside of the DLT observation window during the dose-escalation phase 
and during the expansion phase, G-CSF may be administered in each cycle of therapy 


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as primary prophylaxis for neutropenia, according to the American Society of Clinical 
Oncology (ASCO), EORTC, and European Society for Medical Oncology (ESMO) 
guidelines (Smith et al. 2006) or according to each site’s institutional standards.
Prophylactic treatment with antibiotics should be administered as per standard practice.  
Necessary supportive measures for optimal medical care will be given throughout the 
study according to institutional standards. 
4.4.2
Prohibited and Cautionary Therapy
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study:

Any anti-cancer therapy, approved or investigational, other than intrathecal central 
nervous system prophylaxis

Hormonal therapy other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate

Biologic agents other than hematopoietic growth factors (as described in 
Section 4.4.1)

Vaccination with live vaccines is not recommended during treatment with 
obinutuzumab or rituximab and until B-cell recovery
MDM2 antagonists were shown in vitro to affect all types of hematopoietic progenitors, 
including megakaryocytic differentiation.  They inhibit both early and late stages of 
megakaryopoiesis, including ploidization and proplatelet formation (Mahfoudhi et al. 
2016).  As a consequence, the effect on early progenitors might induce long-lasting 
thrombocytopenia in vivo.  
Therefore, because of the potential severity and duration of thrombocytopenia induced 
by study treatment, patients in clinical need for chronic treatment with oral or parenteral 
anticoagulant/antiplatelet agents (e.g., warfarin, chronic daily treatment with aspirin 
[325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban, systemic LMWH, or 
subcutaneous anticoagulant prophylaxis) are excluded from this study.  For patients 
considered eligible for the study because they are able to tolerate interruption of 
anticoagulant or antiplatelet treatment, these agents must be discontinued 7 days (or 
5 half-lives, whichever is shorter) prior to initiating study treatment (except used as 
flushes for indwelling catheters).  After the study treatment completion or discontinuation 
visit, treatment with anticoagulant/antiplatelet agents may be re-initiated for patients with 
transfusion-independent adequate platelet levels as clinically indicated.
Idasanutlin is metabolized mainly by multiple pathways such as CYP3A, CYP2C8, and 
UGT (UDP glucuronosyltransferase) enzymes.  Due to the fact that idasanutlin PK 
exposure is only minimally changed during treatment with a strong CYP3A inhibitor 
posaconazole as summarized in Section 1.3.2.1, it is not a sensitive CYP3A or CYP2C8 


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substrate and thus its metabolism may only be affected by concomitant CYP3A or 
CYP2C8 inducers. Venetoclax is metabolized by CYP3A4 and CYP3A5 enzymes and is 
a P-glycoprotein and BRCP substrate; metabolism may be affected by concomitant 
CYP3A inhibitors and inducers, or P-glycoprotein inhibitors.  Idasanutlin M4 metabolite 
and venetoclax are organic anion-transporting polypeptide (OATP)-1B1/3 transporter 
inhibitors that may affect concomitant OATP1B1/3 substrates.  Idasanutlin inhibits 
CYP2C8 metabolism, which may affect concomitant CYP2C8 substrates.  Venetoclax 
inhibits P-glycoprotein and BCRP, which may affect concomitant P-glycoprotein and 
BCRP substrates.  Thus, in order to prevent undesirable DDIs during the study, the use 
of any of the medications listed in Table 8 (CYP2C8 substrates) and Table 10
(OATP1B1/3 substrates) is prohibited, while the use of any of the medications listed in 
Table 9 (strong and moderate CYP3A inhibitors and inducers) is either prohibited within 
the DLT evaluation window (first two cycles in the escalation phase) or allowed after the 
DLT evaluation window after being washed out in sufficient duration (for inhibitors) or 
concomitant use with caution (for inducers).  Note that gemfibrozil is also a potent 
UGT1A3 inhibitor that will be excluded from use in this study.  Medications listed in
Table 11 should be used with caution because of potential DDIs with venetoclax.
The UGT1A3 inhibitor gemfibrozil, the CYP2C8 substrates listed in Table 8, the CYP3A 
inhibitors and moderate CYP3A inducers listed in Table 9, and the OATP1B1/3 
substrates listed in Table 10 must be discontinued 7 days prior to start of study 
treatment.  Strong CYP3A inducers listed in Table 9 must be discontinued 14 days prior 
to the start of study treatment.
Table 8
Prohibited CYP2C8 Substrates
Substrates
Amiodarone
Amodiaquine
Cerivastatin
Chloroquine
Ibuprofen
Lovastatin
Montelukast
Paclitaxel
Pioglitazone
Repaglinide
Rosiglitazone
Simvastatin
Toresamide


 
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Table 9 
Examples of Strong and Moderate CYP3A Inhibitors and Inducers 
CYP3A Inhibitors 
CYP3A Inducers  
Strong a 
Moderate b 
Strong c 
Moderate c 
boceprevir 
aprepitant 
carbamazepine 
bosentan 
clarithromycin 
cimetidine 
enzalutamine 
efavirenz 
cobicistat 
ciprofloxacin 
mitotane 
etravirine 
conivaptan  
clotrimazole 
phenytoin 
rifampin 
modafinil 
danoprevir/ritonavir 
crizotinib d 
St. John’s wort 
 
diltiazem 
cyclosporine d 
 
 
elvitegravir/ritonavir 
dronedarone 
 
 
idelalisib d 
erythromycin 
 
 
indinavir 
fluconazole 
 
 
itraconazole 
fluvoxamine 
 
 
ketoconazole 
imatinib d 
 
 
lopinavir/ritonavir 
tofisopam 
 
 
nefazodone 
verapamil 
 
 
nelfinavir 
 
 
 
ritonavir 
 
 
 
paritaprevir/ritonavir combinations 
 
 
 
posaconazole 
 
 
 
saquinavir/ritonavir 
 
 
 
telaprevir 
 
 
 
tipranavir/ritonavir 
 
 
 
troleandomycin 
 
 
 
voriconazole 
 
 
 
a Concomitant use of venetoclax with strong CYP3A inhibitors is to be avoided to prevent 
venetoclax exposure elevation with potentially increased toxicities; use an alternative 
medication that is not an inhibitor.  If must be used medically, they are allowed during the study 
only if the patient has completed the DLT evaluation window (if patient is in a dose escalation 
cohort) and venetoclax is withheld in that cycle.  After discontinuation of the strong CYP3A 
inhibitor, wait for 7 days before restarting venetoclax treatment. As obinutuzumab and 
idasanutlin (not a sensitive CYP3A substrate with regard to CYP3A inhibition) PK exposures 
are not expected to be affected from CYP3A inhibition, their dosing schedules should continue 
in 28-d cycles if venetoclax has to be withheld in the study. 
b Concomitant use of venetoclax with moderate CYP3A inhibitors is to be avoided to prevent 
venetoclax exposure elevation with potentially increased toxicities; use an alternative 
medication that is not an inhibitor.  If must be used medically, they are allowed during the study 
only if the patient has completed the DLT evaluation window (if patient is in a dose escalation 
cohort) and a 50% dose reduction for venetoclax is implemented in that cycle.  After 
discontinuation of the moderate CYP3A inhibitor, wait for 3 days before increasing venetoclax 
back to the initial dose 


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Table 9
Examples of Strong and Moderate CYP3A Inhibitors and Inducers
(cont.)
c Concomitant use of venetoclax and idasanutlin with strong or moderate CYP3A inducers is to 
be avoided to prevent venetoclax and idasanutlin exposure loss compromising efficacy; 
consider alternative medications.  If the patient requires use of these medications, use with 
caution and contact Roche Medical Monitor (refer to Section 5.4.1) for guidance.  The inducers 
are allowed during the study only if the patient has completed the DLT evaluation window (if 
patient is in a dose escalation cohort).
d These are anti-cancer agents; consult with the Medical Monitor before use.
Table 10 Prohibited OATP1B1/3 Substrates
OATP1B1/3 Substrates a
Asunaprevir
Atorvastatin
Atrasentan
Bosentan
Cerivastatin
Danoprevir
Docetaxel
Ezetimibe
Fexofenadine
Fluvastatin
Glyburide
Irinotecan
Nateglinide
Olmesartan
Paclitaxel
Pitavastatin
Pravastatin
Repaglinide
Rifampin
Rosuvastatin
Simvastatin acid
Telmisartan
Valsartan
a OATP1B1/3 substrates with t1/2 shorter than 1 day are allowed, except during idasanutlin 
treatment and for 72 hours after the last dose of idasanutlin.


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Table 11 Cautionary Medications for Venetoclax
CYP3A
P-Glycoprotein
Weak Inhibitors
Weak Inducers
Substrates
Inhibitors
alprazolam
amiodarone
amlodipine
bicalutamide a
chlorzoxazone
cilostazol
cimetidine
fluoxetine
fosaprepitant
ginkgo
goldenseal
isoniazid
istradefylline
ivacaftor
lomitapide
nilotinib a
oral contraceptives
pazopanib a
ranitidine
ranolazine
tacrolimus
tipranavir/ritonavir
ticagrelor
zileuton
amprenavir
aprepitant
armodafinil
clobazamechin
acea
prednisone
rufinamide
vemurafenib a
aliskiren
ambrisentan
colchicine
dabigatran 
etexilate
digoxin
everolimus a
fexofenadine
lapatinib a
loperamide
maraviroc
nilotinib a
ranolazine
saxagliptin
sirolimus a
sitagliptin
talinolol
tolvaptan
topotecan a
amiodarone 
azithromycin
captopril
carvedilol
dronedarone
felodipine
propafenone
quinidine
ranolazine
ticagrelor
BCRP
Substrates
Inhibitors
methotrexate a
mitoxantrone a
lapatinib a
sulfasalazine
topotecan a
geftinib a
a These are anti-cancer agents; consult with the Medical Monitor before 
use.
The lists of medications are not necessarily comprehensive.  Thus, the investigator 
should consult the prescribing information for any concomitant medication as well as the 
Internet references provided below when determining whether a certain medication 


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should be inhibited by the above rationale.  In addition, the investigator should contact
the Medical Monitor if questions arise regarding any medications not listed above.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm093664.htm
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.4.3
Additional Restrictions
Use of the following foods is prohibited during the study and for at least 3 days before
initiation of study treatment:

Grapefruit

Grapefruit juice

Products that contain grapefruit

Seville oranges (including marmalade that contains Seville oranges)

Star fruit
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 and Appendix 2 for the schedules of activities performed during 
the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent, and within the defined window, may be used as screening and baseline 
assessments (see Appendix 1 and Appendix 2); such tests do not need to be repeated 
for screening purposes (e.g., screening tumor assessment).  
Study treatment should be initiated within 28 days after the Informed Consent Form has 
been signed. Those patients who fail screening based on longer waiting times for 
certain results or due to study technical reasons (such as cohort on hold) can be 
rescreened once at a later date if they were deemed eligible before the screen failure. 
The decision to rescreen individual patients will be made jointly by the Roche Medical 
Monitor and the investigator and any other person the investigator or Medical Monitor 
considers necessary to assist with this decision. Any such decision and the reasons for 


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it will be clearly documented. Any out-of-window assessments need to be repeated and 
undergo a complete review by the Roche Medical Monitor.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, and alcohol and drug abuse.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 14 days prior to the screening period 
will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
The following clinical parameters relative to disease history, diagnosis, and prognostic 
indices will be recorded at screening: 

Date of initial diagnosis

ECOG performance status (see Appendix 7)

Ann Arbor staging (see Appendix 8)

For patients with FL:  FLIPI and FLIPI2 (see Appendix 9)

For patients with DLBCL:  IPI (see Appendix 9)

B symptoms (unexplained fever 38°C, night sweats, and unexplained weight loss 
10% of body weight over 6 months) 

Previous lines of anti-lymphoma treatment as well as response to prior therapy, date 
of disease progression in relation to start date of prior treatment, and date of last 
dose of prior treatment
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, GI, genitourinary, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
As part of tumor assessment, the physical examination should include evaluation for the 
presence of enlarged nodes, palpable hepatomegaly, and splenomegaly.  This 
information will be recorded on the appropriate Tumor Assessment eCRF.
At subsequent visits (or as clinically indicated), targeted (limited, symptom-directed) 
physical examinations should be performed.  Targeted physical examinations should be 
limited to systems of primary relevance (e.g., cardiovascular and respiratory systems), 
systems associated with symptoms (newly emergent or monitored from baseline), and 
areas associated with tumor assessment (lymph nodes, liver, spleen, and any other 
areas identified at baseline; see Section 4.5.5).  


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Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
In cases that physical examinations reveal visible manifestations of lymphoma or of 
toxicities (skin involvement, rashes, etc.), additional assessments and measures (such as 
pictures, measurements) could be undertaken upon additional patient consent.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
and systolic and diastolic blood pressure while the patient is in a seated position.  Vital 
sign measurements will be performed as outlined in the schedules of activities 
(see Appendix 1 and Appendix 2), but the associated data, other than the data collected 
at screening, do not need to be recorded on the eCRF (except in the case of an 
adverse event).
4.5.5
Tumor and Response Evaluations
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation.  Response will be assessed by the IRC and the 
investigator on the basis of PET and CT scans using the Lugano 2014 criteria (see 
Appendix 4), taking into account results of bone marrow assessments for patients with 
bone marrow involvement at screening.
In this study, the Lugano 2014 criteria for a PET-CTbased CR have been slightly 
modified to require normal bone marrow for patients with bone marrow involvement at 
screening (see Appendix 4).  Additionally, designation of a PET-CTbased PR requires 
that CT-based response criteria for a CR or PR be met in addition to the PET-CTbased 
response criteria for PR (see Appendix 4).
4.5.5.1
Radiographic Assessments
PET scans should include the base of the skull to mid-thigh.  Full-body PET scans 
should be performed when clinically appropriate.
CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans.  
CT scans of the neck should be included if clinically indicated (i.e., if evidence of disease 
upon physical examination) and must be repeated throughout the study if there is 
disease involvement at baseline.  
PET-CT scans and diagnostic CT scans should be acquired according to a standardized 
imaging manual, which will be provided to all sites.
If contrast is medically contraindicated (e.g., patients with contrast allergy or impaired 
renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically 
indicated) and a non-contrast CT scan of the chest may be performed.  If MRI scans 


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cannot be obtained, CT scans without contrast are permitted as long as these allow 
consistent and precise measurement of the targeted lesions during the study 
treatment period.
The same radiographic assessment modality must be used for all response evaluations 
to ensure consistency across different timepoints (including unscheduled assessments).
A full tumor assessment, including radiographic assessment, must be performed any 
time disease progression or relapse is suspected.
Additional details regarding imaging procedures will be provided in the imaging manual.
4.5.5.2
Bone Marrow Assessments
Bone marrow assessments, consisting of bone marrow biopsy and aspiration, are 
required at screening for staging purposes in all patients and should be performed within 
approximately 3 months prior to Day 1 of Cycle 1. 
For patients with bone marrow involvement at screening, a repeat assessment will be 
performed if there is radiologic evidence of a complete response or if clinically indicated 
(e.g., if there is clinical suspicion of progressive disease in the bone marrow with no 
radiologic evidence of progression) (see Appendix 1 for details).
Any additional (unscheduled) bone marrow assessments performed during the study will 
be at the discretion of the investigator. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Local Laboratory Assessments
Samples for the following laboratory tests will be analyzed at the study site’s local 
laboratory for analysis:

Hematology:  hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent or absolute WBC differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells) 

Chemistry panel (serum or plasma):  sodium, potassium, glucose, BUN or urea, 
creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, amylase, lipase, LDH, and 
uric acid

2 microglobulin

Coagulation:  INR, aPTT (or PTT), and PT

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening (within 7 days of Day 1 of Cycle 1).  Because of the suspected effect 
idasanutlin on embryo-fetal development, monthly pregnancy testing is strongly 
recommended for women of childbearing potential.


 
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• 
Viral serology  
Hepatitis B testing includes HBsAg and total HBcAb.  
Hepatitis C testing includes HCV antibody. 
• 
Quantitative immunoglobulins:  IgA, IgG, and IgM  
• 
Bone marrow assessment 
  
Central Laboratory Assessments 
The following samples will be sent to one or several Sponsor-designated central 
laboratories or to the Sponsor for analysis: 
• 
Serum samples for obinutuzumab PK analysis using a validated assay 
• 
Serum samples for rituximab PK analysis using a validated assay 
• 
Plasma samples for idasanutlin (and metabolites) PK analysis using a 
validated assay 
• 
Plasma samples for venetoclax (and metabolites) PK analysis using a 
validated assay 
• 
Tumor tissue samples and the corresponding pathology report collected at baseline 
for retrospective central confirmation of the diagnosis of FL or DLBCL and for 
exploratory research on biomarkers (see Table 12) 
The specimen must contain adequate evaluable tumor cells (≥ 20% for excisional 
biopsy and ≥ 50% for core biopsy).  
FFPE tissue blocks are preferred over slides.  Tissue blocks that are not formalin 
fixed will be accepted in countries that use a fixative other than 
paraformaldehyde, but information on the type of fixative should be included.  If a 
tissue block is not available, 17−22 serial, freshly cut, unstained slides 
accompanied by a punch biopsy may be sent.  A tumor block or punch biopsy is 
required for construction of a tissue microarray.  If fewer than 17−22 unstained, 
serial slides are available, the study site should consult the Sponsor (or delegate) 
regarding the acceptability of a fewer number of slides. 
If archival tissue is unavailable or is deemed unacceptable according to criteria 
above, a pretreatment core-needle, excisional, or incisional tumor biopsy is 
required.  Cytological or fine-needle aspiration samples are not acceptable.  
If the patient received anti-lymphoma treatment between the time of the most 
recent available biopsy and initiation of study treatment, a core-needle biopsy is 
strongly recommended. 
The sample should be shipped according to instructions provided in the 
laboratory manual.  The remainder of the tissue blocks will be returned to the 
local pathology laboratory, according to country-specific procedures. 
Analysis methods will be detailed in the Biomarker Analysis Plan. 


 
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• 
Tumor biopsy samples obtained at the time of progression (unless no adequate 
tumor site is accessible) for exploratory research on biomarkers (see Table 12) 
 
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 12. 
Table 12 Proposed Non-Inherited Biomarkers for Exploratory Analysis 
Sample Type  
Timing 
Proposed Biomarkers 
Serum 
Baseline and subsequent 
timepoints during 
treatment 
• MIC-1 
Blood for MRD 
Baseline and subsequent 
timepoints during and after 
treatment 
• Circulating lymphoma cells 
• Cell-free circulating-tumor DNA 
Blood  
Baseline and subsequent 
timepoints during and after 
treatment 
• Lymphocyte immunophenotyping, 
including B-cell counts (CD19), 
T-cell counts (CD3, CD4, and 
CD8), and NK cell counts (CD16 
and CD56) 
Archival or fresh tumor 
tissue 
Prior to study (archival) or 
baseline (fresh) 
Fresh biopsy at time of 
progression 
• mRNA (DLBCL only):  cell-of-
origin subtype (ABC vs. GCB)  
• Lymphoma-related genetic 
changes (DNA) and gene 
expression (mRNA) 
• Identification of lymphoma clone 
identifier (B cell−receptor 
sequence) for subsequent MRD 
assessment in blood 
• TP53 mutation status 
• IHC (ex p53, MDM2, PUMA, 
BCL2, and MYC) 
• mRNA expression for MDM2, 
XPC, BBC3 (PUMA,) and 
CDKN2A (p16/INK4A, ARF,) 
BCL-2, MYC (myc in DLBCL only) 
• Fluorescence in situ hybridization 
for MYC and BCL-2 gene 
amplification 
ABC = activated B cell–like (subgroup); DLBCL = diffuse large B-cell lymphoma; GCB = germinal-
center B cell−like (subgroup); ICH = immunohistochemistry; MRD =  minimal residual disease; 
NK = natural killer; PBMC = peripheral blood mononuclear cell. 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her remaining samples to be stored 
for optional exploratory research (Section 4.5.9), biological samples will be destroyed 


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when the final Clinical Study Report (CSR) has been completed, with the following 
exception:

Plasma or serum samples collected for PK analysis will be destroyed no later than 
5 years after the final CSR has been completed.

Blood, plasma, serum, and tumor tissue samples collected for biomarker research 
will be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.
Data arising from sample analysis, including data on germ-line mutations, will be subject 
to the confidentiality standards described in Section 8.4.
4.5.7
Electrocardiograms 
Resting 12-lead ECG recordings will be obtained in triplicate at specified timepoints, as 
outlined in the schedule of activities (see Appendix 1 and Appendix 2), and may be 
obtained at unscheduled timepoints as clinically indicated.  ECGs for each patient should 
be obtained using the same machine wherever possible.  All ECG recordings must be 
performed using a standard high-quality, high-fidelity digital electrocardiograph machine 
equipped with computer-based interval measurements. Lead placement should be as 
consistent as possible. ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes. All ECGs are to be obtained prior to 
other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws) and under no conditions while the patient is receiving premedication or an IV 
infusion of study drug. Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings. Paper copies of ECG tracings will be kept as part of a patient’s 
permanent study file at the site. The following should be recorded on the appropriate 
eCRF: ECG abnormality (including waveform); heart rate; PQ, PR, RR, and QRS 
intervals; and QT interval and corrected QTcF interval based on the machine readings of 
the individual ECG tracings. Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF. 
If at a particular post-dose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs. The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, co-medications known to prolong 
the QT interval, severe bradycardia, etc.) and provide this information on the eCRF.  In


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the event a patient presents with an episode of Grade 2 supraventricular arrhythmia 
(e.g., atrial fibrillation, atrial flutter, sinus tachycardia), an unscheduled ECG should be 
reported.  Standard-of-care treatment may be instituted at the discretion of the 
investigator. If a PK sample is not scheduled for that timepoint, an unscheduled 
idasanutlin PK sample should be obtained. 
ECG sampling assessment windows are as follows:

Pre-dose:  within 2 hours prior to idasanutlin dosing

Post-dose:  6 hours after idasanutlin dose (5%; equal to 18 minutes) or after the 
end of obinutuzumab or rituximab infusion, whichever occurs later
4.5.8
Multigated Acquisition Scan or Echocardiogram
Multigated acquisition (MUGA) scans will be obtained prior to treatment (see Appendix 1
and Appendix 2).  Echocardiogram is to be used if MUGA is not available.  Any clinical 
significant changes in cardiac function are to be reported within 7 days.
4.5.9
Samples for Research Biosample Repository
4.5.9.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or 
disease progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 


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approval for RBR sampling, this section of the protocol (Section 4.5.9) will not be 
applicable at that site.
4.5.9.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to obinutuzumab, rituximab,
idasanutlin, venetoclax, FL, DLBCL, or other types of cancer:

Remaining tumor tissue samples (except for remaining blocks, which will be 
returned to the sites)

Blood for serum

Remaining peripheral blood
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germ-line mutations, somatic mutations via whole genome 
sequencing (WGS), next-generation sequencing (NGS), or other genomic analysis 
methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.


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Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and patient 
number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a patient's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study.


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4.5.9.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determination that it is in the best interest of the patient

Patient non-compliance (e.g., consistent failure to show up for scheduled visits)
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.
If a patient withdraws consent, this request must be documented in the source 
documents and signed by the investigator.  Study personnel may use a public 
information source (e.g., county records) to obtain information about survival status.
4.6.2
Study Treatment Discontinuation
Study treatment should be permanently discontinued in patients who experience any of 
the following:

A DLT during the DLT window in patients enrolled in the dose-escalation phase

Anaphylaxis, acute respiratory distress, or Grade 4 IRR
If a Grade 3 IRR is recurrent during the second and subsequent cycles, study 
treatment may be discontinued at the discretion of the investigator, following an 
individual benefitrisk assessment.  

Any adverse event that leads to a delay of more than 21 days in the start of the next 
treatment cycle


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
Any hematologic adverse event that meets criteria for permanent discontinuation 
according to the guidelines provided in Section 5.1.8

Hy’s Law cases

Grade 3 non-hematologic adverse event that has a reasonable possibility of being 
related to study treatment and either is life threatening or does not resolve to
Grade 2 within 21 days

Disease progression

Pregnancy
In case of toxicity solely attributable to one drug of the combination requiring 
discontinuation, the other study drugs may be continued for patients experiencing clinical 
benefit as determined by the investigator after discussion with the Medical Monitor.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients who discontinue study treatment will not be replaced, except as outlined below:

During the dose-escalation phase, patients who discontinue study treatment prior to 
completing the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level.

Patients who discontinue before having received at least one dose of each 
component of the combination will be replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
GCP

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with study 
treatment components in completed and ongoing studies.  The anticipated important 
safety risks of IMPs in this study (i.e., obinutuzumab, rituximab, idasanutlin, and 
venetoclax) are outlined below.  Please refer to the Obinutuzumab, Rituximab,
Idasanutlin, and Venetoclax Investigator’s Brochures for a complete summary of safety
information.
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk of toxicities (see 
Section 4.1).  In addition, patients will undergo adequate safety monitoring during the 
study, as described in this section and in Section 4.5.  Guidelines for managing adverse 
events, including criteria for dosage modification and treatment delays or discontinuation, 
are provided in Section 5.1.8.
5.1.1
Risks Associated with Obinutuzumab
As of 4 July 2016, the following adverse events are considered to be important risks 
associated with obinutuzumab:  IRRs, TLS, neutropenia (including prolonged and late-
onset neutropenia), prolonged B-cell depletion, thrombocytopenia (including acute 
thrombocytopenia), infections (including PML and HBV reactivation), impaired 
immunization response, worsening of preexisting cardiac conditions, GI perforation,
immunogenicity, and second malignancies.  These events, with the exception of 
prolonged B-cell depletion, immunogenicity, and second malignancies, are described 
below.
5.1.1.1
Infusion-Related Reactions
IRRs have been reported predominantly during the first infusion of obinutuzumab.  The 
incidence and severity of IRRs decreased substantially with the second and subsequent 
infusions.  In the majority of patients, IRRs were mild or moderate and resolved with the 
slowing or interruption of the infusion and supportive care.  The commonly experienced 
IRRs have been characterized by hypotension, fever, chills, flushing, nausea, vomiting, 
hypertension, fatigue, and other symptoms. 
IRRs may be clinically indistinguishable from IgE-mediated allergic or anaphylactic 
reactions; anaphylaxis has been reported in patients treated with obinutuzumab. 
Hypotension may occur during obinutuzumab IV infusions.  Therefore, withholding of 
anti-hypertensive treatments should be considered for 12 hours prior to and throughout 
each obinutuzumab infusion and for the first hour after administration.  Patients at acute 
risk of hypertensive crisis should be evaluated for the benefits and risks of withholding 
their antihypertensive medication.


 
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Patients who have preexisting cardiac or pulmonary conditions should be monitored 
carefully throughout the infusion and the post-infusion period. 
Guidelines for medical management of IRRs and anaphylaxis are provided in 
Section 4.3.2.1 and Appendix 10.  
5.1.1.2 
Tumor Lysis Syndrome 
TLS, including fatal events, has been reported with obinutuzumab administration.  
Patients at risk of TLS (e.g., because of bulky disease or renal insufficiency) should 
receive adequate hydration and premedication with allopurinol or an alternative 
uricostatic agent as indicated in Section 4.3.2.5 (see Table 8).  Additional guidelines for 
management of TLS in this study are provided in Section 5.1.6. 
5.1.1.3 
Neutropenia 
Grade 3 or 4 neutropenia, including febrile neutropenia, has been reported with 
obinutuzumab administration.  Neutropenia resolved spontaneously or with use of 
hematopoietic growth factors.  Patients who experience Grade 3 or 4 neutropenia 
should be closely monitored until neutrophil values return to at least Grade 2.  Cases of 
late-onset neutropenia (ANC < 1000 cells/μL occurring ≥ 28 days after obinutuzumab 
treatment has been completed or stopped) or prolonged neutropenia (ANC 
< 1000 cells/μL) that does not resolve after 28 days without obinutuzumab treatment 
have also been reported.  Prophylactic treatment with antibiotics should be administered 
as per standard practice.  The use of G-CSF is allowed for treatment of neutropenia in 
this study.  Guidelines for treatment and primary prophylaxis with G-CSF are provided in 
Section 4.4.1.  
5.1.1.4 
Thrombocytopenia 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia 
(occurring within 24 hours after the infusion), has been observed during treatment with 
obinutuzumab.  In patients with CLL exposed to obinutuzumab, fatal hemorrhagic events 
have also been reported during Cycle 1.  A clear relationship between thrombocytopenia 
and hemorrhagic events has not been established.  Patients receiving concomitant 
medication that could possibly worsen thrombocytopenia-related events (e.g., platelet 
inhibitors and anticoagulants) may be at greater risk of bleeding and will not be included 
in the study.  Patients should be closely monitored for thrombocytopenia, especially 
during the first cycle.  For patients who experience thrombocytopenia, regular laboratory 
tests should be performed until the event resolves, and dose delays should be 
considered in case of severe or life-threatening thrombocytopenia.  Transfusion of blood 
products (i.e., platelet transfusion) may be performed at the discretion of the treating 
physician, according to institutional practice.  


 
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5.1.1.5 
Infections 
On the basis of its mechanism of action, resulting in profound B-cell depletion, 
obinutuzumab may be associated with an increased risk of infections.  Obinutuzumab 
should not be administered to patients with active infection, and caution should be 
exercised when including patients with a history of recurrent or chronic infections.   
Serious bacterial, fungal, and new or reactivated viral infections can occur during and 
following the completion of obinutuzumab therapy.  Fatal infections have been reported. 
Reactivation of hepatitis B in patients with chronic hepatitis (HBsAg positive) with 
evidence of prior hepatitis B exposure, or in patients who are carriers (HBsAg negative 
and HBcAb positive) has been reported with other anti-CD20 antibodies.  The risk is 
increased particularly when anti-CD20 antibodies are administered with 
immunosuppressive therapies, such as steroids or chemotherapy.  Particular attention 
should be given to patients who have previously received highly immunosuppressive 
treatment, such as high-dose chemotherapy and SCT.  Patients positive for HBsAg and 
HBcAb are not eligible for this study. 
John Cunningham (JC) viral infection resulting in PML has been reported in patients 
treated with obinutuzumab.  The diagnosis of PML should be considered in any patients 
presenting with new-onset neurologic manifestations.  The symptoms of PML are 
unspecific and can vary, depending on the affected region of the brain.  Motor symptoms 
with corticospinal tract findings (e.g., muscular weakness, paralysis, and sensory 
disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are 
common.  Some signs or symptoms regarded as “cortical” (e.g., aphasia or visual-spatial 
disorientation) may occur.  Evaluation of PML includes, but is not limited to, consultation 
with a neurologist, brain MRI, and lumbar puncture (cerebrospinal fluid testing for JC 
viral DNA).  Additional guidelines for medical management of PML in this study are 
provided in Table 19.  
5.1.1.6 
Immunizations 
The safety of immunization with live virus vaccines following obinutuzumab therapy has 
not been studied.  Thus, vaccination with live virus vaccines is not recommended during 
treatment and until B-cell recovery. 
5.1.1.7 
Worsening of Preexisting Cardiac Condition 
In patients with underlying cardiac disease and treated with obinutuzumab, adverse 
events such as angina pectoris, acute coronary syndrome, myocardial infarction, heart 
failure, and arrhythmias, including atrial fibrillation and tachyarrhythmia, have been 
observed.  These events may occur as part of an IRR and can be fatal.  Therefore, 
patients with a history of cardiac disease should be monitored closely.  In addition, these 
patients should be hydrated with caution to prevent a potential fluid overload. 


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5.1.1.8
Gastrointestinal Perforation
GI perforation has been reported in patients with NHL treated with obinutuzumab, 
including fatal events.  Patients with GI involvement should be monitored for signs of 
GI perforation.
5.1.2
Risks Associated with Rituximab
The following adverse events are considered to be important risks associated or 
potentially associated with rituximab:  IRRs, infections (including severe infections), PML, 
hepatitis B reactivation, neutropenia (including prolonged neutropenia), TLS, impaired 
immunization response, severe skin reactions (Stevens-Johnson syndrome/toxic 
epidermal necrolysis), and GI perforation.  Details for these risks are provided below; 
refer to the Rituximab Investigator’s Brochure for full information.
5.1.2.1
Infusion-Related Reactions
Acute IRRs are very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, serious IRRs are uncommonly 
reported (occurring in 1 of 1,000 and 1 of 100 patients) and are rarely fatal (occurring 
in 1 of 10,000 and 1 of 1,000 patients).  Most IRRs occur with the first administration 
of rituximab.  Most IRRs are mild to moderate in severity (Grade 1/2) and can be 
managed by slowing or stopping the rituximab infusion. IRRs can be severe and in rare 
cases can result in death. Rituximab-induced IRRs consist of a cluster of symptoms and 
signs occurring during or within 24 hours of a rituximab infusion, which may be related to 
cytokine release and/or other chemical mediators, and these acute IRRs overlap with 
“cytokine release syndrome.”  Anaphylactic and other hypersensitivity reactions have 
been reported following rituximab administration, and clinical manifestations of these 
reactions are similar to cytokine release syndrome.  In contrast to cytokine release 
syndrome, true hypersensitivity reactions typically occur within minutes of starting the 
rituximab infusion.
5.1.2.2
Infections (Including Serious Infections)
Serious infections, including fatal bacterial, fungal, and new or reactivated viral infections, 
can occur during and up to 1 year following completion of rituximab-based therapy.  
5.1.2.3
Hepatitis B Reactivation
Reactivation of hepatitis B ranges from asymptomatic reactivations (detected by 
changes in laboratory parameters only) to fulminant liver failure and death.  Patients with 
chronic hepatitis B (HBsAg positive) viral infection are at risk for reactivation and will be 
excluded from the study.  Patients with evidence of prior hepatitis B exposure or who are 
carriers (defined as HBsAg negative and anti-HBcAb positive) are at a lower risk for 
reactivation.  Patients who demonstrate evidence of reactivation while receiving an 
appropriate anti-viral therapy will be discontinued from study treatment.


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5.1.2.4
Progressive Multifocal Leukoencephalopathy
Rare cases of PML have also been reported in patients treated with rituximab alone or in 
combination with other immunosuppressive medications (Goldberg et al. 2002; 
Calabrese et al. 2007; Carson and Bennett 2009).  In a review of 57 patients who 
developed PML after rituximab administration, all patients had received prior therapies 
with alkylating agents, corticosteroids, purine analogs, or drugs to prevent allogeneic 
stem cell or solid-organ graft rejection.  The diagnosis of PML in any patient treated with 
rituximab is rare, but it should be suspected in any patient who develops new-onset 
neurologic manifestations.  The majority of patients with hematologic malignancies 
diagnosed with PML received rituximab in combination with chemotherapy or as part of a 
hematopoietic SCT.  Most cases of PML were diagnosed within 12 months of the 
patients’ last infusion of rituximab.
5.1.2.5
Neutropenia (Including Prolonged Neutropenia)
Neutropenia is very common in patients receiving rituximab (occurring in 10% of 
patients) based on clinical trial experience.  However, delayed onset neutropenia is very 
rare (occurring in 1 of 10,000 patients), and the incidence of prolonged neutropenia is 
unknown.  Neutropenia may lead to serious or overwhelming infection, especially if 
profound (Grades 34), prolonged, associated with breaches in natural mucosal barriers 
(e.g., diarrhea and/or mucositis), and/or other immunological defects (e.g., lymphopenia, 
hypogammaglobulinemia, and acquired immunodeficiency syndrome).  Despite an 
increase in incidence of neutropenia and Grade 34 neutropenia associated with 
rituximab, most studies have not reported a significant increase in serious neutropenic 
infections.
5.1.2.6
Tumor Lysis Syndrome
Patients treated with rituximab may be at risk for TLS.  Severe tumor TLS is very rare in 
patients receiving rituximab (occurring in 1 of 10,000 patients), based on 
postmarketing experience.  Signs and symptoms (e.g., hyperuricemia, hyperkalemia, 
hypocalcemia, hyperphosphatemia, acute renal failure, and elevated LDH) that are 
consistent with TLS have been reported to occur after the first rituximab IV infusion in 
patients with high numbers of circulating malignant lymphocytes.  A high number of 
circulating malignant cells (25,000/mm3) or high tumor burden confers a greater risk of 
TLS.  For patients with evidence of TLS, rituximab should be discontinued, and the 
patient should be treated as clinically indicated.
5.1.2.7
Impaired Immunization Response
B-cell depletion is expected (and desired) during rituximab therapy and is directly related 
to its mechanism of action. In theory, peripheral B-cell depletion may reduce the 
effectiveness of immunization, since patients may not be able to mount an effective 
humoral immune response to foreign antigens.


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5.1.2.8
Stevens Johnson Syndrome and Toxic Epidermal Necrolysis
Severe reactions, including fatal mucocutaneous reactions, can occur in patients 
receiving rituximab.  The onset of these reactions in patients treated with rituximab has 
varied from 1 to 13 weeks following rituximab exposure. The majority of the TEN/SJS 
cases reported with rituximab were associated with additional risk factors. Fatal 
outcome also appeared to increase in patients who were exposed to multiple risk factors 
for TEN/SJS.
5.1.2.9
Gastrointestinal Perforation
Abdominal pain, bowel obstruction, and perforation, in some cases leading to death, can 
occur in patients receiving rituximab in combination with chemotherapy.  In 
postmarketing reports of rituximab, the mean time to documented GI perforation was 
6 days (range: 177 days) in patients with NHL.
5.1.3
Risks Associated with Idasanutlin
Information related to idasanutlin-associated risks is based mainly on review of data 
from Phase I experience in patients with solid tumors and AML (Studies NP27872, 
NP28902, and NP28679, respectively) as described in the Idasanutlin Investigator’s 
Brochure.  In Study NP27872 and NP28902, 160 patients with advanced malignancies 
(excluding leukemia) have received idasanutlin in the Phase I, entry-into-human, dose-
escalation study NP27872 (99 patients) and in the Phase I DDI and relative 
bioavailability study NP28902 (61 patients).  Study BH29812 (idasanutlin plus 
obinutuzumab in R/R FL and DLBCL) had enrolled 1 patient as of 1 May 2016.
Many of the toxicities experienced by patients with solid tumors appear to be 
manageable with appropriate prophylaxis, supportive therapies, and/or reversible with 
discontinuation of idasanutlin. Identified risks include GI disorders (diarrhea, nausea, 
and vomiting), myelosuppression (thrombocytopenia, neutropenia, and anemia), TLS, 
infectious complications, and electrolyte abnormalities.  Potential risks include 
coagulation abnormalities and liver function test abnormalities.
Please refer to the current version of the Idasanutlin Investigator’s Brochure for 
additional information on the identified and potential risks.
5.1.3.1
Gastrointestinal Disorders
The adverse GI events in the Phase I idasanutlin studies include primarily diarrhea, 
nausea, vomiting, and anorexia.  Diarrhea is the most common adverse event observed
across treatment groups and indications.  It has been reported in a large majority of 
patients treated with idasanutlin and rarely presented as severe.  Nausea and vomiting 
have also been reported during clinical experience with idasanutlin.  Clinical monitoring 
for potential complications is required.  Patients who develop GI disorders should have 
other or concomitant causes ruled out.  Appropriate event management and prophylaxis 
should be considered.


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5.1.3.2
Myelosuppression
Idasanutlin was associated with myelosuppression (thrombocytopenia, neutropenia, 
anemia, and aplasia) in Study NP27872, evaluating idasanutlin in patients with solid 
tumors.
Thrombocytopenia
MDM2 antagonists were shown in vitro to affect all types of hematopoietic progenitors, 
including megakaryocytic differentiation.  They inhibit both early and late stages of 
megakaryopoiesis, including ploidization and proplatelet formation (Mahfoudhi et al. 
2016).  As a consequence, the effect on early progenitors might induce long-lasting 
thrombocytopenia in vivo.  Clinical data on the severity and duration of
thrombocytopenia with idasanutlin are limited. Study NP27872, evaluating idasanutlin in 
patients with solid tumors, has shown possible exposure-dependent thrombocytopenia
with an association between AUC/cycle and platelet nadir of the first cycle treatment for 
the daily dosing schedule, together with AUC/cycle as a determinant for Grade 4 
thrombocytopenia.  The potential relation between thrombocytopenia and hemorrhagic 
events has not been confirmed.  
Neutropenia and Febrile Neutropenia
In Study NP27872, a possible exposure-dependent neutropenia was shown, with AUC/ 
cycle as a determinant for Grade 4 neutropenia within the first two cycles in the daily 
schedule. 
Blood counts will be monitored closely throughout study treatment (see the schedules of 
activities in Appendix 1 and Appendix 2); a Grade 3 decrease in neutrophil levels 
should be followed until resolution (to Grade 2 or baseline value) and additional 
measures considered as clinically indicated (see Section 5.1.8).  Use of hematopoietic 
growth factors is encouraged during study treatment, particularly for patients who 
experience a first event of Grade 3 neutropenia during the study treatment phase. 
Guidelines for treatment and primary prophylaxis with G-CSF are provided in 
Section 4.4.1.
5.1.3.3
Infections
Infections of various etiologies (including infections with fatal outcome) have been 
reported in patients treated with idasanutlin, primarily in patients with AML.  The disease 
under study itself is associated with impaired immune function and increased 
susceptibility to infections. Assessment of causality for these cases can be difficult, and 
it is unclear whether or how much the incidence could be increased due to idasanutlin 
treatment. Because of the potential of idasanutlin to induce myelosuppression, patients 
should be carefully screened for evidence of active or uncontrolled infection or other 
uncontrolled disorder prior to enrollment.  Patients in this study will be closely monitored 
for infection, and prompt therapy will be instituted as necessary.  In any patient with 
uncontrolled and/or severe diarrhea, the presence of C. difficile infection should be 
investigated. 


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5.1.3.4
Tumor Lysis Syndrome
There is a potential for TLS in patients treated with idasanutlin.  Laboratory evidence of 
TLS has been reported for patients with AML treated in Study NP28679 and in patients 
considered to be at high risk of TLS owing to initial high WBC count.  Clinical features 
were rare.  For TLS-specific management and recommendations, refer to Section 5.1.6.
5.1.3.5
Electrolyte Disorders
Electrolyte disorders (hypercalcaemia, hyperkalaemia, hypernatraemia, hypocalcaemia, 
hypokalaemia, hypomagnesaemia, hyponatremia, hyperphosphataemia, and 
hypophosphataemia) were commonly observed in patients treated with idasanutlin.  In 
addition to institutional guidelines, electrolytes should be monitored during the treatment 
phase. Electrolyte disorders should be treated according to institutional guidelines.
5.1.3.6
Other Adverse Events
Other adverse events commonly reported with idasanutlin included fatigue/asthenia, 
pyrexia, peripheral edema, headache, dyspnea, dizziness, and chills.  These adverse 
events have been of mild severity and controllable with symptomatic treatment and/or 
nutritional support.
5.1.4
Risks Associated with Venetoclax
Phase I experience with venetoclax has demonstrated that it is generally well tolerated, 
and toxicities appear to be mostly manageable and/or reversible; see the Investigator’s
Brochure for more information.  On the basis of clinical data to date, the following known 
and suspected risks with venetoclax are described.  Guidelines for the management of 
these risks through dose and schedule modifications are described in Section 5.1.8.
5.1.4.1
Tumor Lysis Syndrome
To date, the principal adverse reaction associated with venetoclax in the ongoing, 
single-agent Phase I dose-escalation study M12-175 has been TLS (primarily, but not
exclusively, related to the first dose). TLS, including cases that have led to clinical 
sequelae and death, has been observed in patients with CLL at venetoclax doses of 
50 mg.  
Very few cases of nonclinically relevant electrolyte changes (e.g., elevated phosphate 
levels marginally above the ULN and 25% changes from baseline in uric acid levels that 
remained within the normal reference range) have been observed in NHL patients to 
date.  However, TLS is a risk for patients with NHL who are treated with high cell-killing 
agents.  Risk is highest for patients with bulky disease, elevated leukocyte count, 
elevated pretreatment LDH levels, compromised renal function, and dehydration.  In this 
study, TLS will be monitored closely (see Section 5.1.6 and the schedules of activities in 
Appendix 1 and Appendix 2).


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5.1.4.2
Cytopenia
Effects on lymphocyte numbers are expected on the basis of the mechanism of action,
and modest reductions in neutrophils have been observed with venetoclax therapy in
patients. Thrombocytopenia and anemia have been reported with venetoclax in the
ongoing Phase I, single-agent, dose-escalation study M12-175 that is being conducted
in heavily pretreated patients with CLL and NHL. In most cases, the condition was
preexisting. Adverse events of neutropenia and thrombocytopenia, including Grade 3
events, have been reported in the oncology studies, with a slightly higher frequency in
studies in which venetoclax was combined with other chemotherapeutic agents. In this
study, blood counts will be monitored closely throughout treatment (see the schedules of
activities in Appendix 1 and Appendix 2). 
5.1.4.3
Infectious Complications
Infections of various types have occurred in patients in the ongoing Phase I, single-agent 
dose-escalation study M12-175. NHL can be associated with impaired immune function 
and increased infections. Patients in this study will be closely monitored for infections,
and prompt therapy will be instituted as necessary. 
5.1.4.4
Effects on Cardiac Function
Nonclinical studies demonstrated decreases of approximately 20% in cardiac function in
healthy laboratory animals. No pattern of adverse events indicating changes in cardiac
function has been reported in clinical studies to date. However, the number of patients
exposed and the duration of exposure are still relatively low. Patients enrolled in this
study are required to have ECGs and assessments of left ventricular ejection fraction at
screening and as clinically indicated thereafter.
5.1.4.5
Effects on Fertility
There is a potential for decreased spermatogenesis. Male patients who are considering
preservation of fertility should bank sperm before treatment with venetoclax. Male
patients must refrain from sperm donation starting from initial study drug administration
until 3 months after the last dose of study treatments. The long-term effects of 
venetoclax on either male or female reproductive potential are unknown.
5.1.5
Risk of Overlapping Toxicities
The overlapping toxicities from the combined administration of obinutuzumab or 
rituximab, idasanutlin, and venetoclax are anticipated during study treatment phase.  
Overlapping toxicities across obinutuzumab, idasanutlin, and venetoclax are 
myelosuppression (thrombocytopenia, neutropenia, and febrile neutropenia), infectious 
complications, TLS, and GI disorders (diarrhea, nausea, and vomiting; see Table 13).  
Overlapping toxicities across rituximab, idasanutlin, and venetoclax are 
myelosuppression (thrombocytopenia, neutropenia, and febrile neutropenia), TLS, and
infections (Table 14). Such events should be closely monitored and managed 
throughout the study. 


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Table 13 Overlapping Toxicities:  Obinutuzumab, Idasanutlin, 
and Venetoclax
Adverse Event
Idasanutlin a QD5 d
“All Comers” 
Monotherapy in 
Solid Tumors (n38)
Venetoclax b
Monotherapy
NHL (n128)
Obinutuzumab c
Monotherapy
NHL (n215)
Overall 
%
Grade 3 
Events
Overall 
%
Grade 3 
Events
Overall 
%
Grade 3 
Events
Thrombocytopenia
47%
45%
14%
10% 
18%
5%-8%
Neutropenia/
febrile neutropenia
24%/
12%
24%/
12%
20%/
2.3%
13%/
2.3%
36%/
5%
5%-14%/
3%
Infections (SOC)
27%
9%
40%
11%
43%
3%
Diarrhea
68%
8%
42%
3%
5%-8%
NA
Nausea/
vomiting
68%/
50%
13%/
3%
46%/
20%
NA
5%-
9%/
5%
NA
TLS
NA d
NA d
2%
2%
1%
1%
AMLacute myeloid leukemia; MTDmaximum tolerated dose; NAnot applicable; 
NHLnon-Hodgkin’s lymphoma; QD5 donce a day every 5 days; SOCSystem Organ 
Class; TLStumor lysis syndrome.
a Study NP27872:  All patients dosed for 5 days (includes dose-escalation and biomarker 
cohorts).  This includes 20 patients treated above the MTD of 250 mg (Idasanutlin
Investigator’s Brochure, Version 7, July 2015).
b Study M12-175 (Arm B), M13-834, M13-835 (Investigator’s Brochure, Version 7, 
15 February 2016).
c Study BO21003 (final Clinical Study Report).
d Five TLS cases reported in Study NP28679 (Phase I study of idasanutlin in AML).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Table 14 Overlapping Toxicities:  Rituximab, Idasanutlin, and Venetoclax
Adverse Event
Idasanutlin a QD5 d
“All Comers” 
Monotherapy in 
Solid Tumors (n38)
Venetoclax b
Monotherapy
NHL (n128)
Rituximab c
Monotherapy
(n356)
Overall 
%
Grade 3 
Events
Overall 
%
Grade 3 
Events
Overall 
%
Grade 3 
Events
Thrombocytopenia
47%
45%
14%
10% 
9.6%
1.7%
Neutropenia/
febrile neutropenia
24%/
12%
24%/
12%
20%/
2.3%
13%/
2.3%
11.2%/
<1%
4.2%/
<1%
Infections (SOC)
27%
9%
40%
11%
30.3%
3.9%
Nausea/
vomiting
68%/
50%
13%/
3%
46%/
20%
NA
17.1%/
6.3%
0.3%/
0.3%
TLS
NA d
NA d
2%
2%
<1%
<1%
AMLacute myeloid leukemia; MTDmaximum tolerated dose; NAnot applicable; 
NHLnon-Hodgkin’s lymphoma; QD5 donce a day every 5 days; SOCSystem Organ 
Class; TLStumor lysis syndrome.
a Study NP27872:  All patients dosed for 5 days (includes dose-escalation and biomarker 
cohorts).  This includes 20 patients treated above the MTD of 250 mg (Idasanutlin 
Investigator’s Brochure, Version 7, July 2015).
b Study M12-175 (Arm B), M13-834, M13-835 (Investigator’s Brochure, Version 7, 
15 February 2016).
c Data from rituximab monotherapy in oncology trials.
d Five TLS cases reported in Study NP28679 (Phase I study of idasanutlin in AML).
5.1.5.1
Thrombocytopenia
Theoretical synergistic effects on megakaryopoiesis are to be expected with combination 
therapy.  Thrombocytopenia has been defined as an on-target PK/PD effect for 
idasanutlin, potentially inhibiting early progenitors.  Venetoclax given as monotherapy 
spares Bcl-XLinduced thrombocytopenias.  Emerging data from Study GO27878 with 
venetoclax in combination with CHOP and either rituximab or obinutuzumab suggest that 
the frequency and severity of thrombocytopenias are greater than previously expected.  
Thrombocytopenia is also an identified risk with obinutuzumab and rituximab, with the 
greatest risk being present during the first cycle of therapy.  Fatal hemorrhages have 
been reported in patients being treated with obinutuzumab.
Therefore, owing to the potential severity and duration of thrombocytopenia induced by 
the study treatment combination, blood counts will be performed regularly (see the 
schedule of activities in Appendix 1 and Appendix 2).  Anticoagulant and antiplatelet 
agents are not allowed during study treatment period.  For patients who experience 
thrombocytopenia, close count monitoring should be performed until resolution.  Other 


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measures (e.g., dose delays; see Section 5.1.8) or platelet transfusions should be 
considered as clinically indicated.
5.1.5.2
Neutropenia and Febrile Neutropenia
There is a theoretical concern for synergistic neutropenia when venetoclax, idasanutlin, 
and obintuzumab or rituximab are used in combination therapy.  Neutropenia has been 
reported in patients treated with idasanutlin with an apparent exposure response, with
AUC/cycle as a determinant for Grade 4 neutropenia probability.  Neutropenia is an 
identified risk with both venetoclax and obinutuzumab, and to a lesser extent with 
rituximab.  Incoming data from Study GO27878, with venetoclax in combination with 
CHOP and either rituximab or obinutuzumab, indicate that venetoclax in combination 
with obinutuzumab and CHOP resulted in a higher than anticipated reporting of 
neutropenia and febrile neutropenia (in the setting of mandatory G-CSF prophylaxis), 
resulting in a modification of the venetoclax dosing regimen from QD dosing to a non-
continuous 10-day dosing. 
In anticipation of a potential increase in both the duration and intensity of neutropenia 
with the study treatment combination, adherence to the blood count schedule is required 
throughout study treatment (see the schedule of activities in Appendix 1 and Appendix 2).  
Severe events of Grade 3 neutropenia are to be carefully monitored and managed as 
clinically indicated (see Section 5.1.8).  Use of G-CSF as primary prophylaxis for 
neutropenia (starting at Cycle 3 and continuing through each additional cycle of study 
treatment) in the dose-escalation phase, or as primary prophylaxis in each cycle of 
therapy for the expansion phase may be considered as clinically appropriate and is 
required for patients who experience a first event of Grade 3 neutropenia during the 
study treatment period (see Section 5.1.8).
5.1.5.3
Infectious Complications
Patients with B-cell NHL and DLBCL have an intrinsic susceptibility for infections 
(including opportunistic infections). Serious infections, including cytomegalovirus (CMV),
have been reported in patients treated with venetoclax in combination with rituximab or 
obinutuzumab.  Infections were prevalent in patients who received treatment with 
idasanutlin, venetoclax, and/or obinutuzumab.  No clear link has been established
between serious infectious events and neutropenia.  Patients should be carefully 
screened for evidence of active or uncontrolled infections prior to enrollment.  Patients 
receiving antimicrobial agents with therapeutic intent are not permitted to begin study 
treatment (see Section 4.1.2).
If clinically indicated, anti-infective prophylaxis for viral, fungal, bacterial, or 
pneumocystis infections should be administered.  Patients who experience infections of 
any degree on study treatment combination should be carefully observed and managed 
conservatively. 


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5.1.5.4
Gastrointestinal Disorders
Diarrhea has been the most common adverse events reported across indications during 
idasanutlin clinical experience.  It is very common, with acute onset, and is rarely severe.  
Diarrhea was also a common event reported during the venetoclax NHL combination 
studies.  Clinical monitoring for potential diarrhea complications is required.  Patients 
who develop diarrhea should have other or concomitant causes ruled out (including 
infection due to C. difficile), and if appropriate, prompt treatment with antidiarrheal 
agents must be administered (see Section 5.1.8).
Supportive therapies, including prophylaxis for diarrhea and nausea, are encouraged in 
this study.  Electrolyte monitoring, correction, and IV hydration are advisable should GI 
events arise during treatment. Owing to the high incidence of diarrhea, C. difficile
infections could go unnoticed.  In the event of uncontrolled and/or severe diarrhea, it is 
advised to test for microbiological evidence of C. difficile.  If presence is confirmed, 
aggressive therapy (e.g., metronidazole, vancomycin, fidaxomicin) should be introduced 
according to individual patient risk.
5.1.5.5
Tumor Lysis Syndrome
There is the identified risk of TLS with obinutuzumab or venetoclax treatment since 
these agents can result in the rapid destruction of a large number of tumor cells. 
Idasanutlin has been linked to tumor lysis events in AML patients.  Therefore, 
overlapping toxicity in regard to TLS cannot be excluded. Guidelines for management of 
patients who develop TLS are provided in Section 5.1.6. Risks of TLS with rituximab are 
very low (see Table 14).
5.1.6
Prophylaxis and Monitoring for Tumor Lysis Syndrome
TLS is a risk for patients with NHL who are treated with high cell-killing agents, including 
venetoclax.  Changes in blood chemistries consistent with TLS that require prompt 
management can occur as early as 6 to 8 hours following the first dose of venetoclax.  
The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities.  Risk is highest for patients with bulky disease, elevated leukocyte count, 
elevated pretreatment LDH levels, compromised renal function, and dehydration.  
Assessment of tumor burden with CT scan and CBC with WBC differential, as well as
blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine), should be 
performed in all patients and correct preexisting chemistry abnormalities prior to initiation 
of treatment with venetoclax.  
All patients must receive prophylaxis for TLS before the initiation of the first dose of 
venetoclax (see also Section 4.3.2.5). Prophylaxis will include the following: 

Appropriate hydration, consisting of a fluid intake of approximately 23 L/day 
starting 2448 hours before the start of treatment

Administration of an agent to reduce uric acid (such as allopurinol 300 mg/day orally 
beginning 72 hours before dose and continuing for 3−7 days afterwards) or 


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rasburicase IV (for those high risk patients with elevated uric acid levels before 
treatment, or when otherwise judged to be appropriate by the investigator) until 
normalization of serum uric acid and other laboratory evidence of TLS (e.g., 
elevated serum LDH levels)

Laboratory results should be reviewed and electrolyte values should not 
demonstrate any clinically significant abnormalities before the first dose of 
venetoclax, or the patient should receive additional prophylactic treatment and 
hydration before the initiation of dosing

Patient at higher risk of TLS will be hospitalized for the initial venetoclax dose. 
Patients not considered at higher risk of TLS may be hospitalized after discussion 
with the investigator and Medical Monitor
On the day of the initial visit with administration of venetoclax (Day 1 of Cycle 1), serial 
vital signs, serum chemistry, and hematology samples will be drawn before the dose of 
venetoclax and 8 and 24 hours following the dose (see Appendix 1 and Appendix 2). 
These samples are to be sent immediately to the laboratory and the investigator or 
designee must review the results promptly. Laboratory values obtained prior to 
venetoclax dosing are to be used to determine whether a patient developed a change 
related to TLS. Laboratory results obtained 24 hours post-dose must be reviewed
before receiving the dose of venetoclax on that day. Patients who develop electrolyte
changes suggestive of TLS should undergo aggressive management and further
monitoring according to the guidance in Appendix 12, Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome.
In addition, if TLS is observed in the initial cohorts, staggering the dosing of venetoclax 
may be explored (venetoclax dosing may be initiated 2 or 3 days after the first 
idasanutlin dose during the first cycle of therapy), or starting at a lower dose of 
venetoclax and reaching the specified dose in a step-wise fashion after discussion with 
the Medical Monitor to prevent or promptly treat TLS.
5.1.7
Prophylaxis and Monitoring for All Patients
5.1.7.1
Guidelines for Hospitalization of Patients at Risk for Tumor 
Lysis Syndrome
Patients exhibiting specific characteristics at screening or after initiation of venetoclax 
treatment are considered to be at high risk of developing TLS and must be hospitalized 
for more intensive prophylaxis and monitoring for the initial dose of venetoclax.  These 
patients are identified by the presence of any of the following:

Any lymph mass 10 cm in size on the screening CT scan

Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte 
count (ALC) or the presence of abnormal cells in the peripheral blood differential 
signifying circulating lymphoma cells


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In addition to characteristics requiring mandatory hospitalization, other patient 
characteristics may suggest an increased risk of TLS. These include, but are not limited 
to, the following:

Overall disease burden (e.g., several enlarged lymph nodes, even if none are 10 cm
in size)

Elevated LDH levels

Compromised renal function, as evidenced by low creatinine clearance

Extensive bone marrow involvement

Dehydration
Hospitalization is not mandatory for patients exhibiting these characteristics, but these 
and any other factors considered relevant to TLS should be considered in the overall 
assessment of a patient’s state and the risk of TLS. Investigators should use their 
judgment in assessing the risk of TLS for their patients and may optionally hospitalize 
any patient they consider to be at risk of TLS for the first dose of venetoclax, with 
approval of the Medical Monitor. 
5.1.7.2
Hospitalization Procedures
For patients requiring hospitalization, hospitalization will begin the evening before the 
first dose of venetoclax and continue for 24 hours after. Upon admission, serum 
chemistry and hematology laboratory samples should be drawn and IV hydration should 
be started with a target of 150200 cc/hr or as clinically appropriate. Laboratory results 
should be reviewed, and electrolyte values should not demonstrate clinically significant 
abnormalities before the first dose of venetoclax; otherwise, the patient should receive 
additional prophylactic treatment and hydration before the initiation of dosing. A 
nephrology (or acute dialysis) service must be consulted/contacted on hospital 
admission (per institutional standards) 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. 
Serial vital signs will be measured and TLS laboratory samples will be drawn (serum 
chemistry as defined in Section 4.5.6) before the first dose administration of venetoclax 
and 8, 12, and 24 hour post-dose.  In addition, hematology samples will be drawn 8 and 
24 hours post-dose (see Appendix 1 and Appendix 2). Samples are to be sent 
immediately to the laboratory and the investigator or designee must review the results 
promptly. Laboratory values obtained before the dose of venetoclax are to be used to 
determine whether a patient developed a change related to TLS. Laboratory results 
obtained 24 hours post-dose must be reviewed before administration of the dose of 
venetoclax on that day. Patients who develop electrolyte changes suggestive of TLS 
should undergo aggressive management and further monitoring according to the 
guidance in Appendix 12.


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For patients assessed by the investigator to be at particularly high risk of TLS may, in 
addition to hospitalization, the investigator after discussion with the Medical Monitor may 
stagger the dosing of venetoclax (venetoclax dosing may be initiated 2 or 3 days after 
the first idasanutlin dose during the first cycle of therapy), or start the patient at a lower 
dose of venetoclax and reach the specified dose in a step-wise fashion.
5.1.8
Management of Patients Who Experience Specific 
Adverse Events
Patients should be assessed clinically before each study treatment administration.
Guidelines for management of toxicities are based on laboratory values obtained within
48 hours prior to Day 1 of each scheduled drug administration or within 24 hours prior to 
Days 8 and 15 of Cycle 1. Dosing will occur only if a patient’s clinical assessment and 
laboratory test values are acceptable.
During induction, study treatment may be delayed for toxicity for a maximum of 21 days.  
If study treatment is delayed for more than 21 days, obinutuzumab or rituximab, 
idasanutlin, and venetoclax treatment will be permanently discontinued (see Table 18).  
There will be no dose reductions of obinutuzumab or rituximab.  Treatment delays apply 
to all toxicities described below; dose modifications apply only to toxicities that are 
considered to be related to either idasanutlin and/or venetoclax.  The dose of idasanutlin 
may be reduced as outlined in Table 15.  The dose of venetoclax may also be reduced. 
In parallel cohorts, in which one drug only is escalated, the dose of that drug can be 
reduced only once per treatment cycle.  In diagonal cohorts, in which the doses of both 
drugs have been escalated, the dose of both drugs will be reduced once per treatment 
cycle.  There will be no more than one dose reduction per treatment cycle.  If the doses
of idasanutlin and venetoclax are reduced, re-escalation is not permitted.


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Table 15 Idasanutlin Dose-Reduction Steps
Initial Dose
Dose Reduction in Milligrams
Step 1
Step 2
Step 3
100 mg
Minus 50 mg
No further 
reduction a 
No further reduction a 
150 mg
Minus 50 mg
No further 
reduction a 
No further reduction a 
200 mg
Minus 50 mg
Minus 50 mg
No further reduction a 
250 mg
Minus 100 mg
Minus 50 mg
No further reduction a 
300 mg
Minus 100 mg
Minus 50 mg
Minus 50 mg
350 mg
Minus 100 mg
Minus 100 mg
Minus 50 mg
400 mg
Minus 100 mg
Minus 100 mg
Minus 50 mg
a When no further idasanutlin dose reduction is possible, the patient will be 
discontinued from the study.
The dose of venetoclax will be reduced by at least 25% from the current dose (rounded 
to the lower closest 50 mg) or return to the previous dose, with a minimum final dose of 
200 mg.  If the dose level reaches 200 mg, no further reduction will be allowed and the 
patient will be discontinued from the study.
Toxicities that occur during the cycle and subside prior to the next cycle should not 
trigger the suggested dose modifications. Guidelines for management of toxicities 
during induction treatment are provided in Section 5.1.8.1 and during consolidation or 
maintenance treatment in Section 5.1.8.2.
5.1.8.1
Toxicities during Induction Treatment
Hematologic Toxicities during Induction Treatment
Guidelines for management of hematologic toxicities that occur during induction 
treatment, with the exception on Days 8 and 15 of Cycle 1 when obinutuzumab are given 
in Table 16. Hematologic toxicity is defined as neutropenia, anemia, or 
thrombocytopenia.  Lymphopenia is not considered a hematologic toxicity but an 
expected outcome of therapy.  


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Table 16 Guidelines for Management of Hematologic Toxicities That Occur 
during Induction Treatment (Except on Days 8 and 15 of Cycle 1)
Event
Action to Be Taken
Grade 3 or 4 
hematologic 
toxicity a, b
For patients who have had one or no prior dose reductions:

Withhold study treatment. a

Administer RBCs or platelets as required.

If patient has not already initiated G-CSF, initiate prophylactic G-CSF for 
current and subsequent cycles.

If improvement to Grade 2 or baseline within 14 days after the scheduled 
date for the next cycle, resume obinutuzumab or rituximab at full dose and 
resume idasanutlin and venetoclax at current dose.

If improvement to Grade 2 or baseline 1521 days after the scheduled date 
for the next cycle, resume obinutuzumab or rituximab at the full dose and 
resume the last escalated drug(s) at a reduced dose according to guidelines in 
Section 5.1.8.1 for current and subsequent cycles.
No more than three dose reductions of idasanutlin or venetoclax are allowed.

If study treatment is withheld for 21 days, permanently discontinue study 
treatment.

Permanently discontinue study treatment if any of the following events occur:
Grade 3 or 4 thrombocytopenia of any duration if associated with Grade ≥ 3
bleeding
Recurrent Grade 3 or 4 neutropenia if associated with fever of 38°C for 
5 days) or a documented infection despite use of G-CSF and after one 
idasanutlin dose reduction and/or one venetoclax dose reduction or reduced 
schedule
Recurrent Grade 4 neutropenia or thrombocytopenia lasting more than 
7 days despite use of G-CSF (for neutropenia) and after one idasanutlin 
dose reduction and/or one venetoclax dose reduction/reduced schedule
For patients who present with recurrent Grade 3
thrombocytopenia/neutropenia in consecutive cycles:
If despite the use of G-CSF, for subsequent cycles, modify the venetoclax 
dose by reducing to next dose level or decrease the dosing schedule; reduce 
idasanutlin to the next dose level (see guidelines in Section 5.1.8.1).
For patients who have had reductions in three doses (either as single drug 
dose reduction or double drug reduction in the same time) or for patients 
who reach the lowest dose level and no further dose reduction is applicable
(see Section 5.1.8):

Permanently discontinue study treatment.
G-CSFgranulocyte colony-stimulating factor.
a Treatment delays apply to all toxicities; dose modifications apply only to toxicities that are 
considered to be related to any of the study treatment components.  
b If cytopenia is thought to be caused mainly by B-cell lymphoma infiltration of the bone marrow, 
the investigator may decide not to reduce idasanutlin or venetoclax doses.


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Table 17 Guidelines for Management of Hematologic Toxicities That Occur 
on Days 8 and 15 of Cycle 1
Event
Action to Be Taken
Febrile 
neutropenia or 
neutropenia with 
infection

Withhold obinutuzumab and venetoclax until resolution of fever and 
infection (as applicable) and resume at the next scheduled dose.

If the patient has not already initiated G-CSF, initiate prophylactic 
G-CSF for current and subsequent cycles. b

If the dose on Day 8 of Cycle 1 is delayed by 2 days, Day 15 of Cycle 1 
should be delayed by the same number of days to retain the treatment 
interval for obinutuzumab.

If the dose on Day 8 of Cycle 1 is delayed by 2 days, omit the Day 8 
dose and administer the Day 15 dose as previously scheduled (if infection 
or neutropenic fever have resolved).

If the dose on Day 15 of Cycle 1 is delayed by 2 days, omit the Day 15 
dose and administer the next dose (Day 1 of Cycle 2) of obinutuzumab, 
venetoclax, and idasanutlin as scheduled (if infection or neutropenic fever 
has resolved). 

If the event is ongoing on Day 1 of Cycle 2, follow the instructions in 
Table 18.
Note:  Obinutuzumab and venetoclax should not be withheld for 
asymptomatic neutropenia.
Severe 
thrombocytopenia a
or symptomatic 
bleeding
(irrespective of 
platelet count)

Withhold obinutuzumab and venetoclax until platelet count is 
50,000 cells/L with resolution of bleeding and resume at the next 
scheduled dose.

Consider prophylactic or therapeutic platelet transfusion as appropriate

In patients with HLA sensitization, HLA-compatible platelet transfusions 
should be administered.

If the dose on Day 8 of Cycle 1 is delayed by 2 days, Day 15 of Cycle 1 
should be delayed by the same number of days to retain the treatment 
interval for obinutuzumab.

If the dose on Day 8 of Cycle 1 dose is delayed by 2 days, omit the Day 
8 dose and administer the Day 15 dose as previously scheduled (if severe 
thrombocytopenia and/or symptomatic bleeding have resolved). 

If the dose on Day 15 of Cycle 1 is delayed by 2 days, omit the Day 15 
dose and administer the next dose (Day 1 of Cycle 2) of obinutuzumab, 
venetoclax, and idasanutlin as scheduled (if severe thrombocytopenia 
and/or symptomatic bleeding have resolved).

If the event is ongoing at Day 1 of Cycle 2, follow instructions in Table 18.
G-CSF granulocyte colony-stimulating factor; HLAhuman leukocyte antigen; 
QDonce a day.
a Severe thrombocytopenia is defined as a platelet count 10,000 cells/L for patients who are 
not receiving concomitant anticoagulants or platelet inhibitors and 20,000 cells/L for patients 
who are receiving concomitant aspirin.
b In the dose-escalation phase, prophylactic G-CSF should start after Cycle 2.
Non-Hematologic Toxicities during Induction Treatment
Guidelines for management of non-hematologic toxicities that occur during induction 
treatment are presented in Table 18.


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Table 18 Guidelines for Management of Non-Hematologic Toxicities
Event
Action to Be Taken
General guidance for 
treatment delays,
discontinuation, and 
resumption

If study treatment is withheld for 21 days because of a toxicity that is attributable to study treatment, permanently 
discontinue study treatment.

Permanently discontinue study treatment for Grade 4 events.

When a treatment cycle is delayed because of toxicity resulting from any component of the regimen, all study 
treatment should be held and resumed together to remain synchronized. 

Dosing may be resumed after resolution to Grade 1 or baseline status.  Resumption of dosing without complete 
resolution of toxicity may be considered in special circumstances after having obtained Medical Monitor agreement.
IRRs and anaphylaxis

Guidelines for the management of IRRs are provided in Section 5.1.1.1.  In case of Grade 4 IRRs or anaphylaxis, 
study treatment should be permanently discontinued.
Clinical and laboratory 
TLS
Grade 4 events:

Permanently discontinue study treatment in the case of Grade 4 events.
Grade 3 events:

Withhold study treatment. a

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including 
dialysis as indicated.

If symptoms (laboratory and clinical) have resolved completely, resume obinutuzumab or rituximab at full dose and 
resume venetoclax and idasanutlin at current dose.
New-onset neurologic 
manifestations 
suggestive of PML

Withhold study treatment. a

Consult with a neurologist if PML is suspected (refer to Section 5.1.1.5 for guidance on investigations).

If PML is ruled out, resume obinutuzumab or rituximab at the full dose and resume idasanutlin and venetoclax at the 
current dose. 

If PML is confirmed, permanently discontinue study treatment. 


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Table 18 Guidelines for Management of Non-Hematologic Toxicities (cont.)
AST, ALT, or bilirubin 
increase:
Grade 4 events: 

Permanently discontinue study treatment in the case of Grade 4 events.
Grade 2 or 3 events (or 10 ULN for patients with liver involvement):

Withhold study treatment. a

If improvement to Grade 1 (or 5 ULN (Grade 2) for patients with liver involvement), resume obinutuzumab or 
rituximab and idasanutlin at full dose and resume venetoclax at next lower dose a for current and subsequent cycles 
per guidelines in Section 5.1.8.  No more than three dose reductions of venetoclax are allowed.  Patients who have 
had three prior dose reductions of venetoclax and/or idasanutlin should be permanently discontinued.  Permanently 
discontinue study treatment for life-threatening liver toxicity (including Hy’sLaw cases).
Diarrhea
Grade 4 diarrhea: permanently discontinue study treatment.
IRRinfusion-related reaction; PMLprogressive multifocal leukoencephalopathy; ULNupper limit normal.
a Treatment delays apply to all events; dose modifications apply only to events that are considered to be related to any of the study treatment 
components.
b Clinical judgment should prevail, reserved for events having a significant effect on a patient’s clinical situation, and upon consultation with the 
Medical Monitor.


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Table 18 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Diarrhea (cont.)
Grade 2 or 3 diarrhea:

If Grade 3 diarrhea occurs between Days 1 and 5 of the treatment cycle, withhold study treatment only if 
diarrhea does not improve to Grade 2 within 48 hours with appropriate treatment.  After the study 
treatment is withheld, if diarrhea improves to Grade 2, resume obinutuzumab or rituximab at the full dose 
and resume idasanutlin and venetoclax at a reduced dose according to guidelines in Sections 5.1.8.1 and 
5.1.8.2 for current and subsequent cycles.

If Grade 3 diarrhea is present at the time of the next planned cycle, withhold study treatment.  If diarrhea 
improves to Grade 2, resume obinutuzumab or rituximab at full dose and resume idasanutlin and 
venetoclax at a reduced dose according to guidelines in Sections 5.1.8.1 and 5.1.8.2 for current and 
subsequent cycles.
Management for diarrhea:

Rule out other or concomitant causes, including, but not limited to, medications, Clostridium difficile
infection, malabsorption/lactose intolerance, fecal impaction, and dietary supplements high in fiber.

Initiate treatment at the time of onset.

Administer loperamide 4 mg as loading dose; and up to 2 mg every 4 hours or after every unformed stool 
(for a maximum daily dose of 16 mg), or per institutional standard. 

For subsequent episodes, use 4 mg QD prophylactic loperamide 30 minutes before subsequent dosing.  If 
diarrhea persists after 48 hours despite administration of the maximum recommended daily loperamide 
dose (16 mg/24 hr), second-line agents may be considered (diphenoxylate, atropine, octreotide, 
budesonide, or tincture of opium).
Encourage patients to hydrate abundantly and self-medicate with loperamide 2 mg in the event that 
diarrhea recurs (up to 2 mg every 4 hours or after every unformed stool for a maximum daily dose of 
16 mg), or per institutional standard.

Monitor electrolyte levels closely and correct as appropriate.

Administer IV fluids as clinically indicated.

Upon presentation of Grade 3 diarrhea or diarrhea persists for 24 hours despite maximum recommended 
daily loperamide dose, exclude presence of active infections (e.g., C difficile).  If present, treat infection(s),
according to local guidelines.
IRRinfusion-related reaction; PMLprogressive multifocal leukoencephalopathy; ULNupper limit normal.
a Treatment delays apply to all events; dose modifications apply only to events that are considered to be related to any of the study treatment 
components.
b Clinical judgment should prevail, reserved for events having a significant effect on a patient’s clinical situation, and upon consultation with the 
Medical Monitor.


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Table 18 Guidelines for Management of Non-Hematologic Toxicities (cont.)
Event
Action to Be Taken
Nausea and vomiting
Grade 4 vomiting:

Permanently discontinue study treatment.
Grade 1, 2, or 3 vomiting or nausea:

Consider prophylaxis with second-generation anti-emetics like palonosetron, ondansetron, or granisetron.

If vomiting occurs within 15 minutes of taking idasanutlin and/or venetoclax, and all expelled tablets are still 
intact, another dose may be given and the second dose noted in the drug log.  Otherwise, no replacement 
dose is to be given (see Sections 5.1.8.1 and 5.1.8.2).
Dermatologic toxicity
Permanently discontinue rituximab in the event of Stevens-Johnson syndrome or toxic epidermal necrolysis.
Other non-
hematologic 
toxicities (i.e., not 
described above), 
excluding alopecia 
Grade 3 or 4 Grade 4 events

Permanently discontinue study treatment.
Grade 3 events

Withhold study treatment. a
If improvement to Grade1 or baseline, resume obinutuzumab or rituximab at the full dose and resume 
idasanutlin and venetoclax at reduced (Section 5.1.8) dose a for subsequent cycles.  No more than three 
dose reductions of idasanutlin or venetoclax are allowed.
For patients who have had three prior dose reductions (either as a single drug dose reduction or double 
drug reduction in the same time) or for patients who reach the lowest dose level and no further dose 
reduction is applicable (See Section 5.1.8):

Permanently discontinue study treatment.
Grade 2

Withhold study treatment. a, b

If improvement to Grade1 or baseline, resume obinutuzumab or rituximab at the full dose and resume 
idasanutlin and venetoclax at the current dose.
IRRinfusion-related reaction; PMLprogressive multifocal leukoencephalopathy; ULNupper limit normal.
a Treatment delays apply to all events; dose modifications apply only to events that are considered to be related to any of the study treatment 
components.  Toxicities that occur during the cycle and subside prior to the next cycle should not trigger the suggested dose modifications. 
b Clinical judgment should prevail, reserved for events having a significant effect on a patient’s clinical situation, and upon consultation with the 
Medical Monitor.


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5.1.8.2
Toxicities during Maintenance or Consolidation Treatment
Guidelines for management of toxicities that occur during maintenance or consolidation 
treatment are presented in Table 19.
Table 19 Guidelines for Management of Toxicities That Occur during 
Maintenance or Consolidation Treatment
Event
Action to Be Taken
Hematologic toxicity:
Grade 3 or 4

Withhold study treatment.

Administer myeloid growth factors for neutropenia as allowed 
according to institutional guidelines.

Administer RBCs or platelets as required.

If improvement to Grade 2, resume obinutuzumab or rituximab at 
full dose and resume venetoclax at next lower dose for subsequent 
cycles per guideline in Section 5.1.8.  Patients who are not eligible 
for further venetoclax dose reductions should be permanently 
discontinued.

If study treatment is withheld for 42 days, permanently 
discontinue study treatment.

Withdraw venetoclax and idasanutlin in case of recurrent episodes 
of Grade3 thrombocytopenia and/or neutropenia. 
Non-hematologic toxicity:
Grade 2

Withhold study treatment.

If improvement to Grade 1 or baseline, resume obinutuzumab or 
rituximab at full dose and resume venetoclax at the next lower dose 
for subsequent cycles per guideline in Section 5.1.8.  Patients who 
are not eligible for further venetoclax and/or idasanutlin dose 
reductions should be permanently discontinued.

If study treatment is withheld for 42 days, permanently 
discontinue study treatment.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present 
at baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment

Is a significant medical event in the investigator’s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).


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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study treatment, as defined 
below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of any of the study treatment components is suspected.

TLS of any grade, irrespective of causality

Grade 3 neutropenia, including febrile neutropenia

Grade 3 thrombocytopenia or Grade 2 thrombocytopenia if associated with 
hemorrhage or bleeding)

Grade 2 diarrhea

Grade 2 C. difficile infection 

Second malignancies
5.2.4
Selected Adverse Events
Selected adverse events in this study are defined as adverse events for which additional 
data collection or analyses will be performed. Selected adverse events do not require 
immediate reporting if they are not serious or meet the adverse events of special interest 
definition (see Section 5.2.3).
The following adverse events are considered selected adverse events:

Thrombocytopenia, including acute thrombocytopenia (events occurring during and 
within 24 hours following an obinutuzumab infusion)


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
Hepatitis B reactivation

Cardiac events

TLS

IRRs

All infections, including PML

Neutropenia, including prolonged neutropenia (neutropenia 1000 cells/L that 
does not resolve after 28 days without obinutuzumab treatment) and late-onset 
neutropenia (neutropenia 1000 cells/L occurring 28 days after obinutuzumab 
treatment has been completed or stopped) 

GI perforation
Events for which additional data collection will be required are PML and hepatitis B 
reactivation.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 90 days 
after the last dose of study treatment, and Grade 3 or 4 infections (related and unrelated)
in patients who received obinutuzumab will continue to be reported until up to 2 years 
after the last dose of obinutuzumab.  
Second malignancies will be recorded indefinitely for patients who received 
obinutuzumab (even if the study has been closed) (see Section 5.6).


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 20 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 20 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 


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adverse event is considered to be related to any of the study treatment components, 
indicating “yes” or “no” accordingly.  The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study treatment

Course of the event, with special consideration of the effects of study treatment 
modifications or discontinuation, or reintroduction of study treatment (as applicable)

Known association of the event with the study treatment or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after the end of study treatment 
infusion and are judged to be related to infusion of any of the study treatment 
components should be captured as a diagnosis (e.g., “infusion-related reaction”) on the 
Adverse Event eCRF.  If possible, avoid ambiguous terms such as “systemic reaction.”  
Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF.  If a patient experiences both a local and systemic reaction to the same 
dose of study treatment, each reaction should be recorded separately on the Adverse 
Event eCRF, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 


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report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from “non-serious” 
to “serious,” providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range (e.g., 
“elevated potassium,” as opposed to “abnormal potassium”).  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of lymphoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An IMC will monitor the 
frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 


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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
5.3.5.10
Lack of Efficacy or Worsening of Lymphoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on the modified Lugano 2014 criteria (see Appendix 4).  In 
rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration) 
This includes planned hospitalization for TLS prophylaxis and monitoring (i.e., 
on Day 1 of Cycle 1 hospitalization)


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in 
Treatment Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event (see Section 5.4.4).  
Additionally, all adverse events associated with an overdose or incorrect administration 
of study treatment should be recorded on the Adverse Event eCRF.  If the associated 
adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
No experience with overdose is available from human clinical trials. In clinical trials with 
obinutuzumab doses ranging from 50 mg up to and including 2000 mg per infusion have
been administered. The incidence and intensity of adverse reactions reported in these 
studies did not appear to be dose dependent.
Limited experience with doses higher than the approved IV doses of rituximab is 
available from clinical trials in humans. The highest IV dose tested in humans is 5000
mg (2250 mg/m2). No additional safety signals were identified.
Patients who experience overdose should have immediate interruption or reduction of 
their infusion and should be closely supervised.  Consideration should be given to the 
need for regular monitoring of blood cell count and for increased risk of infections while 
patients are B cell depleted.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 


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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to any of the study treatments:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

DLTs (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for 
details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D. (Primary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 


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to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Treatment Initiation
After initiation of study treatment, all adverse events will be reported until 90 days after 
the last dose of study treatment.  DLTs will be reported during the DLT assessment 
window. Investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit 
the report via the electronic data capture (EDC) system.  A report will be generated and 
sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 18 months after the last 
dose of study treatment for those treated with obinutuzumab, idasanutlin, and 
venetoclax and within 12 months after the last dose of study treatment for those treated 
with rituximab, idasanutlin, and venetoclax.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  


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5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study treatment.  A Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study treatment.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  After the 
authorization has been signed, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is 
higher than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.


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
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
idasanutlin, obinutuzumab or rituximab, and venetoclax, adverse events associated 
with special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with idasanutlin, obinutuzumab or 
rituximab, and venetoclax, regardless of whether they result in an adverse event, should 
be recorded on the Adverse Event eCRF and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event).  Special situations should be 
recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.


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
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug 
misuse" box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.


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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow-up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 90 days after the last 
dose of study drug), all deaths, regardless of cause, should be reported on the 
Long-Term Survival Follow-Up eCRF.  Grade 3 and 4 infections (related and unrelated) 
in patients who received obinutuzumab should be reported on the Adverse Event eCRF 
until up to 2 years after the last dose of obinutuzumab.  In addition, if the investigator 
becomes aware of a serious adverse event that is believed to be related to prior study 
treatment, the event should be reported through use of the Adverse Event eCRF. The 
sponsor should also be notified of events of second malignancies indefinitely (even if the 
study has been closed) for patients who received obinutuzumab.
The investigator should report any other events (excluding related serious adverse 
events 90 days after the last dose of study treatment if the investigator becomes aware 
of any event and Grade 3 and 4 infections, independently of causality, for 2 years) 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number or email address provided to investigators.
During survival follow-up, deaths attributed to progression of lymphoma should be 
recorded only on the Study Completion/Early Discontinuation eCRF.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Obinutuzumab Investigator’s Brochure

Rituximab IV Oncology Investigator’s Brochure

Idasanutlin Investigator’s Brochure

Venetoclax Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Study data will be summarized separately for dose escalation and expansion phase.  
Data from the dose-escalation phase will be summarized by dose level and regimen. 
Data from the expansion phase will be summarized by histologic subtype (i.e., FL or 
DLBCL).
6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Dose Escalation
Dose finding will be conducted during the dose-escalation phase of this study. The 
estimated sample size follows from the dose-escalation rules for a mCRM with over 
dose control (Thall et al. 2003; Neuenschwander et al. 2015). It is anticipated that 
enrollment of up to eight cohorts of 36 patients each, for a total of 960 patients, will be 
required to meet the Part 1 study objective. This number is an approximation based 
upon assumptions and experience from other similar dose-finding studies.  More details 
on the dose-escalation design and its operating characteristics are given in 
Section 3.1.2.3 and Appendix 6.  The estimated probability to require more than 
50 patients in the investigated scenarios in the protocol is generally 5%.
6.1.2
Expansion Cohorts
Approximately 80 patients (40 patients with FL and 40 patients with DLBCL) will be 
enrolled during the expansion phase.
The primary efficacy analysis for the expansion phase will be estimation of the true 
proportion of patients expected to obtain a PET-defined CR at EOI. A sample size of 
40 patients is deemed sufficient to provide adequate precision for the point estimate and 
for the lower end of the 90% CI to rule out a clinically uninteresting probability of 
response of 40% in FL, and 40% in DLBCL assuming an observed PET-defined CR 
rate of 55%. Table 21 provides 90% Clopper-Pearson exact CIs for the probability of 


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achieving a PET-defined CR at the EOI for a range of observed proportions based on a
sample of 40 patients.
Table 21 Potential 90% CI for the True Probability of Achieving a PET-CT−
Defined Complete Response at End of Induction for n40
Observed Proportion of Patients Achieving a 
PET-CT−Defined CR at EOI
Two-Sided 90% Clopper-Pearson CI a for True 
Population PET-CT−Defined CR
0.32
(0.20, 0.46)
0.50
(0.36, 0.64)
0.55
(0.40. 0.68)
0.60
(0.46, 0.73)
0.65
(0.51, 0.77)
0.70
(0.56, 0.82)
0.72
(0.58, 0.83)
0.75
(0.61, 0.86)
0.80
(0.66, 0.89)
0.85
(0.72, 0.93)
CIconfidence interval; CR complete response; CT computed tomography; EOI end of 
induction; PET positron emission tomography.
a Note that the lower limit of a two-sided 90% CI is equivalent to a one-sided 95% CI limit.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol violations, and discontinuations from the study will be listed.  
The incidence of treatment discontinuation for reasons other than disease progression 
will be tabulated.  
Data related to the administration of study treatment components will be listed, and any 
dose modifications will be flagged.  The number of doses, treatment cycles, average 
dose received, and relative dose intensity for each treatment component will be 
summarized using descriptive statistics (mean, standard deviation, median, and range).
6.3
SUMMARIES OF DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS
Demographic and baseline characteristics, such as age, sex, race, and duration of 
malignancy, will be summarized using descriptive statistics (mean, standard deviation, 
median, and range) for continuous variables and frequencies and percentages for 
categorical variables.
6.4
SAFETY ANALYSES
The primary safety objectives are to determine the RP2D dose of idasanutlin and 
venetoclax in combination with obinutuzumab or rituximab during the dose-escalation 


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phase and to evaluate the safety and tolerability of the triplet combination across all 
phases of the study.  
The safety analysis population will include all patients who have received at least one 
dose of any component of the combination, whether patients are prematurely withdrawn 
from the study or not. All safety parameters will be summarized and presented in tables 
based on this safety population. 
All adverse events occurring on or after the first dose of study treatment will be 
summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade.  
All serious adverse events, adverse events of special interest, and selected adverse 
events will be summarized and listed.  
Deaths reported during the treatment period and during post-treatment follow-up will 
be listed.
Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, and blood
pressure) data will be displayed by time, with Grade 3 and 4 values identified as 
appropriate.
6.5
EFFICACY ANALYSES
The primary and secondary efficacy analyses will be performed and will include all 
patients enrolled in the expansion phase who receive one dose of any component of the 
combination.  Data from patients who were dosed at the RP2D and selected regimen
during the dose-escalation phase may be pooled with the corresponding arm of the 
expansion phase, depending on their indication.
Response will be determined on the basis of PET-CT scans or CT scans alone, using 
the modified Lugano 2014 criteria (see Appendix 4).
6.5.1
Primary Efficacy Endpoint
The primary efficacy analysis will be estimation of the proportion of patients achieving a 
CR at EOI, as determined by the IRC through use of the PET-CTbased modified
Lugano 2014 criteria.  Point estimates will be presented, along with the corresponding 
two-sided 90% Clopper-Pearson exact CIs, for the proportion of patients who achieve a 
CR at the EOI.  Patients without a post-baseline tumor assessment will be considered 
non-responders.
6.5.2
Secondary Efficacy Endpoints
The secondary efficacy analyses will be estimation of the proportion of patients 
achieving each of the following endpoints: 

CR at the EOI, as determined by the investigator on the basis of PET-CT scans


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
CR at the EOI, as determined by the IRC and by the investigator on the basis of 
CT scans alone

Objective response (defined as a CR or PR) at the EOI, as determined by the IRC 
and by the investigator on the basis of PET-CT scans

Objective response (defined as a CR or PR) at the EOI, as determined by the IRC 
and by the investigator on the basis of CT scans alone

Best response of CR or PR during the study, as determined by the investigator on 
the basis of CT scans alone
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs.  Patients without a post-baseline tumor assessment will be 
considered non-responders.
6.5.3
Exploratory Efficacy Endpoints
Exploratory efficacy analyses will include an estimation of the proportion of patients 
achieving the following endpoint:

For patients who have positive PET scans at EOI:  
CR at 12 months, as determined by the IRC and by the investigator on the 
basis of PET-CT scans in patients with FL 
CR at EOC, as determined by the IRC and by the investigator on the basis 
of PET-CT scans, in patients with DLBCL 
Additional descriptive analysis based on TP53 mutation status will be performed on the 
following endpoint:

CR at the EOI, as determined by the IRC on the basis of PET-CT scans
Point estimates will be presented, along with the corresponding two-sided 90% Clopper-
Pearson exact CIs. Patients without a post-baseline tumor assessment will be
considered non-responders.
Exploratory efficacy analyses will also be performed on the following endpoints (see 
definitions in Section 2.2.3):

PFS

EFS

DFS

OS
PFS, EFS, DFS, and OS will be summarized descriptively using the Kaplan-Meier 
method (Kaplan and Meier 1958).  For the PFS, EFS, and DFS analyses, data for 
patients without an event of interest will be censored at the date of the last tumor 
assessment.  For patients without post-baseline tumor assessments, data will be 
censored at the date of initiation of study treatment plus 1.  For the OS analysis, data for 


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patients who have not died will be censored at the date the patient was last known to be 
alive.  When medians are reached, the corresponding estimated median will be provided, 
along with the 95% CI using the method of Brookmeyer and Crowley (1982).  In addition, 
estimates of the proportion of patients who are event free at 6 months, 9 months, 1 year, 
and 2 years will be provided, along with 95% asymptotic CIs using Greenwood’s formula 
for standard errors. 
6.6
PHARMACOKINETIC ANALYSES
The PK analyses will include patients with sufficient data to enable estimation of key 
parameters (e.g., AUC, time to maximum concentration [tmax], Cmax, and half-life), with 
patients grouped according to treatment received. 
Serum concentrations of obinutuzumab or rituximab, or plasma concentrations of 
idasanutlin or venetoclax will be tabulated, summarized, and plotted after appropriate 
grouping.  As appropriate, PK parameters (e.g., AUC, tmax, Cmax, and half-life) may also 
be calculated, tabulated, and summarized after appropriate grouping.  Additional PK and 
PK/PD analyses (e.g., population modeling that includes pooled analyses across studies) 
may also be performed as appropriate.  If performed, these additional analyses may be 
reported separately from the CSR.  At the discretion of the Sponsor, all analyses may be 
extended to include relevant biotransformation products of idasanutlin and/or venetoclax.
6.7
BIOMARKER ANALYSES
Exploratory analyses of biomarkers related to tumor biology and study treatment 
mechanisms of action will be conducted.  Analyses will assess the prognostic and/or 
predictive value of candidate biomarkers with respect to both IRC- and investigator-
assessed outcomes.  Specifically, the association between candidate biomarkers and 
PET-CTdefined CR rate and OR rate, and potentially other measures of efficacy and 
safety, will be explored to assess potential prognostic or predictive value.  These 
analyses may not be included in the final study report because of their exploratory 
nature.  In addition to analysis in the context of this study, data will also be explored in 
aggregate with data from other studies.
6.8
INTERIM ANALYSES
During the expansion phase, predictive probabilities may be used to guide early stopping 
for futility by comparing the observed proportion of patients who achieve a PET-
CTdefined CR at EOI with that in historical controls. The design is based on Lee and 
Liu (2008), with the modification that the uncertainty in historical control data is fully 
taken into account by utilizing a distribution on the control response rate. Interim 
analysis decision rules will be based on the predictive probability that this trial will a 
positive outcome if carried out to completion and will use the historical control data 
available at the time of analysis.


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It is anticipated that least one interim analysis per disease indication will be conducted 
during the expansion phase of the study, with the earliest interim analysis taking place 
when at least 15 patients treated have been evaluated for a PET-CTdefined CR at EOI. 
If, at any interim analysis, a low predictive probability suggests that the proportion of 
patients achieving a PET-CTdefined CR at EOI is lower than desired, the IMC will 
review the data and decide whether to recommend an early decision to stop enrollment. 
Additional review of safety and/or efficacy data by the IMC may be requested by and 
carried out at the discretion of the Medical Monitor. Further details regarding the rules 
and guidelines of data will be provided in an IMC charter.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.


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7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If the original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 


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relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the “Consent Forms”) 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient’s agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last 
visit).
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Roche.
An EDC system will be used for this study.  An IxRS will be used to assign patient 
numbers.  A central laboratory will be used for a subset of laboratory assessments as 
specified in Section 4.5.6; otherwise, local laboratories will be used.  A central IRF will 
be used to collect PET-CT and CT scans, and the IRC will perform independent 
assessments of response for all patients enrolled in the study (a separate IRC charter 
will contain all details).  Data from this study will be shared with an expert scientific 
committee that will provide scientific input for the benefitrisk assessment.
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pd
f
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR.  In addition, for all clinical trials in patients involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 


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the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
174/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
Assessment/Procedure
Screening a
Induction (Six 28-Day Cycles)
EOI
Maintenance
(24 Months)d
EOM b
Post-Tx
Follow-
Up 
Period
(Q3M) e
Survival
Follow-
Up 
Period
(Q3M) e
Days 
−28
to −1
Days 
−14
to −1
Cycle 1
(1 day)
Cycle 2
(2 days)
Cycles
36
(2 days)
After 
Last
Induction
Dose c
35 Days
after 
Last
Dose
D
1
D
5
D
8
D
15
D
1
D
15
D
1
D
15
2 microglobulin
x
Hematology p
x
x q,r
x r
x r
x r
x
x r
x
x h
x i
x
Serum chemistry s
x
x q,r
x r
x r
x r
x
x r
x
x h
x i
x
Coagulation (INR, aPTT 
[or PTT], and PT)
x
Pregnancy test t
x
x h
x
Hepatitis B and C, 
testing u
x
Quantitative IgA, IgG, 
and IgM
x
x
x v
x
x w
PK sample for 
obinutuzumab
x x
PK sample for 
idasanutlin
x x
PK sample for 
venetoclax
x x
Exploratory biomarker 
samples
x x


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
175/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
Assessment/Procedure
Screening a
Induction (6 Cycles; 28-Day Cycles)
EOI
Maintenance
(24 Months)d
EOM b
Post-Tx
Follow-Up 
Period
(Q3M) e
Survival 
Follow-
Up 
Period
(Q3M) e
Days 
−28
to −1
Days 
−14
to −1
Cycle 1
(1 day)
Cycle 2
(2 days)
Cycles
36
(2 days)
After 
Last
Induction
Dose c
35 Days
after 
Last
Dose
D
1
D
5
D
8
D
15
D
1
D
15
D
1
D
15
Blood for MRD y
x r
x
x
x v
x
Blood for lymphocyte
immunophenotyping z
x r
x r
x r
x r
x
x v
x
x w
Optional serum for 
RBR aa
x
x
Tumor tissue specimen 
(remaining tissue may 
be used for optional
RBR specimen bb)
x bb
x cc
Concomitant 
medications
x
To be recorded continually until end of treatment
Adverse events dd
x
To be assessed continualy dd
PET-CT scan
x ee
x ff
x gg
CT scan hh
x hh
x ii
x ff
x jj
x kk
x ll
Bone marrow biopsy
and aspirate
x mm
x ff, nn
x nn
x kk, nn
New anti-lymphoma 
treatment
x
x
Survival follow-up
x


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
176/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
BSAbody surface area; CT computed tomography; Dday; DLBCLdiffuse large B-cell lymphoma; ECGelectrocardiogram;
ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; EOIend of induction; EOMend of 
maintenance; FLfollicular lymphoma; FLIPI (2)Follicular Lymphoma International Prognostic Index (2); MRD minimal residual disease; 
MRImagnetic resonance imaging; MUGAmultigated acquisition; PET positron emission tomography; PKpharmacokinetic; Q3Mevery 3 months; 
RBRRoche Biosample Repository; TLStumor lysis syndrome; Txtreatment.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Assessments shaded in gray should 
be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an adverse event).
a The screening period starts with the signing of the Informed Consent Form, including the optional Informed Consent Form if appropriate.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be used as screening and 
baseline assessments; such tests do not need to be repeated for screening purposes.
b Patients who complete maintenance treatment or discontinue maintenance treatment prematurely will undergo assessments at the EOM. 
c EOI assessments should be performed 68 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue induction 
treatment prematurely because of an adverse event may undergo EOI assessments 48 weeks after their last dose of study treatment.
d Maintenance treatment should start 8 weeks (1 week) after Day 1 of the final cycle of induction and will continue until disease progression or 
unacceptable toxicity for up to 2 years.
e Patients who complete treatment or discontinue treatment for reasons other than disease progression will undergo assessments every 3 months during 
the post-treatment FU period, which will continue until disease progression, the start of new anti-lymphoma treatment, or the end of the study, 
whichever occurs first.  The first post-treatment FU visit is 3 months after the EOI visit for patients who do not receive maintenance treatment and 
3 months after the last dose for patients who receive maintenance treatment.  Patients who experience disease progression or start another 
anti-lymphoma treatment will be evaluated for survival status and new anti-lymphoma treatment every 3 months during the survival follow-up period, 
which will continue until the end of the study.  The end of the study is defined as the time when all enrolled FL patients have completed or discontinued 
study treatment and all enrolled DLBCL patients have been followed for at least 1 year after they have completed or discontinued study treatment.
f
Informed consent must be documented before any study-specific screening procedure is performed.
g Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a seated position.  
For obinutuzumab infusions:  For the first cycle and for patients who experience an infusion-related reaction, vital signs will be measured prior to the 
infusion, every 15 (5) minutes for the first 90 minutes of the infusion, and then every 30 (10) minutes until 1 hour after completion of the infusion.  
For the second and subsequent cycles, vital signs will be measured every 30 minutes during the infusion, except for patients who have experienced an 
infusion-related reaction during a prior infusion.  For venetoclax, serial vital signs will be measured and TLS laboratory samples will be drawn (serum 
chemistry as defined in Section 4.5.6) prior to the first dose of venetoclax and 8, 12, and 24 hour post-dose.
h Perform only for patients who will not be receiving maintenance treatment.


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
177/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
i
Vital signs will be measured, a targeted physical examination will be performed, and hematology and serum chemistry will be assessed during 
maintenance every 2 weeks during the first month, every month until Month 6, and every 2 months thereafter.
j
All ECGs should be performed within 2 hours prior to idasanutlin administration and either 6 hours after idasanutlin administration or immediately after 
obinutuzumab administration, whichever occurs later.  ECGs will be performed in triplicate on Days 1 and 5 of Cycles 1 and 4 in the induction phase. 
However, on Day 5 of Cycles 1 and 4 in the induction phase, the postdose ECG should be performed only if the patient is still at the clinic.  
k Perform MUGA or echocardiogram at screening (Day 28 to Day 1), on Day 1, Cycle 4, at the EOI, the EOM, and as clinically indicated.
l
Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems. Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.
m As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable hepatomegaly, and 
splenomegaly.  This information will be recorded on the appropriate tumor assessment eCRF.
n Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
o Unexplained fever 38°C, night sweats, unexplained weight loss 10% of body weight over 6 months.
p Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, and other cells).
q Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 24 hours prior to Day 1 of Cycle 1.  Additional hematology and 
serum chemistry samples must be drawn 04 hours pre-dose and 8 and 24 hours post-dose on Day 1 of Cycle 1 to monitor for TLS. Note that the
24-hour post-dose sample will be obtained on Day 2 of Cycle 1.
r
Perform hematology and serum chemistry tests within 72 hours prior to Day 1 of each cycle and within 24 hours prior to Days 8 and 15 of Cycle 1.  
Samples for exploratory biomarker research should be collected at the same time as hematology and serum chemistry samples.
s Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, total protein, 
albumin, ALT, AST, alkaline phosphatase, amylase, lipase, LDH, and uric acid.
t
All women who are not post-menopausal (12 months of nontherapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test at 
screening within 7 days prior to Day 1 of Cycle 1.  Because of the suspected effect of idasanutlin or venetoclax on embryofetal development, monthly 
pregnancy testing is strongly recommended for women of childbearing potential.
u Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.
v Perform at the same time as tumor assessments at 12, 18, and 24 months after initiation of induction treatment.
w Perform every 3 months until recovery to either normal range or baseline level, disease progression, or the start of new anti-lymphoma treatment, 
whichever occurs first.


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
178/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
x Refer to Appendix 3 for detailed schedule.
y Includes circulating lymphoma cells and/or cell-free circulating-tumor DNA.
z Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and natural killer cell counts (CD16 and CD56).
aa Requires separate patient consent for RBR participation.  Not applicable for a site that has not been granted approval for RBR sampling.
bb Availability of adequate archival or freshly biopsied tumor tissue samples should be confirmed at screening (see Section 4.5.6 for details).
cc A tumor biopsy sample is preferred and recommended at the time of progression unless no adequate tumor site is accessible.
dd After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days after the last dose of study 
treatment. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment (see Section 5.6).  An exception is made for Grade 3 and 4 infections (related and unrelated) in patients who received 
obinutuzumab, which should be reported until up to 2 years after the last dose of study treatment.  The investigator should follow each adverse event 
until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient 
withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to any of the study treatment 
components or trial-related procedures until a final outcome can be reported.
ee The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1.
ff Perform only for patients who receive at least two cycles of induction treatment.
gg If PET-CT scan is positive at the EOI, perform 12 months after initiation of induction treatment, within 14 days prior to study treatment administration.
hh CT scan of the neck (if clinically indicated), chest, abdomen and pelvis.  If contrast is medically contraindicated (e.g., patients with contrast allergy or 
impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a non-contrast CT scan of the chest may 
be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans but only according to the technical guidelines in the imaging 
manual.  Screening CT scan must be performed within 35 days prior to Day 1 of Cycle 1.
ii Perform within 7 days prior to Day 1 of Cycle 3.
jj Perform 12, 18, and 24 months after initiation of induction treatment, within 14 days prior to treatment administration.
kk Perform only if not done within the previous 3 months.
ll Perform every 6 months.
mmBone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1.
nn For patients with bone marrow involvement at screening, a repeat assessment will be performed at the EOI, during maintenance, or at the EOM
whenever there is radiologic evidence of a complete response or if clinically indicated (e.g., if there is clinical suspicion of progressive disease in the 
bone marrow with no radiologic evidence of progression).  Additional bone marrow assessments may be performed at the discretion of the investigator.


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
179/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
Study Treatment Administration: Dose Escalation before the Bridging Cohorts (Regimen A)
Study Treatment
Induction (Six 28-Day Cycles)
Maintenance
Every 2 Months a
Cycle 1 (1 day)
Cycles 26 (2 days)
Day 1
Day 5
Day 8
Day 10
Day 15
Day 1
Day 5
Day 10
Day 1
Day 5
Day 10
Obinutuzumab b
(1000 mg IV)
x
x
x
x
x
Idasanutlin b
(PO QD)
Days 15
Days 15
TBD c
Venetoclax b
(PO QD)
Days 15 or Days 110 d
Days 15 or Days 110 d
TBD c
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; POby mouth; QDonce a day; TBDto be determined.
a Total duration of maintenance is 24 months for obinutuzumab and 6 months for idasanutlin and venetoclax.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c Regimen will be defined based on available safety, tolerability, PK, and PD data.
d Regimen is defined according to the dose-escalation plan (see Section 3.1.2).


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
180/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
Study Treatment Administration: Dose Escalation for the Bridging Cohorts (Regimen B)
Study Treatment
Induction (Six 28-Day Cycles)
Maintenance
Every 2 Months a
Cycle 1 (1 day)
Cycles 26 (2 days)
Day 1
Day 5
Day 8
Day 10
Day 15
Day 1
Day 5
Day 10
Day 1
Day 5
Day 10
Obinutuzumab b
(1000 mg IV)
x
x
x
x
x
Idasanutlin b
(PO QD)
Days 15
TBD c
Venetoclax b
(PO QD)
Days 15 or Days 110 d
TBD c
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; PO by mouth; QDonce a day; TBDto be determined.
a Total duration of maintenance is 24 months for obinutuzumab and 6 months for idasanutlin and venetoclax.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c Regimen will be defined based on available safety, tolerability, PK, and PD data.
d Regimen is defined according to the dose-escalation plan (see Section 3.1.2).


Obinutuzumab or Rituximab, Idansanutlin, Venetoclax—F. Hoffmann-La Roche Ltd
181/Protocol BH39147, Version 4
Appendix 1
Schedule of Activities for Patients with Follicular Lymphoma:  
Dose-Escalation and Expansion Phases (cont.)
Study Treatment Administration: Expansion Phase (Regimen A or Regimen B as defined after the 
escalation phase)
Study Treatment
Induction (Six 28-Day Cycles)
Maintenance
Every 2 Months a
Cycle 1 (1 day)
Cycles 26 (2 days)
Day 1
Day 5
Day 8
Day 10
Day 15
Day 1
Day 5
Day 10
Day 1
Day 5
Day 10
Obinutuzumab b
(1000 mg IV)
x
x
x
x
x
Idasanutlin b, c
(PO QD)
Days 15
Days 15
TBD d
Venetoclax b, c
(PO QD)
Days 15 or Days 110 e
Days 15 or Days 110 e
TBD d
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; PO by mouth; QDonce a day; TBDto be determined.
a Total duration of maintenance is 24 months for obinutuzumab and 6 months for idasanutlin and venetoclax.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c May only be given in Cycles 26 if this regimen is chosen.
d Regimen will be defined based on available safety, tolerability, PK, and PD data.
e  Regimen is defined according to the dose-escalation plan (see Section 3.1.2).




Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
183/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
Assessment/Procedure
Screening a
Induction (Six 28-Day Cycles)
EOI
Consol-
idation 
(6 Mo) d
EOC b
Post-Tx
Follow-Up 
Period
(Q3M) e
Survival 
Follow-Up
Period
(Q3M) e
Days 
28
to 1
Days 
14
to 1
Cycle 1
(1 day)
Cycle 2
(2 days)
Cycles
36
(2 days)
After 
Last
Induction
Dose c
35 Days 
after 
Last 
Dose
D
1
D
5
D
8
D
15
D
1
D
15
D
1
D
15
2 microglobulin
x
Hematology p
x
x q, r
x r
x r
x r
x
x r
x
x h
x i
x
Serum chemistry s
x
x q, r
x r
x r,t
x r
x t
x r
x t
x h
x i
x
Coagulation (INR, aPTT 
[or PTT], and PT)
x
Pregnancy test u
x
x h
x
Hepatitis B and C, 
testing v
x
Quantitative IgA, IgG, 
and IgM
x
x
x w
x
x x
PK sample for 
obinutuzumab
x y
PK sample for rituximab
PK sample for 
idasanutlin
x y
PK sample for 
venetoclax
x y
Exploratory biomarker 
sample
x y
Blood for MRD z
x r
x
x
x w
x


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
184/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
Assessment/Procedure
Screening a
Induction (Six 28-Day Cycles)
EOI
Consol-
idation 
(6 Mo) d
EOC b
Post-Tx
Follow-Up 
Period
(Q3M) e
Survial 
Follow-Up
Period
(Q3M) e
Days 
28
to 1
Days 
14
to 1
Cycle 1
(1 day)
Cycle 2
(2 days)
Cycles
36
(2 days)
After 
Last
Induction
Dose c
35 Days 
after 
Last 
Dose
D
1
D
5
D
8
D
15
D
1
D
15
D
1
D
15
Blood for lymphocyte 
immunophenotyping aa
x r
x r
x r
x r
x
x w
x
x x
Optional serum for 
RBR bb
x
x
Tumor tissue specimen 
(remaining tissue may be 
used for optional RBR 
specimen) cc
x cc
x dd
Concomitant medications
To be recorded continually until end of treatment
Adverse events ee
To be assessed continually ee
PET-CT scan 
x ff
x gg
x oo
CT scan hh
x hh
x ii
x gg
x jj
x kk
x ll
Bone marrow biopsy and 
aspirate
x mm
x gg, nn
x nn
x kk, nn
New anti-lymphoma 
treatment
x
x
Survival follow-up
x


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
185/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
BSAbody surface area; CT computed tomography; Dday; DLBCLdiffuse large B-cell lymphoma; ECGelectrocardiogram; 
ECHOechocardiogram; eCRFelectronic Case Report Form; ECOG Eastern Cooperative Oncology Group; EOIend of induction; 
EOCend of consolidation; IPIInternational Prognostic Index; MRDminimal residual disease; MRImagnetic resonance imaging; 
MUGAmultigated acquisition; PET positron emission tomography; PKpharmacokinetic; Q3Mevery 3 months; RBRRoche Biosample 
Repository; TLStumor lysis syndrome; Txtreatment.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Assessments shaded in gray
should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case of an adverse 
event).
a The screening period starts with the signing of the Informed Consent Form, including the optional Informed Consent Form if appropriate.  
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be 
used as screening and baseline assessments; such tests do not need to be repeated for screening purposes.
b Patients who complete consolidation treatment or discontinue consolidation treatment prematurely will undergo assessments at the EOC.
c EOI assessments should be performed 68 weeks after Day 1 of the last induction cycle.  As an exception, patients who discontinue 
induction treatment prematurely because of an adverse event may undergo EOI assessments 48 weeks after their last dose of study 
treatment.
d Consolidation treatment should start 8 weeks (1 week) after Day 1 of the final cycle of induction and will continue until disease 
progression or unacceptable toxicity for up to 6 months.
e Patients who complete treatment or discontinue treatment for reasons other than disease progression will undergo assessments every 
3 months during the post-treatment follow-up period, which will continue until disease progression, the start of new anti-lymphoma 
treatment, or the end of the study, whichever occurs first.  The first post-treatment follow-up visit is 3 months after the EOI visit for 
patients who do not receive maintenance treatment and 3 months after the last dose for patients who receive maintenance treatment.  
Patients who experience disease progression or start another anti-lymphoma treatment will be evaluated for survival status and new anti-
lymphoma treatment every 3 months during the survival follow-up period, which will continue until the end of the study.  The end of the 
study is defined as the time when all enrolled FL patients have completed or discontinued study treatment and all enrolled DLBCL 
patients have been followed for at least 1 year after they have completed or discontinued study treatment.
f
Informed consent must be documented before any study-specific screening procedure is performed.
g Vital signs include respiratory rate, pulse rate, body temperature, and systolic and diastolic blood pressures while the patient is in a 
seated position.  For obinutuzumab infusions:  For the first cycle and for patients who experience an infusion-related reaction, vital signs 
will be measured prior to the infusion, every 15 (5) minutes for the first 90 minutes of the infusion, and then every 30 (10) minutes until 
1 hour after completion of the infusion.  For the second and subsequent cycles, vital signs will be measured every 30 minutes during the 
infusion, except for patients who had experienced an infusion-related reaction during a prior infusion. For rituximab infusions:  Vital sign
monitoring during infusion should be determined as per local label.  


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
186/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
h Perform only for patients who will not be receiving consolidation treatment.
i
Vital signs will be measured, a targeted physical examination will be performed, and hematology and serum chemistry will be assessed 
during consolidation every 2 weeks during the first month, every month until EOC. 
j
All ECGs should be performed within 2 hours prior to idasanutlin administration and either 6 hours after idasanutlin administration or 
immediately after obinutuzumab/rituximab administration, whichever occurs later.  ECGs will be performed in triplicate on Days 1 and 5 of 
Cycles 1 and 4 in the induction phase.  However, on Day 5 of Cycles 1 and 4 in the induction phase, the postdose ECG should be 
performed only if the patient is still at the clinic.
k Perform MUGA or echocardiogram at screening (Day 28 to Day 1), on Day 4, Cycle 4, at the EOI, the EOC, and as clinically indicated.
l
Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.
m As part of tumor assessment, the physical examination should include evaluation for the presence of enlarged nodes, palpable 
hepatomegaly, and splenomegaly.  This information will be recorded on the appropriate Tumor Assessment eCRF.
n Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly
emergent or monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas 
identified at baseline).  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
o Unexplained fever 38°C, night sweats, and unexplained weight loss 10% of body weight over 6 months.
p Includes hemoglobin, hematocrit, platelet count, RBC count, WBC count, and percent or absolute WBC differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
q Screening laboratory assessments may be used for Day 1 of Cycle 1 if performed within 24 hours prior to Day 1 of Cycle 1.  Additional 
hematology and chemistry samples must be drawn 04 hours pre-dose and 8 and 24 hours post-dose on Day 1 of Cycle 1 to monitor for 
TLS. Note that the 24-hour post-dose sample will be obtained on Day 2 of Cycle 1.
r
Perform hematology and chemistry tests within 72 hours prior to Day 1 of each cycle and within 24 hours prior to Days 8 and 15 of 
Cycle 1.  Samples for exploratory biomarker research should be collected at the same time as hematology and serum chemistry samples.
s Includes sodium, potassium, glucose, BUN or urea, creatinine, calculated creatinine clearance, calcium, total bilirubin, direct bilirubin, 
total protein, albumin, ALT, AST, alkaline phosphatase, amylase, lipase, LDH, and uric acid.
t
Perform only for patients treated with obinutuzumab.
u All women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or surgically sterile will have a serum 
pregnancy test at screening within 7 days prior to Day 1 of Cycle 1.  Because of the suspected effect of idasanutlin or venetoclax on 
embryofetal development, monthly pregnancy testing is strongly recommended for women of childbearing potential.
v Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.
w Perform at the same time as tumor assessments at 3 months after initiation of consolidation treatment.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
187/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
x Perform every 3 months until recovery to either normal range or baseline level, disease progression, or the start of new anti-lymphoma 
treatment, whichever occurs first.
y
Refer to Appendix 3 for detailed schedule.
z
Includes circulating lymphoma cells and/or cell-free circulating-tumor DNA.
aa Includes B-cell counts (CD19), T-cell counts (CD3, CD4, and CD8), and natural killer cell counts (CD16 and CD56).
bb Requires separate patient consent for RBR participation.  Not applicable for a site that has not been granted approval for RBR sampling.
cc Availability of adequate archival or freshly biopsied tumor tissue samples should be confirmed at screening (see Section 4.5.6 for 
details).
dd A tumor biopsy sample is preferred and recommended at the time of progression unless no adequate tumor site is accessible.
ee After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-
mandated intervention should be reported. After initiation of study treatment, all adverse events will be reported until 90 days after the 
last dose of study treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse 
event that is believed to be related to prior study treatment (see Section 5.6).  An exception is made for Grade 3 and 4 infections (related 
and unrelated) in patients who received obinutuzumab, which should be reported until up to 2 years after the last dose of obinutuzumab.  
The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as 
stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to any of the study treatment components or trial-related procedures until a final 
outcome can be reported.
ff
The screening PET-CT scan must be performed within 35 days prior to Day 1 of Cycle 1.
gg Perform only for patients who have received at least two cycles of induction treatment.
hh CT scan of the neck (if clinically indicated), chest, abdomen, and pelvis. If contrast is medically contraindicated (e.g., patients with 
contrast allergy or impaired renal clearance), MRI scans of the chest, abdomen, and pelvis (and neck, if clinically indicated) and a 
non-contrast CT scan of the chest may be performed.  Combined PET/CT scanners may be used to collect diagnostic CT scans but only
according to the technical guidelines in the imaging manual.  Screening CT scan must be performed within 35 days prior to Day 1 of 
Cycle 1.
ii
Perform within 7 days prior to Day 1, Cycle 3.  
jj
Perform 3 months after initiation of consolidation treatment.
kk Perform only if not done within the previous 3 months.
ll
Perform every 6 months. 
mm Bone marrow biopsy and aspirate must be performed within approximately 3 months prior to Day 1 of Cycle 1.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
188/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
nn For patients with bone marrow involvement at screening, a repeat assessment will be performed at the EOI, during consolidation, or at 
the EOC whenever there is radiologic evidence of a complete response or if clinically indicated (e.g., if there is clinical suspicion of 
progressive disease in the bone marrow with no radiologic evidence of progression).  Additional bone marrow assessments may be 
performed at the discretion of the investigator.
oo A PET-CT scan should be performed at end of consoliation if the PET-CT scan is posiive at end of induction.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
189/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phase (cont.)
Study Treatment Administration: Dose Escalation before the Bridging Cohorts
Study Treatment
Induction (Six 28-Day Cycles)
Consolidation 
Every 2 Months a
Cycle 1 (1 day)
Cycles 26 (2 days)
Day 1
Day 5
Day 8
Day 10
Day 15
Day 1
Day 5
Day 10
Day 1
Day 5
Day 10
Obinutuzumab b
(1000 mg IV)
x
x
x
x
x
Idasanutlin b
(PO QD)
Days 15
Days 15
TBD c
Venetoclax b
(PO QD)
Days 15 or Days 110 d
Days 15 or Days 110 d
TBD c
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; POby mouth; QDonce a day; TBDto be determined.
a Total duration of consolidation is 6 months.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c Regimen will be defined based on available safety, tolerability, PK, and PD data.
d Regimen is defined according to the dose-escalation plan (see Section 3.1.2).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
190/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phase (cont.)
Study Treatment Administration: Dose Escalation for the Bridging Cohorts
Study Treatment
Induction (Six 28-Day Cycles)
Consolidation 
Every 2 Months a
Cycles 16 (1 day)
Day 1
Day 5
Day 10
Day 1
Rituximab b
(375 mg/m2 IV)
x
x
Idasanutlin b
(PO QD)
Days 15
TBD c
Venetoclax b
(PO QD)
Days 15 or Days 110 d
TBD c
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; PO by mouth; QDonce a day; TBDto be determined.
a Total duration of maintenance is 24 months for obinutuzumab and 6 months for idasanutlin and venetoclax.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c Regimen will be defined based on available safety, tolerability, PK, and PD data.
d Regimen is defined according to the dose-escalation plan (see Section 3.1.2).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
191/Protocol BH39147, Version 4
Appendix 2
Schedule of Activities for Patients with Diffuse Large B-Cell Lymphoma: 
Dose-Escalation and Expansion Phases (cont.)
Study Treatment Administration: Expansion Phase
Study Treatment
Induction (Six 28-Day Cycles)
Consolidation 
Every 2 Months a
Cycles 16 (1 day)
Day 1
Day 5
Day 10
Day 1
Rituximab b
(375 mg/m2 IV)
x
x
Idasanutlin b
(PO QD)
Days 15
TBD c
Venetoclax b
(PO QD)
Days 15 or Days 110 d
TBD c
IVintravenous; PDpharmacodynamic; PKpharmacokinetic; PO by mouth; QDonce a day; TBDto be determined.
a Total duration of maintenance is 24 months for obinutuzumab and 6 months for idasanutlin and venetoclax.
b Refer to Section 4.3.2 for instructions on study treatment administration.
c Regimen will be defined based on available safety, tolerability, PK, and PD data.
d  Regimen is defined according to the dose-escalation plan (see Section 3.1.2).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
192/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule
Dose-Escalation Phase (Induction Treatment for FL and DLBCL Patients; 28-Day Cycles) in Regimen A
Study Visit
Serum Obinutuzumab 
PK Sample b
Serum Rituximab 
PK Sample a,b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax PK 
Sample
Cycle 1
Day 1 d
Pre-infusion (any time prior 
to dose on that day) e
30 (10 min) after end of 
infusion
Pre-infusion (any time 
prior to dose on that day)
e
30 (10 min) after end of 
infusion
Pre-administration (any time 
prior to dose on that day); e
6 hr (20 min) post-
idasanutlin administration
Pre-administration (any time 
prior to dose on that day);
6 hr (20 min) post-
venetoclax administration
Day 5

Pre-administration (within 1 
hr prior to dose);
2 hr (10 min) post-
idasanutlin administration;
4 hr (10 min) post-
idasanutlin administration;
6 hr (20 min) post-
idasanutlin administration
Pre-administration (within 1 
hr prior to dose);
2 hr (10 min) post-
venetoclax administration;
4 hr (10 min) post-
venetoclax administration;
6 hr (20 min) post-
venetoclax administration
Cycle 2
Day 1
Pre-infusion (within 5 hr prior 
to dose)
30 (10) min after end of 
infusion
Pre-infusion (within 5 hr 
prior to dose)
Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
idasanutlin administration
Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
venetoclax administration;
ADAanti-drug antibody; DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; HACAhuman anti–chimeric antibody; HAHAhuman
anti-human antibody; PK pharmacokinetic.  Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, HACA, and/or ADA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d If the Day 1, Cycle 1 dose of obinutuzumab or rituximab is split over 2 days, take the 30 minutes post end of infusion obinutuzumab or rituximab 
PK sample relative to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.
e The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
193/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Dose-Escalation Phase (Induction Treatment for FL and DLBCL Patients; 28-Day Cycles) in Regimen A (cont.)
Study Visit
Serum Obinutuzumab 
PK Sample b
Serum Rituximab 
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax PK 
Sample
Cycle 2 
(cont.)
Day 5

Pre-administration (within 1 
hr prior to dose);
6 (20 min) hr post-
idasanutlin administration
Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
venetoclax administration
Cycle 4
Day 1
Pre-infusion (within 5 hr prior 
to dose);
30 (10) min after the end of 
infusion
Pre-infusion (within 5 hr 
prior to dose)
Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
idasanutlin administration
Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
venetoclax administration
Day 5

Pre-administration (within 1 
hr prior to dose);
6 hr (20 min) post-
idasanutlin administration
Pre-administration (within 1 
hr prior to dose);
6 hr (± 20 min) post-
venetoclax administration
Cycle 6
Day 1
Pre-infusion (within 5 hr prior 
to dose);
30 (10) min after the end of 
infusion
Pre-infusion (within 5 hr 
prior to dose);
30 (10) min after the 
end of infusion


ADAanti-drug antibody; DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; HACAhuman anti–chimeric antibody; HAHAhuman
anti-human antibody; PK pharmacokinetic.  Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, HACA, and/or ADA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d If the Day 1, Cycle 1 dose of obinutuzumab or rituximab is split over 2 days, take the 30 minutes post end of infusion obinutuzumab or rituximab
PK sample relative to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.
e   The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
194/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Expansion Phase (Induction Treatment for FL and DLBCL Patients; 28-Day Cycles) in Regimen A
Study Visit
Serum Obinutuzumab 
PK Sample b
Serum Rituximab
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax 
PK Sample
Cycle 1 Day 1 d Pre-infusion (any time prior to 
dose on that day); e
30 (10) min after the end of 
infusion
Pre-infusion (any time prior to 
dose on that day); e
30 (10) min after the end of 
infusion
Pre-administration (any time 
prior to dose on that day);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (any time 
prior to dose on that day);
6 hr (20 min) post-venetoclax 
administration
Day 5

Pre-administration (within 1 hr 
prior to dose);
2 hr (10 min) post-idasanutlin 
administration;
4 hr (10 min) post-idasanutlin 
administration;
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr 
prior to dose);
2 hr (10 min) post-venetoclax 
administration;
4 hr (10 min) post-venetoclax 
administration;
6 hr (20 min) post-venetoclax 
administration
Cycle 2
Day 1
Pre-infusion (within 5 hr prior 
to dose);
30 (10 min) after the end of 
infusion
Pre-infusion (within 5 hr prior to 
dose)
Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration 
(within 1 hr prior to dose);
6 hr (20 min) post-venetoclax 
administration
ADAanti-drug antibody; DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; HACAhuman anti–chimeric antibody; HAHAhuman
anti-human antibody; PK pharmacokinetic.  Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, HACA, and/or ADA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  
e If the Day 1, Cycle 1 dose of obinutuzumab or rituximab is split over 2 days, take the 30 minutes post-infusion obinutuzumab or rituximab PK 
sample relative to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
195/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Expansion Phase (Induction Treatment for FL and DLBCL Patients; 28-Day Cycles) in Regimen A (cont.)
Study Visit
Serum Obinutuzumab 
PK Sample b
Serum Rituximab
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax 
PK Sample
Cycle 
2
(cont.)
Day 5

Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-venetoclax 
administration
Cycle 
4
Day 1
Pre-infusion (within 5 hr 
prior to dose); 
30 (10) min after the 
end of infusion
Pre-infusion (within 5 hr prior to 
dose)
Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration 
(within 1 hr prior to dose);
6 hr (20 min) post-venetoclax 
administration
Day 5

Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr 
prior to dose);
6 hr (20 min) post-venetoclax 
administration
Cycle 
6
Day 1
Pre-infusion 
(within 5 hr prior to 
dose);
30 (10) min after the 
end of infusion
Pre-infusion 
(within 5 hr prior to dose);
30 (10) min after the end of 
infusion


DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; PKpharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, HACA, and/or ATA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  
e If the Day 1, Cycle 1 dose of obinutuzumab or rituximab is split over 2 days, take the 30 minutes post-infusion obinutuzumab or rituximab PK 
sample relative to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
196/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Dose-Escalation Phase (Induction Treatment for FL Patients; 28-Day Cycles) In Regimen B
Study Visit
Serum Obinutuzumab 
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax PK Sample
Cycle 1
Day 1 d
Pre-infusion (any time prior to 
dose on that day); e
30 (10 min) after end of infusion
Pre-administration (any time prior 
to dose on that day) e
Pre-administration (any time prior 
to dose on that day)
Day 5



Cycle 2
Day 1
Pre-infusion (within 5 hr prior to 
dose);
30 (10) min after end of infusion
Pre-administration (any time prior 
to dose on that day);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (any time prior 
to dose on that day);
6 hr (20 min) post-venetoclax 
administration
DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; PK pharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, and/or ATA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d If the Day 1, Cycle 1 dose of obinutuzumab is split over 2 days, take the 30 minutes post end of infusion obinutuzumab PK sample relative 
to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.
e The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
197/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Dose-Escalation Phase (Induction Treatment for FL Patients; 28-Day Cycles) in Regimen B (cont.)
Study Visit
Serum Obinutuzumab 
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax PK Sample
Cycle 2 
(cont.)
Day 5

Pre-administration (within 1 hr prior 
to dose);
Pre-administration (within 1 hr prior 
to dose);
2 hr (10 min) post-idasanutlin 
administration;
4 hr (10 min) post-idasanutlin 
administration;
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr prior to dose);
2 hr (10 min) post-venetoclax administration;
4 hr (10 min) post-venetoclax administration;
6 hr (20 min) post-venetoclax administration
Cycle 4
Day 1
Pre-infusion (within 5 hr 
prior to dose);
30 (10) min after the end 
of infusion
Pre-administration (within 1 hr prior 
to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr prior to dose);
6 hr (20 min) post-venetoclax administration
Day 5

Pre-administration (within 1 hr prior 
to dose);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (within 1 hr prior to dose);
6 hr (± 20 min) post-venetoclax administration
Cycle 6
Day 1
Pre-infusion (within 5 hr 
prior to dose);
30 (10) min after the end 
of infusion


DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; PK pharmacokinetic.
Note: A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, and/or ATA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
198/Protocol BH39147, Version 4
  Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Dose-Escalation Phase (Induction Treatment for FL Patients; 28-Day Cycles) in Regimen B (cont.)
d If the Day 1, Cycle 1 dose of obinutuzumab is split over 2 days, take the 30 minutes post end of infusion obinutuzumab PK sample relative 
to the end of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.
e   The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
199/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Expansion Phase (Induction Treatment for FL Patients; 28-Day Cycles) in Regimen B
Study Visit
Serum Obinutuzumab 
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax 
PK Sample
Cycle 1
Day 1 d
Pre-infusion (any time prior to 
dose on that day); e
30 (10) min after the end of 
infusion
Pre-administration (any time prior to 
dose on that day)
Pre-administration (any time prior to dose on that 
day)
Day 5



Cycle 2
Day 1
Pre-infusion (within 5 hr prior to 
dose);
30 (10 min) after the end of 
infusion
Pre-administration (any time prior to 
dose on that day);
6 hr (20 min) post-idasanutlin 
administration
Pre-administration (any time prior to dose on that 
day);
6 hr (20 min) post-venetoclax administration
DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; PKpharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, and/or ATA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  
e If the Day 1, Cycle 1 dose of obinutuzumab is split over 2 days, take the 30 minutes post-infusion obinutuzumab PK sample relative to the end 
of the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
200/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Expansion Phase (Induction Treatment for FL Patients; 28-Day Cycles) in Regimen B (cont.)
Study Visit
Serum Obinutuzumab 
PK Sample a, b
Plasma Idasanutlin PK and 
Serum MIC-1 Sample c
Plasma Venetoclax 
PK Sample
Cycle 
2
(cont.)
Day 5

Pre-administration (within 1 hr prior to dose);
2 hr (10 min) post-idasanutlin administration;
4 hr (10 min) post-idasanutlin administration;
6 hr (20 min) post-idasanutlin administration
Pre-administration (within 1 hr prior to dose);
2 hr (10 min) post-venetoclax administration;
4 hr (10 min) post-venetoclax administration;
6 hr (20 min) post-venetoclax administration
Cycle 
4
Day 1
Pre-infusion (within 5 hr 
prior to dose); 
30 (10) min after the end 
of infusion
Pre-administration (within 1 hr prior to dose);
6 hr (20 min) post-idasanutlin administration
Pre-administration 
(within 1 hr prior to dose);
6 hr (20 min) post-venetoclax administration
Day 5

Pre-administration (within 1 hr prior to dose);
6 hr (20 min) post-idasanutlin administration
Pre-administration (within 1 hr prior to dose);
6 hr (20 min) post-venetoclax administration
Cycle 
6
Day 1
Pre-infusion 
(within 5 hr prior to dose);
30 (10) min after the end 
of infusion


DLBCLdiffuse large B-cell lymphoma; FLfollicular lymphoma; PKpharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HACA, and/or ATA assay development and validation, and additional 
immunogenicity characterization, at the discretion of the clinical pharmacologist and/or the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.
d The Day 1, Cycle 1 predose PK sample may be taken any time prior to the first dose that day.  
e If the Day 1, Cycle 1 dose of obinutuzumab is split over 2 days, take the 30 minutes post-infusion obinutuzumab PK sample relative to the end of 
the infusion on Day 2, and ensure that the date and time of the PK collection are accurately recorded.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
201/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Post-Induction Treatment (Eligible FL Patients)
Study Visit
Serum Obinutuzumab 
PK Sample a, b
Plasma Idasanutlin PK 
and Serum MIC-1 
Sample c
Plasma 
Venetoclax 
PK Sample
Month 1, Day 1
Pre-infusion (within 5 hr prior to dose)


Month 7, Day 1
Pre-infusion (within 5 hr prior to dose)


Month 13, Day 1
Pre-infusion (within 5 hr prior to dose)


Month 19, Day 1
Pre-infusion (within 5 hr prior to dose)


Post-treatment



Treatment discontinuation
Any time during visit


120 days after the last 
dose
Any time during visit


12 years after the last 
dose
Any time during visit 
(if patient is in the clinic)


FLfollicular lymphoma; PKpharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HAHA, and/or ATA assay development and 
validation, and additional immunogenicity characterization, at the discretion of the clinical pharmacologist and/or
the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
202/Protocol BH39147, Version 4
Appendix 3
Pharmacokinetic and Biomarker Sampling Schedule (cont.)
Post-Induction Treatment (Eligible DLBCL Patients)
Study Visit
Serum Rituximab 
PK Sample a, b
Plasma Idasanutlin PK 
and Serum MIC-1 
Sample c
Plasma 
Venetoclax 
PK Sample
Post-treatment



Treatment discontinuation
Any time during visit


120 days after the last 
dose
Any time during visit


12 years after the last 
dose
Any time during visit 
(if patient is in the clinic)


DLBCLdiffuse large B-cell lymphoma; PKpharmacokinetic.
Note:  A ““ indicates not applicable.
a Sample collection timing is relative to the specified drug.
b Samples collected for PK analysis may be used for additional PK, HACA, and/or ATA assay development and 
validation, and additional immunogenicity characterization, at the discretion of the clinical pharmacologist and/or 
the clinical scientist.
c Two tubes for plasma and serum, respectively, at each sampling timepoint.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
203/Protocol BH39147, Version 4
Appendix 4
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014)
In this study, the designation of a complete response (CR) using positron emission tomographycomputed tomography 
(PET-CT)–based response requires normal bone marrow by morphology for patients with bone marrow involvement at baseline.  
If indeterminate by morphology, immunohistochemistry must be negative.  Additionally, designation of PET-CT−based partial 
response (PR) requires that computed tomography (CT)-based response criteria for a CR or a PR be met in addition to the 
PET-CTbased response criteria for a PR.
Revised Criteria for Response Assessment 
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3 a with or without a residual mass on 5PS b
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater than normal 
mediastinum and/or liver.  In this circumstance, complete 
metabolic response may be inferred if uptake at sites of 
initial involvement is no greater than surrounding normal 
tissue even if the tissue has high physiologic uptake.
Target nodes/nodal masses must regress to 1.5 cm in 
LDi
No extralymphatic sites of disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
204/Protocol BH39147, Version 4
Appendix 4
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Revised Criteria for Response Assessment 
Response and Site
PET-CT–Based Response
CT-Based Response
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5 b with reduced uptake compared with baseline 
and residual mass(es) of any size
50% decrease in the sum of the product of the diameters 
SPD of up to 6 target measurable nodes and extranodal 
sites
At interim, these findings suggest responding disease
When a lesion is too small to measure on CT, assign 
5 mm 5 mm as the default value
At end of treatment, these findings indicate residual disease When no longer visible, 0 0 mm
For a node 5 mm 5 mm, but smaller than normal, use 
actual measurement for calculation
Non-measured lesion
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by 50% in length beyond 
normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy allowed).  If 
there are persistent focal changes in the marrow in the 
context of a nodal response, consideration should be given 
to further evaluation with MRI or biopsy or an interval scan.
Not applicable


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
205/Protocol BH39147, Version 4
Appendix 4
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Revised Criteria for Response Assessment 
Response and Site
PET-CT–Based Response
CT-Based Response
No response or stable disease 
No metabolic response
Stable disease
Target nodes/nodal masses, 
extranodal lesions
Score 4 or 5 b with no significant change in FDG uptake 
from baseline at interim or end of treatment
50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met
Non-measured lesion
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
206/Protocol BH39147, Version 4
Appendix 4
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
Revised Criteria for Response Assessment 
Response and Site
PET-CT–Based Response
CT-Based Response
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 1 of the following 
Individual target nodes/nodal 
masses
Score 4 or 5 b with an increase in intensity of uptake from 
baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment
An individual node/lesion must be abnormal with:
LDi 1.5 cm and
Increase by 50% from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions 2 cm
1.0 cm for lesions 2 cm
In the setting of splenomegaly, the splenic length must 
increase by 50% of the extent of its prior increase 
beyond baseline (e.g., a 15-cm spleen must increase to 
16 cm).  If no prior splenomegaly, must increase by at 
least 2 cm from baseline.
New or recurrent splenomegaly 
New or clear progression of preexisting non-measured 
lesions
New lesions
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation); if uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered
Regrowth of previously resolved lesions
A new node 1.5 cm in any axis
A new extranodal site 1.0 cm in any axis; if 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma
Assessable disease of any size unequivocally attributable 
to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
207/Protocol BH39147, Version 4
Appendix 4
Lugano Response Criteria for Malignant Lymphoma
(Cheson et al. 2014) (cont.)
5PS5-point scale; CTcomputed tomography; FDGfluorodeoxyglucose; GIgastrointestinal; IHCimmunohistochemistry; LDilongest transverse 
diameter of a lesion; MRImagnetic resonance imaging; PETpositron emission tomography; PPDcross product of the LDi and perpendicular 
diameter; SDishortest axis perpendicular to the LDi; SPDsum of the product of the perpendicular diameters for multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.  However, in trials 
involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  
Measured dominant lesions:  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters.  Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas.  
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation.  
Non-measured lesions:  Any disease not selected as measured; dominant disease and truly assessable disease should be considered not measured.  
These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to 
follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other 
lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake 
may be greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake 
(e.g., with marrow activation as a result of chemotherapy or myeloid growth factors).
b
PET 5PS:  1no uptake above background; 2uptake mediastinum; 3uptake mediastinum but liver; 4uptake moderately liver; 5uptake 
markedly higher than liver and/or new lesions; Xnew areas of uptake unlikely to be related to lymphoma.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
208/Protocol BH39147, Version 4
Appendix 5
Classification of Tumor Lysis Syndrome Based on Howard Definition 
To qualify for laboratory tumor lysis syndrome (TLS), a patient must have two or more 
metabolic abnormalities as defined in Table 1 during the same 24-hour period within 
3 days before the start of therapy or up to 7 days afterward (TLS risk decreases along 
treatment cycles).  To qualify for clinical TLS, a patient must qualify for laboratory tumor 
lysis syndrome and have clinical signs of hyperkalemia, hypocalcemia, or acute kidney 
injury, such as (but not limited to) oliguria, increased creatinine, seizures, cardiac 
dysrhythmia, or death.
Table 1
Criteria for Classification of Laboratory and Clinical Tumor Lysis 
Syndrome
Metabolic 
Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome a
Criteria for Classification of 
Clinical Tumor Lysis Syndrome b
Hyperuricemia
Uric acid 8.0 mg/dL (475.8 mol/L) 
in adults or above the upper limit of 
the normal range for age in children
Not applicable
Hyperphosphatemia Phosphorus 4.5 mg/dL (1.5 mol/L) 
in adults or 6.5 mg/dL (2.1 mol/L) 
in children
Not applicable
Hyperkalemia
Potassium 6.0 mol/L
Cardiac dysrhythmia or sudden 
death probably or definitely caused 
by hyperkalemia
Hypocalcemia
Corrected calcium 7.0 mg/dL 
(1.75 mol/L) or ionized calcium 
1.12 (0.3 mol/L) c
Cardiac dysrhythmia, sudden death, 
seizures, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau’s sign, Chvostek’s sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure probably 
or definitely caused by hypocalcemia
Acute kidney injury c Not applicable
Increase from baseline creatinine of 
0.3 mg/dL (26.5 mol/L), anuria, 
oliguria (defined as an average urine 
output of 0.5 mL/kg/hr for 6 hours
or more), or other clinical symptoms 
indicative of acute kidney injury
Source:  Howard SC, Jones P, Pui CH. The tumor lysis syndrome. N Engl J Med 
2011:12;364:184454.
a To qualify for laboratory tumor lysis syndrome, a patient must have two or more metabolic 
abnormalities during the same 24-hour period within 3 days before the start of therapy or up to 
7 days afterward.  
b To qualify for clinical tumor lysis syndrome, a patient must qualify for laboratory tumor lysis 
syndrome and have clinical signs of hyperkalemia, hypocalcemia, or acute kidney injury, such 
as (but not limited to) oliguria, increased creatinine, seizures, cardiac dysrhythmia, or death.
c Corrected calcium (mg/dL)measured calcium (mg/dL)0.8(4albumin [g/dL]).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
209/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
In order to evaluate the operating characteristics of the modified Continual 
Reassessment Model (mCRM), simulations were performed under four different true 
scenarios, with each scenario describing the true relationship between dose-limiting 
toxicity (DLT) rate and dose combinations of idasanutlin and venetoclax (see Figure 1).
Figure 1
True Scenarios Describing the Toxicity of Each Combination of 
Idasanutlin and Venetoclax
The parameters of the mCRM corresponding to the four scenarios are presented in 
Table 1.  In the first two scenarios, the true value for each parameter is set to the mean 
value of the corresponding prior distribution (prior), with the exception of , for which 
Scenario 1 assumes 0 (no interaction between idasanutlin and venetoclax) and 
Scenario 2 assumes 1.0 (synergistic interaction).  Scenarios 3 and 4, in which the 
value of is set to 0.5, consider cases in which the slope of the marginal logistic model 
signifies that venetoclax is more toxic than the prior assumption (Scenario 3) or that 
idasanutlin is less toxic than the prior assumption (Scenario 4).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
210/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Table 1:
Parameters of the mCRM Corresponding to Different Scenarios
Scenario
1
2
1
2

1
2.0
3.9
2.5
5.4
1.0
2
2.0
3.9
2.5
5.4
0.0
3
2.0
3.9
2.5
11.0
0.5
4
2.0
3.9
1.3
5.4
0.5
mCRMmodified Continual Reassessment Model.
The following possible dose levels were considered for idasanutlin (to be given in 
combination with venetoclax):  50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 
and 600 mg.  The following possible dose levels were considered for venetoclax (to be 
given in combination with idasanutlin):  100, 200, 300, 400, 500, 600, 700, and 800 mg.
For each scenario, 1000 simulations were performed, with each simulation mimicking a 
complete dose-escalation study outcome.
A fixed sample size of 42 patients (14 cohorts of 3 patients each) was considered, with 
the possibility of dosing for up to a maximum of two cohorts in parallel.
All possible combinations of doses to be potentially explored in the simulations and in 
this study are shown Figure 2, in which a grid score (in this case, a number ranging from 
2 to 20) is reported for each combination and represents how far the corresponding 
combination lies from the origin (the left bottom corner).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 2
All Possible Dose Combinations of Idasanutlin and Venetoclax
The starting dose combination for each simulation was 100 mg for idasanutlin and
200 mg for venetoclax.  Dose combinations for subsequent cohorts were selected using 
the algorithm described below:
1.
The following terms are represented in the algorithm: 

Imax and Vmax are the maximum doses for idasanutlin (I) and venetoclax (V), 
respectively, from all dose combinations already tested (e.g., if only the first 
cohort had been tested, Imax100 mg and Vmax200 mg)

[I, V] is one of the possible idasanutlin and venetoclax dose combinations for the 
next cohort(s)
2.
The mCRM is updated with information on DLTs from all cohorts (dose 
combinations) already tested


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
3.
From all possible combinations of doses [I, V], only those fulfilling the following 
criteria are further considered as potential dose(s) for the next cohort(s):
a)
The probability of having a DLT rate of 33% is 35%
b)
The grid score is not above the maximum grid score (across all dose 
combinations already tested) plus 2 (e.g., the starting dose for the simulations
had a grid score of 4; thus, the next dose combination had to have a grid 
score of 6)
c)
IImax or VVmax (which means that only one of the doses can be higher than
the maximum dose already tested for that drug)
d)
IImax100 mg and VVmax200 mg (which means that only 100-mg and 
200-mg increments are allowed above the maximum dose already tested for 
idasanutlin and venetoclax, respectively)
4.
Among the remaining dose combinations, only those with the maximum grid score 
are considered further (referred to as “Set” Ω) and the next dose combination(s) are
chosen among Ω as described below:
a)
If Ω was composed of one dose combination, this is selected as the dose
combination for the next cohort of 3 patients.
b)
If Ω is composed of two or more dose combinations, the next dose 
combination(s) are chosen as follows:

If one of the dose combinations in Ω is located on the diagonal 
(highlighted in yellow in Figure 2) and has not been tested before, this 
is selected as the dose combination for the next cohort of 3 patients.

Otherwise, the two dose combinations in Ω with the highest probability 
of being within the target toxicity interval are selected to be tested in 
parallel in the next two cohorts of 3 patients.
Each simulation was stopped once 14 cohorts of 3 patients were tested and the outcome 
was the predicted maximum tolerated dose (MTD; one or a maximum of two dose 
combinations), obtained using the algorithm described above for selection of the next 
dose.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Results of the simulations for the different scenarios are reported in Figures 3, 4, 5, and
6 (for Scenarios 1, 2, 3, and 4, respectively), as well as in Table 2. The figures show the 
number of times each dose combination was predicted to be the MTD (after all 14 
cohorts were tested) across the 1000 simulations. If the algorithm suggested two dose 
combinations as the MTD, only the combination with the highest probability of being 
within the target toxicity interval, as predicted by the model, was used in these plots.  
The true toxicity at each dose combination for the corresponding true scenario is 
overlaid on each plot, allowing the figures to clearly capture the performance of the 
mCRM.  
Figure 3
Number of Times Each Dose Combination Was Selected as MTD 
for Scenario 1
MTDmaximum tolerated dose.


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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 4
Number of Times Each Dose Combination Was Selected as MTD 
for Scenario 2
MTDmaximum tolerated dose.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 5
Number of Times Each Dose Combination Was Selected as MTD 
for Scenario 3
MTDmaximum tolerated dose.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
216/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 6
Number of Times Each Dose Combination Was Selected as MTD 
for Scenario 4
MTDmaximum tolerated dose.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Table 2 shows the following information for each scenario across the 1000 simulations:

The percentage of times (out of 1000) the "best" model-predicted MTD (the 
combination with the highest probability of achieving the target toxicity interval [DLT 
rate of 16%33%] in case two dose combinations were predicted as the MTD) had 
true toxicity within the target toxicity interval

The percentage of times either of the two model-predicted MTDs (in case two dose 
combinations were predicted as the MTD) had true toxicity within the target toxicity 
interval

The median number of patients (together with 10th and 90th percentiles) who 
received a dose combination for which the true toxicity was above the target toxicity 
interval (DLT rate 33%; overdosing)

The median number of patients (together with 10th and 90th percentiles) who 
received a dose combination for which the true toxicity was unacceptable (DLT rate 
60%).
Table 2:
mCRM Design across the Different Scenarios
Scenario
Percentage of 
Times the Best 
MTD Was Truly in 
the Target Toxicity 
Range
Percentage of 
Times at Least One 
of the Best Two 
MTDs Was Truly in 
the Target Toxicity 
Range
No. of Patients Who 
Were Treated
Above the Target 
Toxicity Interval 
(Median [10th, 90th 
Percentiles]
No. of Patients 
Who Were 
Treated at 
Unacceptable 
Toxicity (Median 
[10th, 90th 
Percentiles]
1
62%
81%
0 [0, 12]
0 [0, 0]
2
67%
81%
0 [0, 3]
0 [0, 0]
3
56%
83%
6 [0, 15]
0 [0, 3]
4
70%
84%
0 [0, 9]
0 [0, 0]
mCRMmodified Continual Reassessment Model; MTDmaximum tolerated dose.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figures 7, 8, 9, and 10 show for Scenarios 1, 2, 3, and 4, respectively, two examples 
(from the simulations) of how a complete dose escalation (with up to 42 patients) would 
occur using the proposed mCRM.
As indicated by the results shown in Figures 7, 8, 9, and 10, it can be concluded that the 
proposed mCRM provides overall very good performance in selecting the correct MTD, 
while at the same time limiting the amount of overdosing across all scenarios, with the 
assumed sample size of 42 patients.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
219/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 7
Example of Two Complete Trial Realizations in Scenario 1
Idaidasanutlin; Venvenetoclax.
Note:  Random noise was added to the data along both axis to allow seeing points that otherwise 
would have overlapped.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
220/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 8
Example of Two Complete Trial Realizations in Scenario 2
Idaidasanutlin; Venvenetoclax.
Note:  Random noise was added to the data along both axis to allow seeing points that otherwise 
would have overlapped.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
221/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 9
Example of Two Complete Trial Realizations in Scenario 3
Idaidasanutlin; Venvenetoclax.
Note:  Random noise was added to the data along both axis to allow seeing points that otherwise 
would have overlapped.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
222/Protocol BH39147, Version 4
Appendix 6
Operating Characteristics of the Modified Continual 
Reassessment Model for Dose Escalation with Overdose Control
(cont.)
Figure 10 Example of Two Complete Trial Realizations in Scenario 4
Idaidasanutlin; Venvenetoclax.
Note:  Random noise was added to the data along both axes to allow visibility of points that 
otherwise would have overlapped.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
223/Protocol BH39147, Version 4
Appendix 7
ECOG Performance Status Scale
Grade
Description
0
Fully active; able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office work).
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about 50% of waking hours.
3
Capable of only limited self-care; confined to a bed or chair 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to
bed or chair.
5
Dead.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 8
Ann Arbor Staging
Grade
Description
Stage I
Involvement of a single lymph node region (I) or of a single 
extralymphatic organ or site (IE) a
Stage II
Involvement of two or more lymph node regions or lymphatic 
structures on the same side of the diaphragm alone (II) or with 
involvement of limited, contiguous extralymphatic organ or tissue 
(IIE)
Stage III
Involvement of lymph node regions on both sides of the diaphragm
(III), which may include the spleen (IIIS) or limited, contiguous 
extralymphatic organ or site (IIIE), or both (IIIES)
Stage IV b
Diffuse or disseminated foci of involvement of one or more 
extralymphatic organs or tissues, with or without associated 
lymphatic involvement
Note:  All cases are subclassified to indicate the absence (A) or presence (B) of the systemic 
B symptoms of significant unexplained fever (38C), night sweats, or unexplained weight loss 
exceeding 10% of body weight during the 6 months prior to diagnosis.
a The designation "E" generally refers to extranodal contiguous extension (i.e., proximal or 
contiguous extranodal disease) that can be encompassed within an irradiation field appropriate 
for nodal disease of the same anatomic extent.  A single extralymphatic site as the only site of 
disease should be classified as IE, rather than Stage IV. 
b Involvement of bone marrow at screening will always qualify for Ann Arbor Stage IV and 
should be recorded as extranodal involvement.
Adapted from:
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease 
Staging Classification. Cancer Res 1971;31:18601.
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the 
evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol 
1989;7:16306.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 9
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index
Table 1
Follicular Lymphoma International Prognostic Index
FLIPI Risk Factor
Ann Arbor Stage III or IV
Age 60 years
Serum LDH 1ULN
Anemia (hemoglobin 120 g/L)
Involved nodal areas 4
FLIPI Risk Group
Number of FLIPI Risk Factors
Low
0 or 1
Intermediate
2
High
3 to 5
FDGfluorodeoxyglucose; FLIPIFollicular Lymphoma International Prognostic Index; 
PET positron emission tomography; ULNupper limit of normal.
Note:  The results of FDG-PET should not be taken into account for calculation of FLIPI since this 
prognostic score was established without FDG-PET.
Adapted from:
Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. 
Blood 2004;104:1258–64.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 9
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.)
Table 2
Follicular Lymphoma International Prognostic Index 2
FLIPI2 Risk Factor
Bone marrow involvement
Age 60 years
2 microglobulin 1ULN
Anemia (hemoglobin 120 g/L)
Longest diameter of largest involved node6 cm
FLIPI2 Risk Group
Number of FLIPI2 Risk Factors
Low
0 
Intermediate
1 or 2
High
3 to 5
FDGfluorodeoxyglucose; FLIPI2Follicular Lymphoma International Prognostic Index 2; 
PET positron emission tomography; ULNupper limit of normal.
Note:  The results of FDG-PET should not be taken into account for calculation of FLIPI2 since 
this prognostic score was established without FDG-PET.
Adapted from:
Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: 
a new prognostic index for follicular lymphoma developed by the International Follicular 
Lymphoma Prognostic Factor Project. J Clin Oncol 2009;27:455562.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
227/Protocol BH39147, Version 4
Appendix 9
Follicular Lymphoma International Prognostic Index and 
International Prognostic Index (cont.)
Table 3
International Prognostic Index
IPI Risk Factor
Ann Arbor Stage III or IV
Age 60 years
Serum LDH 1ULN
ECOG Performance Status 2
Extranodal involvement 2
IPI Risk Group
Number of IPI Risk Factors
Low
0 or 1
LowIntermediate
2
HighIntermediate
3
High
4 or 5
ECOGEastern Cooperative Oncology Group; FDGfluorodeoxyglucose; IPIInternational 
Prognostic Index; PET positron emission tomography; ULNupper limit of normal.
Note:  The results of FDG-PET should not be taken into account for calculation of IPI since this 
prognostic score was established without FDG-PET.
Adapted from:  
Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive non-Hodgkin’s 
lymphoma. N Engl J Med 1993;329:98794.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 10
Anaphylaxis Precautions
Equipment Needed

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous , and/or endotracheal use in accordance 
with standard practice 

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
Procedures
In the event of a suspected anaphylactic reaction during study treatment infusion, the 
following procedures should be performed:

Stop the study treatment infusion.

Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
treatment.  Do not obstruct arterial flow in the limb.

Maintain an adequate airway.

Administer glucocorticoids, antihistamines, epinephrine, or other medications as 
required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 11
Calculation of Creatinine Clearance Using the modified 
Cockcroft-Gault Formula
eCCR(140Age)IBM a (kg)[0.85 if female])/(72serum creatinine [mg/dL])
Or, if serum creatinine is in micromoles per liter (mol/L):
eCCR(140Age)IBM a (kg)[1.23 if male, 1.04 if female])/(serum creatinine 
[mol/L])
eCCRestimated creatinine clearance; IBMideal body weight.
a IBM (kg) ([height in cm 154] 0.9)] (50 if male, 45.5 if female).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 12
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax
First Dose of Venetoclax or a Dose Increase

Within the first 24 hours after either the first dose or a dose increase, if any of the 
following laboratory criteria are met, the patient should be hospitalized for 
monitoring and the investigator notified. No additional doses of venetoclax should 
be administered until resolution. A rapidly rising serum potassium level is a medical 
emergency.

Nephrology (or acute dialysis service) must be consulted/contacted on admission. 
(according to institutional standards to ensure emergency dialysis is available).

Intravenous fluids (e.g., D5 ½ normal saline) should be initiated at a rate of at least 
1 mL/kg/hr rounded to the nearest 10 mL (target: 150200 mL/hr; not50 mL/hr).

Modification of fluid rate should also be considered for individuals with specific 
medical needs.

Monitoring for symptoms or signs of tumor lysis syndrome (e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches,
weakness, paresthesias, mental status changes, confusion, and seizures)
If any clinical features are observed, recheck potassium, phosphorus, uric acid, 
calcium, and creatinine within 1 hour immediately.

Vital signs should be measured at time of all blood draws or any intervention.
The management recommendations in the following table focus on the minimal initial 
responses required.  If a diagnosis of tumor lysis syndrome is established, ongoing 
intensive monitoring and multidisciplinary management will be followed according to 
institutional protocols.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 12
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)
Abnormality
Management Recommendations
Hyperkalemia (including rapidly rising potassium)
Potassium greater than the ULN
•
Perform ECG immediately and commence 
telemetry.
•
Perform nephrology assessment with 
consideration of initiating dialysis.
•
Administer Kayexalate® 60 g (or 
Resonium A® 60 g).
•
Administer furosemide 20 mg IV1.
•
Administer calcium gluconate 100200 
mg/kg IV slowly if there is ECG or telemetry 
evidence of life-threatening arrhythmias.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.
•
If potassium is less than the ULN 1 hour 
later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 1, 2, and 
4 hours later if no other evidence of tumor 
lysis.
Potassium 0.5 mol/L increase from prior 
value (even if potassium is WNL)
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.  If 
there is a further increase 0.2 mol/L in 
potassium, but still less than the ULN, 
manage per potassium greater than the 
ULN.  Otherwise, recheck in 1 hour.
•
Resume per protocol testing if change in 
potassium is 0.2 mol/L and potassium is 
less than the ULN and no other evidence of 
tumor lysis.
•
At the discretion of the investigator, may 
recheck before hospitalization.  If potassium 
is stable or decreased and still WNL, 
hospitalization will be at the discretion of the 
investigator.  Potassium, phosphorus, uric 
acid, calcium, and creatinine must be 
rechecked within 24 hours.
ECGelectrocardiogram; IVintravenous; STAT immediately; ULNupper limit of normal; 
WNLwithin normal limit.


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232/Protocol BH39147, Version 4
Appendix 12
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)
Abnormality
Management Recommendations
Hyperkalemia (including rapidly rising 
potassium) (cont.)
Potassium 6.0 mol/L (6.0 mEq/L) and/or
patient is symptomatic (e.g., muscle cramps, 
weakness, paresthesias, nausea, vomiting, 
and diarrhea)
•
Perform STAT ECG and commence 
telemetry.
•
Perform nephrology assessment with 
consideration of initiating dialysis.
•
Administer Kayexalate® 60 g (or 
Resonium A® 60 g).
•
Administer furosemide 20 mg IV1.
•
Administer insulin 0.1 U/kg IVD25 2 mL/kg 
IV.
•
Administer sodium bicarbonate 12 mEq by 
IV push.
If sodium bicarbonate is used, rasburicase 
should not be used as this may exacerbate 
calcium phosphate precipitation.
•
Administer calcium gluconate 100200 
mg/kg IV slowly if there is ECG or telemetry 
evidence of life-threatening arrhythmias.  Do 
not administer in same IV line as sodium 
bicarbonate.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine every hour STAT.
Hyperuricemia
Uric acid 8.0 mg/dL  (476 mol/L)
•
Consider rasburicase (dose per institutional 
guidelines).
If rasburicase is used, sodium bicarbonate 
should not be used as this may exacerbate 
calcium phosphate precipitation.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.
ECGelectrocardiogram; IVintravenous; STAT immediately; ULNupper limit of normal; 
WNLwithin normal limit.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
233/Protocol BH39147, Version 4
Appendix 12
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)
Abnormality
Management Recommendations
Hyperuricemia (cont.)
Uric acid 10 mg/dL (595 mol/L)
or
uric acid 8.0 mg/dL (476 mol/L) with 25% 
increase and creatinine increase 0.3 mg/dL 
(0.027 mol/L) from pre-dose level
•
Administer rasburicase (dose per 
institutional guidelines).
If rasburicase is used, sodium bicarbonate 
should not be used as this may exacerbate 
calcium phosphate precipitation.
•
Consult nephrology.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.
•
If uric acid 8.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium, 
and creatinine 2 and 4 hours later if no other 
evidence of tumor lysis.
Hypocalcemia
Calcium 7.0 mg/dL
(1.75 mol/L)
and 
patient is symptomatic
(e.g., muscle cramps,
hypotension, tetany,
cardiac arrhythmias)
•
Administer calcium gluconate 50100 mg/kg 
IV slowly with ECG monitoring.
•
Perform telemetry.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.
•
If calcium normalized 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium, 
and creatinine 2 and 4 hours later if no other 
evidence of tumor lysis.
•
Calculate corrected calcium and check 
ionized calcium if albumin is low.
Hyperphosphatemia
Phosphorus 5.0 mg/dL (1.615 mol/L) with
0.5 mg/dL (0.16 mol/L) increase
•
Administer a phosphate binder (e.g., 
aluminum hydroxide, calcium carbonate, 
sevelamer hydroxide, or lanthanum 
carbonate).
•
Notify nephrology dialysis required for 
phosphorus 10 mg/dL)
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 1 hour STAT.
•
If phosphorus 5.0 mg/dL 1 hour later, 
repeat potassium, phosphorus, uric acid, 
calcium, and creatinine 2 and 4 hours later if 
no other evidence of tumor lysis.
ECGelectrocardiogram; IVintravenous; STAT immediately; ULNupper limit of normal; 
WNLwithin normal limit.


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
234/Protocol BH39147, Version 4
Appendix 12
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome in the 
Setting of Treatment with Venetoclax (cont.)
Abnormality
Management Recommendations
Hyperphosphatemia (cont.)
Creatinine
Increase 25% from baseline
•
Start or increase rate of IV fluids.
•
Recheck potassium, phosphorus, uric acid, 
calcium, and creatinine in 12 hours STAT.
ECGelectrocardiogram; IVintravenous; STAT immediately; ULNupper limit of normal; 
WNLwithin normal limit.
Ongoing Dosing with Venetoclax
Management of electrolyte changes from last value at 24-hour intervals after either the 
first dose or dose increase (e.g., 48 or 72 hours) is described below. Note: If the patient 
is hospitalized, no additional doses of ventoclax should be administered until resolution.

For potassium, admit patient for any increase 1.0 mol/L (1.0 mEq/L) or any level
greater than the ULN.
Refer to the management guidelines for electrolyte changes observed within the first 
24 hours after either the first dose or a dose increase (see table).

If a smaller increase in potassium is observed that does not meet the criteria for
admission above, recheck potassium, phosphorus, uric acid, calcium, and creatinine
within 24 hours and confirm no evidence of tumor lysis before further venetoclax
dosing.

For uric acid, calcium, phosphorus, and creatinine, refer to the management
guidelines for electrolyte changes observed within the first 24 hours after either the
first dose or dose increase (see table).


Obinutuzumab or Rituximab, Idasanutlin, and Venetoclax—F. Hoffmann-La Roche Ltd
235/Protocol BH39147, Version 4
Appendix 13
Safety Overview in Solid Tumor Study NP27872, Including 
3 Patients with NHL
Adverse Event
Idasanutlin 
MBP
100 mg QD to
1600 BID
Weekly 
(n48), n (%)
Idasanutlin 
MBP
500 mg BID to 
800 BID
Daily3 (n48), 
n (%)
Idasanutlin 
MBP
100 mg QD to 
500 BID
Daily  5 (n34), 
n (%)
Idasanutlin 
MBP
All Patients 
(n86), n (%)
Thrombocytopenia
7 (15)
7 (47)
16 (47)
30 (32)
Anemia
3 (7)
6 (40)
5 (15)
14 (15)
Nausea
4 (9)
2 (13)
4 (12)
10 (11)
Diarrhea
2 (4)
2 (13)
2 (6)
6 (6)
Febrile neutropenia

2 (13)
4 (12)
6 (6)
Decreased appetite
2 (4)

2 (6)
4 (4)
Asthenia
1 (2)
2 (13)

3 (3)
Leukopenia
1 (2)
1 (7)
1 (3)
3 (3)
Hypokalemia
1 (2)
1 (7)
1 (3)
3 (3)
Fatigue
1 (2)

1 (3)
2 (2)
Vomiting
1 (2)

1 (3)
2 (2)
Abdominal pain

1 (7)

1 (1)
Hyponatremia
1 (2)


1 (1)
Hypophosphatemia


1 (3)
1 (1)
Increased ALT
1 (2)


1 (1)
Dehydration


1 (3)
1 (1)
Pancytopenia

1 (7)

1 (1)
Decreased weight


1 (3)
1 (1)
Tinnitus
1 (2)


1 (1)
Stomatitis
1 (2)


1 (1)
Pyrexia

1 (7)

1 (1)
Pulmonary 
embolism


1 (Grade 5) (3) a
1 (1)
QT prolonged


1 (3)
1 (1)
BIDtwice a day; MBP microprecipitated bulk; NHL non-Hodgkin’s lymphoma; QD once a day.
a The Grade 5 event of pulmonary embolism was assessed by the investigator to be remotely 
related to study treatment in a patient with urothelial cancer that occurred on Day 32.  The 
patient had concurrent thrombocytopenia (highest, Grade 4), anemia, and febrile neutropenia 
(highest, Grade 3) with onset on Day 29.

SAP_001.pdf: 
 
Official Title: 
A Phase Ib/II Study Evaluating the Safety and Efficacy of 
Obinutuzumab in Combination With Idasanutlin and Venetoclax in 
Patients With Relapsed or Refractory Follicular Lymphoma and 
Obinutuzumab or Rituximab in Combination With Idasanutlin and 
Venetoclax in Patients With Relapsed or Refractory Diffuse Large B-
Cell Lymphoma 
NCT Number: 
NCT03135262 
Document Date: 
DAP Version 3: 02-April-2019 
 
 
 


1 
 
DATA ANALYSIS PLAN (DAP) MODULE 2 
Title: 
Harmonized Specifications Document for the InHarmony studies 
Protocol numbers: 
BO29561, BO29562, BO29563, GO29833, GO29834, BH29812, 
BH39147  
Author: 
 
 
 
, Study Statistician & 
 
 
Date 
Approver: 
 
 
 
 
 
 * 
 
Date 
 
 
 
* The approver has ensured that key team members have been involved, contributed and reviewed 
the content of the List of Planned Outputs as described in the DAP Module 2 guideline. 
 
 
 


2 
 
 
TABLE OF CONTENTS 
Page 
1 
INTRODUCTION ...................................................................................................... 6 
2 
DATA HANDLING SPECIFICATIONS ............................................................................. 6 
2.1 
Datacut ................................................................................................ 6 
2.2 
Treatment Definition .............................................................................. 6 
2.3 
Patient Allocation to Reporting Periods ..................................................... 7 
2.4 
Handling of Missing and Incomplete Data .................................................10 
3 
SUBGROUPS..........................................................................................................11 
3.1 
ABC/GCB subtypes for DLBCL patients......................................................11 
3.2 
BCL-2 subgroups for DLBCL patients.........................................................11 
3.3 
Double hit subgroup (FISH) for DLBCL patients ..........................................12 
3.4 
Double positive subgroup (IHC) for DLBCL patients ....................................12 
3.5 
IPI / FLIPI .............................................................................................12 
4 
DEMOGRAPHICS, BASELINE DISEASE CHARACTERISTICS AND PROGNOSTIC MARKERS......13 
4.1 
Demographics ......................................................................................13 
4.2 
Baseline Disease Characteristics and Prognostic Markers ............................13 
5 
EFFICACY ANALYSES ...............................................................................................14 
5.1 
Analysis of Primary Endpoint ..................................................................15 
5.2 
Analysis of Secondary Endpoints .............................................................15 
5.3 
Analysis of Exploratory Endpoints ............................................................16 
5.4 
Interim Analyses ...................................................................................17 
6 
SAFETY ANALYSES ..................................................................................................17 
6.1 
Exposure..............................................................................................17 
6.2 
Adverse Events .....................................................................................18 
6.3 
Concomitant Medications ......................................................................25 
6.4 
Laboratory Data ....................................................................................25 
7 
PHARMACOKINETIC ANALYSES ................................................................................29 
8 
PROTOCOL DEVIATIONS..........................................................................................30 
9 
REFERENCES .........................................................................................................30 
10 
OUTPUT TEMPLATE................................................................................................30 
OUTPUT TEMPLATES ......................................................................................................31 
10.1 
Output 1 Summary of Enrollment by Country and Investigator ....................31 
10.2 
Output 2  Patient Disposition ..................................................................32 
10.3 
Output 3  Analysis Populations................................................................33 


3 
 
10.4 
Output 4  Listing of Patients Excluded from Analysis Populations .................33 
10.5 
Output 5  Summary of Study Drug Completion Status and Reasons of 
Withdrawals from Study Drug .................................................................34 
10.6 
Output 6  Summary of Duration on Treatment and Follow-up......................35 
10.7 
Output 7  Listing of Patients Who Discontinued Early from Study Drug..........36 
10.8 
Output 8  Major Protocol Deviations ........................................................37 
10.9 
Output 9  Listing of Major Protocol Deviations ..........................................38 
10.10 
Output 10  Demographics and Baseline Characteristics...............................39 
10.11 
Output 11  Baseline Disease Characteristics and Prognostic Markers ............41 
10.12 
Output 12  Peripheral Neuropathy History ................................................46 
10.13 
Output 13  Medical History.....................................................................47 
10.14 
Output 14  Listing of Previous Systemic Anti-lymphoma Therapy .................48 
10.15 
Output 15  Previous Systemic Anti-lymphoma Therapy ...............................49 
10.16 
Output 16  Response to Previous Systemic Anti-lymphoma Therapy .............51 
10.17 
Output 17  Listing of Follow-up New Anti-lymphoma Therapy .....................52 
10.18 
Output 18  Follow-up New Anti-lymphoma Therapy ...................................53 
10.19 
Output 19  Concomitant Medication ........................................................54 
10.20 
Output 20 Previous-Concomitant Medications ..........................................55 
10.21 
Output 21 Previous Medications .............................................................55 
10.22 
Output 22  Surgery and Procedure History ................................................55 
10.23 
Output 23  Glossary of Superclass terms, Preferred Terms and Verbatim 
Terms for Concomitant Medications ........................................................56 
10.24 
Output 24  Listing of Study Drug Exposure ................................................57 
10.25 
Output 25  Study Drug Exposure during Induction Phase.............................58 
10.26 
Output 26  Study Drug Exposure During Maintenance/Consolidation Phase...59 
10.27 
Output 27  Glossary of Adverse Event Preferred Terms and Investigator-
Specified Terms ....................................................................................60 
10.28 
Output 28  Listing of Adverse Events ........................................................61 
10.29 
Output 29  Listing of Serious Adverse Events .............................................62 
10.30 
Output 30  Listing of Grade 3, 4, 5 Adverse Events .....................................62 
10.31 
Output 31  Listing of Adverse Events Leading to Discontinuation of Any Study 
Drug....................................................................................................62 
10.32 
Output 32  Listing of Adverse Events Leading to Dose Modification or 
Interruption of Any Study Drug ...............................................................62 
10.33 
Output 33  Listing of Adverse Events Leading to Death ...............................62 
10.34 
Output 34  Listing of Adverse Events of Special Interest ..............................63 
10.35 
Output 35  Listing of Selected Adverse Events ...........................................63 
10.36 
Output 36  Safety Summary ....................................................................64 
10.37 
Output 37  Adverse Events .....................................................................65 
10.38 
Output 38 Grade 3, 4, 5 Adverse Events ...................................................66 
10.39 
Output 39  Serious Adverse Events ..........................................................66 
10.40 
Output 40  Adverse Events Leading to Discontinuation of Any Study Drug .....66 
10.41 
Output 41  Adverse Events of Special Interest ...........................................66 
10.42 
Output 42  Selected Adverse Events.........................................................66 
10.43 
Output 43  Categorical Summary of Adverse Events of Special Interest  ........68 


4 
 
10.44 
Output 44  Categorical Summary of Selected Adverse Events ......................69 
10.45 
Output 45  Adverse Events by Cycle .........................................................69 
10.46 
Output 46  AE Special Interest by Cycle ....................................................69 
10.47 
Output 47  Selected AE by Cycle ..............................................................70 
10.48 
Output 48  Adverse Events by Highest NCI CTCAE Grade .............................70 
10.49 
Output 49 Most Common Adverse Event with Incidence ≥ 5% by Preferred 
Term ...................................................................................................72 
10.50 
Output 50 Most Common Grade 3, 4, 5 Adverse Event with Incidence ≥ 5% 
by Preferred Term .................................................................................72 
10.51 
Output 51 Duration from First Study Treatment Date to Onset of Peripheral 
Neuropathy..........................................................................................73 
10.52 
Output 52  Listing of Deaths ...................................................................74 
10.53 
Output 53  Deaths .................................................................................75 
10.54 
Output 54  Laboratory Test Results Shift Table – Highest NCI CTCAE Grade 
Post-Baseline........................................................................................76 
10.55 
Output 55  Neutrophil Count Recovery.....................................................77 
10.56 
Output 56  Vital Signs Change from Baseline by Visit ..................................78 
10.57 
Output 57 ECG Results Shift Table ...........................................................79 
10.58 
OUTPUT 58  Listing of Time-to-Event Endpoints ...........................................81 
10.59 
Output 59  Listing of Tumor Response Assessment.....................................82 
10.60 
Output 60  CR Rate at End of Induction ....................................................83 
10.61 
Output 61  OR Rate at End of Induction ....................................................85 
10.62 
Output 62  CR Rate at 12 Months after Initiation of Induction......................87 
10.63 
Output 63  Best Overall Response Rate ....................................................88 
10.64 
Output 64  Concordance Analysis Between the IRC Determined and the 
Investigator Determined CR Status ..........................................................89 
10.65 
Output 65  Duration of Response ............................................................90 
10.66 
Output 66  Kaplan-Meier Curve of Duration of Response ............................91 
10.67 
Output 67  Waterfall Plot of Best Change from Baseline (%) in Indicator 
Lesion Size ...........................................................................................92 
10.68 
Output 68  Spider Plot of Change from Baseline (%) in Indicator Lesion Size 
over Time ............................................................................................93 
10.69 
Output 69  Swimmer Plot of Time to Response and Duration of Response .....94 
10.70 
Output 70  Progression-Free Survival .......................................................96 
10.71 
Output 71  Kaplan-Meier Curve of Progression-free Survival........................96 
10.72 
Output 72  Event-Free Survival................................................................97 
10.73 
Output 73  Kaplan-Meier Curve of Event-Fee Survival.................................97 
10.74 
Output 74  Disease-Free Survival .............................................................97 
10.75 
Output 75  Kaplan-Meier Curve of Disease-Fee Survival ..............................97 
10.76 
Output 76  Summary of Overall Survival ...................................................98 
10.77 
Output 77  Kaplan-Meier Curve of Overall Survival.....................................98 
 
 


5 
 
 
LIST OF APPENDICES 
Page 
Appendix 1 
Region Categories .................................................................................99 
DAP M 2 UPDATE LOG .................................................................................................. 100 
 
 


6 
 
 
1 Introduction 
The purpose of this document is to define the specifications required for the analyses and output 
production for the InHarmony studies (BO29561, BO29562, BO29563, GO29833, GO29834, BH29812). 
This document should be referred to alongside the harmonized List of Planned Outputs (LoPO) 
spreadsheet. 
 
2 Data Handling Specifications 
2.1 
Datacut 
For primary CSR analyses, each study will have data cut based on the ‘clinical cutoff date’ (CCOD). Data 
collected on or before the CCOD will be included in. 
For the datacut rules refer to the instructions for ‘fixed-cutoff datacut’ type on the Global Data 
Standards Repository (GDSR) Browser - Rules and Definitions for Analysis Data Cuts.   
2.2 
Treatment Definition 
“Chemotherapy” (CT) is defined as at least one dose > 0 of Doxorubicin, Bendamustine, 
Cyclophosphamide, Vincristine or Prednisone/Prednisolone/Methylprednisolone (=steroids). Steroids 
are only counted as part of Chemotherapy if they were given as part of CHOP according to the study 
drug eCRF page (EX domain).  
“Study treatment” is defined as at least one dose > 0 of any component of combination therapy (e.g. 
obinutuzumab, atezolizumab, polatuzumab vedotin, venetoclax, lenalidomide, idasanutlin) or 
chemotherapy.  
2.2.1 Treatment Groups 
The treatment arm labels to be included in the outputs are displayed as described below in following 
order: 
Atezolizumab will be replaced by ‘Atezo’ 
Obinutuzumab will be replaced by ‘G’ 
Rituximab will be shown as ‘R’ 
Polatuzumab vedotin will be replaced by ‘P’ 
Venetoclax will be replaced by ‘V’ 
Idasanutlin will be replaced by ‘I’ 
Lenalidomide will be replaced by ‘L’ 
Bendamustine will be replaced by ‘B’ 


7 
 
CHOP will be shown as ‘CHOP’ 
 
We also should show dose levels after each treatment. So for illustration purposes, a treatment arm 
of “Obinutuzumab 1000mg + Polatuzumab vedotin 1mg/kg + Lenalidomide 10mg” would be shown as 
“G (1000MG)  P (1MG/KG)  L (10MG)”, or “Obinutuzumab 1000mg + Atezolizumab 1mg + CHOP” would 
be shown as “Atezo (1MG) - G (1000MG) - CHOP”. 
 
2.2.2 
New Anti-lymphoma Treatment 
A new anti-lymphoma treatment (NALT) is defined as any treatment reported on the ‘Follow-up New 
Anti-Lymphoma Therapy’ or ‘New Anti-Lymphoma Surgery and Procedure’ eCRF pages.  
If a patient has more than one, use the first date from any of the NALTs.   
 
2.3 
Patient Allocation to Reporting Periods 
The following definitions will be used to allocate AEs and laboratory data to study periods. The same 
definitions will also be used in other cases where applicable, e.g. patient disposition. Adverse events 
are assigned to the study periods based on the AE onset date. 
2.3.1 
Study Day 1 
Study day 1 is the day of first administration of any study treatment (see Section 2.2).  
2.3.2 
Before Therapy 
 Any AE that occurs before study day 1 is considered to have occurred before therapy unless the end 
date is after the date of first study drug intake and the most extreme intensity is higher than the initial 
intensity (see treatment emergent rules in Section 6.2.1).  For handling of pre-dose laboratory 
assessments, see definition of baseline (Section 2.3.3). 
 
2.3.3 
Baseline 
The baseline assessment is the last valid assessment in the 28 day window before first administration 
of a study treatment component (see Section 2.2 for study treatment definition). If no time is linked 
to a laboratory or vital sign assessment at study day 1, it is assumed that the assessment was done 
before the drug administration. For patients who never received study treatment, baseline is defined 
as the last valid assessment prior to or on the day of enrolment – note though that this is only 
applicable to parameters not being reported out using the safety population, as otherwise these 
patients are anyway excluded. 
 
2.3.4 
Study Periods 
All periods below end at the study completion or early withdrawal visit. For all periods, NALT refers to 
the first occurrence of NALT post study-treatment. 


8 
 
If a patient is ongoing in any period at the time of reporting, then consider last known alive date as 
the period end date just for the purpose of duration calculations and to ensure events are still mapped 
to this period. 
 
2.3.4.1 
Treatment Period 
The treatment period will be defined as the time between study day 1 and last administration of any 
component of the study treatment + 28 days or if a NALT starts within 28 days, then treatment period 
ends one day prior to the start of the NALT.  
 
2.3.4.2 
Induction Treatment Period 
Only relevant for studies with a maintenance or consolidation treatment period: For patients receiving 
maintenance or consolidation therapy, the induction treatment period will be defined as the time 
between study day 1 and 1 second before the first dose of maintenance or consolidation therapy, or 
if a NALT starts prior to the start of maintenance or consolidation, the induction treatment period 
ends one day prior to the start of the NALT. For those not receiving maintenance or consolidation 
therapy, the induction treatment period follows the same rules as given above for the treatment 
period (see Section 2.3.4.1).  
 
2.3.4.3 
Maintenance or Consolidation Period  
Only relevant for studies with a maintenance or consolidation treatment period: The maintenance or 
consolidation period starts on the day of the patient’s first dose of any treatment in maintenance or 
consolidation  and ends one day prior to the start of NALT or 28 days after the last dose of any 
maintenance or consolidation  treatment.  
Note: Safety outputs produced on the maintenance or consolidation period will only show the 
maintenance or consolidation treatment arm, and these outputs will only include those patients that 
enter the maintenance or consolidation period. 
 
2.3.4.4 
Post treatment Follow-up Period  
The follow-up period refers to the phase of the study that is post study treatment. Only patients who 
have an induction treatment completion eCRF page completed (for patients without a dose of 
maintenance or consolidation treatment) and a maintenance/consolidation treatment completion 
eCRF page completed (for patients who received maintenance or consolidation treatment) will be 
included in the follow-up period. 
The follow-up period starts the day after the end of the treatment period (see Section 2.3.4.1). The 
follow-up period ends at the date recorded on the post treatment follow-up phase completion eCRF 
page, or at the last recorded date in the eCRF for patients ongoing in the period.  
 
2.3.4.5 
Survival Follow-up 


9 
 
Survival follow-up starts the day after the follow-up period ends. Survival follow-up ends at the date 
recorded on the study completion/early discontinuation eCRF page, or at the last recorded date in the 
eCRF for patients ongoing in the period.  For patients who withdrew from induction, post-induction or 
follow up phase due to PD, survival follow up starts the day after the date of study completion/early 
discontinuation.   
 
2.3.5 
Treatment Cycle 
A treatment cycle starts on the day of the first administration of a study treatment component and 
ends the second before the start of the next cycle. For example, cycle 1 will start at the first valid cycle 
1 study drug administration and will end at the start date of the cycle 2 dose (or cycle 3, or 4 etc. if 
cycle 2 dose is missing) minus 1 second. The last cycle ends when the treatment period ends. 
 
2.3.6 
Observation Time 
Observation time is the time between enrolment date and the day of death or the last assessment in 
the database (=last known alive date, see Section 2.3.7).   
 
2.3.7 
Last known alive date 
The last known alive date is derived from the latest of dates in the following CRF fields: AE start and 
end dates (including start and end dates of IRR symptoms), tumor response assessment dates, study 
drug exposure dates, lab assessment dates, vital signs assessment dates, ECG assessment dates, 
survival follow-up pages where the status is confirmed as ‘ALIVE’, death date, enrolment date and 
date of informed consent.  
As per STREAM standard rules only partial dates from tumor response or death data are included. In 
this case missing day is replaced by 1st of the month if only month and year are given. Dates where 
month and/or year are missing are not imputed but excluded. For partial death dates STREAM applies 
the following additional rule: If month/year of last known alive date from all other dates* is equal to 
the month/year of partial death date then last known alive date is set to * + 1 day. 
 
2.3.8 
Study Drug Exposure Time 
Study drug exposure time is defined as the last study treatment administration end date (where dose 
is > 0) minus the first study treatment administration date (where dose is >0) plus 1 day. This could be 
calculated individually by study drug or collectively for all study drugs.  
 
2.3.9 
General Rules 
In the analysis of laboratory data by cycle, if there are several observations per cycle the last value is 
used. If there are two valid assessments per day and no time is available, the scheduled valid 
assessment will be taken. In the analysis of follow-up data by visit, patients will be assigned to visits 
using the clinical planned event (CPE). 


10 
 
All derivations of duration are initially done based on days and converted to months and years if 
needed using 30.4375 and 365.25, respectively, as denominator if not otherwise specified. Unless 
otherwise specified, months will be used in outputs. 
Computation of durations: any duration in days is computed as end date minus start date + 1 day. 
 
2.4 
Handling of Missing and Incomplete Data 
Laboratory values with either a ‘<’ or ‘>’ included in the lab result will have the inequality symbol 
removed and 0.001 will be either subtracted (when ‘<’ is included) or added (when ‘>’ is included) to 
the numeric value of the result for the purpose of summarizing (the original value will be displayed in 
listings). For example, laboratory values given as “ <7” or “>7” are treated as follows: 
Recorded data value 
When reported as numerical value 
When reported in a listing 
<7 
6.999 
<7 
>7 
7.001 
>7 
 
Each AE is assigned to a time period, i.e. pre-treatment, during treatment (could be further split as 
induction/maintenance or consolidation) or follow-up (Section 2.3).  
In listings AEs with partial dates will be shown by having a missing study day. 
For AEs and concomitant treatment (not including NALTs), the following rules will be applied: 
• 
Incomplete onset dates for AEs will be handled as follows: 
o in case the day is missing, it is replaced by the 1st of the month, unless a trial 
treatment exists within that month (not necessarily first treatment) then set to the 
date of that treatment 
o in case the day and month are missing, they are replaced by 1st of January, unless 
the first trial treatment exists within that year then set to the date of that treatment 
o in case imputation leads to the AE occurring before treatment, the onset date will be 
set to the treatment start date 
o resolution dates are checked to ensure imputed onset dates do not become later 
than the resolution date 
• 
In case AE most extreme intensity is missing, it will be replaced by the initial intensity 
• 
AEs with missing grades will be included in the summaries for grade 3 to 5 AEs 
• 
AEs with missing relationship to trial medication are included in the summaries of related AEs 
• 
AE with missing seriousness will be included in all summaries of serious adverse events (SAEs)  


11 
 
• 
For partial concomitant treatment start dates the 1st of the month will be imputed (if only day is 
missing) or 1st January will be imputed (if day and month are missing).  
 
Partial dates of NALT will be imputed as follows, in order to use the most conservative (i.e. earliest) 
date without shortening the treatment period: 
• 
If only the year is available then the difference between 1st January of the year and the last 
administration date of any component of study treatment will be checked: if the difference 
is >28 days then 1st January will be imputed; otherwise, if the difference is ≤28 days then the 
date of the last study drug administration* + 29 days will be imputed. 
• 
If the month and year are both available then the difference between the 1st of the month and 
last study drug administration will be checked: if the difference is >28 days then the 1st of the 
month will be imputed; otherwise, if the difference is ≤28 then the date of the last study drug 
administration* +29 days will be imputed. However, if this leads to the imputed date having the 
month following the month in the partial date, then the last day of the partial date month will be 
imputed. 
*For B-cell and Immunoglobulin outputs, use the last antibody administration date; for other outputs use the last of all 
study medication dates. 
 
Partial study drug administration dates will not be imputed. A valid study drug administration record 
is one with a complete begin date and a >0 actual dose for antibody or chemotherapy. Only valid 
records should be used for all analyses where information of study drug administration is used. 
Handling of partial or missing dates for other assessments are discussed within their corresponding 
sections. 
 
3 Subgroups 
 
Definitions of potential subgroups are included in this section. Please refer to LOPO to determine 
which analyses these subgroups are applied to. 
3.1 
ABC/GCB subtypes for DLBCL patients 
DLBCL cell-of-origin (COO) prognostic subgroups (ABC and GCB), defined using gene expression 
profiling, have been associated with different clinical outcomes in patients receiving R-CHOP for DLBCL, 
with GCB subgroups demonstrating a better prognosis than ABC. DLBCL patients will be classified as 
having the ABC or GCB cell of origin subtypes.  
3.2 
BCL-2 subgroups for DLBCL patients 
BCL-2 overexpression has been shown to have prognostic value in DLBCL. DLBCL patients will be 
classified as having high/low BCL-2 expression. 


12 
 
3.3 
Double hit subgroup (FISH) for DLBCL patients 
Approximately 9%−17% of patients with newly diagnosed DLBCL harbor an underlying MYC 
rearrangement, and these patients are at high risk of treatment failure with R-CHOP. A subset of 
patients with MYC-positive DLBCL also harbors an additional BCL2 rearrangement. These “double-hit” 
lymphomas are associated with a very poor outcome Subgroup of ‘Double hit’ DLBCL patients vs. rest 
of DLBCL patients will be set up. 
3.4 
Double positive subgroup (IHC) for DLBCL patients 
Overexpression of BCL-2 and Myc in DLBCL has also been observed in the absence of translocation. 
This “double-positive” DLBCL status is also associated with worse prognosis. Therefore subgroup of 
double positive (IHC) DLBCL patients will be set up.  
Cell of Origin (COO) and BCL-2 for DLBCL patients: COO and BCL-2 based subgroups will be set up for 
DLBCL patients: ABC-BCL-2 high, ABC-BCL-2 low, GCB-BCL-2 high, GCB-BCL-2 low.  
Cell of Origin (COO) and Myc for DLBCL patients: COO and Myc based subgroups will be set up for 
DLBCL patients: ABC-BCL-2 positive-MYC positive, GCB-BCL-2 positive-MYC positive. 
 
3.5 
IPI / FLIPI  
For FL patients FLIPI based subgroups may be created. For DLBCL patients IPI based subgroups may be 
created.  
 
Applicable 
for Study 
BO29563 
Atezo-G-
B 
BO29563 
Atezo-
G/R-CHOP 
BO29562 
BO29561 
GO29833 GO29834 
BH29812  
ABC/GCB 
  
x 
  
x 
  
  
x 
BCL-2 
  
x 
  
x 
  
  
x 
Double hit 
  
x 
  
x 
  
  
x 
Double 
positive 
  
x 
  
x 
  
  
x 
COO&Myc 
  
x 
  
x 
  
  
x 
MRD 
x 
x 
x 
x 
  
  
x 
IPI/FLIPI 
x 
x 
x 
x 
  
  
x 
p53 
 
 
 
 
 
 
x 
CD8 
x 
x 
x 
x 
  
  
  
PDL1 
x 
x 
x 
x 
  
  
  
CD58 
 
x 
 
 
 
 
 
CD79 
 
 
 
x 
 
 
 
 
 
 


13 
 
4 Demographics, Baseline Disease Characteristics and Prognostic 
Markers  
 
4.1 
Demographics 
Demographics are collected at enrollment and generally may include: 
• 
Gender 
• 
Age at BL 
• 
Race 
• 
Ethnicity 
• 
Weight 
• 
Height 
• 
BMI (= body mass index) 
• 
BSA (= body surface area) 
• 
ECOG Performance score at BL 
 
4.2 
Baseline Disease Characteristics and Prognostic Markers 
Baseline Disease Characteristics and Prognostic Markers are baseline conditions specifically related to 
the indication under study. These may include: 
• 
Histology/ pathologic diagnosis  
• 
Ann Arbor stage  
• 
Time since first histologic or pathologic diagnosis 
• 
Biomarker status from tumor tissue or blood samples at BL 
o COO 
o BCL-2 
o MYC 
o COO and BCL-2 
o BCL-2 and MYC(FISH) 
o BCL-2 and MYC(IHC) 
o COO and BCL-2 and MYC 


14 
 
o P53 (in studies with idasanutlin) 
• 
IPI 
• 
FLIPI  
• 
Follicular Lymphoma Grade 
• 
Any B symptoms at BL 
• 
Individual B-symptoms, i.e. fever, weight loss, night sweats, at BL 
• 
Bulky disease (threshold 70 mm) at BL 
• 
Number of Indicator Lesions at BL 
• 
Number of non-Indicator Lesions at BL 
• 
Spleen Assessment at BL: Palpable yes/no or >13 cm in vertical length vs. <=13 cm (r/r DLBCL/FL) 
• 
Liver Assessment at BL : Palpable yes/no 
• 
SPD of Indicator Lesions at BL 
• 
Number of prior anti-lymphoma therapies 
• 
Prior radiotherapies 
• 
Prior surgeries or procedures 
• 
Serum LDH at BL(>normal vs. <=normal) 
• 
Extranodal Involvement at BL yes/no 
• 
If yes, Number of extranodal sites at BL  
• 
Bone Marrow Involvement 
• 
Status (relapsed/refractory or previously untreated)  (BO29563) 
• 
PET score at BL 
• 
Presence of FDG avid lesions representing lymphoma at BL yes/no (detected by PET scan) 
• 
Evidence of FDG avid disease in bone marrow at BL yes/no (detected by PET scan) 
 
5 Efficacy Analyses 
The efficacy analyses will be performed on the efficacy evaluable population, which includes all 
patients who received at least one dose of any components of the combination during the expansion 


15 
 
phase. Patients who received any study drugs at the RP2D during the dose-escalation/safety run-in 
phase may be pooled with the efficacy evaluable population depending on protocol.  
For studies which have specific definition of the efficacy population, refer to protocol for the definition. 
For example, Study BH29812:  The primary and secondary efficacy analyses will include all patients 
enrolled in the expansion phase. 
 
5.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the proportion of patients achieving a CR at EOI, as determined by 
the IRC on the basis of PET-CT scans according to modified Lugano 2014 criteria.  Point estimates will 
be presented, along with the corresponding 90% Clopper-Pearson exact CIs.  Patients without a 
post-baseline tumor assessment will be considered non-responders. 
 
5.2 
Analysis of Secondary Endpoints 
The secondary efficacy analyses will be estimation of the proportion of patients who achieve each of 
the following endpoints:  
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of CT scans alone 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the 
investigator on the basis of PET-CT scans 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the 
investigator on the basis of CT scans alone 
• 
Best response of CR or PR during the study, as determined by the investigator on the basis of CT 
scans alone 
 
Study BO29563: 
• 
CR at EOI, as determined by the investigator on the basis of PET-CT scans using modified Lugano 
2014 criteria 
• 
CR at EOI, as determined by the IRC and by the investigator on the basis of PET-CT and CT scans  
using modified Cheson 2007 criteria 
• 
Objective response (defined as a CR or PR) at EOI, as determined by the IRC and by the 
investigator using modified Lugano 2014 criteria and modified Cheson 2007 criteria 
• 
Best objective response (defined as a CR or PR) during the study (including all tumor 
assessments), as determined by the investigator using modified Cheson 2007 
 
Point estimates will be presented, along with the corresponding two-sided 90% Clopper-Pearson exact 
CIs.  Patients without a post-baseline tumor assessment will be considered non-CRs and non-
responders, respectively. 


16 
 
 
5.3 
Analysis of Exploratory Endpoints 
Exploratory efficacy analyses will include estimation of the proportion of patients achieving each of 
the following endpoints:  
• 
For patients who have positive PET scans at EOI:  CR at 12 months, as determined by the IRC 
and by the investigator on the basis of PET-CT scans 
• 
CR at 12 months, as determined by the investigator on the basis of CT scans alone (BO29561) 
• 
CR at 12, 24, and 30 months in patients with previously untreated FL, as determined by the 
investigator using modified Cheson 2007 criteria (BO29563) 
• 
Additional descriptive analysis based on TP53 status will be performed on the following 
endpoint: CR at EOI, as determined by the IRC on the basis of PET-CT scans (BH29812) 
 
Point estimates will be presented, along with the corresponding two-sided 90% Clopper-Pearson 
exact CIs.  Patients without a post-baseline tumor assessment will be considered non-CRs and 
non-responders, respectively. 
Exploratory efficacy analyses will also be performed on the following endpoints:  
• 
PFS, defined as the time from initiation of study treatment to first occurrence of disease 
progression or relapse, as determined by investigator on the basis of CT scans alone, or death 
from any cause 
• 
EFS, defined as the time from initiation of study treatment to any treatment failure, including 
disease progression or relapse, as determined by investigator on the basis of CT scans alone, 
initiation of new anti-lymphoma therapy, or death from any cause, whichever occurs first 
• 
DFS, defined, among patients achieving a CR, as the time from the first occurrence of a 
documented CR to relapse, as determined by the investigator on the basis of CT scans alone, or 
death from any cause, whichever occurs first 
• 
DOR, defined as the time from the initial response to disease progression or death among 
patients who have experienced a CR or PR during study (Study BO29561/BO29562).   
• 
OS, defined as the time from initiation of study treatment to death from any cause 
 
PFS, EFS, DFS, DOR, and OS will be summarized descriptively using the Kaplan-Meier method (Kaplan 
and Meier 1958).  For the PFS, EFS, and DFS analyses, data for patients without an event of interest 
will be censored at the date of the last tumor assessment.  For the PFS and EFS analyses, data for 
patients without post-baseline tumor assessments will be censored at the date of initiation of study 
treatment plus 1. For the DFS analysis, data for patients without a tumor assessment after the first CR 
will be censored at the date of first CR tumor assessment + 1 day. For the DOR analysis, data for 
patients without a tumor assessment after the Objective Response (OR) of CR or PR will be censored 
at the date of OR tumor assessment +1 day. For the OS analysis, data for patients who have not died 
will be censored at the date the patient was last known to be alive.  Where medians are reached, the 
corresponding estimated median will be provided, along with the 95% CI using the method of 


17 
 
Brookmeyer and Crowley (1982).  In addition, landmark estimates of the proportion of patients who 
are event free at 6 months, 9 months, 1 year, and 2 years will be provided, along with 95% asymptotic 
CIs using Greenwood’s formula for standard errors. 
 
5.4 
Interim Analyses 
It is anticipated that at least one interim analysis will be conducted during the expansion phase of the 
study, when at least 15 patients in one treatment arm have been evaluated for PET-CT−defined CR at 
the EOI.  
 
6 Safety Analyses 
Safety analyses will be based on all patients who received at least 1 component of study medication. 
For safety analyses, patients will be reported by the treatment actually received. Patients who only 
received certain treatments from a combination group, but not all, will be reported by the planned 
treatment group.  
Study data will be summarized separately for each phase. Data from the dose-escalation/safety run-
in phase will be summarized by cohort (assigned dose level). Data from the expansion phase will be 
summarized by histological subtype (i.e., FL or DLBCL) and treatment group if applicable. 
 
6.1 
Exposure  
Exposure summaries will be done by study period, i.e. there will be separate outputs for induction and 
post-induction phase. Exposure summaries will also be done by cycle if necessary. 
 
6.1.1 
Extent of Exposure to Study Drug 
At least one component of study treatment (i.e. obinutuzumab, rituximab, atezolizumab, polatuzumab 
vedotin, venetoclax, lenalidomide, idasanutlin or chemotherapy as defined in section 2.2) per cycle 
requires a received dose of >0 to be considered as a received cycle.  
 
 
6.1.2 
Dose Intensity 
The dose intensity will be calculated based on the total received dose as compared to total planned 
dose (based on planned dose of first intake). Patients who withdrew prematurely from one study drug 
component but are still receiving other components of the study drug will be included in the 
calculation of the dose intensity up until the last day on which they received any study drug 
component.  


18 
 
E.g a patient in Atezo-G-Benda arm in BO29563 in induction had 5 doses of G with last dose on Cycle 
3 Day 1, and 7 doses of Bendamustine with last dose on Cycle 4 Day 1. Number of expected doses for 
G would be 6, dose intensity for G would be 5 * 1000 mg / 6 * 1000 mg. 
The intensity categories are: <60%, 60 - <80%, 80 - <90%, >=90%, Missing. Summary statistics (mean, 
s.d., median, range) will also be used to summarize the dose intensity. 
Dose intensity will be summarized separately for the induction and post-induction phase. For drugs in 
Prednisone category in BO29563, i.e. Methylprednisolone, Prednisone, Prednisolone and 
Dexamethasone, dose intensity is calculated for the whole category as number of actually received 
doses divided by number of expected doses up to the last time point any component of study drug 
was received.  
 
6.2 
Adverse Events 
 
6.2.1 
General AE Reporting 
Listings will include all AEs. A flag will indicate to which study period an AE is assigned to: before 
treatment, initial/induction treatment, maintenance/consolidation treatment or follow up. 
Study periods are as defined in Section 2.3.4. An AE is assigned to a period using the AE onset date, 
Unless otherwise specified, AE and SAE summary tables will be restricted to those that are treatment 
emergent, defined as starting on or after the day of first dose of any drug. For summary tables on the 
follow-up period, no upper time window is implemented, that is, all AEs from start of follow-up 
onwards will be included. 
Generally AE will be summarized by study period. 
In addition selected adverse events and AESI (see categories in subsequent tables) may be summarized 
by treatment cycle. An AE will be assigned to a cycle based on the AE onset day relative to cycle start 
day. Cycle start day is the first day on which any study medication was administered. AEs with onset 
on cycle start day will be included in the respective cycle. 
In studies BO29561, BO29562 and BO29563 AESI based on tickbox in CRF page and on  causality to 
any study drug will be reported separately  . 
 
6.2.2 
Selected AEs and AE of Special Interest (AESI) 
Selected AE and AESI were defined based on the clinical experience with study treatment components 
that represent an IMP. Also anticipated potentially overlapping toxicities as specified in respective 
study protocols need to be taken into account. 
Definitions for selected AE and AESI are provided in subsequent tables.  
 
 














25 
 
6.3 
Concomitant Medications 
Outputs for concomitant medications will include any treatment reported on the “Concomitant 
Medications” form eCRF pages, with additional pages included as required per study. Prophylactic 
medication and premedication, such as anti-coagulant agents including aspirin and LMWHs, will be 
summarized separately. 
 
6.3.1 
Corticosteroids 
For any analyses requiring identification of corticosteroids we will use the company standard 
‘corticosteroids’ drug 
basket 
created 
by 
the 
Drug 
Basket Committee 
(DBC) 
at: 
http://we2.collaboration.roche.com/team/2012137a/SitePages/Default.aspx. We will use the full list 
of terms from this basket. 
For atezolizumab contained studies, impact of steroids on atezolizumab and IRR prevention will be 
explored. 
6.4 
Laboratory Data 
Laboratory data that have been obtained will be converted to System International (SI) units. Grading 
system will be from NCI-CTC version 4. Where normal ranges are required to be converted, the Roche 
References Ranges will be used (cf. gcp_spt000144).  The grading will be defined as follows:  
Project-specific Gradings: 
Parameter 
SI Unit 
Grade 4 Low 
Grade 3 Low 
Grade 2 Low 
Grade 1 Low 
LYMPH 
10**9/L 
< 0.2 
0.2 to < 0.5              
0.5 to < 0.8         
0.8 to < 1        
NEUTR 
10**9/L 
< 0.5 
0.5 to < 1            
1 to < 1.5           
1.5 to < 1.8      
CRCL 
mL/min        
< 15                  
15 to < 30            
30 to < 60           
60 to < LLN        
 
Parameter 
SI Unit 
Grade 1 High 
Grade 2 High 
Grade 3 High 
Grade 4 High 
LYMPH 
10**9/L 
- 
> 4 to 20                
> 20                    
- 
NEUTR 
10**9/L 
- 
- 
- 
- 
CRCL 
mL/min        
- 
- 
- 
- 
 
6.4.1 
Hematology and Chemistry Laboratory Data 
Summary tables will be produced for the hematology and chemistry laboratory parameters 
(LBCAT=HEMATOLOGY, LBCAT=CHEMISTRY). 
 
6.4.2 
General Derivation Rules on Absolute Counts/Percentages 
The laboratory parameters such as lymphocytes, eosinophils, basophils and monocytes might be 
recorded as absolute count or percentage in the eCRF. If on the same day and time, the absolute count 


26 
 
of the laboratory parameter is missing but the percentage is not missing, then the absolute count will 
be derived from the percentage to absolute count as follows:  
ABSOLUTE_COUNT = PERCENTAGE x WBC, where WBC is white blood cell (LBTESTCD=WBC) and 
expressed as cells per microliter (LBSTRESU = 10^9/L, or 10^3/uL). Note that WBC values collected on 
the same date and time will be used in the derivation of absolute count. If the WBC value is missing 
on the same day and time then the absolute count of the laboratory parameter will also be missing. 
Note: If a patient has multiple values of the same assessment on the same day and at the same time, 
the minimum values recorded will be retained for the calculation of the absolute counts. 
 
6.4.3 
Absolute Neutrophil Counts 
Neutrophil count recovery is defined as absolute neutrophil count ANC ≥ 1.0 × 109/L, given 
ANC was collected after the patient has had his last dose of antibody, and ANC < 1.0 × 109/L 
at the last previous visit before EOT. Neutrophil count recovery (ANC ≥ 1.0 × 109/L) should 
not be immediately followed by ANC < 1.0 × 109/L, or a missing assessment, but only by ANC 
≥ 1.0 × 109/L at the next visit. 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
OUTCOME 
< 1.0 × 109/L 
≥ 1.0 × 109/L 
missing 
missing 
Not 
RECOVERED 
< 1.0 × 109/L 
≥ 1.0 × 109/L 
≥ 1.0 × 109/L 
< 1.0 × 109/L 
RECOVERED 
< 1.0 × 109/L 
≥ 1.0 × 109/L 
< 1.0 × 109/L 
< 1.0 × 109/L 
NOT 
RECOVERED 
< 1.0 × 109/L 
≥ 1.0 × 109/L 
missing  
< 1.0 × 109/L 
NOT 
RECOVERED 
 
Time to neutrophil count recovery is defined as the number of days between the date of last dose of 
antibody and the date of single recovery. In case a patient was not depleted at last dose of antibody, 
no time to single recovery will be calculated. Where no ANC value occurs at the last drug intake, the 
next valid ANC assessment will be taken. For instance, ANC values at the EOT visit might be used 
instead if there is no ANC assessment on the day of the last dose of the antibody. If there are multiple 
ANC records at a visit, the last ANC assessment will be retained provided there is a valid identifier. If a 
study does not have a valid identifier, the lowest ANC value at the visit will be used instead. 
 
 
6.4.4 
Serum Creatinine Clearance 
Serum creatinine clearance will be derived using the Cockcroft-Gault formula (where needed). 
 
6.4.5 
Hy’s Law Cases 


27 
 
Patients with ALT > 3x BL  OR AST > 3x BL AND Total Bilirubin >2xULN within 14 days, at any time for 
post baseline measurement, will be investigated for potential Hy’s Law cases in a patient listing.  
A summary table showing the proportion of patients with elevated ALT, AST, ALP and Total Bilirubin 
will also be produced. 
 
6.4.6 
B-Cell Depletion and Recovery  
B-cell depletion is defined as CD19 B-cell count < 0.07x109/L and can only occur after at least one dose 
of antibody has been administered.  
Time to depletion is defined as the number of days between the first intake of study drug and the date 
of first depletion (assessments at study day 1 after start of the infusion are considered as after 
baseline). 
Note that CD19 B-cells with no time record are assumed to be collected before the first treatment 
dose.  Hence B-cells with no associated time that are collected on the same day as the last dose of the 
antibody will be assumed to be pre-dose. 
 
6.4.6.1 
B-cell recovery 
B-cell recovery is defined as CD19 B-cell count  >= 0.07x109/L, and B-cell was collected after LAA, the 
patient’s B-cells were previously depleted and recovery is not followed exclusively by further depletion, 
i.e. B-cell recovery at a visit cannot be immediately followed by B-cell depletion, or a missing 
assessment, but only by recovery at the next visit. Assuming the situation 4 B-cell assessments at 4 
visits:  
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
OUTCOME 
DEPLETED 
RECOVERED 
missing 
missing 
Not 
RECOVERED 
DEPLETED 
RECOVERED 
RECOVERED 
DEPLETED 
RECOVERED 
DEPLETED 
RECOVERED 
DEPLETED 
DEPLETED 
NOT 
RECOVERED 
DEPLETED 
RECOVERED 
missing  
DEPLETED 
NOT 
RECOVERED 
   
Time to B-cell recovery is defined as the number of days between the date of LAA and the date of 
single recovery. In case a patient was not depleted at last dose of antibody, no time to single recovery 
will be calculated. Where no CD19 value occurs at LAA, the next valid CD19 assessment will be taken. 
For instance, CD19 values at the EOT visit might be used instead if there is no CD19 assessment on the 
day of LAA. If there are multiple CD19 records at a visit, the last CD19 assessment will be retained 
provided there is a valid identifier. If a study does not have a valid identifier, the lowest CD19 value at 
the visit will be used instead. 
The Nadir is the lowest absolute CD19 value for the patient across all visits after baseline (assessment 
at study day 1 after start of the infusion is considered as after baseline). The time to nadir is the study 


28 
 
day of the earliest occurrence of the nadir value. In case of consecutive visits with the same value, the 
earliest date of assessments will be used. The time to nadir will be calculated as the study day of the 
earliest occurrence of the nadir value. 
The parameters to be summarized will be CD19 + B-cell depletion and recovery over time, time to 
depletion, duration of depletion, time to recovery, and time to follow up without recovery. 
Disease progression will be taken into account in the summary of B-cell recovery: patients with PD 
before B-cell recovery or PD within 45 days after recovery will be accounted for in ‘Recovery with PD’; 
other patients will accounted for in ‘Recovery without PD’.  Time to B-cell recovery will be summarized 
separately for all patients and for patients who were in response at the time of recovery (no PD before 
or within 45 days from recovery). Patients with PD before recovery or within 45 days after recovery 
will be censored at the minimum of progressive disease date and B-cell recovery date. 
B-cell depletion and recovery will be assessed up to the first day of NALT. Missing CD19 values might 
be recorded as "NOT DONE" or ".". 
 
6.4.7 
T cell and NK cell counts 
The summary of the mean (+/-SD) for the T cell (CD3, CD4, CD8)  and NK cell counts (CD16 and CD56)  
will be shown over time in a figure where T-cell and NK-cell data are available. 
 
6.4.8 
PD-L1 (CD274), PD-1, B7-1( CD80) 
The appropriate outputs, summary or listing, will be produced for studies with atezolizumab. 
 
6.4.9 
 Pharmacokinetik Samples, HAHA, HACAand ATA 
PK serum concentration of obinutuzumab, atezolizumab, lenalidomide, polatuzumab vedotin, 
venetoclax, Idasanutlin will be analysed.  Immunogenicity to obinutuzumab, atezolizumab, Rituximab 
and polatuzumab vedotin will be explored analytically based on the immune response relative to the 
HAHA, HACA or ATA prevalence at baseline.    
 
6.4.10 Immunoglobulins  
 
6.4.10.1 Immunoglobulin Depletion and Recovery  
Immunoglobulin depletion and recovery during follow up will be derived according to the following: 
Lower immunoglobulin thresholds:  
o IgA: 0.5 g/L 
o IgM: 0.3 g/L 
o IgG: 5 g/L 


29 
 
 
• 
Depletion after Baseline:  
o YES = (Lab value < Lower Threshold) 
o NO =  (Lab value >= Lower Threshold) 
 
• 
Recovery: 
o YES = (Lab value >= Lower Threshold), and the lab value was collected after 
the last dose of antibody and patient was previously depleted 
o NO = (Lab value < Lower Threshold) and the lab value was collected after the 
last dose of antibody and patient was previously depleted (only displayed for 
last value in patient listing) 
 
Recovery (single) is the first recovery based on definition above which is not followed exclusively by 
further depletion i.e. recovery at a visit cannot be immediately followed by depletion, or a missing 
assessment, but only by recovery at the next visit. Time to single recovery is defined as the number of 
days between the date of last dose of antibody and date of single recovery. In case a patient was not 
depleted at the last dose of antibody no time to single recovery will be calculated. Where no 
immunoglobulin value occurs at the last dose of antibody, the next valid immunoglobulin assessment 
will be taken. If there are multiple immunoglobulin records at a visit, the last immunoglobulin 
assessment will be retained provided there is a valid identifier. If a study does not have a valid 
identifier, the lowest immunoglobulin value at the visit will be used instead. Recovery will be assessed 
up to the first day of NALT. 
Analysis will be done separately for IgA, IgM and IgG. No time windows will be applied. Only visits with 
a valid date and non-missing values will be considered for the derivation of immunoglobulin recovery 
and depletion. Immunoglobulins with no associated time that are collected on the same day as the 
last dose of the antibody will be assumed to be pre-dose. 
Descriptive statistics (n, mean, sd, median, range) will be produced at each timepoint where 
immunoglobulin values are available to describe the course of IgA, IgG and IgM.  
An output will be produced to look at the proportion of patients with low immunoglobulin levels at 
each timepoint where immunoglobulin values are available. 
 
7 Pharmacokinetic Analyses 
PK analyses will be defined in a separate analysis plan.   
 


30 
 
8 Protocol Deviations 
Major protocol deviations will be taken from the PDMS system. All major deviations from PDMS will 
be listed and summarized and will be reported in the CSR.   
 
9 References 
 
10 Output Template 
 












36 
 
Output 7  Listing of Patients Who Discontinued Early from Study Drug 
 
Center/ 
Patient ID 
Age/Sex/Race 
Drug* 
Date of First 
Study Drug 
Administration 
Day of Last 
Study Drug 
Administration 
Day of Study 
Discontinuation* 
Reason for 
Discontinuation 
from study drug* 
Reason for 
Discontinuation 
from study 
Treatment1 
12 
14 
Adverse event 
Adverse event 
 
Treatment2 
36 
65 
Lost to follow-up 
Lost to follow-up 
Treatment3 
 
36 
65 
Lost to follow-up 
Lost to follow-up 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  DSL02  
3. Program name: L_DS_DRG 
4. Reason for Discontinuation from study: leave blank if a patient discontinued from study drug but not discontinued from study 
5. Date of first study drug administration: use the first date of any drug 
6. Day of last study drug administration: use the day for the certain drug 
7. *：one line for each drug 
 
 
 
 








40 
 
1. Analysis population: ITT 
2. Template ID:  DMT01 
3. Program name: T_DM 
4. CRF: Demographics, ECOG Performance Status, Vital Signs 
5. See section 4.1 for identifying further variables that may be included in this 
output. 
 
 
 


41 
 
10.11 Output 11  Baseline Disease Characteristics and Prognostic 
Markers 














48 
 
10.14 Output 14  Listing of Previous Systemic Anti-lymphoma Therapy 
 
Center/ 
Patient ID 
Age/Sex/Race 
Line of 
Therapy 
Chemotherapy 
Regimen 
Chemotherapy 
Cycles 
First 
Agent 
Day 
Last 
Agent 
Day 
Best Response 
PD 
Anti-CD20 
Agent 
Abti-CD20 
Dose 
Autologous 
Stem Cell 
Transplant 
1st 
CHOP 
6 
 
 
CR 
YES 
Rituximab 
 
YES 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
1. Analysis population: ITT 
2. Program name: l_cm 
3. CRF: Prior anti-lymphoma therapy, prior anti-CD20 agents, prior autologous stem cell transplant  
 




50 
 
Programming notes: 
1. Analysis population: ITT 
2. Program name: T_PALT 
3. CRF: Prior anti-lymphoma therapy, prior anti-CD20 agents, prior autologous 
stem cell transplant 
 
 
 
 
 




52 
 
10.17 Output 17  Listing of Follow-up New Anti-lymphoma Therapy 
 
Center/ 
Patient ID 
Age/Sex/Race 
Line of 
Therapy 
Regimen 
Last 
Study 
Dose 
Day 
First 
Agent 
Day 
Last 
Agent 
Day 
Anti-CD20 
Agent 
 
 
Surgery/Procedure 
description 
 
 
Site 
 
 
Surgery/Procedure 
Day 
1st 
CHOP 
 
 
 
Rituximab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
1. Analysis population: Safety 
2. Program name: L_PALT 
3. CRF: Follow-up New Anti-Lymphoma Therapy, Regimen 
 










57 
 
10.24 Output 24  Listing of Study Drug Exposure  
 
Center/ 
Patient ID 
Age/Sex/Race 
Date of First 
Study Drug 
Administration 
Cycle 
Treatment 
Start Day 
End Day 
Dose 
Unit 
Reason for 
Dose 
Adjustment 
1 
Study drug 1 
Study drug 2 
Study drug 3 
 
x 
x 
x 
 
x 
x 
x 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
Adverse event 
 
n 
xx 
nn 
nn 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
Programming notes: 
1. Analysis population: Safety 
2. Program name: L_EX 
3. CRF: study drug administration 
4. For BO29563 and BO29561 display visit label instead of Cycle 
 




59 
 
Treatment duration is the date of the last dose of study medication minus the date of the first 
dose plus 1 day.  
 Dose intensity (%) is the cumulative total dose actually received up to the last cycle actually 
received divided by the expected dose up to the last time point when any component of study 
medication was actually received. 
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  EXT01 
3. Program name: T_EX_IN 
4. Treatment duration (days)=(date of last dose-date of first dose)+1 
5. Treatment cycles: based on the actual cycles 
6. Exposure by Cycle is optional  
 
 
10.26 Output 26  Study Drug Exposure During 
Maintenance/Consolidation Phase 
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  EXT01 
3. Program name: T_EX_MC 
4. Treatment duration (days)=(date of last dose-date of first dose)+1 
5. Treatment cycles: based on the actual cycles 
6. Exposure by Cycle  is optional. 
 




61 
 
 
10.28 Output 28  Listing of Adverse Events 
                                                                                     
Center/Patient ID-
Age/Sex/Race 
MedDRA Preferred Term 
Date of First 
Study Drug 
Administration 
 
 
Study Day 
of Onset 
AE 
Duration 
in Days 
Most 
Extreme 
CTC 
Grade 
Outcome 
(1) 
Treatment 
for AE  
Relation to  
Study drug 
Action with 
Study drug 
(2) 
Reason 
Classified 
as Serious 
(3) 
nnnnnn/nnnnn-nn/x/x 
xxxxxxxxxxxx* 
nnxxxnnnn 
nn 
12 
4 
2 
xxx 
A:No, G:No, 
V:Yes 
A:3, G:2, V:3 
n 
  *: SAE (1) Outcome: 1 = fatal; 2 = not recovered/not resolved; 3 = recovered/resolved; 4 = recovered/resolved with sequelae;                
  5 = recovering/resolving; 6 = unknown.                                                                                               
  (2) Action taken with study drug:  1 = dose not changed; 2 = dose reduced; 3 = drug interrupted; 4 = drug withdrawn;                 
  5 = not applicable; 6 = unknown.                                                                                                     
  (3) Reason classified as serious: 1 = resulted in death; 2 = life threatening; 3 = required prolonged in patient hospitalization;   
  4= disabling; 5 = a congenital anomaly/birth defect in offspring of study subject; 6 = does not meet any of the above serious        
  criteria, but may jeopardize the subject, and may require medical or surgical intervention to prevent one of the outcomes listed     
  above.                    
  Relation to Study Drug & Action with Study drug:  A = Atezolizumab; G = GA101; V = Venetoclax;   
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AE 
4. The final footnote is dependent on which study drugs are given 


62 
 
10.29 Output 29  Listing of Serious Adverse Events 
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AES 
      
10.30 Output 30  Listing of Grade 3, 4, 5 Adverse Events 
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AE345 
 
10.31 Output 31  Listing of Adverse Events Leading to Discontinuation of 
Any Study Drug  
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AEW 
 
10.32 Output 32  Listing of Adverse Events Leading to Dose Modification or 
Interruption of Any Study Drug 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AEM 
 
10.33 Output 33  Listing of Adverse Events Leading to Death  
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AED 
 


63 
 
 
10.34 Output 34  Listing of Potential Adverse Events of Special Interest 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AESI 
4. Definition: see Table in 6.2.2 Selected AEs and Potential AE of Special Interest 
Note: For BO29561-3 an additional listing based on AESI ticked on eCRF AESI page will be created. 
AESI will be summarized by tickbox categories. Only AESI with causality to Atezo suspected and 
onset >= cycle 2 start will be included. 
10.35 Output 35  Listing of Selected Adverse Events 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL02 
3. Program name: L_AESE 
4. Definition of selected AE (see table in section 6.2.2) 
 
Note: listing 34 and 35 may be combined depending on individual studies.  The title 
becomes “Listing of Adverse Events of Selected and Special Interest” 
 
 






66 
 
10.38 Output 38 Grade 3, 4, 5 Adverse Events 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET02 
3. Program name: T_AE345 
 
10.39 Output 39  Serious Adverse Events 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET02 
3. Program name: T_AES 
 
10.40 Output 40  Adverse Events Leading to Discontinuation of Any Study 
Drug 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET02 
3. Program name: T_AEW 
 
10.41 Output 41  Potential Adverse Events of Special Interest 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET02 
3. Program name: T_AESPECIAL 
4. Summarized by AESI category (see table 6.2.2)  
Note: “Adverse events of special interest” may be combined with “Selected Adverse Events”.  
Note: For BO29561-3 an additional summary based on AESI ticked on eCRF AESI page will be created. 
AESI will be summarized by tickbox categories. Only AESI with causality to Atezo suspected and 
onset >= cycle 2  will be included. 
10.42 Output 42  Selected Adverse Events 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET02 
3. Program name: T_AESELECT 
4. Summarized by AESI category (SMQ) and Preferred Term 
 
Note: “Adverse events of special interest” may be combined with “Selected Adverse Events”.  
 


67 
 
 
 
 


68 
 
 
10.43 Output 43  Categorical Summary of Adverse Events of Special Interest  
  
 
Treatment Group 1 
(N =  xx)  
No. of patients with at least one AE 
xx (xx %)  
 
 
No. of patients with grade 1 AEs 
xx (xx %)  
No. of patients with grade 2 AEs 
xx (xx %)  
No. of patients with grade 3 AEs 
xx (xx %)  
No. of patients with grade 4 AEs 
xx (xx %)  
No. of patients with grade 5 AEs 
xx (xx %)  
No. of patients with missing grade  AEs 
xx (xx %)  
 
 
No. of patients with serious AE 
xx (xx %)  
 
 
Total No. of AEs 
xx 
 
No. of grade 1 AEs    
xx 
 
No. of grade 2 AEs    
xx 
 
No. of grade 3 AEs    
xx 
 
No. of grade 4 AEs    
xx 
 
No. of grade 15 AEs    
xx 
 
No. of AEs with missing grade     
xx 
 
 
 
No. of serious AEs 
xx 
 
No. of AEs with missing seriousness 
xx 
 
 
Total No. of patients with at least one AE: 
xx 
 
No. of patients with ant body dose interrupted  due to AE 
xx (xx %)  
 
No. of patients with ant body withdrawn due to AE 
xx (xx %)  
 
 
 
No. of patients with atezolizumab interrupted  due to AE 
xx (xx %)  
 
No. of patients with atezolizumab withdrawn due to AE 
xx (xx %)  
 
xx (xx %)  
 
No. of patients with chemotherapy dose reduced due to AE 
xx (xx %)  
 
No. of patients with chemotherapy interrupted due to AE 
xx (xx %)  
 
No. of patients with chemotherapy withdrawn due to AE 
xx (xx %)  
 
xx (xx %)  
 
No. of patients with any treatment dose reduced due to AE 
xx (xx %)  
 
No. of patients with any treatment interrupted due to AE 
xx (xx %)  
 
No. of patients with any treatment withdrawn due to AE 
xx (xx %)  
 
 
 
No. of patients with at least one AE unresolved or ongoing 
xx (xx %)  
 
No. of patients with treatment received for AE 
xx (xx %)  
 
No. of patients without treatment received for AE 
xx (xx %)  
 
Percentages are based on the number of patients with at least one AE (except the first  block of the 
output where the percentages are based on N).                                  
When calculating the number of patients with AEs of a specific grade only the highest AE   grade per 
patient is taken into account.                                                    
All occurrences of the same adverse event in one patient are counted separately.            
Investigator text for AEs encoded using MedDRA vxx.x.                                    
Programing notes: 
1. Analysis population: Safety 
2. Program name: T_AE_C_AESPECIAL 
3. Definition: see Table in 6.2.2 Selected AEs and Potential AE of Special Interest 
4. ‘Chemotherapy’ can be replaced by the actual study chemotherapy term, e.g. Bendamustine 
 
 


69 
 
 
10.44 Output 44  Categorical Summary of Selected Adverse Events  
Programing notes: 
1. Analysis population: Safety 
2. Program name: T_ AE_C_AESELECT 
3. Definition: see Table in 6.2.2 Selected AEs and Potential AE of Special Interest 
 
 
 
 
10.45 Output 45  Adverse Events by Cycle  
  
Treatment Cycles 
Treatment Group 1 
(N =  xx) 
Cycle 1  
 
 
Patients with at least one AE 
xx (xx%) 
 
Number of AEs 
xx 
 
Number of grade 3-4 AEs 
xx 
 
Number of fatal AEs 
xx 
 
Number of serious AEs 
xx 
 
Number of AEs leading to ant body withdrawal 
xx 
 
Number of AEs leading to atezolizumab withdrawal  
xx 
 
Number of AEs leading to chemotherapy withdrawal 
xx 
 
n 
xx 
 
 
Cycle 2 
 
 
Patients with at least one AE 
xx (xx%) 
 
Number of AEs 
xx 
 
Number of grade 3-4 AEs 
xx 
 
Number of fatal AEs 
xx 
 
Number of serious AEs 
xx 
 
Number of AEs leading to ant body withdrawal 
xx 
 
Number of AEs leading to atezolizumab withdrawal  
xx 
 
Number of AEs leading to chemotherapy withdrawal 
xx 
 
n 
xx 
Cycle x 
 
 
Investigator text for AEs encoded using MedDRA vxx.x.                                       
n is a number of patients received study drug at each cycle.                                
Percentages are based on n.                                                                 
Multiple occurrences of the same adverse event in one individual counted only once for each cycle.      
 
Programing notes: 
1. Analysis population: Safety 
2. Program name: T_AE_C_AECYC 
3. ‘Chemotherapy’ can be replaced by the actual study chemotherapy term, e.g. Bendamustine 
 
10.46 Output 46  Potential Adverse Events of  Special Interest by Cycle  
Programing notes: 




71 
 
 
 


72 
 
 
10.49 Output 49 Most Common Adverse Event with Incidence ≥ 5% by 
Preferred Term 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET08 
3. Program name: T_AE_PT_P5 
4. Display only by preferred term, not by SOC 
 
10.50 Output 50 Most Common Grade 3, 4, 5 Adverse Event with Incidence ≥ 
5% by Preferred Term 
Programing notes: 
1. Analysis population: Safety 
2. Template ID:  AET08 
3. Program name: T_AE345_PT_P5 
 
 
 
 




74 
 
 
10.52 Output 52  Listing of Deaths  
 
Center/ 
Patient ID 
Age/Sex/Race 
Date of First 
Study Drug 
Administration 
Day of Last 
Study Drug 
Administration  
Day 
of 
Death 
Associated 
SAE 
Preferred 
Term 
Autopsy 
Performed?   
 
Cause 
of 
Death 
12 
62 
Myocardial 
infarction 
Yes 
xxxxxx 
36 
37 
Ischemic 
Stroke 
No 
xxxxxx 
 
Programming notes: 
1. Analysis population: Safety 
2. Template ID:  AEL04 
3. Program name: L_DD 




76 
 
10.54 Output 54  Laboratory Test Results Shift Table – Highest NCI CTCAE 
Grade Post-Baseline 
 
Hemoglobin 
g/L (Low) 
  
Status at Baseline 
  
From 
0 
1 
2 
3 
4 Total 
Missing 
To 
  
  
  
  
  
  
  
  
0   
13(xx%) 
0 (xx%) 
1(xx%) 
0 
0 
14 
0 
1   
58(xx%) 
63(xx%) 
4(xx%) 
0 
0 
125 
0 
2   
39(xx%) 
105(xx%) 
28(xx%) 
0 
0 
172 
0 
3   
14(xx%) 
23(xx%) 
13(xx%) 
0 
0 
50 
0 
4   
3(xx%) 
5(xx%) 
0(xx%) 
0 
0 
8 
0 
Total 
  
127(100%) 196(100%) 46(100%) 
0 
0 
360 
0 
Missing 
  
6 
6 
0 
0 
0 
12 
0 
 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
  “n” denotes the number of patients with baseline and post-baseline lab data within this time interval.  
For a patient with multiple post-baseline lab abnormalities, the highest (worst) grade of these 
abnormalities for the given lab test is reported.  
 
Programing notes: 
1. Analysis population: Safety 
2. Template ID: LBT14 
3. Program name: T_LB_SHIFT 
4. Use EXT_NCICTC4 for NCI-CTCAE Grades 
5. Include all hematology and chemistry lab parameters split into 2 separate outputs. 
 
 
 


77 
 
10.55 Output 55  Neutrophil Count Recovery 
 
 
Treatment 
Group 1 (N=nn) 
Treatment Group 
2 (N=nn) 
  
 
 
ANC <1.0 × 109/L at EOT/EOI* 
Yes 
No  
n 
 
ANC Recovery** within 3 months of 
follow up   
 
xx (xx.x%) 
xx (xx.x%) 
xxx 
 
 
xx (xx.x%) 
xx (xx.x%) 
xxx 
 
 Yes 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 n 
xxx 
xxx 
  
 
 
ANC Recovery** within 6 to 9 months of 
follow up 
 
 
 Yes 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 n 
xxx 
xxx 
  
 
 
ANC Recovery** within 9 to 12 months 
of follow up 
 
 
 Yes 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 n 
 
xxx 
xxx 
 A ANC Recovery** after 12 months of 
follow up 
Yes 
 
xx (xx.x%) 
 
xx (xx.x%) 
 No 
n 
xx (xx.x%) 
xxx 
xx (xx.x%) 
xxx 
** Neutrophil recovery is defined as ANC ≥ 1.0 × 109/L, given ANC was collected after the 
patient received his last dose of antibody, and ANC < 1.0 × 109/L the last previous visit 
before EOT/EOI. Where no ANC value occurs at the last drug intake, the next valid ANC 
assessment was taken. 
Percentages are based on the number of patients with ANC < 1.0 × 109/L at the last previous 
visit before EOT/EOI. 
Programing notes: 
1. Analysis population: Safety 
2. Program name: T_LB_ANC 
 
 




79 
 
 
10.57 Output 57 ECG Results Shift Table 
 
Treatment x (N=xx)                                                                                                                     
  _____________________________________________________________________________________________________ 
                                                                                                        
                                                                   Shift FROM: Baseline                 
                                                    ___________________________________________________ 
                                                                                                        
                                                     Abnormal,     Abnormal,                            
                                                    clinically   not clinically                         
  Shift TO: ECG Result at Visit                     significant   significant      Normal      Total    
  _____________________________________________________________________________________________________ 
                                                                                                        
  END OF INDUCTION COMPLETION / DISCONTINUATION                                                                                        
    Abnormal, clinically significant                    0          0              0            0          
    Abnormal, not clinically significant                0          xx (xx.xx%)    xx (xx.xx%)  xx (xx.xx%) 
    Normal                                              0          xx (xx.xx%)    xx (xx.xx%)  xx (xx.xx%) 
    Total                                               0          xx (xx.xx%)    xx (xx.xx%)  xx (xx.xx%) 
  END OF MAINTENANCE COMPLETION / DISCONTINUATION                                                                                      
    Abnormal, clinically significant                    0          0              0            0          
    Abnormal, not clinically significant                0          xx (xx.xx%)    0            xx (xx.xx%) 
    Normal                                              0          0              0            0          
    Total                                               0          xx (xx.xx%)    0            xx (xx.xx%) 
  _____________________________________________________________________________________________________                                
  Baseline assessment is the last valid assessment in the 28 day window before first administration of a study treatment 
component.   
 
Programing notes: 


80 
 
1. Analysis population: Safety 
2. Template ID:  EGT01 
3. Program name: T_EG_CB 
4. Analysis variables: Electrocardiogram (ECG) 
 






83 
 
10.60 Output 60  CR Rate at End of Induction  
 
  
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
Based on Modified LUGANO 2014 - PET-CT 
  As Determined by the IRC 
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
       90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator  
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on LUGANO 2014 - PET 
 
 
  As Determined by the IRC 
 
 
    Complete Response (CR)        
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      90% CI for Response Rates     
( xx.x, xx.x) 
( xx.x, xx.x) 
 
 
 
  As Determined by the Investigator 
 
 
    Complete Response (CR)        
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      90% CI for Response Rates     
( xx.x, xx.x) 
( xx.x, xx.x) 
 
 
 
Based on Modified CHESON 2007 - CT or MRI 
 
 
  As Determined by the IRC 
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator                    
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on Modified CHESON 2007 - CT or MRI and PET 
 
  As Determined by the IRC 
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator                    
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
90% CI for rates were constructed using Clopper-Pearson method.  
 


84 
 
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  RSPT01 
3. Program name: T_CRR 
4. EOI time window: TBD 
5. Some studies may require CR tabulation based on Cheson criteria, Lugana, or modified 
Lugano, follow SMT instruction. 
 


85 
 
10.61 Output 61  OR Rate at End of Induction 
  
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
Based on Modified LUGANO 2014 - PET-CT 
  As Determined by the IRC 
 
 
    Objective Response (CR, PR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
       90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator  
 
 
    Objective Response (CR, PR) 
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on LUGANO 2014 – PET 
 
 
  As Determined by the IRC 
 
 
    Objective Response (CR, PR)        
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      90% CI for Response Rates     
( xx.x, xx.x) 
( xx.x, xx.x) 
 
 
 
  As Determined by the Investigator 
 
 
    Objective Response (CR, PR)   
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      90% CI for Response Rates     
( xx.x, xx.x) 
( xx.x, xx.x) 
 
 
 
Based on Modified CHESON 2007 - CT or MRI 
 
 
  As Determined by the IRC 
 
 
    Objective Response (CR, PR)  
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator                    
 
 
    Objective Response (CR, PR)  
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on Modified CHESON 2007 - CT or MRI and PET 
 
  As Determined by the IRC 
 
 
    Objective Response (CR, PR)  
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
  As Determined by the Investigator                    
 
 
    Objective Response (CR, PR)  
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
      90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
90% CI for rates were constructed using Clopper-Pearson method.  
 
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  RSPT01 


86 
 
3. Program name: T_ORR 
4. EOI time window: TBD 


87 
 
10.62 Output 62  CR Rate at 12 Months after Initiation of Induction 
 
  
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
Based on PET-CT as Determined by the IRC using 
Lugano 2014 Criteria                    
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on PET-CT as Determined by the 
Investigator using Lugano 2014 Criteria                    
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on PET-CT as Determined by the IRC using 
modified  Lugano 2014 Criteria                   
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on PET-CT as Determined by the 
Investigator using modified Lugano 2014 Criteria        
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on CT alone as Determined by the IRC            
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
 
 
 
Based on CT alone as Determined by the 
Investigator                    
 
 
    Complete Response (CR)        
 xxx  ( xx.x %)   
 xxx  ( xx.x %)   
    90% CI for Response Rates     
 ( xx.x, xx.x)    
 ( xx.x, xx.x)    
90% CI for rates were constructed using Clopper-Pearson method.  
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  RSPT01 
3. Program name: T_CRR12 
4. Patient subset: Patients who have positive PET scans (CR/PR) at EOI 
 
 
 
 


88 
 
10.63 Output 63  Best Overall Response Rate  
 
  
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
Based on CT as Determined by the Investigator         
 
    Best Overall Response (BOR)        
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       CR 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       PR 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
    90% CI for Response Rates     
( xx.x, xx.x) 
( xx.x, xx.x) 
    
 
90% CI for rates were constructed using Clopper-Pearson method.  
 
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  RSPT01 
3. Program name: T_BORR 
 
 
 
 


89 
 
10.64 Output 64  Concordance Analysis Between the IRC Determined and 
the Investigator Determined CR Status 
 
  
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
Based on PET-CT  using Lugano 2014 Criteria 
 
 
Number of patients evaluable for concordance              
nn 
nn 
CR occurrence 
 
 
   Concordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      No CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
 
 
 
   Discordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       No CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
 
 
 
Based on PET-CT using modified Lugano 2014 
Criteria 
 
 
Number of patients evaluable for concordance              
nn 
nn 
CR occurrence 
 
 
   Concordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      No CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
 
 
 
   Discordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       No CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
 
 
 
Based on CT alone 
 
 
Number of patients evaluable for concordance              
nn 
nn 
CR occurrence 
 
 
   Concordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
      No CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
 
 
 
   Discordance 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       CR per investigator and no CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
       No CR per investigator and CR per IRC 
xxx  ( xx.x %) 
xxx  ( xx.x %) 
Programming Note: 
1. Analysis population: Safety 
2. 
Template ID:  IRCT01 
3. 
Program name: T_EF_CONCORD_CR 


90 
 
10.65 Output 65  Duration of Response 
 
 
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
 Patients with event (%)                 
 xxx ( xx.x %)   
 xxx ( xx.x %)   
   PD 
 xxx 
 xxx 
   Death 
 xxx 
 xxx 
 Patients without event (%)#              
xxx ( xx.x %)   
 xxx ( xx.x %)   
                                         
                
                 
 Time to event (month)                    
                
                 
   Median                                
    xxx.x       
     xxx.x       
   95% CI                             
  (xxx, xxx)    
   (xxx, xxx)    
   25% and 75%-ile                       
  xxx, xxx      
   xxx, xxx      
   Range##                                 
 xxx to xxx#    
   xxx to xxx#  
 
 
# Censored value, ## Including censored observations 
Summaries of <Time-to-Event Endpoint> (median, percentiles) are Kaplan-Meier estimates. 95% CI 
for median was computed using the method of Brookmeyer and Crowley.  
 
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  TTET01 
3. Program name: T_DOR 
4. Based on CT assessment as determined by the investigators 
5. Patient subset: Patients who have CR or PR 
 
 
 
 
 


91 
 
10.66 Output 66  Kaplan-Meier Curve of Duration of Response 
 
 
Programming Note: 
1. Analysis population: Safety 
2. Template ID:  KMG01 
3. Program name: G_KM_DOR 
4. Based on CT assessment as determined by the investigators 
 
 




93 
 
10.68 Output 68  Spider Plot of Change from Baseline (%) in Indicator Lesion Size over Time 
 
Programming Note: 
1. Analysis population: Safety 
2. Program name: G_EF_SPIDER 
3. Based on CT assessment as determined by the investigators 
 
 
 




95 
 
1. Analysis population: Safety 
2. Program name: G_EF_SWIM 
3. Based on Lugano 2014 PET-CT assessment as determined by the investigators 
4. Details: TBD 
 
 


96 
 
10.70 Output 70  Progression-Free Survival  
 
 
 
Treatment Group 1 
(N=nn) 
Treatment Group 2 
(N=nn) 
 Patients with event (%)                 
 xxx ( xx.x %)   
 xxx ( xx.x %)   
   PD 
 xxx 
 xxx 
   Death 
 xxx 
 xxx 
 Patients without event (%)#              
xxx ( xx.x %)   
 xxx ( xx.x %)   
                                         
                
                 
 Time to event (month)                    
                
                 
   Median                                
    xxx.x       
     xxx.x       
   95% CI                             
  (xxx, xxx)    
   (xxx, xxx)    
   25% and 75%-ile                       
  xxx, xxx      
   xxx, xxx      
   Range##                                 
 xxx to xxx#    
   xxx to xxx#  
 
 
 
Time Point Analysis 
 
 
6 months duration 
 
 
    Patients remaining at risk 
xx 
xx 
    Event free rate (%) 
xx.x 
xx.x 
    95% CI   
(xx.x, xx.x) 
(xx.x, xx.x) 
# Censored value, ## Including censored observations 
Summaries of <Time-to-Event Endpoint> (median, percentiles) are Kaplan-Meier estimates. 95% CI for 
median was computed using the method of Brookmeyer and Crowley. 95% CI for landmark estimate was 
computed using Greenwood method. 
 
Programming Note: 
1. Analysis population: Safety 
2. Program name: T_EF_TTE_PFS 
3. Based on CT assessment as determined by the investigators 
4. Landmark estimates of the proportion of patients who are event free at 6 months, 9 months, 1 
year, and 2 years will be provided, along with 95% asymptotic Cis  using Greenwood’s formula for 
standard errors. 
 
10.71 Output 71  Kaplan-Meier Curve of Progression-free Survival 
Programming Note: 
1. Analysis population: Safety 
2. Program name: G_EF_KM_PFS 
3. Based on CT assessment as determined by the investigators 
 


97 
 
10.72 Output 72  Event-Free Survival 
Programming Note: 
1. Analysis population: Safety 
2. Program name: T_EF_TTE _EFS 
3. Based on CT assessment as determined by the investigators 
4. Landmark estimates of the proportion of patients who are event free at 6 months, 9 months, 1 
year, and 2 years will be provided, along with 95% asymptotic CIs  using Greenwood’s formula 
for standard errors. 
 
10.73 Output 73  Kaplan-Meier Curve of Event-Fee Survival  
Programming Note: 
1. Analysis population: Safety 
2. Program name: G_EF_KM_EFS 
3. Based on CT assessment as determined by the investigators 
 
10.74 Output 74  Disease-Free Survival 
Programming Note: 
1. Analysis population: Safety 
2. Program name: T_EF_TTE _DFS 
3. Based on CT assessment as determined by the investigators 
4. Landmark estimates of the proportion of patients who are event free at 6 months, 9 
months, 1 year, and 2 years will be provided, along with 95% asymptotic Cis  using 
Greenwood’s formula for standard errors. 
 
10.75 Output 75  Kaplan-Meier Curve of Disease-Fee Survival  
Programming Note: 
1. Analysis population: Safety 
2. Program name: G_EF_KM_DFS 
3. Based on CT assessment as determined by the investigators 
 
 


98 
 
10.76 Output 76  Overall Survival 
Programming Note: 
1. Analysis population: Safety 
2. Program name: T_EF_TTE _OS 
3. Landmark estimates of the proportion of patients who are event free at 6 months, 9 
months, 1 year, and 2 years will be provided, along with 95% asymptotic CIs  using 
Greenwood’s formula for standard errors. 
 
10.77 Output 77  Kaplan-Meier Curve of Overall Survival 
Programming Note: 
1. Analysis population: Safety 
2. Program name: G_EF_KM_OS 
 
 
 
 


99 
 
Appendix 1 Region Categories  
We only display regions and countries here where actually patients were enrolled. 
Input needed from Study SPA/BioStats: Add any other countries to this table if your study has a site there 
with patients enroled 
Region 
Member Countries 
Western Europe 
Belgium, Finland, France, Germany, Italy, 
Spain, Sweden, United Kingdom 
Eastern Europe 
Czech Republic, Hungary, Russia 
North America 
Canada, United States 
Asia 
China, Japan, Taiwan, South Korea 
Other 
Australia, Israel, New Zealand 
 


100 
 
DAP M 2 Update Log  
Date 
Section 
Description  
Author 
24MAY2017 
Output 57 
Changed Change from Baseline to Shift Table 
16MAY2017 
Output36 
Added “Total number of patients with at least one AE” 
category instead of displaying sub-category under
“Total number of patients with at least one” category 
07JUN2017 
Output53 
Added “Other” as sub-category under “Causes of
Death” category 
14JUN2017 
Output5 
Updated “Induction Phase” categorie as “Induction
started”, similarly “Maintenance/Consolidation Phase”  
to “Maintenance / Consolidation Phase  started” . Also 
added “Discontinued Induction” & “Discontinued
Maintenance/Consolidation” categories. 
17JUL2017 
Table 
Selected AE  
Removed tick for bo29561 for Late onset/prolonged
neutropenia. Updated definition of Neutropenia for
BO29561-3 
21JUL2017 
Table 
Selected 
AE/AESI 
Titles 
of 
summaries 
Second Malignancy and TLS moved to AESI 
In Summaries titles ‘Summary of’ removed 
26JUL2017 
Safety 
Summary 
(Ouput 36) 
Removed last row as this is not part of original STREAM 
template and is not appropriate to use: No connection 
between related AE and AE given as reason for study 
discontinuation (based on study completion page) 
08AUG2017 
Output 24 
Add programming note: Use visit instead of cycle for 
BO29561 and BO29563 
14AUG2017 
Table 6.2.2, 
Title of AESI 
outputs 
AESI categories updated in Table.  AESI renamed to 
‘potential AESI’ in output titles. 
11AUG2017 
6.2.1, output 
34, 
output 
41 
In BO29561/2/3 additional AESI tables based on eCRF 
tickbox. 
14Aug2017 
Output 78   
Use categories Low/Intermediate/High for FLIPI. 
Low/High for IPI. 
22AUG2017 
Table 6.2.2 
AESI category Hypersensitivity updated  


101 
 
17OCT2017 
6.4.5  
Hy’s law: use BL instead of ULN for AST/ALT  
29JAN2017 
output 36 
Added 2 rows into template 
06SEP2018 
Output53 
Removed “Deaths during the treatment are those 
occurred within 28 days after last study drug.” footnote. 
10OCT2018 
Table 6.2.2 
Added AESI category ‘Auto-immune hemolytic 
anaemia’, updated AESI categories for Diabetes 
mellitus and Rash as requested by
in 
email on 09OCT2018 
17OCT2018 
Table 6.2.2 
Updated AESI categories IRR and myocarditis as 
requested by 
 in email on 17OCT2018 
10DEC2018 
6.4.9 
Added HACA in this section 
29JAN2019 
6.2.1/6.2.2 
Added conditions for Atezo specific AESI (onset >= 
cycle 2, causality to Atezo suspected)