Clinical trial NCT04029688
Conditions: Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Neuroblastoma Solid Tumors
Sponsor: Hoffmann-La Roche
Start date: 2020-01-27; Completion date: 2024-05-06
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin, administered as a single agent or in combination with chemotherapy or venetoclax, in pediatric and young adult participants with acute leukemias or solid tumors.

This study is divided into three parts: Part 1 will begin with dose escalation of idasanutlin as a single agent in pediatric participants with relapsed or refractory solid tumors to identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and to characterize dose-limiting toxicities (DLTs). Following MTD/MAD identification, three separate safety run-in cohorts in neuroblastoma, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) will be conducted to identify the recommended Phase 2 dose (RP2D) of idasanutlin in each combination, with chemotherapy or venetoclax. Part 2 will evaluate the safety and early efficacy of idasanutlin in combination with chemotherapy or venetoclax in newly enrolled pediatric and young adult participants in neuroblastoma, AML,and ALL cohorts at idasanutlin RP2D. Part 3 will potentially be conducted as an additional expansion phase of the idasanutlin combination cohorts in neuroblastoma, AML, or ALL for further response and safety assessment.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: Idasanutlin intervention 2: Venetoclax intervention 3: Cyclophosphamide intervention 4: Topotecan intervention 5: Fludarabine intervention 6: Cytarabine intervention 7: Intrathecal Chemotherapy
Intervention descriptions: intervention 1: Idasanutlin will be administered as an oral medication once daily on Days 1-5 of a 28-day cycle. intervention 2: Venetoclax will be administered orally at the adult dose equivalent (adjusted by body weight) of 400 milligrams (mg) in participants with neuroblastoma and the adult dose equivalent of 600 mg in participants with leukemia. intervention 3: Cyclophosphamide will be administered once daily on Days 1-5 of each 28-day cycle at 250 milligrams per meter squared of body surface area (mg/m\^2) as an intravenous (IV) infusion. intervention 4: Topotecan will be administered once daily on Days 1-5 of each 28-day cycle at 0.75 mg/m\^2 as an IV infusion. intervention 5: Fludarabine will be administered once daily on Days 1-5 of each 28-day treatment cycle at 30 mg/m\^2 as an IV infusion. intervention 6: Cytarabine will be administered once daily on Days 1-5 of each 28-day treatment cycle at 2000 mg/m\^2 as an IV infusion. intervention 7: All participants with leukemia, irrespective of arm, will receive intrathecal chemotherapy on Day 1 of each 28-day treatment cycle. Intrathecal chemotherapy will consist of either single-agent cytarabine or methotrexate, or a combination of methotrexate, cytarabine, and hydrocortisone, at appropriate age-based dosing as specified in the protocol.

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
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.
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
Protocol GO40871, Version 4
PROTOCOL
TITLE:
A PHASE I/II, MULTICENTER, OPEN-LABEL, MULTI-ARM 
STUDY EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND PRELIMINARY ACTIVITY OF 
IDASANUTLIN IN COMBINATION WITH EITHER 
CHEMOTHERAPY OR VENETOCLAX IN THE TREATMENT OF 
PEDIATRIC AND YOUNG ADULT PATIENTS WITH 
RELAPSED/REFRACTORY ACUTE LEUKEMIAS OR SOLID 
TUMORS 
PROTOCOL NUMBER:
GO40871
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004579-11
IND NUMBER:
117005
NCT NUMBER:
NCT04029688
TEST PRODUCT:
Idasanutlin (RG7388; RO5503781-020)
Venetoclax (GDC-0199; ABT-199; RO5537382)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
19-Mar-2021 15:10:36
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
2/Protocol GO40871, Version 4
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocol
Version
Date Final
Country
Version
Date Final
4
see electronic date stamp on 
title page



3
15 June 2020



2
19 July 2019
France
2
4 October 2019
1
11 January 2019





Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
3/Protocol GO40871, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
The idasanutlin development program in adults has been discontinued following a 
negative read out in the pivotal study in adults with relapsed/refractory acute myeloid 
leukemia.  While efficacy data were negative (no improvement in overall survival with 
idasanutlin/cytarabine vs placebo/cytarabine), no new safety signal has been identified 
for idasanutlin.  Based on promising preclinical data and different disease biology in 
pediatric cancers as well as an ongoing positive benefit risk assessment, the pediatric 
development of idasanutlin continues.  However, adaptations of the ongoing GO40871 
have been made. Changes to the protocol, along with a rationale for each change, are 
summarized below:

Initiation of the safety run-in cohorts for the planned combinations in neuroblastoma
may occur asynchronously (Figure 1).  Thus, the randomization of patients with 
neuroblastoma in study Part 2 to either chemotherapy or venetoclax has been 
removed (Section 3.1.2).

An early efficacy gate was added at the end of the safety run-in (Gate 1b) for the 
neuroblastoma cohorts, which will include patients treated at the recommended 
Phase II dose (RP2D).  This gate allows for discontinuation of a cohort at an earlier 
point should there be a lack of efficacy observed (Section 3.1.1.2).

A requirement for a minimum of 6 patients treated at the RP2D in neuroblastoma 
safety run-in has been added.  This change allows more certainty in the 
determination of the RP2D and allows for the early efficacy gate noted above 
(Section 3.1.1.2).

Patients with TP53 wild-type neuroblastoma treated at the RP2D in the safety runin 
will also be included in the ten patients for the efficacy analysis at Gate 2
(Section 3.1.1.2).

Initiation of the leukemia cohorts may start asynchronously relative to the 
neuroblastoma cohorts (Figure 1)

The nomenclature for the various study parts has been revised to coincide with the 
current study design (Section 3.1).

The pre-defined maximum dose of idasanutlin has been eliminated.  As there is not 
a clearly defined efficacious exposure in adults and the tolerability of idasanutlin 
may differ between adults and children, there is no reason to arbitrarily limit the 
dose of idasanutlin in the pediatric population if it is well tolerated (Section 3.1.1.1).

In order to minimize the risk of neutropenia, the prophylactic use of granulocyte 
stimulating factor support is now recommended for all solid tumor patients receiving 
combination with cyclophosphamide and topotecan (Sections 3.1.1.1 and 4.3.3).

The definition of dose-limiting toxicities has been revised to accommodate the 
known and manageable toxicities of the chemotherapy combination agents, as well 
as to be more consistent with the standards used in other pediatric clinical trials 
(Section 3.1.1.3).


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
4/Protocol GO40871, Version 4

The inclusion criterion on the ability to swallow tablets or liquid has been removed 
since the administration of idasanutlin via nasogastric tube is possible 
(Section 4.1.1).

Dosing of topotecan and cyclophosphamide is now based on body weight rather 
than body surface area for patients weighing less than 12 kg.  This is more 
consistent with standard dosing for this regimen (Section 4.3.2.3).

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.4).

The guidelines for dose modifications due to hematologic toxicity have been revised 
to include modification of the combination agents as well as idasanutlin, as 
cytopenias are risk factors for both (Section 5.1.5.1). 

Addition of mucosal inflammation as an adverse event of special interest 
(Section 5.2.3).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.10).

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

Language regarding investigator reporting of pregnancies has been clarified
(Section 5.4.3.2).

A new section has been added to describe the implementation of a system to 
manage the quality of the study (Section 9.3).

Language has been modified to clarify that Roche’s global policy on data sharing 
does not have requirements that must be met before study results can be made 
available.  The name of a Roche policy on data sharing has been corrected 
(Section 9.6).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
5/Protocol GO40871, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM......................................................14
PROTOCOL SYNOPSIS ...............................................................................................15
1.
BACKGROUND.....................................................................................................31
1.1
Background on Neuroblastoma ......................................................31
1.2
Background on Acute Myeloid Leukemia........................................31
1.3
Background on Acute Lymphoblastic Leukemia .............................32
1.4
Background on The test products...................................................33
1.4.1
Idasanutlin......................................................................................33
1.4.1.1
Clinical Studies of Idasanutlin in Adults ..........................................34
1.4.2
Venetoclax .....................................................................................37
1.4.3
Nonclinical Activity of Idasanutlin as Single Agent and 
in Combination with Chemotherapy and Venetoclax in 
Pediatric Cancers...........................................................................39
1.4.3.1
Idasanutlin as Single Agent and in Combination in 
Neuroblastoma...............................................................................39
1.4.3.2
Idasanutlin as Single Agent and in Combination in 
Acute Myeloid Leukemia ................................................................40
1.4.3.3
Idasanutlin as Single Agent and in Combination in 
Acute Lymphoblastic Leukemia......................................................41
1.4.3.4
Idasanutlin as Single Agent in Other Solid Tumors.........................42
1.5
Study Rationale and Benefit-Risk Assessment...............................42
2.
OBJECTIVES AND ENDPOINTS..........................................................................44
2.1
Safety Objectives ...........................................................................44
2.2
Pharmacokinetic Objectives ...........................................................45
2.3
Efficacy Objectives.........................................................................45
2.3.1
Primary Efficacy Objective..............................................................45
2.3.2
Secondary Efficacy Objective.........................................................46
2.4
Exploratory Biomarker Objectives ..................................................47
2.5
Health Status Utility Objective ........................................................47
3.
STUDY DESIGN ...................................................................................................47
3.1
Description of the Study .................................................................47


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3.1.1
Study Part 1Dose Escalation and Safety Run-In.........................51
3.1.1.1
Study Part 1a:  Single-Agent Dose Escalation ...............................51
3.1.1.2
Study Part 1b:  Combination Therapy Safety Run-In .....................53
3.1.1.3
Definition of Dose-Limiting Toxicity.................................................55
3.1.1.4
Dose-Limiting Toxicity Re-Treatment Criteria .................................58
3.1.2
Study Part 2Initial Expansion for Early Efficacy 
Evaluation ......................................................................................59
3.1.3
Study Part 3Additional Expansion Phase....................................61
3.1.4
Stopping Rules by Cohort...............................................................61
3.1.4.1
Temporary Halt ..............................................................................61
3.1.4.2
Temporary Pause in Enrollment .....................................................62
3.1.4.3
Final End of Dosing by Cohort........................................................62
3.1.5
Internal Monitoring Committee and Scientific 
Oversight Committee......................................................................63
3.2
End of Study and Length of Study..................................................63
3.3
Rationale for Study Design.............................................................64
3.3.1
Rationale for Study Treatment Dose and Schedule........................64
3.3.1.1
Idasanutlin......................................................................................64
3.3.1.2
Venetoclax .....................................................................................64
3.3.2
Rationale for Patient Population .....................................................65
3.3.2.1
Patients with TP53 Mutations .........................................................65
3.3.2.2
Adolescent and Young Adult Patients.............................................66
3.3.3
Rationale for Biomarker Assessments............................................66
3.3.3.1
TP53 Mutations and p53 Activity ....................................................67
3.3.3.2
MDM2 Expression and Idasanutlin Efficacy....................................67
3.3.3.3
MIC-1 Expression in Serum............................................................68
3.3.3.4
Additional Exploratory Biomarker Analyses ....................................68
3.3.4
Rationale for Efficacy Endpoints.....................................................69
3.3.4.1
Neuroblastoma...............................................................................69
3.3.4.2
Acute Myeloid Leukemia and Acute Lymphoblastic 
Leukemia .......................................................................................69
3.3.4.3
Minimal Residual Disease Assessments for Leukemia 
Cohorts ..........................................................................................70
3.3.5
Rationale for Combination Therapies .............................................70


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3.3.5.1
Cyclophosphamide/Topotecan Combination in 
Patients with Neuroblastoma and Other Solid Tumors ...................70
3.3.5.2
Fludarabine and Cytarabine in Patients with Acute 
Myeloid Leukemia ..........................................................................71
3.3.5.3
Venetoclax Combination in Patients with 
Neuroblastoma, Acute Lymphoblastic Leukemia, and 
Acute Myeloid Leukemia ................................................................71
3.3.6
Rationale for Safety Run-In Design ................................................72
3.3.7
Rationale for Randomization in AML Cohorts, Initial 
Response Assessment, and Target Effect Size..............................73
3.3.8
Rationale for Additional Response Assessment and 
Target Effect Size...........................................................................74
4.
MATERIALS AND METHODS...............................................................................74
4.1
Patients..........................................................................................74
4.1.1
Inclusion Criteria ............................................................................74
4.1.1.1
Additional Inclusion Criteria for Patients with Solid 
Tumors (including Neuroblastoma).................................................76
4.1.1.2
Additional Inclusion Criteria for Patients with 
Leukemia .......................................................................................77
4.1.2
Exclusion Criteria ...........................................................................77
4.2
Method of Treatment Assignment...................................................79
4.3
Study Treatment and Other Treatments Relevant to 
the Study Design............................................................................80
4.3.1
Study Treatment Formulation, Packaging, and 
Handling.........................................................................................80
4.3.1.1
Idasanutlin......................................................................................80
4.3.1.2
Venetoclax .....................................................................................80
4.3.1.3
Chemotherapy................................................................................81
4.3.2
Study Treatment Dosage, Administration, and 
Compliance ....................................................................................81
4.3.2.1
Idasanutlin......................................................................................81
4.3.2.2
Venetoclax .....................................................................................82
4.3.2.3
Chemotherapy................................................................................83
4.3.2.4
Intrathecal Chemotherapy in Patients with Leukemia .....................84
4.3.3
Prophylactic Medication..................................................................84
4.3.3.1
Gastrointestinal Toxicity .................................................................85


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4.3.3.2
Tumor Lysis Syndrome...................................................................85
4.3.3.3
Infections........................................................................................86
4.3.4
Investigational Medicinal Product Accountability ............................89
4.3.5
Continued Access to Idasanutlin and Venetoclax ...........................89
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions....................................................................90
4.4.1
Permitted Therapy..........................................................................90
4.4.2
Cautionary Therapy........................................................................90
4.4.2.1
Medications Associated with QT Prolongation................................90
4.4.3
Prohibited Therapy.........................................................................90
4.4.4
Prohibited Food..............................................................................96
4.5
Study Assessments........................................................................96
4.5.1
Informed Consent Forms and Screening Log .................................96
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data .........................................................................97
4.5.3
Physical Examinations ...................................................................97
4.5.4
Growth and Development Assessments.........................................97
4.5.5
Tumor and Response Evaluations..................................................97
4.5.5.1
Tumor Assessments.......................................................................97
4.5.5.2
Response Criteria...........................................................................99
4.5.6
Laboratory, Biomarker, and Other Biological Samples ...................99
4.5.7
Clinical Outcomes AssessmentAcceptability Survey.................102
4.5.8
Electrocardiograms ......................................................................103
4.5.9
Cardiac Function ..........................................................................104
4.5.10
Optional Tumor Tissue Samples ..................................................104
4.5.11
Optional Samples for Research Biosample 
Repository....................................................................................104
4.5.11.1
Overview of the Research Biosample Repository.........................104
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee....................................................................................105
4.5.11.3
Sample Collection ........................................................................105
4.5.11.4
Confidentiality...............................................................................106
4.5.11.5
Consent to Participate in the Research Biosample 
Repository....................................................................................106


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4.5.11.6
Withdrawal from the Research Biosample Repository..................107
4.5.11.7
Monitoring and Oversight .............................................................107
4.6
Treatment, Patient, Study, and Site Discontinuation.....................107
4.6.1
Study Treatment Discontinuation..................................................107
4.6.2
Patient Discontinuation from the Study.........................................108
4.6.3
Study Discontinuation...................................................................109
4.6.4
Site Discontinuation......................................................................109
5.
ASSESSMENT OF SAFETY ...............................................................................109
5.1
Safety Plan...................................................................................109
5.1.1
Risks Associated with Idasanutlin.................................................110
5.1.1.1
Gastrointestinal Toxicity ...............................................................110
5.1.1.2
Cytopenias ...................................................................................111
5.1.1.3
Tumor Lysis Syndrome.................................................................111
5.1.1.4
Infections......................................................................................111
5.1.1.5
Electrolyte Disorders ....................................................................112
5.1.1.6
Testicular Toxicity.........................................................................112
5.1.1.7
Other Adverse Events ..................................................................112
5.1.2
Risks Associated with Venetoclax ................................................112
5.1.2.1
Tumor Lysis Syndrome.................................................................113
5.1.2.2
Neutropenia..................................................................................114
5.1.2.3
Infections......................................................................................114
5.1.2.4
Cytopenias ...................................................................................114
5.1.2.5
Effects on Fertility and Reproductive Toxicity ...............................115
5.1.2.6
Treatment-Emergent Malignancies (Second Primary 
Malignancies)...............................................................................115
5.1.2.7
Food Effect...................................................................................115
5.1.3
Risks Associated with Chemotherapy...........................................115
5.1.3.1
Risks with Cyclophosphamide and Topotecan .............................115
5.1.3.2
Risks with Fludarabine and Cytarabine ........................................116
5.1.4
Risk of Overlapping Toxicities ......................................................116
5.1.5
Management of Patients Who Experience Adverse 
Events..........................................................................................117
5.1.5.1
Dose Modifications.......................................................................117


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5.1.5.2
Treatment Interruption..................................................................117
5.1.5.3
Hospitalization Requirements.......................................................118
5.1.5.4
Management Guidelines for Specific Adverse Events ..................119
5.2
Safety Parameters and Definitions ...............................................127
5.2.1
Adverse Events ............................................................................127
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor).................................................................................127
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ..........................................................128
5.2.4
Dose-Limiting Toxicities (Immediately Reportable to 
the Sponsor).................................................................................129
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters........................................................................129
5.3.1
Adverse Event Reporting Period ..................................................129
5.3.2
Eliciting Adverse Event Information ..............................................129
5.3.3
Assessment of Severity of Adverse Events ..................................130
5.3.4
Assessment of Causality of Adverse Events.................................130
5.3.5
Procedures for Recording Adverse Events...................................131
5.3.5.1
Diagnosis versus Signs and Symptoms........................................131
5.3.5.2
Adverse Events That Are Secondary to Other Events ..................132
5.3.5.3
Persistent or Recurrent Adverse Events.......................................132
5.3.5.4
Abnormal Laboratory Values ........................................................132
5.3.5.5
Abnormal Liver Function Tests.....................................................133
5.3.5.6
Deaths..........................................................................................134
5.3.5.7
Preexisting Medical Conditions.....................................................134
5.3.5.8
Lack of Efficacy or Worsening of AML, ALL, or Solid-
Tumor Cancer ..............................................................................134
5.3.5.9
Hospitalization or Prolonged Hospitalization.................................135
5.3.5.10
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse.................................................................................135
5.3.5.11
Patient-Reported or Observer-Reported Outcome 
Data .............................................................................................137
5.3.5.12
Safety Biomarker Data .................................................................137
5.4
Immediate Reporting Requirements from Investigator 
to Sponsor....................................................................................138


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5.4.1
Emergency Medical Contacts.......................................................138
5.4.2
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest........................................139
5.4.2.1
Events That Occur prior to Study Drug Initiation...........................139
5.4.2.2
Events That Occur after Study Drug Initiation...............................139
5.4.3
Reporting Requirements for Pregnancies.....................................139
5.4.3.1
Pregnancies in Female Patients...................................................139
5.4.3.2
Pregnancies in Female Partners of Male Patients ........................140
5.4.3.3
Abortions......................................................................................140
5.4.3.4
Congenital Anomalies/Birth Defects .............................................141
5.4.4
Reporting Requirements for Medical Device 
Complaints ...................................................................................141
5.5
Follow-Up of Patients after Adverse Events..................................141
5.5.1
Investigator Follow-Up..................................................................141
5.5.2
Sponsor Follow-Up.......................................................................142
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period ..........................................................................142
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees..................................................................................142
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN................................143
6.1
Determination of Sample Size ......................................................143
6.2
Summaries of Conduct of Study...................................................146
6.3
Summaries of Demographic and Baseline 
Characteristics .............................................................................146
6.4
Safety Analyses ...........................................................................146
6.4.1
Primary Safety Model (mCRM-EWOC) for Single-
Agent Dose Finding......................................................................146
6.5
Pharmacokinetic Analyses ...........................................................147
6.6
Efficacy Analyses .........................................................................147
6.6.1
Primary Efficacy Endpoints...........................................................147
6.6.2
Secondary Efficacy Endpoints......................................................148
6.6.2.1
Solid Tumors including Neuroblastoma ........................................148
6.6.2.2
Leukemias....................................................................................148
6.7
Biomarker Analyses .....................................................................148


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6.8
Health Status Utility analysis ........................................................149
7.
DATA COLLECTION AND MANAGEMENT ........................................................149
7.1
Data Quality Assurance................................................................149
7.2
Electronic Case Report Forms......................................................149
7.3
Source Data Documentation ........................................................150
7.4
Use of Computerized Systems .....................................................150
7.5
Retention of Records....................................................................151
8.
ETHICAL CONSIDERATIONS ............................................................................151
8.1
Compliance with Laws and Regulations .......................................151
8.2
Informed Consent.........................................................................151
8.3
Institutional Review Board or Ethics Committee ...........................152
8.4
Confidentiality...............................................................................153
8.5
Financial Disclosure .....................................................................154
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION..............................................................................................154
9.1
Study Documentation...................................................................154
9.2
Protocol Deviations ......................................................................154
9.3
Management of Study Quality...................................................154
9.4
Site Inspections............................................................................154
9.5
Administrative Structure ...............................................................155
9.6
Dissemination of Data and Protection of Trade 
Secrets.........................................................................................155
9.7
Protocol Amendments..................................................................156
10.
REFERENCES....................................................................................................157
LIST OF TABLES
Table 1
Response Criteria, Assessment Timepoints, and Primary Efficacy 
Endpoints.............................................................................................60
Table 2
Prophylactic Medication .......................................................................87
Table 3
List of CYP2C8, CYP3A4, or OATP1B1/3 Inhibitors, Inducers, or 
Substrates............................................................................................93
Table 4
List of P-gp Inhibitors or Substrates .....................................................95
Table 5
Guidelines for Management of Patients Who Experience Adverse 
Events................................................................................................120


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Table 6
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE .........................................................................130
Table 7
Causal Attribution Guidance...............................................................131
Table 8
Sample Size for Initial and Additional Response Assessment............145
LIST OF FIGURES
Figure 1
Study Schema......................................................................................48
LIST OF APPENDICES
Appendix 1
Schedule of Activities for Patients with Solid Tumors (Single-Agent 
Dose-Escalation Cohort) ....................................................................165
Appendix 2
Schedule of Activities for Patients with Neuroblastoma (Study 
Parts 1b, 2 and 3) ..............................................................................169
Appendix 3
Schedule of Activities for Patients with ALL and AML.........................173
Appendix 4
Schedule of Pharmacokinetic Samples ..............................................177
Appendix 5
International Neuroblastoma Response Criteria.................................178
Appendix 6
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ...........182
Appendix 7
AML Response Assessment ..............................................................192
Appendix 8
ALL Response Assessment ...............................................................194
Appendix 9
Lansky Performance Status Scale (Patients 16 years of age) ..........196
Appendix 10
Karnofsky Performance Status Scale (Patients 16 years of age)......197
Appendix 11
Modified Continual Reassessment Method of Escalation with 
Overdose Control Design...................................................................198
Appendix 12
Howard Definition and Classification of Tumor Lysis Syndrome.........207
Appendix 13
Acceptability Survey for Patients........................................................208
Appendix 14
Age and Weight Adjusted Adult-Equivalent Venetoclax Dosing 
Table..................................................................................................211
Appendix 15
Dosing Tables for Intrathecal Therapy................................................212


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
14/Protocol GO40871, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE I/II, MULTICENTER, OPEN-LABEL, 
MULTI-ARM STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND 
PRELIMINARY ACTIVITY OF IDASANUTLIN IN 
COMBINATION WITH EITHER CHEMOTHERAPY 
OR VENETOCLAX IN THE TREATMENT OF 
PEDIATRIC AND YOUNG ADULT PATIENTS WITH 
RELAPSED/REFRACTORY ACUTE LEUKEMIAS 
OR SOLID TUMORS
PROTOCOL NUMBER:
GO40871
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004579-11
IND NUMBER:
117005
NCT NUMBER:
NCT04029688
TEST PRODUCT:
Idasanutlin (RG7388; RO5503781-020)
Venetoclax (GDC-0199; ABT-199; 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 of 
the signed form to the Sponsor or designee.  


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
15/Protocol GO40871, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE I/II, MULTICENTER, OPEN-LABEL, MULTI-ARM STUDY 
EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND PRELIMINARY ACTIVITY OF 
IDASANUTLIN IN COMBINATION WITH EITHER 
CHEMOTHERAPY OR VENETOCLAX IN THE TREATMENT OF 
PEDIATRIC AND YOUNG ADULT PATIENTS WITH 
RELAPSED/REFRACTORY ACUTE LEUKEMIAS OR SOLID 
TUMORS
PROTOCOL NUMBER:
GO40871
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004579-11
IND NUMBER:
117005
NCT NUMBER:
NCT04029688
TEST PRODUCT:
Idasanutlin (RG7388; RO5503781-020)
Venetoclax (GDC-0199; ABT-199; RO5537382)
PHASE:
Phase I/II
INDICATION:
Relapsed/refractory acute leukemias and solid tumors
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, tolerability, and pharmacokinetics of idasanutlin as a single 
agent and the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin in 
combination with either chemotherapy or venetoclax in children and young adults with acute 
leukemias or solid tumors that are recurrent or refractory to standard therapy.
In this protocol, "study treatment" refers to the single agent or combination of treatments 
assigned to patients as part of this study (i.e., idasanutlin with or without chemotherapy or 
venetoclax).  
Specific objectives and corresponding endpoints for the study are outlined below.
Safety Objectives
The safety objectives for this study are to evaluate the safety and tolerability of idasanutlin as a 
single agent, in combination with chemotherapy, and in combination with venetoclax; to 
determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of 
idasanutlin administered as a single agent; and to define the recommended Phase 2 dose 
(RP2D) of idasanutlin in combination with either chemotherapy or venetoclax on the basis of the 
following endpoints:

Incidence and severity of adverse events with severity determined according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 
(NCI CTCAE v5.0)

Changes from baseline in physical findings

Changes from baseline in targeted clinical laboratory test results and ECG parameters


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16/Protocol GO40871, Version 4

Incidence of dose-limiting toxicities (DLTs) assessed during the first cycle of study 
treatment of single-agent idasanutlin and again with idasanutlin in combination with 
chemotherapy or venetoclax
The exploratory safety objective for this study is to evaluate the impact of idasanutlin as a single 
agent and in combination with chemotherapy and venetoclax on growth and development on 
the basis of the following endpoints:

Changes from baseline in growth patterns (relative to age-specific standards for height and 
weight)

Changes from baseline in development patterns (relative to onset of menarche [for females] 
and pubertal changes)
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are as follows: 

To characterize the PK profile of idasanutlin as a single agent and in combination with 
chemotherapy or venetoclax on the basis of the following endpoints:
-
Plasma concentration of idasanutlin (and M4 metabolite RO6802287, where relevant) 
as a single agent at specified timepoints
-
Plasma concentration of idasanutlin in combination with chemotherapy or venetoclax at 
specified timepoints

To characterize the PK profile of venetoclax in combination with idasanutlin on the basis of 
the following endpoint:
-
Plasma concentration of venetoclax at specified timepoints
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study (Study Parts 1b, 2, and 3) is to evaluate the 
anti-cancer activity of idasanutlin in combination with chemotherapy or venetoclax on the basis 
of the following endpoints:
Neuroblastoma

Objective response rate (ORR), defined as the proportion of patients with complete 
response or partial response (PR) at any time during study treatment, on two consecutive 
occasions 4 weeks apart, as determined by the investigator according to INRC for patients 
with neuroblastoma. 
Primary efficacy analysis will be conducted on patients with TP53 wild-type (WT) tumors in 
Study Parts 1b, 2, and 3.
Leukemia

Complete remission rate (CRR), defined as the proportion of patients with morphologic 
complete remission, complete remission with incomplete blood count recovery (CRi) or 
complete remission with incomplete platelet count recovery (CRp), within 2 cycles of study 
treatment 

For patients with acute lymphocytic leukemia (ALL):  minimal residual disease (MRD)-
negative rate, defined as the proportion of patients with ALL who have an MRD value 
0.01%, as measured by next-generation sequencing (NGS), within 2 cycles of study 
treatment
Primary efficacy analyses will be conducted on patients with TP53 WT tumors in Study Parts 2 
and 3.
Secondary Efficacy Objective
The secondary efficacy objective for this study (Study Parts 1, 2, and 3) is to evaluate the 
anti-cancer activity of idasanutlin as single agent, in combination with chemotherapy, and in 


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
17/Protocol GO40871, Version 4
combination with venetoclax (in patients with TP53 WT tumors, as well as in all patients 
regardless of mutation status) on the basis of the following endpoints:
Solid tumors (including Neuroblastoma)

Clinical benefit rate (CBR), defined as the proportion of patients achieving confirmed 
complete response, PR, or SD on two consecutive occasions 4 weeks apart during the 
total study period

Duration of objective response (DOR), defined as the time from the first tumor assessment 
that supports a patient’s objective response to the time of disease progression or death 
from any cause (whichever occurs first), as determined by the investigator using INRC for 
patients with neuroblastoma or RECIST v1.1 for patients with other solid tumors

Progression-free survival (PFS), defined as the time from initiation of study drug to the first 
documented occurrence of disease progression or death from any cause (whichever occurs 
first), as determined by the investigator using INRC for patients with neuroblastoma and 
RECIST v1.1 for patients with other solid tumors

Overall survival (OS), defined as the time from initiation of study drug to death from any 
cause

ORR of efficacy-evaluable population irrespective of TP53 mutation status
Leukemia

Number of patients receiving transplant after study treatment

DOR, defined as the time from the first tumor assessment that supports the patient's 
objective response (CR, CRp, CRi) to the time of relapse, or death from any cause, 
whichever occurs first

EFS, defined as the time from initiation of study drug to the first documented occurrence of 
M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi after Cycle 2, disease progression, 
relapse subsequent to achieving CR/CRp/CRi, or death from any cause, whichever occurs 
first.

OS, defined as the time from initiation of study drug to death from any cause 

CRR of efficacy-evaluable population irrespective of TP53 mutation status

For patients with acute myeloid leukemia (AML):  MRD-negative rate, defined as the 
proportion of patients with AML who are MRD negative within 2 cycles of study treatment 
Exploratory Biomarker Objectives
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to idasanutlin as a single agent or in combination with chemotherapy or venetoclax;
are early surrogates of efficacy; are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers); are associated with acquired resistance to idasanutlin as a single 
agent or in combination with chemotherapy or venetoclax; are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring or investigation 
(i.e., safety biomarkers); can provide evidence of idasanutlin activity (i.e., pharmacodynamic 
biomarkers) as a single agent or in combination with chemotherapy or venetoclax; or can 
increase the knowledge and understanding of disease biology and drug safety, on the basis of 
the following endpoints:

Relationship between biomarkers identified in blood versus tissue and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate the acceptability and 
palatability of idasanutlin on the basis of the following endpoint:

Acceptability Survey scores at Cycle 1, Day 5


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Study Design
Description of Study
The study is divided into three parts: 

Study Part 1:  
-
Part 1a: Dose escalation to assess safety, tolerability, and pharmacokinetics of 
idasanutlin as a single-agent treatment in the pediatric population with relapsed or 
refractory solid-tumors; to identify the single-agent MTD/MAD; and to characterize 
DLTs.  Patients in dose escalation after one cycle will either continue single-agent 
idasanutlin or start early combination of idasanutlin with chemotherapy (for precise 
rules, see protocol).  
-
Part 1b: Following single-agent MTD/MAD identification, separate safety run-in cohorts
will be conducted in neuroblastoma with newly enrolled patients to identify the RP2Ds
of idasanutlin in combination with cyclophosphamide and topotecan and in combination 
with venetoclax.  These cohorts will also provide early efficacy assessments of these
combinations in the patients with TP53 WT tumors treated at the RP2Ds.  Additional 
safety run-in cohorts will be conducted in AML to identify the RP2D of idasanutlin 
in combination with fludarabine and high-dose cytarabine (FLA) and in AML and 
ALL to identify the RP2D of idasanutlin in combination with venetoclax in patients 
with leukemia. 

Study Part 2:  In cohorts that pass the safety and efficacy criteria for Part 1b (Gate 1b), 
evaluation of safety and efficacy of idasanutlin in combination with chemotherapy or 
venetoclax will be continued in neuroblastoma, AML, and/or ALL at the RP2D(s) for the 
combinations.

Study Part 3:  Potential expansion of idasanutlin combination cohorts in neuroblastoma, 
AML, and/or ALL meeting the pre-defined efficacy criteria for expansion (Gate 2), also 
taking into account practical considerations (e.g., enrollment feasibility), nonclinical findings, 
biomarker analysis, safety profiles, and any other relevant information. 
In Study Part 1a, only patients 18 years of age will be enrolled.  In Study Parts 1b, 2, and 3, 
pediatric and young adult patients with neuroblastoma or acute leukemias (age:  birth to 
30 years) will be enrolled. 
Idasanutlin will be administered orally to patients once daily for Days 15 of each cycle, 
followed by 23 days of rest, for a total cycle duration of 28 days.  All patients will be closely 
monitored for adverse events (regardless of relationship to study drug) throughout the study and 
for at least 30 days after the last dose of study treatment or until initiation of a new anti-cancer 
therapy, whichever comes first. 
Patients will be enrolled regardless of their TP53 mutation status, as not all TP53 mutations 
may be inactivating; therefore, responses may still be observed in some patients with TP53
mutations.  A pre-idasanutlin tumor biopsy of current disease within 6 months of screening and 
after the last anti-cancer therapy is required for patients with solid tumors unless approved by 
the Medical Monitor.  A bone marrow aspirate (BMA) specimen is required within the 
screening period for patients with leukemia.  Samples will be analyzed for TP53 mutation status 
by centralized molecular testing.  If available, sites must also report any local molecular testing 
results for TP53 mutation status in the eCRF.
An internal monitoring committee and external scientific oversight committee (IMC/SOC) will be 
established for safety monitoring at pre-defined study milestones and approximately every 
6 months.
Study Part 1aSingle-Agent Dose Escalation
The study will begin with a dose-escalation phase with idasanutlin in patients with solid tumors 
using the modified continual reassessment method of escalation with overdose control 
(mCRM-EWOC) to identify the single-agent MTD/MAD.  Approximately 924 DLT-evaluable 
patients are anticipated to be enrolled in this phase.  Based on physiologically-based 
pharmacokinetic (PBPK)-predicted exposures in children, the starting dose in this escalation 
cohort is defined as 2 mg/kg/day (dose level 1).  Dose-level escalation or de-escalation (if 
required) will be decided following review of PK and safety data.  


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The single-agent DLT window will be 28 days (one cycle duration) and until ANC 0.75 109/L 
and platelet count 75 109/L are achieved.  Following the first cycle, patients will undergo 
response and DLT assessment.  Any delay 14 days in treatment due to delayed platelet 
recovery will also be considered a DLT; therefore, DLT assessment may extend until platelet 
count recovery.

Patients who do not experience a DLT or progressive disease will have the option (with 
investigator approval) to continue single-agent idasanutlin or start combination therapy with 
cyclophosphamide/topotecan with a dose reduction in idasanutlin of 20%.  

Patients who do not experience a DLT but do experience progressive disease may continue 
idasanutlin (with a 20% dose reduction) in combination with cyclophosphamide/topotecan 
with investigator and Medical Monitor approval, but will not be permitted to continue 
idasanutlin monotherapy.

Patients who experience a DLT but have CR, PR, or SD will have the option to continue 
single-agent treatment (dose reduced by 20%) upon adequate recovery from toxicities and 
depending on the nature of the specific toxicity, as jointly judged by investigator and the 
Medical Monitor.

Patients who experience a DLT and progressive disease will permanently discontinue study 
therapy.
Patients will start subsequent cycles of therapy after Day 28 and when ANC 0.75 109/L and 
platelet count 75 109/L are achieved.  Patients who remain on study therapy (single agent or 
combination) will continue until the occurrence of disease progression as determined by the 
investigator, death, unacceptable toxicity, or patient/guardian or investigator decision to 
discontinue treatment. 
Study Part 1bCombination Therapy Safety Run-In
Once the idasanutlin single-agent MTD/MAD has been identified, a safety run-in phase with 
newly enrolled pediatric patients will be conducted to identify RP2Ds for idasanutlin in 
combination with chemotherapy or venetoclax in separate neuroblastoma, AML, and ALL 
combination cohorts.  The safety run-in phase will start at a maximum of 80% of the idasanutlin 
MTD/MAD identified in the dose-escalation phase, combined with the following regimens in the 
listed diseases:

Idasanutlin chemotherapy:
-
Neuroblastoma:  cyclophosphamide topotecan 
-
AML:  fludarabine cytarabine 

Idasanutlin venetoclax:
-
Neuroblastoma
-
ALL and AML, with different DLT rules for hematologic toxicity
Assignment of patients to either the chemotherapy or venetoclax cohort will be at the 
investigator's discretion and in accordance to the availability of open slots for enrollment.
The DLT criteria (disease-type dependent) are modified from those used in the single-agent 
dose escalation cohort in order to determine more appropriately the RP2D in the setting of 
combinations with agents that have anticipated effects on bone marrow suppression.  
Dose-escalation decisions will be dependent on pharmacokinetics and totality of data.  Only the
idasanutlin dose will be escalated, while chemotherapies or venetoclax doses will not be 
escalated. However, idasanutlin, chemotherapy, and/or venetoclax doses may be de-escalated 
based on the totality of the data as determined by the Medical Monitor. 
For each combination cohort, the first patient at the first dose level must complete at least 
5 days of treatment without a DLT before subsequent patients can be treated at the same dose 
level.  Dose modifications will be conducted according to design similar to a 3+3 design, except 
with additional restrictions: a maximum of one higher dose level from the starting dose-level 
cohort, or one lower dose-level cohorts of idasanutlin, will be permitted.  If one dose level below 
the starting dose of idasanutlin is considered intolerable, the combination will be discontinued.  


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20/Protocol GO40871, Version 4
As the safety profile of idasanutlin may differ among combinations, the idasanutlin RP2D may 
also differ among cohorts. 
Upon identification of the appropriate RP2D, patients treated at lower dose levels (including 
those patients treated in the single-agent dose escalation who go on to receive combination 
therapy with cyclophosphamide/topotecan) will be allowed to escalate to the RP2D. 
Patients will be treated with combination therapy until the occurrence of disease progression as 
determined by the investigator, death, unacceptable toxicity, study termination, or 
patient/guardian or investigator decision to discontinue treatment, except in the following 
instances:

Patients with AML treated with FLA) will receive up to 2 cycles of combination therapy, 
followed by idasanutlin monotherapy in subsequent cycles.  

Patients with leukemia who 1) do not meet criteria for progression or relapse but have M3 
marrow after Cycle 1 of therapy or 2) fail to achieve morphologic CR/CRi/CRp after 2 cycles 
of therapy will be required to discontinue study therapy unless the investigator views the 
benefitrisk ratio of continued therapy as favorable (and with approval of the Medical 
Monitor).  Patients will still be recorded as having had an event for EFS analysis.
Study Part 2Initial Expansion for Early Efficacy Evaluation
The preliminary efficacy for the RP2D idasanutlin combinations will be evaluated in Study 
Part 2.  Upon determination of the appropriate idasanutlin RP2D and passage of Gate 1b for 
each disease and combination, additional patients will be enrolled in Study Part 2.  For 
neuroblastoma cohorts, approximately 46 patients will be added to reach a total of 
10 patients with TP53 wild type (WT) tumors (including those patients enrolled in 
Study Part 1b at the RP2D).
For AML, patients will be randomly allocated between two combination arms (FLA versus 
venetoclax) and evaluated for safety and preliminary efficacy.  For these AML arms, 
ten patients with TP53 WT AML will be enrolled per arm, not counting those enrolled in 
Study Part 1b.  For ALL, patients will be non-randomly assigned to receive idasanutlin plus 
venetoclax.  Ten patients with TP53 WT ALL will be required for this cohort.  On the basis of 
the frequency of TP53 mutations in the selected tumor types, the overall number of patients 
enrolled in each individual cohort is not expected to exceed approximately 20% more than the 
target minimum of 10 patients.  Patients enrolled in the study whose cancers are found to have 
TP53 mutations will be allowed to continue study therapy but will be replaced for efficacy 
analysis.  The different cancer types will be evaluated independently of one another. 
Patients included in the safety run-in phase will not be included in the 10-patient initial response 
assessment for the leukemia arms.
Study Part 3Additional Expansion Phase
A minimum number of responders among the 10 patients with TP53 WT enrolled in Study 
Parts 1b and 2 for the neuroblastoma cohorts or Study Part 2 for the leukemia cohorts will be 
required for cohort expansion and advancement to the additional response assessment (Study 
Part 3).  The minimum number of responders is defined separately for each disease and is 
based on an expected observation of improvement over response rates to backbone therapies.  
A decision to expand a cohort will take into account safety and tolerability of the combination 
regimen in addition to the number of responders.  Practical considerations will also be taken into 
account, such as enrollment feasibility, nonclinical findings, biomarker analysis, safety profiles, 
and any other relevant information.  In general, cohorts will not expand if the minimum number 
of responders is not met.  However, the study team (only with endorsement of the IMC/SOC) 
will be permitted to expand a cohort even if the minimum number of responders is not met, if the 
totality of the efficacy and other data support cohort expansion.  The maximum number of 
additional patients enrolled in any tumor cohort in Study Part 3 will range from 2030 patients 
with TP53 WT tumors.  Tumor assessments will be performed utilizing the same response 
criteria used in Study Part 2.
Number of Patients
Approximately 15108 patients will be enrolled in the Study Parts 1 and 2.  After completion of 
the initial response assessment, an additional 2030 patients may be enrolled for a combination 
regimen in each tumor type, up to a total sample size of approximately 183 patients.


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
21/Protocol GO40871, Version 4
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed informed consent before any study-specific screening procedures are conducted, 
and age-appropriate assent when considered appropriate according to local, regional, or 
national guidelines

Age 18 years at the time of signing informed consent for Part 1a, 30 years at time of 
signing informed consent for Parts 1b, 2, and 3
Note:  The Sponsor may decide to stop enrollment of patients who are 18 years at 
any time during the study to ensure adequate enrollment of patients who are 
18 years.

Study Part 1a (single-agent therapy dose escalation):  histologically confirmed diagnosis of 
neuroblastoma or other solid tumor that has progressed or recurred despite standard 
therapy, and for which there is no therapy proven to prolong survival with an acceptable 
quality of life

Study Part 1b (safety run-in), Study Part 2, and Study Part 3:  histologically confirmed 
diagnosis of neuroblastoma, AML, or precursor-B ALL that has progressed or recurred 
despite, or is refractory to, standard therapy 

Adequate performance status:
Patients 16 years of age:  Lansky 50%
Patients 16 years of age:  Karnofsky 50%

Adequate end-organ function defined by the following laboratory results obtained within 
28 days prior to initiation of study drug:
Renal and liver function 
-
Creatinine 1.5 ULN for age; if higher, an estimate GFR based on the 
Schwartz equation (Schwartz et al. 2017) or as per institutional guidelines must 
be 60mL/min/1.73 m2
-
Bilirubin 1.5 ULN for age (or 2.5 ULN if liver infiltrated with leukemia or 
metastases)
-
AST and ALT 3 ULN for age (or 5 ULN if liver infiltrated with leukemia or 
metastases)
Cardiac function
-
Fractional shortening (FS) 28% or left ventricular ejection fraction (LVEF) 
50%, as determined by echocardiography or multigated acquisition scan 
(MUGA) within 28 days prior to initiation of study therapy
Depending on institutional standard, either FS or LVEF is adequate for 
enrollment if only one value is measured; if both values are measured, 
then both values must meet the above criteria.

For females of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, agreement to refrain from donating eggs, as 
defined below:
Females must remain abstinent or use two methods of contraception with a failure rate 
of 1% per year during the treatment period and for 6 weeks after the final dose of
idasanutlin, 30 days after the final dose of venetoclax, 12 months after final treatment 
for patients receiving cyclophosphamide/topotecan (or longer if required according to 
national prescribing information), 6 months after final treatment for patients receiving 
FLA (or longer if required according to national prescribing information), or in 
accordance with national prescribing information guidance regarding abstinence, 
contraception, and egg donation for any non-Investigational Medicinal Products listed 
in the protocol.  Females must refrain from donating eggs during this same period.  


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A female is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
A barrier method may be used as the second contraceptive method.
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 postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For males:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, males must 
remain abstinent or use a condom during the treatment period and for 90 days after 
the final dose of idasanutlin, 12 months after final treatment with 
cyclophosphamide/topotecan (or longer if required according to national prescribing 
information), 6 months after final treatment with fludarabine to avoid exposing the 
embryo (or longer if required according to national prescribing information), or in 
accordance with national prescribing information guidance regarding abstinence, 
contraception, and sperm donation for any non-Investigational Medicinal Products 
listed in the protocol.  Males must refrain from donating sperm during this same period.  
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 postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Additional Inclusion Criteria for Patients with Solid Tumors (including Neuroblastoma)

At least one evaluable or measurable radiological site of disease as defined by standard 
criteria for the patient’s tumor type (e.g., INRC), or measurable bone marrow disease by 
morphology

Adequate end-organ hematologic function, as specified in the following parameters:
-
Hemoglobin 8 g/dL (transfusion allowed)
-
Peripheral ANC 0.75 109/L (no G-CSF support for 72 hours)
-
Platelet count 75 109/L (unsupported for 72 hours)

Tumor tissue from relapsed disease, obtained subsequent to last anti-cancer therapy 
regimen administered and obtained within 6 months prior to study enrollment, or willingness 
to undergo a core or excisional biopsy sample collection prior to enrollment 
-
Patients must submit a tissue block or 15 slides containing unstained, freshly cut, serial 
sections available for submission. 
-
Fine needle aspirations, brush biopsies, bone metastasis samples, and lavage samples 
are not acceptable.


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-
Patients with 15 slides available, or whose tumor tissue does not otherwise meet 
criteria above, may be eligible for study entry after Medical Monitor approval has been 
obtained.  See protocol for detailed tissue requirements.

Life expectancy 12 weeks, in the investigator's judgment
Additional Inclusion Criteria for Patients with Leukemia

Bone marrow with 5% lymphoblasts by morphologic assessment at screening

Available bone marrow aspirate or biopsy from screening
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Primary CNS tumors

Symptomatic CNS metastases that result in a neurologically unstable clinical state or 
require increasing doses of corticosteroids or local CNS-directed therapy to control the CNS 
disease

CNS3 leukemia (total nucleated cell count 5/L with blasts on cytocentrifuge in an 
atraumatic lumbar puncture, or clinical signs of CNS leukemia including cranial nerve palsy)

Acute promyelocytic leukemia

White blood cell count 50 109/L
-
Prior cytoreduction with leukapheresis or hydroxyurea (HU) is allowed to meet this 
criterion.  HU must be discontinued at least 24 hours prior to the initiation of study 
treatment.
-
Prior cytoreduction with leukapheresis or hydroxyurea is allowed in patients with a WBC 
count 50 109/L if the patient is symptomatic from hyperleukocytosis, or if consistent 
with institutional guidelines.

Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known 
bone marrow failure predisposition syndrome (including, but not limited to, Fanconi anemia 
or dyskeratosis congenita) 

Burkitt-type acute lymphoblastic leukemia (mature B-cell) 

T-cell lymphoblastic leukemia

Prior treatment with an MDM2 antagonist

Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm)

Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk 
to the patient upon induction of neutropenia, including patients who are, or should be, on 
antimicrobial agents for the treatment of active infection such as the following:
-
Fungal infection, other than mucosal candidiasis, with 2 weeks of appropriate 
systemic antifungal therapy
-
Bacterial infection with positive cultures in the 7 days prior to dosing
-
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 dosing
-
History of symptomatic Clostridium difficile (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.


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
Pregnant or breastfeeding, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test result 
within 1 week prior to initiation of study drug.

Active GI disease (e.g., gut graft-versus-host disease, Crohn's disease, ulcerative colitis) or 
GI conditions that may significantly alter drug absorption of oral drugs (e.g., uncontrolled 
vomiting, diarrhea, or malabsorption syndrome)

Active viral hepatitis or human immunodeficiency virus (HIV) infection

Presence of any CTCAE Grade 2 clinically significant treatment-related toxicity with the 
exception of alopecia, ototoxicity, peripheral neuropathy and parameters otherwise 
permitted in the inclusion criteria (e.g., hematological criteria)

Clinically relevant QTc prolongation (QTcF 450 ms using the Fridericia correction)

Any uncontrolled medical condition or other identified abnormality that precludes the 
patient's safe participation in and completion of the study, as judged by the investigator

Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to 
initiation of study treatment
-
Requirement may be waived at the investigator's request, with approval of the Medical 
Monitor, if the patient has recovered from therapeutic toxicity to the degree specified in 
the protocol.
-
Intrathecal chemotherapy per protocol prior to starting study therapy is permissible.

Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy 
(e.g., CAR-T cell infusion) for anti-neoplastic intent within 30 days prior to initiation of study 
treatment

I-131 MIBG therapy within 6 weeks prior to initiation of study treatment

Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 
100 days of study treatment initiation

Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of 
study treatment initiation

Radiotherapy (non-palliative) within 3 weeks prior to study treatment initiation 

Known hypersensitivity to any study drug or component of the formulation that could 
potentially be allocated according to tumor type

Received the following within 7 days prior to initiation of study treatment:
-
Strong CYP2C8 inhibitors
-
CYP2C8 substrates
-
OATP1B1/3 substrates

Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the initiation 
of study treatment 

For patients assigned or randomized to venetoclax arms:
-
Strong or moderate CYP3A4 inhibitors or moderate inducers or P-gp inhibitors within 
7 days of study drug initiation 
-
Grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville 
oranges), or starfruit within 3 days prior to the initiation of study treatment
-
Vaccination with a live vaccine 28 days prior to randomization

Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study 
treatment initiation


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
Underwent major surgical procedure within 21 days of study treatment initiation, or 
anticipate need for major surgical procedure during the course of the study
Gastrostomy, tumor biopsy, and insertion of central venous access devices are not 
generally considered major surgery, but the Medical Monitor should be notified of 
these or other minor procedures prior to initiating therapy.
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or 1 year after 
the last patient is enrolled, whichever occurs first. For an individual patient, the completion of 
the study (i.e., the last visit) will occur when the patient withdraws consent, has been lost to 
follow-up, dies, or when the study is stopped.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are idasanutlin, venetoclax, 
cyclophosphamide, topotecan, fludarabine, and cytarabine.
Test Product (Investigational Drug)
Idasanutlin
Idasanutlin will be supplied as 5-mg and 20-mg dispersible tablets.  The dispersible tablets can 
either be swallowed or used to prepare a suspension (ad hoc) for patients not able to swallow 
tablets.  Idasanutlin will be administered as an oral medication once daily on Days 15 of a 
28-day cycle.  The starting daily dose of idasanutlin in the dose-escalation phase of the study 
will be 2 mg/kg/day and will be modified according to the protocol.  
Venetoclax
Venetoclax (GDC-0199/ABT-0199) will be supplied as oral film-coated tablets of 10-mg, 50-mg, 
and 100-mg strength.  Venetoclax will also be provided as 2.5-mg, 10-mg, and 25-mg tablets for 
oral suspension for patients not able to swallow tablets.  
Venetoclax (in combination with idasanutlin) will be administered at the adult dose equivalent 
(adjusted by body weight) of 400 mg in patients with neuroblastoma and the adult dose 
equivalent of 600 mg in patients with leukemia once daily on Days 128 of a 28-day cycle.  For 
patients with neuroblastoma, venetoclax will ramp-up to the target dose over 2 days (200 mg
equivalent Day 1 to 400 mg equivalent Day 2).  Patients with neuroblastoma receiving 
venetoclax should be hospitalized during the ramp-up phase until the target dose has been 
administered.  For patients with leukemia, venetoclax will ramp-up to the target dose over 
3 days (150 mg equivalent Day 1; 300 mg equivalent Day 2; 600 mg equivalent Day 3).  If lower 
doses of venetoclax are required, intermediate doses for the ramp up will be proportionally 
adapted based on the duration of ramp-up period (2 or 3 days), the final dose to be achieved, 
and the available formulation dose strength. For guidance on dose reductions in case of 
co-administration with CYP3A4 or P-gp, refer to protocol.
Chemotherapy
For patients assigned to arms combining idasanutlin with chemotherapy, chemotherapy should 
be administered at the doses prescribed below.  Infusion duration, prophylactic medications, 
and monitoring guidelines should be managed in accordance with institutional standard unless 
specified in the protocol.


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Neuroblastoma
Cyclophosphamide and topotecan will be administered once daily on Days 15 of each 28-day 
cycle at the following doses:

Cyclophosphamide 250 mg/m2 (8.33 mg/kg for patients 12 kg) as an intravenous (IV) 
infusion over 1 hour

Topotecan 0.75 mg/m2 (0.025 mg/kg for patients 12 kg) as an IV infusion over 1 hour
Acute Myeloid Leukemia
FLA (fludarabine and high-dose cytarabine) chemotherapy will be administered during each
28-day combination treatment cycle as per the following regimen: 

Fludarabine 30 mg/m2 IV Days 1 to 5 over 30 minutes

Cytarabine 2000 mg/m2 IV Days 1 to 5 over 4 hours
Note:  Cytarabine infusion is administered 4 hours after the start of the fludarabine infusion.
Non-Investigational Medicinal Products
The non-IMPs in the study include the prophylactic medications (anti-diarrheal agents, 
antibiotics, anti-fungal agents, uric acid reducing agents, anti-PCP therapy, growth factors, and 
5-HT3-receptor antagonists) and the intrathecal chemotherapy agents (intrathecal cytarabine, 
methotrexate, and hydrocortisone).
Statistical Methods
Safety Analyses
Safety will be characterized by incidence of adverse events and DLTs, as well as change from 
baseline in ECG parameters and clinical laboratory results. Study treatment exposure (such as 
treatment duration, total dose received, and number of cycles and dose modifications) will be 
summarized with descriptive statistics.
All safety analyses will be based on the safety-evaluable population, which includes all patients 
who received any amount of the study treatment, whether prematurely withdrawn from the study 
or not.  
Incidence and nature of DLTs assessed during the first cycle of study treatment will be 
summarized using descriptive statistics.  All DLT analyses will be based on the DLT-evaluable
population, which includes all patients enrolled in Part 1 and Part 2 who either have completed 
at least 80% of the prescribed dose of idasanutlin in Cycle 1 or have experienced a DLT in
Cycle 1 of the dose-escalation phase.  
An mCRM-EWOC model will be utilized to inform decision-making regarding the MTD of 
idasanutlin in Study Part Ia.  The MTD is defined as the dose that maximizes the posterior 
probability of a DLT being in the targeted toxicity interval of 20%35%, while controlling the 
probability of a DLT being in the excessive toxicity interval of 35%100% to be 25%. 
The mCRM-EWOC model will adaptively estimate the MTD after gathering cumulative DLT data 
including newly completed cohorts and calculate a recommended next dose for the next cohort.  
Determination of Sample Size
The sample size for the dose-escalation phase of this study is based on the mCRM-EWOC 
design.  The study will enroll approximately 924 DLTevaluable patients in dose escalation to 
reach the MTD/MAD and approximately 39 patients in each cohort in the safety run-in phase to 
reach RP2D.  Explicit power and type I error considerations are not factored into the design of 
the MTD/MAD or RP2D determination, as the dose-escalation and safety run-in phases are 
designed to obtain preliminary safety and PK information for the study drug.
An early response assessment (Gate 1B), will be performed for the neuroblastoma cohorts at 
the end of Study Part 1b after six patients have been treated at the RP2D for the combination.  
Additional response assessments of patients enrolled in Part 2 (also including patients treated 
at the RP2D in Part 1b for the neuroblastoma cohorts) (Gate 2) and of patients enrolled in 
Part 2 and Part 3 (again including patients treated at the RP2D in Part 1b for the 
neuroblastoma cohorts) (Gate 3) are planned in order to make a preliminary assessment of the 
efficacy of the study drug.  


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At least 50% of patients with TP53 wild-type tumors treated at the RP2D in Study Part 1b 
for the neuroblastoma cohorts (Gate 1b) must have an observed objective response prior to 
advancing to Part 2 of the study.  If this benchmark is not reached, the cohort will be 
discontinued for futility.  The minimum number of patients in the response assessment at 
Gate 2 and the minimum number of responders required for advancement to the additional 
response assessment (Part 3) are presented by tumor type in the protocol, taking into account 
historical control ORRs for neuroblastoma and CRR for leukemias.  For neuroblastoma and 
AML, up to one combination regimen may advance to Part 3 for each tumor type, taking into 
account the preliminary efficacy, safety, biomarker data, and enrollment feasibility.  The ALL 
cohort will be considered for expansion similarly, if either morphologic response or 
MRD-negative response criteria are met.
The sample size and minimum number of responders for the additional response assessment 
for each tumor type cohort were determined based on 90% confidence interval (CI) for the 
appropriate response rate parameter for each disease cohort.  Part 3 of this trial will be able to 
detect a large benefit of the idasanutlin in combination with chemotherapy or venetoclax in 
terms of the appropriate response rate for the disease.  For example, an observed response 
rate of 45% in 40 patients with neuroblastoma will have a 90% confidence interval excluding the 
32% historical response rate.  Similarly, an observed CRR of 53% in 30 patients with ALL will 
have a 90% confidence interval excluding 40%.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALL
acute lymphoblastic leukemia
AML
acute myeloid leukemia
AUC
area under the concentrationtime curve
BCL-2
B-cell lymphoma 2
BID
twice a day
BMA
bone marrow aspirate
C. difficile
Clostridium difficile
CAR
chimeric antigen receptor
CBR
clinical benefit ratio
CI
confidence interval
CLL
chronic lymphocytic leukemia
COG
Children's Oncology Group
CR
1. (morphologic) complete remission in context of 
leukemia
2. complete response in the context of solid tumor 
cancer
CRc
composite complete remission
Cri
incomplete blood count recovery
CRp
complete remission with incomplete platelet count 
recovery
CRR
complete remission rate
CTCAE
common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DE
DLT-evaluable
DLT
dose-limiting toxicity
DOR
duration of objective response
EC
ethics committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed paraffin-embedded
FLAG
Fludarabine, cytarabine, and G-CSF
FLA
Fludarabine and high-dose cytarabine
FS
fractional shortening


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Abbreviation
Definition
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HU
hydroxyurea
ICH
International Council for Harmonisation
IMC
internal monitoring committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
INRC
International Neuroblastoma Response Criteria
IRB
Institutional Review Board
IT
intrathecal
ITT
intent-to-treat
IxRS
interactive voice/web-based response system
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
MBP
microprecipitated bulk powder
mCRM-EWOC
modified continual reassessment method of escalation 
with overdose control
MDM2
murine double minute 2
MIBG
meta-iodobenzylguanidine
MIC-1
macrophage inhibitory cytokine-1
MLL
mixed—lineage leukemia
MM
multiple myeloma
MN
mobile nursing
MRD
minimal residual disease
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NCI
National Cancer Institute
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NIMP
non-investigational medicinal product
ORR
objective response rate
OS
overall survival
PBPK
physiologically based pharmacokinetic
PD
pharmacodynamics
PE
polyethylene


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Abbreviation
Definition
PFS
progression-free survival
PK
pharmacokinetic
PPTP
Pediatric Preclinical Testing Program
PR
partial response
PRO
patient-reported outcome
QTcF
QT interval corrected through use of Fridericia's 
formula
RBR
Research Biosample Repository
RP2D
recommended Phase II doses
SD
stable disease
SDP
spray-dried product
SE
safety evaluable
SOC
scientific oversight committee
t1/2
terminal half-life
TLS
tumor lysis syndrome
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing
WT
wild-type


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1.
BACKGROUND
1.1
BACKGROUND ON NEUROBLASTOMA
Neuroblastoma is the most common extra-cranial solid tumor in children and remains a 
major cause of pediatric mortality (Maris 2007). Patient prognosis and therapy are 
determined by a number of risk factors, with less favorable risk features including tumor 
metastasis, patient age 18 months, poor tumor differentiation, presence of MYCN 
amplification or 11q aberration, and DNA diploidy (Cohn et al. 2009).  Patients classified 
as high risk, based on a combination of these features (including the majority of patients 
18 months of age), require frontline multimodal therapy that includes chemotherapy, 
surgery of the primary tumor, high-dose therapy with hematopoietic stem cell rescue, 
radiation to the primary tumor site, differentiation therapy, and immunotherapy (Pinto 
et al. 2015).  Despite such therapy, the long-term survival rates for patients with high-risk 
disease remain unsatisfactory at 50%55% (Kreissman 2013; Ladenstein 2017).  
Novel agents are thus necessary in the treatment of neuroblastoma.  The recent addition 
of maintenance immunotherapy with chimeric anti-GD2 monoclonal antibody has shown 
some promise.  Early efficacy results from a Children's Oncology Group trial of high-risk 
patients given dinutuximab in combination with interleukin-2 and granulocyte-macrophage 
colony-stimulating factor in maintenance showed an improvement in 2-year event-free 
survival (EFS) from 46% to 66% and in 2-year overall survival (OS) from 75% to 86% 
(Yu et al. 2010). Lower long-term OS was reported in high-risk patients who received a 
similar molecule, dinutuximab beta, in the European Union, where the 3-year OS rate has 
been 71%72% in patients without disease at initiation of therapy and 54%63% in 
patients who did not achieve complete response prior to initiation of dinutuximab beta 
therapy (Qarziba SmPC).  Patients with disease relapse fare substantially worse; 5-year 
OS in relapsed neuroblastoma has been reported to be between 12% and 20% (London 
et al. 2011; Basta et al. 2016).
Additionally, patients who have received intensive multimodal therapy face significant 
long-term toxicity with an increased mortality rate, a risk of second malignant neoplasms, 
and a higher rate of chronic health conditions, including hearing loss (49% of patients), 
renal impairment (16%), and endocrine complications (28%) (Lavedière et al. 2009; 
Moreno et al. 2013).  These findings, combined with the apparent plateau in survival 
rates, suggest that the tolerable ceiling of traditional therapy has been reached and 
fine-tuning of conventional treatment is unlikely to solve the remaining clinical 
challenges.  Innovative therapies targeting a different mechanism of action are urgently 
required.
1.2
BACKGROUND ON ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML) is a rare childhood cancer, with an incidence of 
approximately 7 children per million annually (Zwaan et al. 2015), but AML remains a 
significant cause of childhood cancer mortality.  All major cooperative groups report 
similar outcomes for childhood AML, with an EFS around 50%60% and an OS of 


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65%75% (Zwaan et al. 2015; Rubnitz 2017), which reflects an improvement over time.  
This improvement is most likely due to intensification of chemotherapy, more precise risk 
classification based on the biology of the leukemia and response to treatment, and 
improvements in supportive care.  However, the cumulative incidence of relapse remains 
unacceptably high at 25%40% (Hasle et al. 2012; Creutzig et al. 2013; Pession et al. 
2013; Tomizawa et al. 2013; Gamis et al. 2014), with relapsed disease being the most 
common cause of death in AML.  Five-year OS in relapsed AML has been reported to be 
between 23% and 37% (Sander et al. 2010; Kaspers et al. 2013; Nakayama et al. 2014; 
Karlsson et al. 2017).
Treatment remains largely based on non-specific cytotoxic drugs (anthracyclines and 
nucleoside analogues) delivered as 45 courses of intensive therapy, with hematopoietic 
stem cell transplantand its significant associated co-morbiditiesreserved for high-risk
patients with unfavorable cytogenetic abnormalities or a poor response to therapy 
(Rubnitz 2017).  Novel agents are clearly required to tackle the outstanding challenges 
of this disease.  Most notably in the last decade, a Phase III study of gemtuzumab 
ozogamicin demonstrated improved 3-year disease-free survival in patients with AML 
receiving gemtuzumab ozogamicin in addition to standard of care compared with those 
who received standard of care alone, albeit with a modest improvement from 55% 
to 61% (Gamis et al. 2014). 
1.3
BACKGROUND ON ACUTE LYMPHOBLASTIC LEUKEMIA
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting
for approximately 30% of all pediatric malignancies in industrialized countries (Ries
et al. 1999; Stiller 2009). Significant improvements in outcome have been achieved; the 
overall cure rate reported by most cooperative groups is approaching 90%, with an 
outstanding cure rate of 98% in certain subsets (Pui et al. 2012; Cooper et al. 2015). 
This progressive improvement has been largely attributed to accurate identification of 
prognostic factors and more precise risk stratification based on these factors to enable
appropriate treatment intensity choice, as well as improved supportive care (Cooper and 
Brown 2015; Lee and Cho 2017). Populations with poor prognosis have been clearly 
defined and include patients 1 year and 10 years of age, patients with overt CNS 
disease at diagnosis, patients with unfavorable genomic alterations, and patients with 
induction failure or minimal residual disease (MRD) positivity at end of induction 
(Ceppi 2015; Cooper and Brown 2015). Notably, infants harboring translocations in the 
mixed-lineage leukemia (MLL) oncogene experience shorter remission durations and 
markedly lower survival rates of 50% (Pieters 2007).  Traditional cytotoxics delivered in 
multi-agent regimens are the mainstay of frontline treatment that consists of remission 
induction, consolidation, maintenance, and CNS-directed therapy, with an overall 
duration of 23 years (Cooper and Brown 2015). Despite the steady improvements in 
outcome, ALL remains one of the leading causes of pediatric malignant deaths (Curtin 
et al. 2016), with survival post-relapse strongly associated with duration of first CR and 
site of relapse (Ko et al. 2010; Oskarsson et al. 2016). Re-induction of patients with 


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relapsed ALL commonly includes conventional agents largely identical to those used at 
initial diagnosis, with hematopoietic stem cell transplant frequently used as consolidation 
therapy. Successful re-induction of remission becomes increasingly challenging with 
subsequent relapses, and mortality in second or greater relapse is high.  Five-year OS in 
patients with relapsed ALL has been reported to be 40%, with 5-year OS of 
approximately 20% in patients who relapse within 18 months of initial diagnosis, and 
worse 5-year OS in second and third relapses of 27% and 15%, respectively (Einsiedel 
et al. 2005; Nguyen et al. 2008; Ko et al. 2010).  
Novel agents and cellular therapies have recently come to the fore as highly active in the 
relapse setting.  Most notable among these is the anti-CD19 chimeric antigen receptor 
(CAR) T-cell therapy, tisagenlecleucel, which when tested in patients with 
relapsed/refractory disease demonstrated an overall remission rate of 82% (all of whom 
were negative for MRD), and 12-month EFS and OS of 50% and 76%, respectively 
(Maude et al. 2018).  Also notable are results observed with the CD19-targeting 
bispecific T-cell engager blinatumomab.  In a Phase II labelenabling study in patients 
with relapsed/refractory pre-B ALL, 39% of patients treated with single-agent 
blinatumomab achieved morphologic CR, and of these responders, 52% achieved 
MRD-negative status (von Stackelberg et al. 2016).  Even despite these robust response 
rates, a high percentage of patients do not achieve durable remission, thus necessitating 
continued evaluation of new agents in ALL. 
1.4
BACKGROUND ON THE TEST PRODUCTS
1.4.1
Idasanutlin
The tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein 
that plays a central role in protection from tumor development.  The protein p53 is 
frequently inactivated in human cancer. It is a transcription factor that is activated 
following cellular stress and regulates multiple downstream genes implicated in cell cycle 
control, apoptosis, DNA repair, and senescence (Harris and Levine 2005). The p53
protein is regulated through a negative feedback loop by murine double minute 2 
(MDM2), which binds to p53, blocks its transactivation domain, and targets p53 for 
ubiquitin-dependent degradation in the proteasome. Some tumors overexpress MDM2,
thus disabling the effective function of p53, leading to inefficient growth arrest or 
apoptosis.
Idasanutlin is a potent, selective, and orally bioavailable small molecule inhibitor of 
MDM2.  In cell-free assays, idasanutlin has been shown to bind to the MDM2 protein 
with high affinity and to inhibit MDM2p53 binding.  Exposure of tumor cells to 
idasanutlin 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 (Ding et al. 2013). 
In vivo idasanutlin demonstrated marked anti-tumor activity and improved survival when 


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delivered as a single agent in an established osteosarcoma xenograft model and in 
combination with cytarabine in an AML model in immunodeficient mice.  
Refer to the Idasanutlin Investigator’s Brochure for additional details on nonclinical 
studies.
1.4.1.1
Clinical Studies of Idasanutlin in Adults
Idasanutlin has been investigated in adult patients with solid tumors (Phase I 
Studies NP27872, NP28902, NP29910, and NP39051); in adult patients with AML 
(Phase I Study NP28679); in combination with cytarabine and daunorubicin in adult 
patients with newly diagnosed, previously untreated AML (Phase Ib/II GO40800); and in 
combination with cytarabine in adult patients with relapsed/refractory AML (Phase III 
Study WO29519). In parallel, the Phase Ib/II Study GH29914 explored the combination 
of idasanutlin and venetoclax in a chemotherapy-free regimen for older patients with 
relapsed/refractory AML.  Administration of idasanutlin in patients with non-Hodgkin 
lymphoma (NHL) was explored in two Phase Ib/II trials, in combination with 
obinutuzumab or rituximab, either with or without venetoclax (Studies BH39147 and 
BH29812, respectively).  Other studies included a bio-equivalence study in patients with 
solid tumors (Study NP39051) and a Phase I/II, single-agent study in patients with 
polycythemia vera (Study NP39761).
Pharmacokinetics and Recommended Doses
Two different formulations of idasanutlin have been developed: a microprecipitated bulk 
powder (MBP) and a spray-dried product (SDP) formulation. Pharmacokinetic (PK) data 
in adult patients treated with idasanutlin in Studies NP27872, NP28902, and NP28679 
show that half-life (t1/2) was approximately 1 day and that there was apparent dose-
proportionality for the daily schedule (Days 15 in a 28-day cycle) in patients with solid 
tumors or AML.  The SDP formulation is 2-fold more bioavailable than the MBP 
formulation in patients with AML treated with idasanutlin in combination with cytarabine.  
There was no major effect of high-fat or low-fat food on PK exposure.  Metabolite M4 
(RO6802287) was the only major metabolite in human plasma samples, and idasanutlin 
is not excreted through urine.  There was no major impact of a strong CYP3A inhibitor, 
posaconazole, or concomitant cytarabine on idasanutlin pharmacokinetics.
Different maximum tolerated doses (MTDs) were identified depending on the disease 
and combination therapy, as detailed below.

Study NP27872 evaluated idasanutlin as a single agent in adult patients with solid 
tumors using a legacy MBP formulation.  For daily administration regimens, MTDs
for idasanutlin were identified as 500 mg daily5 days or 500 mg twice a day 
(BID)3 days (duration of all cycles was 28 days).  Thrombocytopenia and 
decreased platelet count were the most commonly reported dose-limiting toxicity 
(DLT) events, followed by neutropenia, febrile neutropenia, pancytopenia, and 
diarrhea. 


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
Study NP28679 evaluated idasanutlin as a single agent and in combination with 
cytarabine in adult patients with AML.  Less stringent DLT rules for hematologic 
adverse events were utilized in this study, given the need for dose intensity in AML 
therapy.  The dose-escalation phase of the study utilized the MBP formulation.  The 
MTD was not formally reached, but a decision to halt further dose escalation was 
made due to concerns over increased frequency and severity of adverse events, in 
particular diarrhea, at doses 600 mg BID MBP.  A bridging cohort (n29 patients) 
subsequently explored the safety/PK profile of a new SDP idasanutlin in 
combination with cytarabine.  The 300 mg BID SDP schedule (administered to 
16 patients) was better tolerated than higher doses and had comparable PK 
exposure as the 600 mg BID MBP schedule.  Thus, the relative bioavailability of 
SDP is approximately twice that of MBP.  

Study GH29914 evaluated idasanutlin SDP in combination with venetoclax in 
patients 60 years of age with relapsed/refractory AML. Although a recommended 
idasanutlin dose was not identified prior to study closure, significant clinical 
responses were observed at substantially lower idasanutlin doses (150200 mg 
SDP daily) in combination with venetoclax than were assessed in Study NP28679, 
and higher doses of idasanutlin (up to 400 mg daily) were not considered tolerable 
in this combination.
Safety
As of 13 September 2019, a total of 216 adult patients with solid tumors have been 
treated with idasanutlin in four studies.  Across the solid tumor studies, 98.6% of patients 
had at least one adverse event.  The most common adverse events were diarrhea and
nausea (each 64%), vomiting (48%), decreased appetite (34%), and fatigue (33%) being 
the most frequently reported adverse events.  The most common (30%) related 
adverse events were diarrhea (63%), nausea (61%), and vomiting (43%).
Grade 3 adverse events were reported in 56% of patients, most commonly within the 
system organ classes of blood and lymphatic system disorders, metabolism and nutrition 
disorders, gastrointestinal (GI) disorders, and investigations.  Thrombocytopenia, 
anemia, neutropenia, hypokalemia, and nausea were the most common (5% of 
patients) Grade 3 adverse events.
Serious adverse events were reported in 27% of patients in the pooled dataset, most 
commonly (2% of patients) thrombocytopenia (6.0%), febrile neutropenia (2.3%), and 
pyrexia (2.3%).  In 14% of patients, serious adverse events were considered related to 
idasanutlin, with the most commonly reported (2% of patients) being thrombocytopenia 
(6.0%) and febrile neutropenia (2.3%).
A total of 14 patient deaths were recorded across all four studies, of which 10 deaths 
were attributed to progressive disease.  Of the remaining 4 deaths, 1 death was 
considered remotely related to idasanutlin (pulmonary embolism); the other 3 deaths 
were considered unrelated (intracranial hemorrhage, intra-abdominal hemorrhage with 
concurrent pulmonary embolism, and aspiration pneumonia).


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As of 13 September 2019, a total of 122 patients with AML have received idasanutlin as 
monotherapy or in combination with cytarabine in Study NP28679, 49 patients have 
received combination therapy with venetoclax and idasanutlin in Study GH29914, and 
5 patients have received idasanutlin in combination with cytarabine and daunorubicin in 
Study GO40800.  As of 1 November 2019, a total of 290 patients have received 
idasanutlin in combination with cytarabine in Study WO29519.  A summary of the safety 
data from Studies NP28679, GH29914, GO40800, and WO29519 is presented.
In Study NP28679 the most frequently reported adverse events were diarrhea, nausea, 
hypokalemia, vomiting, and decreased appetite.  The most common Grade 3 adverse
events were from system organ classes infections and infestations; blood and lymphatic 
system disorders; metabolism and nutrition disorders; GI disorders; and general 
disorders and administrative site conditions.  The types of adverse events of patients 
treated with idasanutlin monotherapy were similar to those of patients treated with 
idasanutlin in combination with cytarabine; however, an increase in the frequency of 
adverse events in combination therapy versus monotherapy (at the same idasanutlin 
dose) suggests an additive effect of cytarabine.  Serious adverse events were reported 
in 59% of patients in Study NP28679, most commonly from infections and infestations.  
Twenty-seven patients died in Study NP28679; 11 of the 29 deaths were attributed to 
disease progression, and 16 deaths were associated with serious adverse events.  Most 
of the deaths associated with serious adverse events were due to infectious processes, 
including 5 deaths due to sepsis and 2 deaths due to neutropenic sepsis.
In Study GH29914, four dosing cohorts have been evaluated to date:  6 patients 
received 400/200 mg (venetoclax/idasanutlin), 13 patients received 600/150 mg, 
21 patients received 600/200 mg, and 9 patients received 400/400 mg.  Similar to other 
idasanutlin trials, the most common adverse events were reported from system organ 
classes GI disorders, blood and lymphatic system disorders, infections and infestations, 
and metabolism and nutrition disorders.  Serious adverse events were reported in 
40 patients, of which 19 patients experienced serious adverse events considered related 
to idasanutlin and 19 patients experienced serious adverse events considered related to 
venetoclax.  Death was reported in 38 patients: 29 deaths were due to progressive 
disease, 5 deaths were due to adverse events of cardio-respiratory arrest, nervous 
system disorder, respiratory failure, hemophagocytic lymphohistiocytosis, and sepsis; 
and the remaining 4 deaths were due to other reasons (unspecified causes other than 
adverse event or disease progression).
In Study GO40800, the most common adverse events (3 patients) were diarrhea, 
nausea, thrombocytopenia, febrile neutropenia, anemia, dyspepsia, and leukopenia.  
Four serious adverse events were reported in 3 patients, of which three of the serious
adverse events in the 3 patients were considered related to idasanutlin:  febrile 
neutropenia (2 patients) and respiratory failure (1 patient).  One patient died due to an 
adverse event of respiratory failure (related to idasanutlin). 


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In Study WO29519, there were no new safety concerns identified.  
For additional information on clinical safety, please refer to the current Idasanutlin 
Investigator's Brochure.
Efficacy
In the adult AML dose-escalation study (NP28679), bone marrow clearance, 
demonstrated by CR, complete remission with incomplete platelet count recovery (CRp), 
incomplete blood count recovery (CRi), and MLFS responses, was seen across all 
patients throughout different dose levels and formulations (MBP and SDP) in an all 
comer population (p53 WT and mutant).  The best overall response rate included 4 CR 
(8.7%) and 3 CRi (6.5%) for a composite complete remission (CRc) rate of 15.2% for 
monotherapy.  With regard to combination therapy, there were 20 CR (26.7%), 1 CRp 
(1.3%), and 1 CRi (1.3%), for a CRc rate of 29.3% across all patients treated with 
combination therapy with cytarabine.
Across all adult solid tumor studies, the best overall response to single-agent idasanutlin 
observed was stable disease (SD); there were no objective responses according to 
Response Evaluation in Solid Tumors (RECIST) criteria.  In Study NP27872, which 
investigated idasanutlin in advanced solid malignancies, the rate of SD was 30.6% with 
a median overall duration of SD of 72.5 days (range:  8696 days).
In study WO29519 (MIRROS), idasanutlin showed minimal clinical activity as seen in 
increased overall remission; however, a lack of improvement in OS was observed with 
idasanutlin plus cytarabine versus placebo plus cytarabine.  
Please refer to the current Idasanutlin Investigator's Brochure for additional details on 
the efficacy results.
1.4.2
Venetoclax
B-cell lymphoma 2 (BCL-2) family proteins are important regulators of the intrinsic
apoptosis pathway. The BCL-2 family of genes encodes closely related proteins that
possess either pro-apoptotic or anti-apoptotic activity, the latter mediated by BCL-2,
BCL-XL, BCL-W, A-1, and MCL-1. The ratio of pro-apoptotic to anti-apoptotic proteins is 
associated with the outcome of cell survival or programmed cell death. In contrast to 
other known oncoproteins, BCL-2 does not stimulate cellular proliferation, but rather 
inhibits programmed cell death by protecting cells from a wide variety of pro-apoptotic 
stimuli, including cytotoxic drugs, cytokine withdrawal, irradiation, heat, and deregulated 
oncogenes (Souers et al. 2013).
Venetoclax is a potent, selective, orally bioavailable small molecule BCL-2 inhibitor.  
It binds to BCL-2 with 500-fold higher affinity (Ki0.010 nM) than other BCL-2 family 
members, including BCL-XL (Ki ~48 nM) and BCL-w (Ki ~245 nM) (Souers et al. 2013).  
Over-expression of anti-apoptotic BCL-2 family proteins enables cancer cell survival.  


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Antagonism of these proteins may enhance response to chemotherapeutic agents or 
trigger apoptosis directly in certain tumor cells.
Two pediatric studies are currently evaluating venetoclax as a single agent in pediatric 
and young adult patients with relapsed or refractory malignancies (Study M13-833, 
Clinicaltrials.gov identifier NCT03236857, EudraCT 2017-000439-14), and in 
combination with navitoclax and chemotherapy in patients with relapsed/refractory ALL 
or relapsed/refractory lymphoblastic lymphoma 4 years of age (Study M16-106, 
NCT03181126).
Please refer to the current version of the Venetoclax Investigator's Brochure, Karol et al. 
(2019), and Goldsmith et al. (2020) for additional details regarding the adult and 
pediatric clinical studies.
Pharmacokinetics and Recommended Doses
PK data for venetoclax are available from studies in patients with cancer (chronic 
lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], AML, NHL, multiple 
myeloma [MM]), healthy subjects, and patients with hepatic impairment. Following 
multiple-dose administration, the maximum plasma concentration of venetoclax was 
attained 58 hours after dosing. The harmonic mean t1/2 ranged from 1741 hours 
following a single oral dose of venetoclax. In patients with CLL, venetoclax showed 
minimal accumulation, and steady-state AUC increased proportionally over the dose 
range of 150800 mg. Venetoclax has been administered with food in all clinical 
studies, as food increased the bioavailability of venetoclax by approximately 3- to 5-fold. 
Venetoclax is highly bound to plasma proteins with unbound fraction (fu) 0.01 and is 
primarily eliminated as metabolites in feces with negligible renal elimination (0.1%).  
Drugdrug interaction studies of venetoclax with ketoconazole, rifampin, warfarin,
ritonavir, azithromycin, and digoxin were conducted to provide dosing recommendations
for patients concomitantly taking CYP3A and/or P-gp inhibitors, inducers, and/or
warfarin. PK studies were conducted in healthy Chinese subjects and Japanese 
subjects to provide dosing recommendations for those specific populations. Additionally, 
a dedicated study to evaluate the pharmacokinetics of venetoclax in patients with 
hepatic impairment is ongoing.  Based on the population PK analysis, age, sex, race, 
weight, mild and moderate renal or hepatic impairment do not have an effect on 
venetoclax clearance.
Safety
The safety profile of venetoclax for each indication has been consistent with that of the 
overall population.  Common treatment-emergent adverse events across indications and 
across monotherapy and combination therapy include Grades 12 GI toxicities (nausea 
and diarrhea) and Grades 34 hematologic toxicities (neutropenia, febrile neutropenia, 
thrombocytopenia, and anemia) (see Section 5.1.2).


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Refer to the current version of the Venetoclax Investigator's Brochure for additional 
clinical safety information.  The observed risks of venetoclax and the safety 
management guidelines for these risks are described in Section 5.1.2.
Efficacy
Venetoclax is approved for the treatment of adult patients with CLL or SLL. In the United 
States, venetoclax is also approved in combination with azacitidine or decitabine or 
low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are age 
75 years or older, or who have comorbidities that preclude use of intensive induction 
chemotherapy. In addition, preliminary efficacy results are available for patients with 
AML, NHL, and MM, showing promising efficacy results in oncology patient populations
(Kumar et al. 2017; deVos et al. 2018; Zelenetz et al. 2019).
For additional information on clinical efficacy, please refer to the current Venetoclax 
Investigators’ Brochure.
1.4.3
Nonclinical Activity of Idasanutlin as Single Agent and in 
Combination with Chemotherapy and Venetoclax in Pediatric 
Cancers
1.4.3.1
Idasanutlin as Single Agent and in Combination in Neuroblastoma
Neuroblastoma, even in the relapse setting, does not have frequent mutations in p53 or 
downstream effectors.  Approximately 15% of relapsed neuroblastomas harbor a p53 
mutation; a greater number of p53-inactivating abnormalities in neuroblastoma occur 
upstream of p53 (Carr-Wilkinson et al. 2010).  Thus, targeting this negative regulator has 
been hypothesized to be a potential, and relevant, pro-apoptotic therapeutic approach.  
A predecessor MDM2 inhibitor to idasanutlin, nutlin-3a, was cytotoxic in neuroblastoma 
cell lines (Van Maerken et al. 2006) and sensitized cells to chemotherapy-induced 
apoptotic cell death (Barbieri et al. 2006).
Idasanutlin has subsequently been shown to have nonclinical activity in vitro and in vivo
in nonclinical models of neuroblastoma as a single agent and in combination with 
chemotherapy agents and with venetoclax.  As a single agent, idasanutlin potently 
decreases cell proliferation in multiple neuroblastoma cell lines and xenografts.  In one 
study evaluating 16 TP53 wild-type (WT) cell lines, the mean concentration at which 
idasanutlin induced 50% growth inhibition was 68.2 nM (range 14.8140.3 nM).  Cell 
cycle arrest and apoptosis, p53 stabilization, and induction of p53 downstream targets 
were also observed in treated cell lines (Chen et al. 2015).  Furthermore, 
idasanutlin-induced tumor growth inhibition was consistently observed in TP53 WT 
neuroblastoma cell line xenografts (range 59%75%) (Lakoma et al. 2015). 
When combined with chemotherapy or venetoclax, idasanutlin leads to synergistic
outcomes.  Specifically, combining idasanutlin with cisplatin, doxorubicin, topotecan, 
temozolomide, or busulfan in vitro induced greater cell growth inhibition in TP53 WT cell 
lines than with either agent alone.  Median effect analysis demonstrated that this effect 


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was at least moderately synergistic in all agents tested, and combinations also led to 
greater levels of p53 stabilization, pathway activation, and apoptosis (Chen et al. 2015).  
In vitro cell line combination studies of idasanutlin with 15 targeted agents considered 
relevant in neuroblastoma biology (including the BET inhibitor JQ1, the ALK inhibitor 
crizotinib, the mTOR inhibitor rapamycin, the histone deacetylase inhibitor vorinostat, 
and the reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome
bortezomib) identified that combining with the dual BCL2/BCL-XL inhibitor navitoclax 
was strongly synergistic and yielded the highest level of synergy of any combination 
tested.  Expansion of this cohort to include a larger number of cell lines recapitulated 
strong synergy when combining idasanutlin with either navitoclax or venetoclax.  
To assess the effect of the combination of idasanutlin and venetoclax in vivo, orthotopic 
xenograft tumors of SMS-KCNR/luc human neuroblastoma cells in nude mice were 
treated with vehicle, idasanutlin, venetoclax, or idasanutlin plus venetoclax for 2 weeks.  
In the combination cohort, mean tumor weight at the end of the treatment period was 4% 
of that observed in the vehicle group, and tumors were significantly smaller than those in 
cohorts treated with either drug alone (van Goethem et al. 2017), demonstrating a 
profound effect of this combination on neuroblastoma tumor growth.
1.4.3.2
Idasanutlin as Single Agent and in Combination in Acute Myeloid 
Leukemia
Pediatric AML has a low mutation rate relative to other cancers, and mutations in TP53
are particularly uncommon.  Although TP53 mutations are measurably present in 
approximately 8% of adult AML, they were present at a rate of approximately 1% in 
newly diagnosed pediatric AML in a nearly 1,000-patient series (Boulouri et al. 2018).  
Although clonal evolution at relapse has not been reported to result in acquisition of 
novel TP53 mutations (Farrar et al. 2016), a recent study identified TP53 mutations in 
12% (9 of 73) of AML samples, likely obtained in the relapse setting, as these were 
obtained from samples submitted for gene sequencing as part of clinical care 
(Chmielecki et al. 2017).
Activity of idasanutlin as a single agent and in combination with cytarabine was 
established utilizing an AML cell line xenograft model.
Idasanutlin and venetoclax have complementary mechanisms of action.  In nonclinical 
testing restoration of p53 tumor-suppressor activity through MDM2 antagonism by 
idasanutlin, combined with induction of mitochondrial apoptosis by inhibiting Bcl-2 
inhibition with venetoclax, delivers enhanced anti-tumor activity in AML.  In vitro, the 
combination of idasanutlin and venetoclax demonstrated synergistic anti-apoptotic and 
anti-tumor activity, and superior activity over either agent alone, in the MV4-11 cell line 
(established from a 10-year old male) and the MOLM-13 cell line (established from a 
20-year old male).  Subcutaneous MV4-11 xenografts treated with idasanutlin plus 
venetoclax led to partial tumor regression (55%) relative to control, while tumor 
regressions were not observed with either single agent alone.  Compared with the 


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single-agent treatments, combination treatment resulted in superior tumor growth 
inhibition (>100 %) in MV4-11 xenografts (Lehmann et al. 2016). 
1.4.3.3
Idasanutlin as Single Agent and in Combination in Acute 
Lymphoblastic Leukemia
TP53 mutations occur in a small percentage of patients at diagnosis of ALL, but occur in 
up to 11% of patients at relapse, with 50% of these mutations acquired subsequent to 
diagnosis (Hof et al. 2011).  Overexpression of MDM2 has been observed in a significant 
proportion of both pediatric ALL cell lines and primary leukemic cells expressing WT p53 
(Zhou et al. 1995; Gustafsson et al. 1998) and has been associated with a poorer 
treatment outcome (Zhou et al. 1995; Gustafsson et al. 1998).  Given this degree of 
expression, MDM2 is a rational target in ALL.
Nonclinical testing of an early generation MDM2 antagonist, nutlin-3, showed 
dose-dependent cytotoxic activity in 9 of 9 TP53 WT pediatric ALL cell lines tested and 
29 of 29 TP53 WT primary pediatric ALL samples tested.  A significant positive 
correlation was noted between MDM2 expression levels and nutlin-3induced 
cytotoxicity (Gu et al. 2008).
Marked activity of RG7112 (predecessor to idasanutlin) was demonstrated in 
patient-derived ALL systemic-disease xenograft models in immunocompromised mice 
(Carol et al. 2013).  All seven evaluable pediatric ALL xenografts showed leukemia 
regression (5 complete responses, 1 maintained complete response, and 1 partial 
response) and a significant prolongation of EFS in all complete responders.  Notably, the 
only xenograft to achieve a maintained complete response was an MLL-rearranged 
xenograft derived from an infant.  Evaluation of 6 additional infant MLL-rearranged ALL 
models showed that RG7112 induced a prolonged complete remission in all 6 xenografts 
with leukemia growth delay ranging from 17.144.7 days (Richmond et al. 2015).  In the 
same study, synergy was observed with the addition of idasanutlin to an induction-type 
regimen of vincristine, dexamethasone, and L-asparaginase, with significant extension of 
disease remission in two MLL-ALL xenografts.
Venetoclax has demonstrated robust single-agent activity in nonclinical pediatric ALL 
studies.  Khaw et al. (2016) showed that venetoclax significantly delayed leukemia 
progression in 11 of 19 (58%) xenografts established from pediatric ALL biopsies, with 
superior activity in MLL-rearranged ALL relative to other subtypes.  This, in combination 
with the superior nonclinical activity of dual MDM2/BCL2 targeting in other disease 
areas, and the known clinical activity and tolerability of idasanutlin in combination with 
venetoclax in AML, supports further investigation of the combination in pediatric ALL.  


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1.4.3.4
Idasanutlin as Single Agent in Other Solid Tumors
Besides neuroblastoma, idasanutlin and related nutlin compounds (such as nutlin-3 or 
RG7112) have demonstrated preclinical efficacy in a number of different pediatric solid 
tumor models including:

Rhabdomyosarcoma. Nutlins have shown activity in pediatric preclinical models as a 
single agent and as combination therapy. Single-agent RG7112 demonstrated CR in 
an alveolar rhabdomyosarcoma PDX model tested in the NCI Pediatric Preclinical 
Testing Program (PPTP), and significant tumor growth inhibition was observed in 
4/7 rhabdomyosarcoma models tested (Carol et al. 2013). Nutlin-3 induced cell 
cycle arrest and apoptosis, and demonstrated synergy with vincristine and 
dactinomycin, when tested in TP53 wild-type rhabdomyosarcoma cell lines (Miyachi 
et al. 2009). Embryonal rhabdomyosarcoma cell line xenografts treated with 
idasanutlin showed radiosensitization when treated with idasanutlin in combination 
with radiotherapy, as opposed to radiotherapy alone (Phelps et al. 2015).

Rhabdoid tumor. Targeting of MDM2 has recently been identified as a key 
vulnerability in malignant rhabdoid tumor. Pooled-format RNAi identified that TP53
inhibition significantly promoted cell survival, and unbiased CRISPR-Cas9 screens 
identified MDM2 inactivation as the strongest vulnerability evaluated. In vitro testing 
resulted in upregulation of p53 signaling, and in vivo testing in cell line xenografts 
resulted in tumor regression of all xenografts tested and a 50% complete response 
rate (Howard et al. 2019). Significant tumor growth inhibition was also observed in 
all three rhabdoid tumor xenografts treated with RG7112 by the PPTP, with tumor 
shrinkage and survival prolongation observed in one model (Carol et al. 2013).

Ewing sarcoma. Significant tumor growth inhibition was observed in three out of four 
tumor xenografts treated with RG7112 by the PPTP, with tumor shrinkage and 
survival prolongation observed in one model (Carol et al. 2013).

Wilms tumor. Partial tumor regression was observed in the one Wilms tumor 
xenograft model treated with RG7112 by the PPTP (Carol et al. 2013).

Osteosarcoma. Idasanutlin was tested in SJSA osteosarcoma cell line xenografts 
and demonstrated tumor growth inhibition, regression, and improved mouse survival 
in a dose dependent manner (Filipovic et al. 2011). 

Retinoblastoma. Administration of nutlin-3a has been identified to induce 
retinoblastoma regressions in genetically engineered mouse models of the tumor 
(Brennan et al. 2011, Laurie et al. 2006). 
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Given the compelling nonclinical efficacy of idasanutlin as a single agent and in 
combination with chemotherapy or venetoclax in several pediatric tumor types 
(neuroblastoma, AML, and ALL), idasanutlin represents a strong candidate for clinical 
evaluation in single agent and combination in children and young adults.
This trial has the primary aims of identifying the MTD/maximum administered dose 
(MAD), safety, and pharmacokinetics of idasanutlin in children with relapsed/refractory 


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cancer; the recommended Phase II dose(s) (RP2D[s]) of idasanutlin in combination with 
chemotherapy or venetoclax; and the preliminary efficacy for idasanutlin in combination 
with either chemotherapy or venetoclax in neuroblastoma, AML, or ALL. 
Based on the superior results combining idasanutlin with chemotherapy or venetoclax in 
all of these diseases in nonclinical models, initiation of combination cohorts is justified in 
patients with relapsed/refractory disease after an MTD/MAD is identified for idasanutlin, 
including:

Idasanutlincyclophosphamidetopotecan in neuroblastoma

Idasanutlinfludarabine and cytarabine in AML

Idasanutlinvenetoclax in AML, ALL, and neuroblastoma
The combination chemotherapy regimens proposed are supported not only by evidence 
of synergy between idasanutlin and at least one agent contained in the regimen, but also 
by the established benefitrisk ratio of these chemotherapy regimens in children (see 
Section 3.3.1 for details about tolerability in pediatric regimen).
Venetoclax is an approved therapy in certain adults with CLL and AML, but has not been 
approved for use in children or in any of the indications proposed in this study.  
Venetoclax has shown activity in clinical trials in AML; in a Phase Ib study, adult 
chemotherapy-ineligible patients treated with venetoclax plus azacitidine or decitabine 
had CRCRi rates of 67%, significantly higher than in studies of any of these agents 
singly (DiNardo et al. 2018).  Given the nonclinical results in combination studies of 
idasanutlin and venetoclax described above, and given the differences in biology 
between pediatric and adult AML (Conneely and Rau 2020), evaluation of this 
combination is warranted.
The study is designed to identify response rates in a disease-appropriate manner.  
In neuroblastoma, the primary response endpoint will be objective response rate using 
International Neuroblastoma Response Criteria (INRC).  In leukemias, inducing 
morphologic complete remission following relapse is well recognized as a critical step in 
achieving a long-term cure.  A deeper remission, evidenced by MRD negativity, provides 
a better bridge to transplant and a higher probability of long-term survival.  Achievement 
of CR and MRD negativity will be co-primary endpoints in ALL given the extensive 
literature supporting MRD as a relevant clinical endpoint in early-phase ALL trials, and 
MRD will be a secondary endpoint in AML.  Although progression-free survival (PFS) in 
solid tumors, EFS in leukemias, and OS in all patients will be evaluated as secondary 
endpoints, this study is not designed to definitively identify a survival benefit associated 
with idasanutlin in pediatrics.  
Adult studies have shown idasanutlin to have an acceptable toxicity profile both as a 
single agent and in combination with chemotherapy (cytarabine) and venetoclax.  The 
most commonly reported adverse events for idasanutlin monotherapy include GI toxicity 


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(diarrhea, nausea, and vomiting), with the majority of events Grade 1 or 2, as well as 
hematological events (thrombocytopenia, anemia, and neutropenia) and infections such 
as sepsis and pneumonia.  Refer to the Idasanutlin Investigator’s Brochure for more 
details on the safety data observed to date in humans.  The anticipated and potential 
safety issues associated with the administration of idasanutlin in combination with 
venetoclax or chemotherapy, and the measures that are intended to avoid or to minimize 
such toxicities in this study, are described in detail in Section 5.1.
Both venetoclax and the proposed combination chemotherapy regimens are 
myelosuppressive and, as such, have an overlapping toxicity profile with idasanutlin.  
In the hematological malignancy populations, this risk of this degree of myelosuppression
might prove to be outweighed by increased clearance of blasts and deeper responses for 
the combination treatment.  In evaluating idasanutlin in solid tumors (as single agent and 
in combination), more stringent DLT rules are implemented for hematologic toxicities.  
As a result, lower idasanutlin RP2Ds are expected in solid tumors relative to leukemias.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, tolerability, and pharmacokinetics of idasanutlin as a 
single agent and the safety, tolerability, pharmacokinetics, and preliminary efficacy of 
idasanutlin in combination with either chemotherapy or venetoclax in children and young 
adults with acute leukemias or solid tumors that are recurrent or refractory to standard 
therapy.
In this protocol, "study treatment" refers to the single agent or combination of treatments 
assigned to patients as part of this study (i.e., idasanutlin with or without chemotherapy
or venetoclax).  
Specific objectives and corresponding endpoints for the study are outlined below.
2.1
SAFETY OBJECTIVES
The safety objectives for this study are to evaluate the safety and tolerability of 
idasanutlin as a single agent, in combination with chemotherapy, and in combination 
with venetoclax; to determine the MTD/MAD of idasanutlin administered as a single 
agent; and to define the RP2D of idasanutlin in combination with either chemotherapy or 
venetoclax on the basis of the following endpoints:

Incidence and severity of adverse events with severity determined according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5 (NCI CTCAE v5.0)

Changes from baseline in physical findings

Changes from baseline in targeted clinical laboratory test results and ECG 
parameters


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
Incidence of DLTs assessed during the first cycle of study treatment of single-agent
idasanutlin and again with idasanutlin in combination with chemotherapy or 
venetoclax
The exploratory safety objective for this study is to evaluate the impact of idasanutlin as 
a single agent and in combination with chemotherapy and venetoclax on growth and 
development on the basis of the following endpoints:

Changes from baseline in growth patterns (relative to age-specific standards for 
height and weight)

Changes from baseline in development patterns (relative to onset of menarche 
[for females] and pubertal changes)
2.2
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are as follows: 

To characterize the PK profile of idasanutlin as a single agent and in combination 
with chemotherapy or venetoclax on the basis of the following endpoints:
–
Plasma concentration of idasanutlin (and M4 metabolite RO6802287, where 
relevant) as a single agent at specified timepoints
–
Plasma concentration of idasanutlin in combination with chemotherapy or 
venetoclax at specified timepoints

To characterize the PK profile of venetoclax in combination with idasanutlin on the 
basis of the following endpoint:
–
Plasma concentration of venetoclax at specified timepoints
2.3
EFFICACY OBJECTIVES
2.3.1
Primary Efficacy Objective
The primary efficacy objective for this study (Study Parts 1b, 2, and 3) is to evaluate the 
anti-cancer activity of idasanutlin in combination with chemotherapy or venetoclax on the 
basis of the following endpoints:
Neuroblastoma

Objective response rate (ORR), defined as the proportion of patients with complete 
response or partial response (PR) at any time during study treatment, on two 
consecutive occasions 4 weeks apart, as determined by the investigator according 
to INRC for patients with neuroblastoma
Primary efficacy analysis will be conducted on patients with TP53 WT tumors in Study 
Parts 1b, 2, and 3.
Leukemia

Complete remission rate (CRR), defined as the proportion of patients with 
morphologic CR, CRi, or CRp (see Appendix 7 and Appendix 8), within 2 cycles of 
study treatment 


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
For patients with ALL:  MRD-negative rate, defined as the proportion of patients with 
ALL who have an MRD value 0.01%, as measured by next-generation sequencing 
(NGS), within 2 cycles of study treatment
Primary efficacy analyses will be conducted on patients with TP53 WT tumors in Study 
Parts 2 and 3.
2.3.2
Secondary Efficacy Objective
The secondary efficacy objective for this study (Study Parts 1, 2, and 3) is to evaluate 
the anti-cancer activity of idasanutlin as single agent, in combination with chemotherapy, 
and in combination with venetoclax (in patients with TP53 WT tumors, as well as in all 
patients regardless of mutation status) on the basis of the following endpoints:
Solid tumors (including Neuroblastoma)

Clinical benefit rate (CBR), defined as the proportion of patients achieving confirmed 
CR, PR, or SD on two consecutive occasions 4 weeks apart during the total study 
period

Duration of objective response (DOR), defined as the time from the first tumor 
assessment that supports a patient’s objective response to the time of disease 
progression or death from any cause (whichever occurs first), as determined by the 
investigator using INRC for patients with neuroblastoma or RECIST v1.1 for patients 
with other solid tumors

PFS, defined as the time from initiation of study drug to the first documented 
occurrence of disease progression or death from any cause (whichever occurs first), 
as determined by the investigator using INRC for patients with neuroblastoma and 
RECIST v1.1 for patients with other solid tumors

OS, defined as the time from initiation of study drug to death from any cause

ORR of efficacy-evaluable population irrespective of TP53 mutation status
Leukemia

Number of patients receiving transplant after study treatment

DOR, defined as the time from the first tumor assessment that supports the patient’s 
objective response (CR, CRp, CRi; see Appendix 7 and Appendix 8) to the time of 
relapse, or death from any cause, whichever occurs first

EFS, defined as the time from initiation of study drug to the first documented 
occurrence of M3 marrow after Cycle 1, failure to achieve CR/CRp/CRi after 
Cycle 2, disease progression, relapse subsequent to achieving CR/CRp/CRi, or 
death from any cause, whichever occurs first.

OS, defined as the time from initiation of study drug to death from any cause 

CRR of efficacy-evaluable population irrespective of TP53 mutation status

For patients with AML:  MRD-negative rate, defined as the proportion of patients 
with AML who are MRD negative within 2 cycles of study treatment 


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2.4
EXPLORATORY BIOMARKER OBJECTIVES
The exploratory biomarker objective for this study is to identify biomarkers that are
predictive of response to idasanutlin as a single agent or in combination with 
chemotherapy or venetoclax; are early surrogates of efficacy; are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers); are associated 
with acquired resistance to idasanutlin as a single agent or in combination with 
chemotherapy or venetoclax; are associated with susceptibility to developing adverse 
events or can lead to improved adverse event monitoring or investigation (i.e., safety 
biomarkers); can provide evidence of idasanutlin activity (i.e., pharmacodynamic 
biomarkers) as a single agent or in combination with chemotherapy or venetoclax; or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following endpoints:

Relationship between biomarkers identified in blood versus tissue (listed in 
Section 4.5.6) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.5
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate the acceptability 
and palatability of idasanutlin on the basis of the following endpoint:

Acceptability Survey scores at Cycle 1, Day 5
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
The study is a Phase I/II, multicenter, open-label, multi-arm study designed to evaluate 
the safety, tolerability, pharmacokinetics, and preliminary efficacy of idasanutlin in 
pediatric and young adult patients with acute leukemias or solid tumors for which prior 
treatment has proven to be ineffective (i.e., relapsed or refractory) or intolerable.  
Idasanutlin will be administered as a single agent or in combination with chemotherapy 
or venetoclax.
Figure 1 presents an overview of the study design.  A schedule of activities is provided in
Appendix 1, Appendix 2, and Appendix 3.


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Figure 1
Study Schema


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Figure 1
Study Schema (cont.)
ALLacute lymphoblastic leukemia; AMLacute myeloid leukemia; DEDLT-evaluable; DLT dose-limiting toxicity; FLAfludarabine and high-
dose cytarabine; mCRM-EWOCmodified continual reassessment method of escalation with overdose control; NBLneuroblastoma; 
RP2Drecommended Phase II dose; WTwild-type.
Note:  TP53 mutation status will not be taken into account when enrolling patients in the study.  Study Part 3 requires at least 30, 25, and 20 
patients with TP53 WT tumors in the NBL, AML, or ALL cohorts, respectively.


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The study is divided into three parts: 

Study Part 1:  
–
Part 1a: Dose escalation to assess safety, tolerability, and pharmacokinetics of 
idasanutlin as a single-agent treatment in the pediatric population with relapsed 
or refractory solid tumors; to identify the single-agent MTD/MAD; and to 
characterize DLTs.  Patients in dose escalation after one cycle will either 
continue single-agent idasanutlin or start early combination of idasanutlin with 
chemotherapy (for precise rules, see Section 3.1.1.1).  
–
Part 1b:  Following single-agent MTD/MAD identification, separate safety run-in 
cohorts will be conducted in neuroblastoma with newly enrolled patients to 
identify the RP2Ds of idasanutlin in combination with cyclophosphamide and 
topotecan and in combination with venetoclax.  These cohorts will also provide 
early efficacy assessments of these combinations in the patients with TP53 WT 
tumors treated at the RP2Ds (see Section 3.1.1.2).  Additional safety run-in 
cohorts will be conducted in AML to identify the RP2D of idasanutlin in 
combination with FLA and in AML and ALL to identify the RP2D of 
idasanutlin in combination with venetoclax in patients with leukemia.

Part 2:  In cohorts that pass the safety and efficacy criteria for Part 1b (Gate 1b),
evaluation of safety and efficacy of idasanutlin in combination with chemotherapy or 
venetoclax will be continued in neuroblastoma, AML, and/or ALL at the RP2D(s) 
for the combinations (see Section 3.1.2).

Study Part 3:  Potential expansion of idasanutlin combination cohorts in 
neuroblastoma, AML, and/or ALL meeting the pre-defined efficacy criteria for 
expansion (Gate 2), also taking into account practical considerations (e.g., 
enrollment feasibility), nonclinical findings, biomarker analysis, safety profiles, and 
any other relevant information (see Section 3.1.3). 
In Study Part 1a, only patients 18 years of age will be enrolled.  In Study Parts 1b, 2,
and 3, pediatric and young adult patients with neuroblastoma or acute leukemias (age:  
birth to 30 years) will be enrolled.
Idasanutlin will be administered orally to patients once daily for Days 15 of each cycle, 
followed by 23 days of rest, for a total cycle duration of 28 days.  All patients will be 
closely monitored for adverse events (regardless of relationship to study drug) 
throughout the study and for at least 30 days after the last dose of study treatment or 
until initiation of a new anti-cancer therapy, whichever comes first. 
Patients will be enrolled regardless of their TP53 mutation status, as not all TP53
mutations may be inactivating; therefore, responses may still be observed in some 
patients with TP53 mutations.  A pre-idasanutlin tumor biopsy of current disease within 
6 months of screening and after the last anti-cancer therapy is required for patients with 
solid tumors unless approved by the Medical Monitor.  A bone marrow aspirate (BMA) 
specimen is required within the screening period for patients with leukemia.  Samples 


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will be analyzed for TP53 mutation status by centralized molecular testing.  If available, 
sites must also report any local molecular testing results for TP53 mutation status in the 
eCRF.
An internal monitoring committee and external scientific oversight committee (IMC/SOC) 
will be established for safety monitoring at pre-defined study milestones and 
approximately every 6 months (see Section 3.1.4).
3.1.1
Study Part 1Dose Escalation and Safety Run-In
3.1.1.1
Study Part 1a:  Single-Agent Dose Escalation
The study will begin with a dose-escalation phase with idasanutlin in patients with solid 
tumors using the modified continual reassessment method of escalation with overdose 
control (mCRM-EWOC) to identify the single-agent MTD/MAD.  Approximately 
924 DLT-evaluable patients are anticipated to be enrolled in this phase.  Based on 
physiologically-based pharmacokinetic (PBPK)-predicted exposures in children, the 
starting dose is defined as 2 mg/kg/day (dose level 1) (Section 3.3.1.1).  Dose-level 
escalation or de-escalation (if required) will be decided following review of PK and safety 
data.  
Due to the limitations of predicting exposure in children 2 years of age, patients 
2 years of age require investigator discussion with, and approval of, the Medical 
Monitor for enrollment until at least 6 patients have completed one cycle of treatment.
Exposure data from the first 6 patients will be used to refine predictions for patients 
2 years of age.  The first patient at each dose level must complete at least 5 days of 
treatment without a DLT before subsequent patients can be treated at the same dose 
level.
The single-agent DLT window will be 28 days (one cycle duration; see Section 4.3.2.1) 
and until ANC0.75109/L and platelet count 75109/L are achieved.  Adverse events 
identified as DLTs will be reported to the Sponsor within 24 hours.  Following the first 
cycle, patients will undergo response and DLT assessment.  Any delay 14 days in 
treatment due to delayed platelet recovery will also be considered a DLT; therefore, DLT 
assessment may extend until platelet count recovery.

Patients who do not experience a DLT or progressive disease will have the option 
(with investigator approval) to continue single-agent idasanutlin or start combination 
therapy with cyclophosphamide/topotecan (dose defined in Section 4.3.2) with a
dose reduction in idasanutlin of 20%.  

Patients who do not experience a DLT but do experience progressive disease may 
continue idasanutlin (with a 20% dose reduction) in combination with 
cyclophosphamide/topotecan with investigator and Medical Monitor approval, but 
will not be permitted to continue idasanutlin monotherapy.

Patients who experience a DLT but have CR, PR, or SD will have the option to 
continue single-agent treatment (dose reduced by 20%) upon adequate recovery 


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from toxicities and depending on the nature of the specific toxicity, as jointly judged 
by investigator and the Medical Monitor.

Patients who experience a DLT and progressive disease will permanently 
discontinue study therapy.
Patients will start subsequent cycles of therapy after Day 28 and when 
ANC0.75109/L and platelet count75109/L are achieved.  Patients who remain on 
study therapy (single agent or combination) will continue until the occurrence of disease 
progression as determined by the investigator, death, unacceptable toxicity, or 
patient/guardian or investigator decision to discontinue treatment. 
All patients who experience a DLT will be DLT evaluable.  Patients who discontinue from 
the study prior to completing the DLT assessment window or who complete less than 
80% (i.e., less than 4 doses) of the prescribed therapy for that cycle for reasons other 
than a DLT will be considered non-evaluable for dose-escalation decisions and 
MTD/MAD assessments. DLT non-evaluable patients will be replaced, unless the 
Medical Monitor determines that replacement is not necessary for a dose escalation or 
reduction decision. The Medical Monitor will review all patients who ingest prohibited 
therapies, foods, or supplements (see Section 4.4), or who receive supportive care 
during the DLT assessment window that confounds the evaluation of DLTs (not including 
supportive care described below as part of the DLT definition) to determine DLT-
evaluability and whether they will be replaced.
Patients who experience a DLT during the assessment window (i.e., in the first 28 days) 
are not permitted to continue drug at their current dose. The investigator should use 
guidance in Section 5.1.5 (and if guidance is not specified, investigator discretion) to 
determine whether the patient should permanently discontinue study drug or withhold 
study drug until adequate toxicity resolution.
All patients in the dose-escalation phase, irrespective of diagnosis, will be eligible for 
combination therapy with cyclophosphamide/topotecan after the DLT assessment 
window provided they meet the above criteria. Patients treated with combination therapy 
will be closely monitored for safety for the duration of treatment (i.e., no fixed DLT 
period/assessment).  Dose reductions of idasanutlin and/or 
cyclophosphamide/topotecan can be applied based on the patient's clinical status, as 
jointly judged by investigator and Medical Monitor.  The Medical Monitor may also 
mandate dose reductions for all patients treated with combination in this phase of the 
study based on the combination dose-finding rules established in Section 3.1.1.2.  Any 
emerging safety data will inform the starting dose of the combination safety run-in
cohorts.
The dose-escalation phase will utilize the mCRM-EWOC design to inform 
decision-making regarding the MTD of idasanutlin. The MTD is defined as the dose that 
maximizes the posterior probability of a DLT being in the targeted toxicity interval of 20% 


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to 35%, while keeping the overdose probability below 25%. A minimum of 3 patients will 
be initially enrolled per dose level.  Before declaring MTD, a minimum of 6 patients will 
be enrolled in that dose level.  The mCRM-EWOC model will adaptively estimate the 
MTD after gathering cumulative DLT data from newly completed cohorts and will 
calculate a recommended next dose for the next cohort.  The maximum allowable dose 
increase to the next dose level will be 50%. The mCRM-EWOC design parameters and 
operating characters are described in Appendix 11. Because the mCRM-EWOC model 
does not take into account the type and grade of DLT and non-DLT adverse events, 
clinical judgment will always override model estimates when selecting the next dose.  
Thus, decisions to dose escalate must be approved by the Medical Monitor.  On the 
basis of an ongoing review of safety data and available PK data, increases in dose level 
may be halted by the Sponsor as deemed appropriate, even if the model estimates that 
MTD has not been exceeded.
3.1.1.2
Study Part 1b:  Combination Therapy Safety Run-In 
Once the idasanutlin single-agent MTD/MAD has been identified, a safety run-in phase 
with newly enrolled pediatric patients will be conducted to identify RP2Ds for idasanutlin 
in combination with chemotherapy or venetoclax in separate neuroblastoma, AML, and 
ALL combination cohorts (see Section 4.2 for treatment assignment information).  The 
safety run-in phase will start at a maximum of 80% of the idasanutlin MTD/MAD 
identified in the dose-escalation phase, combined with the following regimens in the 
listed diseases:

Idasanutlinchemotherapy:
–
Neuroblastoma:  cyclophosphamidetopotecan 
–
AML:  fludarabinecytarabine 

Idasanutlinvenetoclax:
–
Neuroblastoma
–
ALL and AML, with different DLT rules for hematologic toxicity, as described in 
Section 3.1.1.3
Assignment of patients to either the chemotherapy or venetoclax cohort will be at the 
investigator's discretion and in accordance to the availability of open slots for enrollment.
The DLT criteria (disease-type dependent) are modified from those used in the 
single-agent dose escalation cohort in order to determine more appropriately the RP2D 
in the setting of combinations with agents that have anticipated effects on bone marrow 
suppression. Dose-escalation decisions will be dependent on pharmacokinetics and 
totality of data.  Only the idasanutlin dose will be escalated, while chemotherapies or 
venetoclax doses will not be escalated (see also Section 4.3.2.2). However, 
idasanutlin, chemotherapy, and/or venetoclax doses may be de-escalated based on the 
totality of the data as determined by the Medical Monitor. 


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For each combination cohort, the first patient at the first dose level must complete 
at least 5 days of treatment without a DLT before subsequent patients can be treated at 
the same dose level. After the first 3 patients at a particular dose level have completed 
1 cycle of therapy (28 days), recruitment will be paused, and safety and tolerability will 
be evaluated as described below:

Should no patients experience DLTs and the regimen is otherwise considered 
tolerable, dose escalation to the next dose level may be considered.  Alternatively, 
3 additional patients may be enrolled at the same dose or, for the leukemia cohorts, 
an RP2D may be declared with endorsement by the IMC/SOC. 

Should 1 of the first 3 patients experience a DLT, dose reduction of idasanutlin 
and/or chemotherapy/venetoclax or additional enrollment of 3 patients at the same 
dose will be considered. 

Should more than 1 patient experience a DLT or the regimen is otherwise 
considered intolerable based on the totality of the data, the dose of idasanutlin 
and/or chemotherapy/venetoclax will be reduced. 
If 3 additional patients are enrolled in a dose-level cohort, safety and tolerability will be 
evaluated as described below:

If 0 or 1 total patients experience a DLT and the regimen is considered tolerable, 
dose escalation to the next dose level may be considered or an RP2D may be 
declared with endorsement by the IMC/SOC.  A minimum of 6 patients are 
required to be treated at a dose level prior to it being declared the RP2D for the 
neuroblastoma cohorts.

If more than 1 patient experiences a DLT or the regimen is otherwise considered 
intolerable based on the totality of the data, the dose of idasanutlin and/or 
chemotherapy/venetoclax will be reduced.
The degree of dose escalation or reduction in each cohort (if necessary) will be 
determined by the Medical Monitor.  For dose escalations, the degree of escalation may 
not exceed 25% of the previously administered dose.  For dose reductions, the degree 
of reduction must be at least 20% of the previous dose.
Although safety and tolerability will be the primary determinants of dose 
recommendation, identification of an RP2D may also be informed by observed 
idasanutlin drug exposures or efficacy.  At each dose level cohort, the process of dose 
selection will restart as described above.  A maximum of one higher dose level from the 
starting dose-level cohort, or one lower dose-level cohorts of idasanutlin, will be 
permitted.  If one dose levels below the starting dose of idasanutlin is considered 
intolerable, the combination will be discontinued.  As the safety profile of idasanutlin may 
differ among combinations, the idasanutlin RP2D may also differ among cohorts. 
Upon identification of the appropriate RP2D, evaluation of the combination will proceed 
to Study Part 2; however, the neuroblastoma cohorts will not proceed unless 50% of 


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the TP53 wild-type patients treated at the RP2D have an objective response by INRC.  
If this criterion for Gate 1b is passed, the safety and preliminary efficacy for the RP2D 
idasanutlin combinations will continue to be evaluated in Study Part 2, where enrollment 
will proceed until a total of 10 TP53-wild type (WT)-evaluable patients per disease 
cohort are enrolled (See Section 3.1.2).  
Once the appropriate RP2D is identified, patients treated at lower dose levels (including 
those patients treated in the single-agent dose escalation who go on to receive 
combination therapy with cyclophosphamide/topotecan) will be allowed to escalate to the 
RP2D. 
Patients will be treated with combination therapy until the occurrence of disease 
progression as determined by the investigator, death, unacceptable toxicity, study 
termination, or patient/guardian or investigator decision to discontinue treatment, except 
in the following instances:

Patients with AML treated with fludarabine and high-dose cytarabine (FLA) will 
receive up to 2 cycles of combination therapy, followed by idasanutlin monotherapy 
in subsequent cycles.

Patients with leukemia who 1) do not meet criteria for progression or relapse but 
have M3 marrow after Cycle 1 of therapy or 2) fail to achieve morphologic 
CR/CRi/CRp after 2 cycles of therapy will be required to discontinue study therapy 
unless the investigator views the benefitrisk ratio of continued therapy as favorable 
(and with approval of the Medical Monitor).  Patients will still be recorded as having 
had an event for EFS analysis.
Patients with neuroblastoma will start subsequent cycles of therapy after Day 28 when 
ANC is0.75109/L and platelet count is 75109/L.  Patients with AML and ALL will 
start subsequent cycles of therapy after Day 28 when ANC is 0.5109/L and platelet 
count is 75109/L (or at Day 56 when ANC is 0.5109/L irrespective of platelet 
counts).
3.1.1.3
Definition of Dose-Limiting Toxicity
During the dose-escalation phase, safety run-in phase, and initial cohort expansion 
phase (Study Parts 1 and 2), any one of the following events will be considered a DLT if 
it occurs during the DLT assessment window and is assessed by the investigator to be 
related or possibly related to idasanutlin (rules for attributing causality are defined in
Section 5.3.4).  Adverse events identified as DLTs, as defined below, must be reported 
to the Sponsor within 24 hours.
Single-Agent Dose Escalation (Solid Tumors, including Neuroblastoma)
The DLT period will be defined as 28 days (1 cycle) plus any additional time required for 
count recovery sufficient to start the next cycle of therapy.  The following will be 
considered a DLT:

Any treatment-related death


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
Elevation of serum hepatic transaminase (ALT/ AST) 5the upper limit of normal 
(ULN) lasting for 72 hours, or 20ULN lasting for any duration of time not 
attributable to disease progression

Severe liver injury, in the absence of cholestasis or other causes of 
hyperbilirubinemia, as defined by Hy’s law:
–
Treatment-emergent ALT/ AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)
–
Treatment-emergent ALT/ AST 3baseline value in combination with clinical 
jaundice

Any non-hematologic toxicity Grade 3 except for the following:
–
Grade 3 fatigue, generalized muscle weakness, fever, anorexia, or constipation
–
Grade 3 laboratory abnormality (except elevations of hepatic transaminases) 
that is asymptomatic and deemed not clinically significant by both the 
investigator and Medical Monitor.

Nausea, vomiting, and/or diarrhea if Grade 3 severity lasts greater than 24 hours 
after initiation of supportive care measures or if Grade 4 or higher

Hematologic toxicity (not applicable for patients with bone marrow involvement at 
baseline):
–
Grade 4 neutropenia (i.e., neutrophil count 0.5109/L) lasting at least 7 days
Treatment with granulocyte colony stimulating factors is acceptable if 
patient has Grade 4 neutropenia and prophylactic use of granulocyte 
colony stimulating factors is recommended for patients who receive 
idasanutlin in combination with cyclophosphamide and topotecan starting 
in Cycle 2.
–
Febrile neutropenia:  Grade 4 neutropenia (i.e., neutrophil count 0.5109/L) 
with a temperature 38.5C or documented infection
–
Grade 4 anemia
–
Grade 4 thrombocytopenia (i.e., platelet count 25.0109/L) or any 
thrombocytopenia requiring platelet transfusion
–
Delay in starting Cycle 2 14 days (Day 42) due to slow recovery from 
thrombocytopenia (platelet count75109/L) or neutrophil count 0.75109/L
Delays will be taken into account for subsequent dosing decisions.

Any related event that results in a dose delay beyond Day 42
Combination Safety Run-in and Expansion (Neuroblastoma)
The DLT period will be defined as 28 days (1 cycle) plus any additional time required for
count recovery sufficient to start the next cycle of therapy. The following will be 
considered a DLT:

Any treatment-related death


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
Elevation of serum hepatic transaminase (ALT/ AST) 5the ULN lasting for 
72 hours, or 20ULN lasting for any duration of time not attributable to disease
progression

Severe liver injury, in the absence of cholestasis or other causes of 
hyperbilirubinemia, as defined by Hy’s law:
–
Treatment-emergent ALT/ AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)
–
Treatment-emergent ALT/ AST 3baseline value in combination with clinical 
jaundice

Any non-hematologic toxicity Grade 3 except for the following:
–
Grade 3 fatigue, generalized muscle weakness, fever, anorexia, or constipation
–
Grade 3 laboratory abnormality (except elevations of hepatic transaminases) 
that is asymptomatic and deemed not clinically significant by both the 
investigator and Medical Monitor.

Nausea, vomiting, and/or diarrhea if Grade 3 severity lasts greater than 24 hours 
after initiation of supportive care measures or if Grade 4 or higher

Hematologic toxicity (not applicable for patients with bone marrow involvement at 
baseline):
–
Grade 4 neutropenia (i.e., neutrophil count 0.5109/L) lasting at least 14 days
Prophylactic use of granulocyte colony stimulating factors is 
recommended per institutional standards
Note:  Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity.
–
Grade 4 anemia
–
Grade 4 thrombocytopenia (i.e., platelet count 25.0109/L) lasting at least 
14 days with assessments on at least two separate days or requiring a platelet 
transfusion on 2 separate days
–
Delay in starting Cycle 2 14 days (Day 42) due to slow recovery from
thrombocytopenia (platelet count75109/L) or neutrophil count 0.75109/L
Delays will be taken into account for subsequent dosing decisions.

Any related event that results in a dose delay beyond Day 42
Combination Safety Run-in and Expansion (Acute Lymphoblastic Leukemia and
Acute Myeloid Leukemia)
The DLT period will be defined as 28 days (1 cycle) plus any additional time required for 
count recovery sufficient to start the next cycle of therapy for consideration of DLT.
The following will be considered a DLT:

Any treatment-related death


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
Elevation of serum hepatic transaminase (ALT/ AST) 5the ULN 72 hours or 
20ULN lasting for any duration of time

Severe liver injury, in the absence of cholestasis or other causes of 
hyperbilirubinemia, as defined by Hy’s law:
–
Treatment-emergent ALT/ AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)
–
Treatment-emergent ALT/ AST 3baseline value in combination with clinical 
jaundice

Any non-hematologic toxicity Grade 3 except for the following:
–
Grade 3 fatigue, generalized muscle weakness, anorexia, or constipation
–
Grade 3 laboratory abnormality that is asymptomatic or can be controlled with 
medical interventions (e.g., electrolyte disturbances due to chemo-induced 
diarrhea) and deemed to be not clinically significant by both the investigator and 
the Medical Monitor
–
Grade 3 or 4 fever or febrile neutropenia
–
Infection, bleeding, or other expected direct complication of cytopenias due to 
active underlying AML/ALL
–
Tumor lysis syndrome (TLS) if it is successfully managed clinically and resolves 
within 7 days without end-organ damage

Nausea, vomiting, and/or diarrhea if Grade 3 severity lasts greater than 24 hours 
after initiation of supportive care measures or if Grade 4 or higher 

Grade 4 neutropenia (ANC0.5109/L) or Grade 2 thrombocytopenia 
(platelets75109/L) in absence of evidence of active leukemia (i.e., < 5% blasts in 
the bone marrow) lasting 42 days
Myelosuppression and associated complications are expected as events during 
leukemia therapy and are part of the treatment success (marrow emptying of 
leukemia cells).  Therefore, myelosuppression and associated complications 
such as fever, infections, bleeding, and related hospitalization will be reported 
in the study summary.

Any related event that results in a dose delay beyond Day 42 
3.1.1.4
Dose-Limiting Toxicity Re-Treatment Criteria
In the single-agent dose-escalation phase of Study Part 1a, if DLT occurs, study 
treatment must be suspended.

For patients with CR/PR/SD at end of Cycle 1, re-start idasanutlin monotherapy at a 
20% reduced dose (see Section 3.1.1.1) once DLT has resolved to Grade 1 or 
baseline. Resumption of idasanutlin may also be considered if approved by the 
investigator and Medical Monitor.

For patients with PD, permanently discontinue study treatment.


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For the safety run-in phase of Study Part 1b, if DLT occurs, study treatment must be 
suspended.

Re-start combination treatment (with idasanutlin at a reduced dose) once DLT has 
resolved to Grade 1 or baseline. Dose reduction of combination agents may also 
be considered with approval of Medical Monitor.  Resumption of study treatment 
may also be considered if approved by the investigator and Medical Monitor.
For Study Part 2, if a DLT occurs, study treatment must be suspended. 

Re-start treatment once the event has resolved to Grade 1 or baseline.  
Resumption of study treatment may also be considered if approved by the 
investigator and Medical Monitor.
See Sections 5.1.5.1 and 5.1.5.4 for additional guidance on dose modifications and 
management of specific adverse events. 
3.1.2
Study Part 2Initial Expansion for Early Efficacy Evaluation 
Upon determination of the appropriate idasanutlin RP2D and passage of Gate 1b for 
each disease and combination, additional patients will be enrolled in Study Part 2.  For 
neuroblastoma cohorts, approximately 46 patients will be added to reach a total of 
10 patients with TP53 WT tumors (including those patients enrolled in Study Part 1b 
at the RP2D).  For AML, patients will be randomly allocated between two combination 
arms FLA versus venetoclax) and evaluated for safety and preliminary efficacy.  For 
these AML arms, ten patients with TP53 WT AML will be enrolled per arm, not 
counting those enrolled in Study Part 1b.  For ALL, patients will not undergo 
randomization, as only one treatment combination (idasanutlin plus venetoclax) will be 
evaluated.  Ten patients with TP53 WT ALL will be required for this cohort. On the 
basis of the frequency of TP53 mutations in the selected tumor types, the overall 
number of patients enrolled in each individual cohort is not expected to exceed 
approximately 20% more than the target minimum of 10 patients.  Patients enrolled in 
the study whose cancers are found to have TP53 mutations will be allowed to continue 
study therapy but will be replaced for efficacy analysis.  The different cancer types will be 
evaluated independently of one another.
Patients included in the safety run-in phase will not be included in the 10-patient initial 
response assessment for the leukemia arms.
Response criteria, assessment timepoints, and primary efficacy endpoints for each 
disease are listed in Table 1.


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Table 1
Response Criteria, Assessment Timepoints, and Primary Efficacy Endpoints
Disease
Response Criteria
Assessment Timepoint
Primary Efficacy Endpoint for 
Determination of Subsequent 
Cohort Expansion
Solid tumors 
(non-neuroblastoma)
RECIST v1.1. for 
patients with other solid 
tumors (see Appendix 6)
Part 1a (single-agent dose 
escalation):  Cycles 1, 3, 5, and 7 
and every fourth cycle thereafter
N/A
Neuroblastoma
International 
Neuroblastoma 
Response Criteria 
(INRC) (see Appendix 5)
Part 1a (single-agent dose 
escalation): Cycles 1, 3, 5, and 7 
and every fourth cycle thereafter
N/A
Part 1b (combination safety 
run-in), Part 2, and Part 3: 
Every two cycles from Cycle 1 
through Cycle 8 and then every 
fourth cycle thereafter
Objective response rate
AML
See Appendix 7
After the first and second cycles 
of therapy, and every 2 cycles 
thereafter
CR within two cycles
ALL
See Appendix 8
After the first and second cycles 
of therapy, and every 2 cycles 
thereafter
CR within two cycles; MRD 
negative within two cycles
ALL acute lymphocytic leukemia; AML acute myeloid leukemia; CR complete response; INRC International 
Neuroblastoma Response Criteria; MRDminimal residual disease; RECIST Response Evaluation Criteria in Solid Tumors.


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Although Part 2 of the study is not dose finding, DLTs will be reported and analyzed in 
conjunction with the efficacy evaluation.  The DLT collection period will take place during 
Cycle 1, lasting 28 days for each patient plus any additional time required for count 
recovery sufficient to start the next cycle of therapy.  The same DLT criteria will be used 
as during the safety run-in portion of Part 1b as defined in Section 3.1.1.3.
Upon completion of enrollment in the initial expansion for efficacy in Part 2, an additional 
safety analysis will be performed at the time of response assessment for all patients 
enrolled in a cohort.  If more than 35% of patients experience a DLT in Part 2, the 
combination may stop enrollment, after taking into account the discussions with 
investigators as well as IMC/SOC recommendation.  
For example, if the true toxicity rate is 20% at a certain combination dose level, there is a 
12% probability of observing DLTs in more than 35% of 10 patients.  On the other hand, 
if the true toxicity rate is 40%, there is a 62% probability of observing DLTs in more than 
35% of 10 patients. 
3.1.3
Study Part 3Additional Expansion Phase
As defined in Section 6.1, a minimum number of responders among the 10 patients with 
TP53 WT enrolled in Study Parts 1b and 2 for the neuroblastoma cohort or Study Part 2 
for the leukemia cohorts will be required for cohort expansion and advancement to the 
additional response assessment (Study Part 3).  The minimum number of responders is 
defined separately for each disease and is based on an expected observation of 
improvement over response rates to backbone therapies (see Section 3.3.7).  A decision 
to expand a cohort will take into account safety and tolerability of the combination 
regimen in addition to the number of responders.  Practical considerations will also be 
taken into account, such as enrollment feasibility, nonclinical findings, biomarker 
analysis, safety profiles, and any other relevant information.  In general, cohorts will not 
expand if the minimum number of responders is not met.  However, the study team (only 
with endorsement of the IMC/SOC) will be permitted to expand a cohort even if the 
minimum number of responders is not met, if the totality of the efficacy and other data 
support cohort expansion.  The maximum number of additional patients enrolled in any 
tumor cohort in Study Part 3 will range from 2030 patients with TP53 WT tumors.  
Tumor assessments will be performed utilizing the same response criteria used in Study 
Part 2 (see Table 1).
3.1.4
Stopping Rules by Cohort
3.1.4.1
Temporary Halt
A temporary dosing halt will be applied in the event that excessively prolonged marrow 
aplasia or deaths attributable to study drug occur in Part 1 of the study (single-agent 
dose-escalation and combination therapy safety run-in).  If any of the applicable adverse 
events described below occur, all patients must stop dosing unless evidence of clinical 
benefit is demonstrated (e.g., decreased tumor-related symptoms, reduced tumor 
burden, or evidence of stable disease) and has already been observed in the 


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investigator’s opinion.  For relevant events in a combination therapy cohort, because 
toxicity is anticipated to be different with different drug combinations, the stopping rule 
will apply only to the disease and drug combination cohort in which the toxicity occurred:

Single-agent cohort 
–
Any Grade 4 neutropenia or Grade 4 thrombocytopenia lasting beyond Day 56 
of any cycle, attributable to study drug
–
Any Grade 5 event attributable to study drug

Combination cohorts
–
Solid tumor combinations with chemotherapy or venetoclax:
–
1 episode of Grade 4 neutropenia or Grade 4 thrombocytopenia lasting 
beyond Day 56 of any cycle, attributable to study drug
–
Any Grade 5 event attributable to study drug 
–
Leukemia combinations with chemotherapy or venetoclax:
–
1 episode of Grade 4 neutropenia or Grade 4 thrombocytopenia lasting 
beyond Day 56 of any cycle, attributable to study drug, AND not 
attributable to disease 
–
1 episode of any Grade 5 infection in the setting of drug-induced 
neutropenia
–
Any other Grade 5 event attributable to study drug
Dosing may not resume in the patients unless and until the IMC/SOC recommend 
resumption of dosing after review of the adverse event(s).
3.1.4.2
Temporary Pause in Enrollment
In study Part 1 (single-agent or combination), if the first patient in a dose level cohort has 
a DLT within 5 days, enrollment will pause in that cohort.  Enrollment will be permitted to 
resume at a lower dose level.  Subsequent enrollment in the specific cohort where the 
DLT event occurred (i.e., at the same dose level as the DLT event occurred) may not 
resume unless and until the IMC/SOC recommend resumption of enrollment after review 
of the adverse event.
For patients in study Parts 2 and 3, meeting the criteria for temporary halting of the 
cohort (see Section 3.1.4.1) will not result in a halt to dosing.  Only enrollment in the 
specific cohort where the event(s) occurred will pause until the IMC/SOC recommend 
resumption of enrollment after review of the adverse event(s).
Additional guidance for stopping enrollment related to DLTs in Part 2 is provided in 
Section 3.1.2.
3.1.4.3
Final End of Dosing by Cohort
In addition to the regular safety reviews planned every 6 months, the IMC/SOC may 
request an ad hoc meeting to review the safety data as needed (see Section 3.1.5 and


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IMC/SOC Charter).  The IMC/SOC may recommend permanent discontinuation of 
dosing in some or all treatment cohorts based on their findings.
3.1.5
Internal Monitoring Committee and Scientific Oversight Committee
An IMC will be established to monitor patient safety throughout the study, to provide 
recommendations on the single-agent MTD/MAD and combination RP2Ds of idasanutlin, 
and to provide recommendations on which cohorts qualify to proceed to the study 
expansion phase.  The IMC will include Sponsor representatives from clinical science, 
biostatistics, safety science, and clinical pharmacology. IMC members will not have 
regular contact with the sites as part of their responsibilities.
In addition to the ongoing assessment by the investigator and the Medical Monitor of the 
incidence and nature of DLTs, adverse events (particularly Grades 3), serious adverse 
events, deaths, and laboratory abnormalities, the IMC will review all necessary 
cumulative data approximately every 6 months during the study. Ad hoc meetings may 
be called in addition to scheduled meetings, as necessary, to obtain IMC
recommendations on management of any new safety issues.
An SOC, which will consist of experts external to the Sponsor (including at least 
2 pediatric oncologists), will also be established for this study. The SOC will leverage 
external experts' scientific expertise by providing advice on data interpretation as well as 
advice on which cohorts qualify to proceed to the expansion phase.  The SOC will 
function as a consultative body to the Sponsor, providing individual expert opinions.
Specific operational detailssuch as committee composition, frequency and timing of 
meetings, and member roles and responsibilitieswill be detailed in an IMC and SOC
Charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or 
1 year after the last patient is enrolled, whichever occurs first. For an individual patient, 
the completion of the study (i.e., the last visit) will occur when the patient withdraws 
consent, has been lost to follow-up, dies, or when the study is stopped.
The Sponsor reserves the right to present interim data to Health Authorities for 
compliance purposes.  The primary analysis will be conducted after the enrollment has 
been completed and all enrolled patients have been followed for at least 6 months.  
A Clinical Study Report will be submitted to Health Authorities by the Sponsor according 
to local/regional regulations.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Study Treatment Dose and Schedule
3.3.1.1
Idasanutlin
The traditional starting dose for pediatric oncology Phase I studies of cytotoxic agents is 
80% of the adult dose (Lee et al. 2005).  Furthermore, according to the evaluation of 
toxicity profiles of targeted agents around 80%100% of the adult dose appears to be a 
safe starting dose (Paoletti et al. 2013).  As noted in Section 1.4.1.1, different MTDs 
have been identified based on the formulation used (MBP versus SDP), the relevant 
DLT rules used for hematologic toxicity in solid tumors versus leukemia, and the 
combination partner used (i.e., cytarabine versus venetoclax).
The single-agent dose finding in this study aims to achieve an MTD of SDP formulation
in pediatric patients.  It is anticipated that the pediatric MTD will achieve at least
similar exposures as adults with solid tumors on Study NP27872.  A pediatric PBPK 
model was used to identify the dose to achieve the initial target exposure AUC024h of 
70 g h/mL observed as the median value after 500-mg MBP formulation daily for 
5 days in adult patients with solid tumors who participated in Study NP27872.  
Simulations with 500 virtual children age 018 years indicated that an SDP formulation 
dose of 2 mg/kg/day5 days would achieve the target exposure. 
In the idasanutlin dose-escalation phase, the starting dose for idasanutlin will be 
2 mg/kg.  Accounting for the estimated 2-fold increased bioavailability of idasanutlin SDP 
over MDP, this dose equates to 56% of the predicted SDP solid tumor dose of 
3.6 mg/kg/day (500 mg/day MBP divided by 70 kg, divided by an SDP/MBP formulation 
correction factor of 2).  Thus, this starting dose provides a sufficient safety margin below 
the adult MTD for initiation of dose finding, while based on PBPK results, also being 
likely to match drug exposure in adults at the MTD for adult solid tumor patients.
The rationale for idasanutlin dosing in the combination safety run-in is provided in 
Section 3.3.6.
3.3.1.2
Venetoclax
Venetoclax is approved for use in adults with CLL or SLL at a dose of 400 mg daily (see 
Venetoclax U.S. Package Insert).  In diseases where a higher degree of marrow toxicity 
is necessary as part of therapy, such as AML and NHL, venetoclax has been evaluated 
in adults at doses as high as 1200 mg daily without exceeding the MTD in combination 
with other anti-cancer therapies, although recommended doses have been capped at 
800 mg daily in these studies (DiNardo et al. 2018; de Vos et al. 2018). 
The pediatric dose for venetoclax is under investigation in a Phase I trial evaluating 
monotherapy followed by the addition of chemotherapy (Place et al. 2018; trial
registration: EudraCT 2017-000439-14, NCT03236857).  The starting dose in this study 
was an adult exposure-equivalent dose of 800 mg daily, adjusted for weight.  Preliminary 


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data from this study by AbbVie indicate that venetoclax administered at this dose 
exceeded the MTD when used in combination with chemotherapy (topotecan/ 
cyclophosphamide) in patients with solid tumors due to prolonged neutropenia; at the 
current time, the optimal dosing for this combination is still being evaluated (S. Kim, 
personal communication; Goldsmith, et al. 2020).  Based on this information, the dose of 
venetoclax administered in combination with idasanutlin in this study will not exceed 
400 mg daily (adjusted for weight) in patients with neuroblastoma.
Because a higher degree of marrow toxicity is tolerated in patients with leukemia in order 
to adequately treat the bone marrow, a higher starting dose of venetoclax will be utilized 
in patients with ALL or AML relative to patients with solid tumors in this study.  In the
ongoing adult study combining idasanutlin with venetoclax in adults with AML 
(NCT02670044), venetoclax doses ranging from 400 to 600 mg have been evaluated 
without exceeding the MTD (Daver et al. 2017).  A dose of venetoclax higher than 
600 mg is not currently planned; as such, the dose of venetoclax on this study will not 
exceed 600 mg adjusted for weight in patients with leukemia.
Further dosing information is provided in Section 4.3.2.2. 
3.3.2
Rationale for Patient Population
The aim of this Phase I/II trial will be to evaluate idasanutlin safety, tolerability and 
pharmacokinetics in pediatric patients with relapsed/refractory solid tumors,
neuroblastoma, AML, and ALL and to derive direct evidence of its efficacy in
combination treatment.
The safety risk mitigation plan for all parts of this study will include management 
measures for adverse events of relevance for idasanutlin.  Mitigation and monitoring 
measures are in place to also cover potential overlapping risks associated with 
chemotherapy or venetoclax (see Section 5.1.4). 
Given the nonclinical activity of idasanutlin in the diseases eligible for this study (outlined 
in Section 1.4.3), it is anticipated that the benefits of idasanutlin in combination with 
chemotherapy or venetoclax will outweigh its potential risks, particularly given the poor 
prognosis of patients with relapsed/refractory solid tumors, neuroblastoma, AML, and 
ALL who have failed standard-of-care regimens.
Significant focus will be put on preventing highly relevant toxicities from idasanutlin
combination therapy through strict adherence to exclusion criteria, rigorous monitoring,
and prophylactic treatments to ensure that any and all adverse events remain 
manageable.
3.3.2.1
Patients with TP53 Mutations
Patient tumors with mutations that render the p53 protein inactive are not expected to 
respond to an MDM2 antagonist.  However, the exact impact of any given TP53


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mutation and possible heterozygosity cannot be fully predicted for the clinical setting 
(Petitjean et al. 2007).
In Study NO21279, a Phase I study of RG7112 (a predecessor MDM2 inhibitor to 
idasanutlin) in adult AML and ALL, patients with mutant TP53 exhibited only SD or 
progressive disease.  Two patients with AML with TP53 mutations demonstrated clinical 
activity by decreased peripheral blast counts, but none had sustained clinical 
improvement (prolonged CRs) (Andreef et al. 2016). In the completed Study NP28679,
1 patient with AML with a TP53 mutation who received idasanutlin in combination with 
cytarabine achieved a confirmed CR (confirmatory assessment approximately 28 days 
following initial CR determination) (Reis et al. 2016).
Given the uncertain role of TP53 mutation status on p53 tumor suppressor activity, 
patients with tumors harboring TP53 mutations will be allowed into this study.  Due to the 
possibility of lower efficacy of idasanutlin treatment in these patients, the primary efficacy 
analyses will be based on patients whose tumors are TP53 wild type. 
Taking all evidence together, the mutation proportion in this study population is not 
expected to exceed 15%20%.  In addition, results from the Sponsor's clinical studies of 
MDM2 antagonists in patients with AML suggest that TP53 mutations are not necessarily 
predictive of lack of treatment response and a better measure of p53 functionality is 
needed. 
3.3.2.2
Adolescent and Young Adult Patients
The Sponsor expects that the majority of enrolled patients will be 18 years of age.  
However, there may be young adult patients with "pediatric-type" tumors who are treated 
in pediatric oncology facilities.  In a specific analysis of adolescent and young adult 
patients in the United States, limited clinical trial participation correlated with the relative 
lack of improvement in survival prolongation and cancer death rates (Bleyer et al. 2006).  
The lower participation of adolescent and young adult patients in clinical trials has 
created significant knowledge gaps with respect to cancer biology, treatment, and other 
factors affecting their survival.  As part of the Sponsor's commitment to the development 
of personalized medicine, adolescent and young adult patients up to 30 years of age will 
be included in Study Parts 1b, 2, and 3.
3.3.3
Rationale for Biomarker Assessments
This study will assess TP53 mutation status, MDM2 amplification and expression status, 
serum MIC-1 expression levels, andin the AML and ALL cohortsMRD.
Idasanutlin activity is derived from the stabilization and accumulation of p53 that can 
function only if it retains its conformation and transcriptional activity.  Therefore, the 
intact status of p53 in cancer cells is important in achieving the desirable 
pharmacodynamic (PD) effects in vivo (that is, inhibition of cancer cell growth and 
apoptosis).  Furthermore, MDM2 amplification/overexpression is believed to result in 


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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 idasanutlin clinical activity.
Additional biomarkers related to p53 and MDM2 activity may be evaluated as 
appropriate.
Venetoclax inhibits the ability of cancer cells to evade cell death, or apoptosis, by 
blocking the activity of the anti-apoptotic protein Bcl-2.  Previous nonclinical and clinical 
studies have demonstrated a pattern of response to venetoclax based on the levels of 
Bcl-2 family proteins.  High levels of Bcl-2 and low levels of Bcl-XL and Mcl-1 are 
generally associated with response to this drug both in vitro and in patients.  In addition, 
high levels of at least one pro-apoptotic "sensor" such as Noxa or Bim is required.
3.3.3.1
TP53 Mutations and p53 Activity
As a single agent, idasanutlin has demonstrated anti-tumor activity in cultured tumor 
cells harboring WT TP53.  At the same concentrations, idasanutlin is approximately 
300-fold less active in cultured cells with mutated TP53.  Nevertheless, not all TP53
mutations may disrupt p53 downstream activity.  For example, in Studies NO21279 
and NP28769, patients with leukemia who exhibited a CR (n1) or peripheral blast 
reduction (n2) harbored TP53 mutations, as did patients in studies of solid tumors.  
In adult tumors, with the exception of a few "hotspot" alterations (e.g., mutations at 
codon R248), TP53 mutations are distributed across the length of the gene.  This 
spectrum is similarly observed in pediatric tumor types (Chmielecki et al. 2017).  
In neuroblastoma, the rate of TP53 mutations is reported to be approximately 15% at 
relapse (Carr-Wilkinson et al. 2010).  In pediatric AML and ALL relapse/refractory 
disease, TP53 alterations are expected to occur in 12%18% of such malignancies 
(Chmielecki et al. 2017).  
Sites are strongly encouraged to provide patients' TP53 mutation status as per local 
molecular testing results, if available.  For central confirmation of TP53 mutation status, 
pre-treatment biopsies from patients with neuroblastoma or other solid tumors, and 
pretreatment BMAs from patients with AML and ALL will be retrospectively tested via 
NGS.  The primary response assessment prior to Gate 2 will be performed on patients 
whose tumors are centrally confirmed to be TP53 wild type.  Furthermore, these data will 
be used to evaluate the role of TP53 mutations toward response to idasanutlin in 
pediatric malignancies. 
3.3.3.2
MDM2 Expression and Idasanutlin Efficacy
Unlike other gene-to-protein relationships, the correlation of MDM2 amplification with 
MDM2 mRNA and/or protein expression is unclear.  MDM2 amplification is extremely 
rare in pediatric neuroblastomas (approximately 3%4%) and is purportedly non-existent 
in pediatric AML and ALL (Chmielecki et al. 2017).  However, in a study of pediatric 


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neuroblastoma, investigators observed that patients whose tumors exhibited MDM2 
mRNA expression above the study median exhibited a statistically shortened EFS rate in 
comparison to patients with below-median MDM2 expression in their tumors (p0.001) 
(Inomistova et al. 2015).  An older nonclinical study interrogating MDM2 mRNA 
expression of 19 pediatric ALL cell lines and 1 pediatric AML cell line showed that 15 of 
the 20 cell lines (75%) expressed MDM2 mRNA (Zhou et al. 1995).  In the same study, a 
similar analysis of primary ALL cells from 7 patients showed that leukemic cells in 3 of 
the 7 patients (43%) exhibited MDM2 mRNA expression levels at or above that observed 
in normal bone marrow mononuclear cells (Zhou et al. 1995).
MDM2 transcript expression from pretreatment blood specimens from patients with AML
trends with clinical response both in Phase I Study NO21279 with RO5045337 and in 
Phase I/Ib Study NP28679 with idasanutlin.  However, the association is not sufficiently 
robust to use MDM2 alone for the selection of responsive patients. In Study NP28679, 
MDM2 protein expression in blast cells analyzed by flow cytometry revealed a stronger 
association with response (Reis et al. 2016).  Gene expression signatures may also 
provide a means of predicting patient response to MDM2 inhibitors. Both nonclinical and 
clinical data (Studies NO21279 and NP28679) suggest that an mRNA gene expression 
signature consisting of the genes MDM2, BBC3/PUMA, XPC, and CDKN2A may be 
associated with response to MDM2 antagonist RO5045337 (Zhong et al. 2015).  
The significance of these biomarkers to pediatric tumor response to idasanutlin is still 
unknown.  As such, this study (GO40871) may assess MDM2 gene amplification and 
gene expression, as well as candidate gene expression signatures and protein 
expression on blasts (flow cytometry) on an exploratory basis.
3.3.3.3
MIC-1 Expression in Serum
When activated, p53 binds to consensus sites on the promoter of MIC-1, a secreted 
protein, to induce expression.  In mice bearing human tumor xenografts, increased 
levels of MIC-1 protein were detected in the blood following treatment with doxorubicin, a 
genotoxic p53 activator (Yang et al. 2003). In the completed Phase I Study NP28679
and the ongoing Phase III Study WO29519, MIC-1 serves as a surrogate biomarker of 
idasanutlin exposure; correlation of MIC-1 expression with patient response is still under 
investigation.  In Study NO21279 for RG7112, which included patients with AML, 
elevated MIC-1 serum levels were observed with RG7112 plasma concentrations of 
2 mg/mL; however, the magnitude of elevation did not correlate with patient response 
(Andreef et al. 2016).  In line with these efforts, Study GO40871 will assess MIC-1 
serum levels in all patients prior to and during idasanutlin exposure by an established 
ELISA as an exploratory PD biomarker.
3.3.3.4
Additional Exploratory Biomarker Analyses
In patients enrolled in any of the idasanutlin plus venetoclax combination cohorts, BMA, 
bone marrow biopsy (BMB), and/or formalin-fixed tissue samples taken at baseline, 
on-treatment, or end-of-treatment may be analyzed for venetoclax-relevant biomarkers 


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including, but not limited to, Bcl-2, Bcl-XL, and Mcl-1 by IHC or NGS, depending on 
sample availability.
Other exploratory biomarkers may include, but will not be limited to, NGS of circulating 
tumor DNA (ctDNA) throughout the course of therapy, NGS of RNA and/or DNA from 
tumor tissues and BMAs (leukemia cohorts), and B-cell receptor repertoire sequencing 
from peripheral blood cells.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
3.3.4
Rationale for Efficacy Endpoints
The primary endpoints for this study will be related to response to therapy.  As this is a 
Phase I/II study primarily designed to interrogate whether drug activity is present, 
survival endpoints (i.e., PFS, EFS, OS) will be secondary.
3.3.4.1
Neuroblastoma
Response assessments will be conducted in accordance with the updated INRC (Park 
et al. 2017) (see Appendix 5).  Compared with the last published INRC revision defined 
in 1993 (Brodeur et al. 1993), these endpoints more clearly incorporate 123I-
meta-iodobenzylguanidine (MIBG) or fluorodeoxyglucose-positron emission tomography 
(FDG-PET) into disease assessments, refine definitions of bone marrow disease, and 
remove urine catecholamines as a measure of response.
3.3.4.2
Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia
As the goal of re-induction therapy is to induce a complete remission, the primary 
outcome measure for patients with AML or ALL will be morphologic CRR within 2 cycles 
of therapy.  
Criteria for response in patients with AML are based on published and widely accepted 
International Working Group criteria (Cheson et al. 2003).
For patients with ALL, morphologic complete remission encompasses all patients who 
experience CR, CRp, or CRi, based on criteria defined by a 2007 American Society of 
Hematology workshop (Appelbaum et al. 2007).  These criteria have been utilized in 
subsequent pediatric ALL trials including a recent trial of tisagenlecleucel in 
relapsed/refractory disease (Maude et al. 2018) that led to drug approval by the U.S. 
Food and Drug Administration (FDA) and the European Medicines Agency.


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3.3.4.3
Minimal Residual Disease Assessments for Leukemia Cohorts
Patients with AML or ALL will undergo additional serial assessments for MRD detection. 
MRD assessments can be made with the use of multiple technologies (e.g., polymerase 
chain reaction technologies) to detect disease-specific translocations or mutations, 
and/or by flow cytometry for abnormal cell phenotypes.
Particularly in pediatric ALL, MRD has been established as a strong predictor of 
likelihood of relapse both in the upfront setting after induction therapy (Borowitz et al. 
2008) and in the pre- and post-transplant setting (reviewed in Campana et al. 2013; 
Lovisa et al. 2018).  Risk stratification of patients and therapy intensification or reduction 
based on MRD status in pediatric ALL and AML has been widely implemented 
(Campana et al. 2013).  MRD has been used as a surrogate endpoint for drug approval 
in relapsed pediatric ALL, including the approvals of tisagenlecleucel and blinatumomab.  
As such, MRD will be a co-primary endpoint in evaluating ALL efficacy.  Although MRD 
is used for risk stratification and treatment decisions in AML, MRD has not been used 
previously as a surrogate endpoint for survival in AML because of limited data to date 
supporting its use (Schuurhuis et al. 2018).  Therefore, MRD will be a secondary 
endpoint in AML.
Leukemia-associated aberrant immunophenotypes relevant for MRD assessment will be 
interrogated via flow cytometry or NGS from BMAs.  MRD will be monitored in patients 
with AML and ALL achieving clinical remission using BMAs at subsequent scheduled 
hematologic malignancy assessments.
BMA analysis to monitor MRD will be prioritized over other exploratory markers requiring 
BMA material.  BMA material from patients with ALL will be assessed using nucleic
acid-based methods including, but not limited to, NGS.  For patients with AML, standard 
flow cytometric methods will be used for MRD (see Section 2.3.1 for further details on 
MRD assessment as an efficacy endpoint).  Nucleic acid-based methods may also be 
explored depending on sample availability.
3.3.5
Rationale for Combination Therapies
Idasanutlin will be combined either with chemotherapy backbone regimens that have 
been well established in pediatric oncology or with venetoclax.
3.3.5.1
Cyclophosphamide/Topotecan Combination in Patients with 
Neuroblastoma and Other Solid Tumors
In neuroblastoma, the combination of cyclophosphamide and topotecan has been shown 
to be tolerable and is anticipated to be acceptable from a safety perspective in 
combination with idasanutlin; no specific risks have been identified beyond the known 
potential overlapping toxicities that relate to the majority of standard cytotoxic agents, 
namely myelosuppression and infection risk.  This chemotherapy combination has 
shown activity in neuroblastoma with an ORR (complete, partial, and mixed responses) 
reported at 47%63% of patients in first relapse or progression of high-risk disease and 


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a 3-year progression-free and overall survival of 11% and 17%33%, respectively 
(London et al. 2010; Ashraf et al. 2013).  Other studies have utilized cyclophosphamide 
and topotecan as a chemotherapy backbone for combination with other novel agents in 
early phase studies, including sorafenib in relapsed/refractory NBL (NCT02298348) and 
bevacizumab in relapsed/refractory NBL and Ewing sarcoma (NCT01492673). 
Additionally, this combination has been shown to be tolerable with evidence of activity in 
other relapsed/refractory pediatric solid tumors including Ewing sarcoma and 
rhabdomyosarcoma.  Patients with solid tumors may be enrolled in Part 1a of the study 
up to the idasanutlin single-agent MTD identification (Saylors et al. 2001).  Therefore, 
safety and PK data gained throughout this study may inform exploration of the 
combination in other pediatric malignancies in the future.
3.3.5.2
Fludarabine and Cytarabine in Patients with Acute Myeloid Leukemia
In AML, the combination of fludarabine, cytarabine, and G-CSF (FLAG) has long been 
established as an appropriate therapy for inducing remissions in the relapse setting.  
Among pediatric patients in first relapse or primary refractory disease, it has been shown 
to deliver a CRR after 2 cycles of 59% and a 4-year OS of 36% (Kaspers et al. 2013).  
This combination has subsequently served as a backbone for evaluating novel agents in 
the relapse setting.  The study of liposomal daunorubicin given in combination with 
FLAG established the tolerability of adding a further myelosuppressive agent to the 
regime.  No marked toxicity differences were seen between the groups (Kaspers et al. 
2013). 
Although G-CSF has been added to fludarabine and cytarabine in many trials 
theoretically to boost the percentage of cells in cell cycle prior to and during 
chemotherapy administration, and thus enhance cytotoxicity, its value in clinical practice 
is debatable.  No significant benefit of adding G-CSF to fludarabine and cytarabine has 
been clinically observed in adults with AML (Estey et al. 1994), and in vitro studies 
indicate no added effect of G-CSF on the cytotoxicity of FLA (Hubeek et al. 2004).  
As G-CSF may increase the risk of hyperleukocytosis, and given the known risk of TLS 
associated with idasanutlin, G-CSF will not be included as a therapeutic component in 
this study.
3.3.5.3
Venetoclax Combination in Patients with Neuroblastoma, Acute 
Lymphoblastic Leukemia, and Acute Myeloid Leukemia
The combination of idasanutlin and venetoclax has shown more substantial nonclinical 
activity in neuroblastoma and AML than either agent alone (see Section 1.4.3), and both 
idasanutlin and venetoclax have demonstrated substantial single-agent activity in ALL, in 
many cases eliciting complete tumor responses.  The combination was evaluated in adult 
patients 60 years of age with relapsed or refractory AML who were not eligible for 
cytotoxic therapy (GH29914, [NCT02670044]).  Preliminary results from the study were 
presented at the American Society of Hematology's annual meeting in 2017.  As of 
25 April 2017, 20 patients were safety evaluable.  Reported DLTs included generalized


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muscle weakness, diarrhea, acute coronary syndrome, and elevated bilirubin (1 instance 
each).  Grade 3 events occurring in more than 1 patient were febrile neutropenia 
(30%), decreased appetite (15%), diarrhea (10%), fatigue (10%), and hypokalemia 
(10%).  At a dose of 600 mg venetoclax and 200 mg idasanutlin daily for 5 days, 3 of 
8 (38%) patients experienced a complete remission (with or without complete count 
recovery) (Daver et al. 2017).  A complete description of the effects in humans to date 
can be found in the combination therapy investigator's brochure (RO5537382 venetoclax
[GDC-0199/ABT-199] in combination with RO5514041 cobimetinib [GDC-0973/XL518] 
or RO5503781 idasanutlin [RG7388]).
3.3.6
Rationale for Safety Run-In Design
The primary objective of the safety run-in component of the study is to identify RP2Ds of 
the individual combination arms across the diseases evaluated.  For neuroblastoma, this 
part of the study will also provide an early efficacy assessment.  Patients will not be 
randomized between different regimens because the relative safety profiles of 
idasanutlin in the proposed combination regimens will not yet have been characterized.  
During the safety run-in phase, treatment assignment will be at the discretion of the 
investigator unless the required number of patients to evaluate the RP2D dose is 
achieved, or the RP2D dose of a specific combination arm has been declared.
A formal dose-escalation approach will not be conducted for idasanutlin in the 
combination regimens proposed here, but an approach focused on dose reduction in the 
event of DLTs will be implemented.  To ensure patient safety, the following principles will 
be adhered to:

A modified 33 design is being implemented for dose reductions.  Enrollment will 
pause after every 3 patients to review totality of data.  Dose reductions will be 
required if 2 patients at a dose level experience a DLT, and to determine whether 
dose reductions should be implemented even in the absence of DLTs. A dose 
reduction may be implemented for idasanutlin and/or the combination agent(s) 
based on the attribution of the observed toxicities as determined by the Medical 
Monitor.

Idasanutlin dosing will be initiated at 80% of its single-agent MTD/MAD in all 
combinations to provide a safety margin for combination initiation.  A decrease in the 
starting dose of the combination agents may also be implemented as determined by 
the Medical Monitor in consultation with the IMC/SOC.

An early discontinuation rule has been implemented if after a dose reduction 
idasanutlin still is not tolerated in combination with other agents.

The IMC/SOC will review all decisions to declare a recommended dose for a 
particular combination.


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3.3.7
Rationale for Randomization in AML Cohorts, Initial Response 
Assessment, and Target Effect Size
Based on the nonclinical and clinical data supporting the use of idasanutlin in the 
combinations proposed, clinical equipoise exists as to whether idasanutlin combinations 
with chemotherapy or venetoclax are the most appropriate development approach for 
this molecule in pediatric AML.  To ensure unbiased distribution of patients to inform 
focused development of one combination, patients with AML in Study Part 2 will be 
randomized to either chemotherapy or venetoclax combinations.  This study does not 
formally test the question of whether idasanutlin combinations with chemotherapy or 
venetoclax are superior.  However, a randomized approach in a limited patient 
population, followed by an initial response assessment based on efficacy and safety 
data, will inform which combination is more likely to meet the study objective of 
identifying an idasanutlin regimen in AML with acceptable tolerability and a potential 
signal of efficacy. 
After 10 patients with TP53 WT cancers are efficacy evaluable in each combination arm 
for a disease, the study team in consultation with the IMC/SOC will determine which, if 
any, combinations meet the predefined efficacy threshold for cohort expansion and 
whether to expand a cohort (see Section 6.2).  The minimum number of responders in 
the initial response assessment for each disease approximates the number of patients 
that would be expected to respond if the desired level of improvement over backbone 
therapy is present, although the study is not powered to definitively detect a difference at 
this stage.
The control response rate is defined from the following backbone therapies:

For neuroblastoma, the ORR observed with the cyclophosphamide/topotecan 
backbone is 32% (London et al. 2010).  For the initial response assessment, this 
study is targeting an ORR of 47%, a 15percentage point improvement.

For AML, the CRR observed with the FLAG regimen is 59% in patients in first 
relapse or with primary refractory disease (Kaspers et al. 2013); as this study will 
allow enrollment of patients in later relapse, a lower baseline response rate is 
expected.  For initial response assessment, the study is targeting a 15-percentage 
point improvement over predicted response rate of 55% of backbone therapy in this 
study's AML population. 

For ALL, the CRR with re-induction therapy in the second or greater relapse 
(reflective of the patient population to be enrolled here) is expected to be 40%
(Ko et al. 2010).  This is comparable to the CRR observed with single-agent 
blinatumomab (von Stackelberg et al. 2016).  Given the large number of ALL 
therapies recently approved or in development in the relapse setting, a large effect 
size (20percentage point improvement) will be targeted.  As MRD is a co-primary 
endpoint, this study will target a 20-point improvement over the MRD-negative rate 
of 20% observed in a Phase I/II trial of blinatumomab in pediatric patients at any 
stage of relapse (von Stackelberg et al. 2016).


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Because the number of targeted responders in the initial response assessment is not 
statistically fully powered to detect the target difference, the study team (only with 
endorsement of the IMC/SOC) will be permitted to expand a cohort even if the minimum 
number of responders is not met, if the totality of the efficacy and data support cohort 
expansion.
3.3.8
Rationale for Additional Response Assessment and Target 
Effect Size
An idasanutlin combination cohort that is selected for expansion will enroll enough 
patients to determine whether the desired effect size is present with a two-sided alpha of 
10%. The number of patients needed for the additional response assessment will also 
take into account practical considerations (e.g., enrollment feasibility), biomarker 
analysis, safety profiles, and any other relevant information.
Targets for effect size will be the same as in initial response assessment, except that a 
higher bar for positive effect size will be set for AML given the availability of superior 
combinations of FLAG with another agent, liposomal daunorubicin (Kaspers et al. 2013).  
In this setting, the idasanutlin combination will be compared with the best available 
relapse therapy, FLAG plus liposomal daunorubicin (69% CR), with a target effect size of 
5 points (74% CR). 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 15108 patients will be enrolled in the Study Parts 1 and 2.  After 
completion of the initial response assessment, an additional 2030 patients may be 
enrolled for a combination regimen in each tumor type, up to a total sample size of 
approximately 183 patients.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed informed consent before any study-specific screening procedures are 
conducted, and age-appropriate assent when considered appropriate according to 
local, regional, or national guidelines

Age 18 years at the time of signing informed consent for Part 1a; 30 years at 
time of signing informed consent for Parts 1b, 2, and 3
Note: The Sponsor may decide to stop enrollment of patients who are 18 
years at any time during the study to ensure adequate enrollment of patients 
who are 18 years.

Study Part 1a (single-agent therapy dose escalation):  histologically confirmed 
diagnosis of neuroblastoma or other solid tumor that has progressed or recurred 
despite standard therapy, and for which there is no therapy proven to prolong 
survival with an acceptable quality of life


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
Study Part 1b (safety run-in), Study Part 2, and Study Part 3:  histologically 
confirmed diagnosis of neuroblastoma, AML, or precursor-B ALL that has 
progressed or recurred despite, or is refractory to, standard therapy 

Adequate performance status:
Patients16 years of age:  Lansky50%
Patients16 years of age:  Karnofsky50%

Adequate end-organ function defined by the following laboratory results obtained 
within 28 days prior to initiation of study drug:
Renal and liver function 
–
Creatinine 1.5 ULN for age; if higher, an estimate GFR based on the Schwartz 
equation (Schwartz et al. 2017) or as per institutional guidelines must be 
60mL/min/1.73 m2
–
Bilirubin 1.5ULN for age (or 2.5ULN if liver infiltrated with leukemia or
metastases)
–
AST and ALT 3ULN for age (or 5ULN if liver infiltrated with leukemia or 
metastases)
Cardiac function
–
Fractional shortening (FS) 28% or left ventricular ejection fraction (LVEF) 
50%, as determined by echocardiography or multigated acquisition scan 
(MUGA) within 28 days prior to initiation of study therapy
Depending on institutional standard, either FS or LVEF is adequate for 
enrollment if only one value is measured; if both values are measured, 
then both values must meet the above criteria.

For females of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, agreement to refrain from donating 
eggs, as defined below:
Females must remain abstinent or use two methods of contraception with a 
failure rate of 1% per year during the treatment period and for 6 weeks after 
the final dose of idasanutlin, 30 days after the final dose of venetoclax, 
12 months after final treatment for patients receiving 
cyclophosphamide/topotecan (or longer if required according to national 
prescribing information), 6 months after final treatment for patients receiving 
FLA (or longer if required according to national prescribing information), or in 
accordance with national prescribing information guidance regarding 
abstinence, contraception, and egg donation for any non-Investigational 
Medicinal Products listed in Section 4.3.  Females must refrain from donating 
eggs during this same period.  
A female is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 


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permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes,
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
A barrier method may be used as the second contraceptive method.
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 postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For males:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, 
males must remain abstinent or use a condom during the treatment period and 
for 90 days after the final dose of idasanutlin, 12 months after final treatment 
with cyclophosphamide/topotecan (or longer if required according to national 
prescribing information), 6 months after final treatment with fludarabine to avoid 
exposing the embryo (or longer if required according to national prescribing 
information), or in accordance with national prescribing information guidance 
regarding abstinence, contraception, and sperm donation for any 
non-Investigational Medicinal Products listed in Section 4.3.  Males must refrain 
from donating sperm during this same period.  
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 postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form.
4.1.1.1
Additional Inclusion Criteria for Patients with Solid Tumors 
(including Neuroblastoma)

At least one evaluable or measurable radiological site of disease as defined by 
standard criteria for the patient’s tumor type (e.g., INRC), or measurable bone 
marrow disease by morphology

Adequate hematologic end-organ function, as specified in the following parameters:
–
Hemoglobin 8 g/dL (transfusion allowed)
–
Peripheral ANC 0.75 109/L (no G-CSF support for 72 hours)


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–
Platelet count 75 109/L (unsupported for 72 hours)

Tumor tissue from relapsed disease, obtained subsequent to last anti-cancer 
therapy regimen administered and obtained within 6 months prior to study 
enrollment, or willingness to undergo a core or excisional biopsy sample collection 
prior to enrollment 
–
Patients must submit a tissue block or 15 slides containing unstained, freshly 
cut, serial sections available for submission.
–
Fine needle aspirations, brush biopsies, bone metastasis samples, and lavage 
samples are not acceptable.
–
Patients with 15 slides available, or whose tumor tissue does not otherwise 
meet criteria above, may be eligible for study entry after Medical Monitor 
approval has been obtained.  See Section 4.5.5.1 for detailed tissue
requirements.

Life expectancy 12 weeks, in the investigator's judgment
4.1.1.2
Additional Inclusion Criteria for Patients with Leukemia

Bone marrow with 5% lymphoblasts by morphologic assessment at screening

Available bone marrow aspirate or biopsy from screening
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Primary CNS tumors

Symptomatic CNS metastases that result in a neurologically unstable clinical state 
or require increasing doses of corticosteroids or local CNS-directed therapy to 
control the CNS disease

CNS3 leukemia (total nucleated cell count 5/L with blasts on cytocentrifuge in an 
atraumatic lumbar puncture, or clinical signs of CNS leukemia including cranial 
nerve palsy)

Acute promyelocytic leukemia

White blood cell count 50109/L
–
Prior cytoreduction with leukapheresis or hydroxyurea (HU) is allowed to meet 
this criterion.  HU must be discontinued at least 24 hours prior to the initiation of 
study treatment.
–
Prior cytoreduction with leukapheresis or hydroxyurea is allowed in patients 
with a WBC count 50 109/L if the patient is symptomatic from 
hyperleukocytosis, or if consistent with institutional guidelines.

Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any 
known bone marrow failure predisposition syndrome (including, but not limited to, 
Fanconi anemia or dyskeratosis congenita) 

Burkitt-type acute lymphoblastic leukemia (mature B-cell)


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
T-cell lymphoblastic leukemia

Prior treatment with an MDM2 antagonist

Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm)

Infection considered by the investigator to be clinically uncontrolled or of 
unacceptable risk to the patient upon induction of neutropenia, including patients 
who are, or should be, on antimicrobial agents for the treatment of active infection 
such as the following:
–
Fungal infection, other than mucosal candidiasis, with 2 weeks of appropriate 
systemic antifungal therapy
–
Bacterial infection with positive cultures in the 7 days prior to dosing
–
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 dosing
–
History of symptomatic Clostridium difficile (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.

Pregnant or breastfeeding, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test 
result within 1 week prior to initiation of study drug.

Active GI disease (e.g., gut graft-versus-host disease, Crohn's disease, ulcerative 
colitis) or GI conditions that may significantly alter drug absorption of oral drugs 
(e.g., uncontrolled vomiting, diarrhea, or malabsorption syndrome)

Active viral hepatitis or human immunodeficiency virus (HIV) infection

Presence of any CTCAEGrade 2 clinically significant treatment-related toxicity 
with the exception of alopecia, ototoxicity, peripheral neuropathy and parameters 
otherwise permitted in the inclusion criteria (e.g., hematological criteria)

Clinically relevant QTc prolongation (QTcF450 ms using the Fridericia correction)

Any uncontrolled medical condition or other identified abnormality that precludes the 
patient's safe participation in and completion of the study, as judged by the 
investigator

Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, 
prior to initiation of study treatment
–
Requirement may be waived at the investigator's request, with approval of the 
Medical Monitor, if the patient has recovered from therapeutic toxicity to the 
degree specified in the protocol.
–
Intrathecal chemotherapy per Section 4.3.2.1.1 prior to starting study therapy is 
permissible.


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
Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy 
(e.g., CAR-T cell infusion) for anti-neoplastic intent within 30 days prior to initiation 
of study treatment

I-131 MIBG therapy within 6 weeks prior to initiation of study treatment

Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue 
within 100 days of study treatment initiation

Immunosuppressive therapy for treatment of graft-versus-host disease within 
2 weeks of study treatment initiation

Radiotherapy (non-palliative) within 3 weeks prior to study treatment initiation 

Known hypersensitivity to any study drug or component of the formulation that could 
potentially be allocated according to tumor type

Received the following within 7 days prior to initiation of study treatment (see
Table 3):
–
Strong CYP2C8 inhibitors
–
CYP2C8 substrates
–
OATP1B1/3 substrates

Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the 
initiation of study treatment (see Table 3)

For patients assigned or randomized to venetoclax arms:
–
Strong or moderate CYP3A4 inhibitors or moderate inducers or P-gp inhibitors
within 7 days of study drug initiation (see Table 3 and Table 4)
–
Grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or starfruit within 3 days prior to the initiation of 
study treatment
–
Vaccination with a live vaccine 28 days prior to randomization

Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to 
study treatment initiation

Underwent major surgical procedure within 21 days of study treatment initiation, or 
anticipate need for major surgical procedure during the course of the study
Gastrostomy, tumor biopsy, and insertion of central venous access devices are 
not generally considered major surgery, but the Medical Monitor should be 
notified of these or other minor procedures prior to initiating therapy.
4.2
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  Patients will be assigned to dose levels in the order in 
which they are enrolled in Study Parts 1a and 1b.  For patients with neuroblastoma or 
AML enrolled in Part 1b, assignment to either the chemotherapy or venetoclax cohort 
will be at the investigator's discretion and in accordance to the availability of open 
slots for enrollment.


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In Study Part 2, for patients in the AML cohorts, after written informed consent has been 
obtained and eligibility has been established, the study site will obtain the patient's 
identification number and treatment assignment from the interactive voice/web-based
response system (IxRS).  Patients will be randomized in a 1:1 ratio to either idasanutlin 
plus chemotherapy or idasanutlin plus venetoclax.  The investigator, patient, and the 
contract research organization will not be blinded to treatment assignment.
The patients in the ALL cohort in Study Parts 1b and 2 will not be randomized and will be 
assigned to receive idasanutlin in combination with venetoclax.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE 
STUDY DESIGN
The investigational medicinal products (IMPs) for this study are idasanutlin, venetoclax, 
cyclophosphamide, topotecan, fludarabine, and cytarabine.
The non-IMPs in the study include the prophylactic medications stated in Section 4.3.3
(anti-diarrheal agents, antibiotics, anti-fungal agents, uric acid reducing agents, anti-PCP 
therapy, growth factors and 5-HT3-receptor antagonists) and the intrathecal (IT)
chemotherapy agents stated in Section 4.3.2.4 (IT cytarabine, methotrexate, and 
hydrocortisone).
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Idasanutlin
Idasanutlin will be supplied as 5-mg and 20-mg dispersible tablets.  The dispersible 
tablets can either be swallowed or used to prepare a suspension (ad hoc) for patients 
not able to swallow tablets.  Idasanutlin will be packaged in high-density polyethylene 
(PE) plastic bottles to accommodate the study design.  
Idasanutlin is a weak acidic drug and high lipophilicity (logP5.6) without clinically 
significant food-effect (both low-fat and high-fat meals) on pharmacokinetics in 
comparison with fasting.  Therefore, it is expected that suspensions prepared from the 
5- and 20-mg dispersible film-coated tablets will not have significant bioavailability 
differences compared to the film-coated tablets utilized in the Phase III adult trial 
WO29519.  This expectation will be evaluated with the PK and tolerability analysis during 
dose escalation from the current study.
For information on the formulation and handling of idasanutlin, see the pharmacy manual 
and the Idasanutlin Investigator's Brochure.
4.3.1.2
Venetoclax
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied
by the Sponsor as oral film-coated tablets of 10-mg, 50-mg, and 100-mg strength.  


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Venetoclax tablets will be packaged in high-density PE plastic bottles to accommodate 
the study design.  Venetoclax tablets must be stored at 15°C25°C (59°F77°F). 
Venetoclax will also be provided as 2.5-mg, 10-mg, and 25-mg tablets for oral 
suspension for patients not able to swallow tablets.
The decision on which formulation to use for each individual patient is at investigator's 
discretion.  One unique formulation should be used throughout the study conduct for 
each individual patient.  Patients may be permitted to switch formulations during the 
course of therapy if there is sufficient medical justification or if a switch is warranted to 
ensure study treatment compliance.  Any potential switch in formulation must be 
discussed with the Medical Monitor.
For information on the formulation and handling of venetoclax, see the pharmacy manual 
and the Venetoclax Investigator's Brochure.
4.3.1.3
Chemotherapy
For information on the formulation, packaging, and handling of cyclophosphamide, 
topotecan, fludarabine, and cytarabine, as well as intrathecally administered therapy, 
see the local prescribing information.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1. Refer to the pharmacy manual 
for detailed instructions on drug preparation, storage, and administration.
At applicable sites, study treatment may be administered by a trained nursing 
professional at the patient's home or another suitable location, if the patient has given 
written informed consent to participate in mobile nursing (MN) visits.
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.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.5.1.
4.3.2.1
Idasanutlin
Idasanutlin will be administered as an oral medication once daily on Days 15 of a 
28-day cycle.  The starting daily dose of idasanutlin in the dose-escalation phase of the 
study will be 2 mg/kg/day and will be modified according to Section 5.1.5.1.  All 
administered doses of idasanutlin will be recorded in a patient diary, whether or not the 
doses are administered at the investigational site.  Idasanutlin should be administered at 
the same time daily.  Idasanutlin should be administered immediately prior to any daily 
doses of combination chemotherapies or venetoclax. 


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Note that no clinically meaningful food effect was found with idasanutlin, which can be 
administered with or without a meal.
Idasanutlin must be administered orally.  If the patient vomits within 15 minutes of taking 
idasanutlin, the drug may be re-administered.  If the patient vomits more than 15 minutes 
after drug administration, no additional dose should be taken that day and the next dose 
should be taken at the usual time the next day. 
Administration via nasogastric tube is allowed with specific restrictions as outlined in the 
Pharmacy Manual.
If a dose of idasanutlin is missed by less than 8 hours, the dose should be taken right 
away.  The next dose should be taken at the usual time the next day.  If a dose of 
idasanutlin is missed by more than 8 hours, the dose should not be taken that day.  The 
next dose should be taken at the usual time the next day.  The time of each drug 
administration will be recorded to the nearest minute in the patient’s diary.
4.3.2.1.1
Dose Modifications after Clearance of Leukemia from Bone Marrow
Patients with leukemia who achieve morphologic CR/CRi/CRp after Cycles 1 or 2 who 
are able to continue therapy will receive idasanutlin at a 50% reduction in dose in
subsequent cycles.  This adjustment accounts for the observation in Study NP28679 that 
patients who continued on full doses of treatment following achievement of CR 
frequently required additional time for blood count recovery. The duration of idasanutlin 
treatment has no maximum predefined duration and will be at investigator discretion, 
provided other criteria necessitating study drug discontinuation are not met.
4.3.2.2
Venetoclax
Venetoclax (in combination with idasanutlin) will be administered at the adult dose 
equivalent (adjusted by body weight) of 400 mg in patients with neuroblastoma and the 
adult dose equivalent of 600 mg in patients with leukemia once daily on Days 128 of a 
28-day cycle (see Appendix 14).  The rationale for starting dose is provided in Section 
3.3.1.2.  Although the dose of venetoclax is not intended to be modified during the safety
run-in phase of the study, the study team (in consultation with the IMC/SOC) may advise 
sites to use a lower dose of venetoclax. 
For patients with neuroblastoma, venetoclax will ramp-up to the target dose over 2 days 
(200 mg equivalent Day 1 to 400 mg equivalent Day 2). Patients with neuroblastoma 
receiving venetoclax should be hospitalized during the ramp-up phase until the target 
dose has been administered. For patients with leukemia, venetoclax will ramp-up to the 
target dose over 3 days (150 mg equivalent Day 1; 300 mg equivalent Day 2; 600 mg
equivalent Day 3 (Appendix 14).  If lower doses of venetoclax are required, intermediate 
doses for the ramp up will be proportionally adapted based on the duration of ramp-up 
period (2 or 3 days), the final dose to be achieved, and the available formulation dose 


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strength.  For guidance on dose reductions in case of co-administration with CYP3A4 or 
P-gp, refer to Section 4.4.3. 
Patients should self-administer venetoclax at approximately the same time each 
morning. Oral venetoclax should be taken with water within 30 minutes after a meal.  
The tablets for oral suspension should be taken within 30 minutes after completion of 
any meal.  Venetoclax administration should follow idasanutlin administration.  On days 
in which predose PK sampling is required, dosing will occur in the morning at the clinic to 
facilitate PK sampling.
If the patient vomits within 15 minutes of taking venetoclax and all expelled tablets are 
still intact, the dose may be re-administered.  If the patient vomits more than 15 minutes 
after taking venetoclax, no additional dose should be taken that day and the next dose 
should be taken at the usual time the next day.
If a dose of venetoclax is missed by less than 8 hours, the dose should be taken right 
away with food.  The next dose should be taken at the usual time the next day.  If a dose 
of venetoclax is missed by more than 8 hours, the dose should not be taken that day.  
The next dose should be taken at the usual time the next day.  The time of each drug 
administration will be recorded to the nearest minute in the patient's diary.
The venetoclax dose may be reduced or interrupted to manage toxicities.
4.3.2.3
Chemotherapy
For patients assigned to arms combining idasanutlin with chemotherapy, chemotherapy 
should be administered at the doses prescribed below.  Infusion duration, prophylactic 
medications, and monitoring guidelines should be managed in accordance with 
institutional standard unless specified in the protocol.
Neuroblastoma
Cyclophosphamide and topotecan will be administered once daily on Days 15 of each 
28-day cycle at the following doses:

Cyclophosphamide 250 mg/m2 (8.33 mg/kg for patients 12 kg) as an intravenous 
(IV) infusion over 1 hour

Topotecan 0.75 mg/m2 (0.025 mg/kg for patients 12 kg) as an IV infusion over 1 
hour
Acute Myeloid Leukemia
FLA (fludarabine and high-dose cytarabine) chemotherapy will be administered during 
each 28-day combination treatment cycle as per the following regimen: 

Fludarabine 30 mg/m2 IV Days 1 to 5 over 30 minutes

Cytarabine 2000 mg/m2 IV Days 1 to 5 over 4 hours


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Note:  Cytarabine infusion is administered 4 hours after the start of the fludarabine 
infusion.
4.3.2.4
Intrathecal Chemotherapy in Patients with Leukemia
All patients with leukemia, irrespective of arm, will receive IT chemotherapy with each 
cycle (see Appendix 15 for appropriate age-based dosing).  For patients on Cycle 3 or 
greater who are in CR/CRp/CRi, lumbar puncture and IT therapy may be deferred by the 
investigator.
Acute Myeloid Leukemia
The following CNS-directed IT chemotherapy will be used:

CNS negative or unknown CNS status: cytarabine at age-adjusted doses by IT 
administration on Day 1.  May be administered up to 1 week prior to Day 1 of each 
cycle.

If blasts present in CSF at screening or traumatic lumbar puncture occurs: 
methotrexate, cytarabine, and hydrocortisone at age-adjusted doses by IT 
administration on Day 1 and then every 7 days until complete clearance of leukemic 
blasts.  In subsequent cycles, patients should receive treatment as CNS-negative.
Investigators may use this triple IT therapy in CNS-negative patients if
consistent with institutional standard.
Acute Lymphoblastic Leukemia
The following CNS-directed IT therapy will be used:

CNS-negative or unknown CNS status: IT administration of methotrexate 
(age-based dosing) on Day 1.  May be administered up to 1 week prior to Day 1 of 
each cycle.

If blasts present in CSF at screening or traumatic lumbar puncture occurs: 
methotrexate, cytarabine, and hydrocortisone at age-adjusted doses by IT 
administration on Day 1 and then every 7 days until complete clearance of leukemic 
blasts.  In subsequent cycles, patients should receive treatment as CNS-negative.
Investigators may use this triple IT therapy in CNS-negative patients if
consistent with institutional standard.
4.3.3
Prophylactic Medication
The use of oral or IV prophylaxis to mitigate Gl toxicity, infections, and TLS is mandatory 
in all patients if permitted according to a patient’s age and standard institutional practice 
(see Section 4.4.1). In addition, the use of prophylactic therapy with granulocyte 
colony stimulating factors to mitigate the risk of neutropenia is recommended in solid 
tumor patients receiving idasanutlin and chemotherapy according to standard 
institutional practice. Administration of a prophylactic medication must be recorded on 
the Concomitant Medication eCRF.  


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4.3.3.1
Gastrointestinal Toxicity
Prophylactic treatment to mitigate GI toxicity is mandatory during study treatment.  
Patients should be instructed on warning signs (e.g., bloody stools, associated fever, 
and dizziness).
Prophylactic anti-diarrheal therapy is to be instituted for all patients based on age and 
local institutional practice, unless waived by Medical Monitor.  Loperamide (per local 
dosing standard) is recommended therapy in patients if permitted according to the 
regional label or if consistent with institutional standard.  Use of pro-kinetic agents such 
as metoclopramide should be avoided.
Prophylactic antiemetic medication should be given 3060 minutes before administration 
of study treatment.  The patient should receive a 5-HT3-receptor antagonist
(e.g., ondansetron, granisetron, or palonosetron) on Days 15 if permitted according to 
local institutional practice based on the patient's age.
4.3.3.2
Tumor Lysis Syndrome
Prior to first administration of study treatment, investigators should:

Assess the risk for TLS based on a clinical assessment and comorbidities 
(e.g., presence of renal dysfunction or cardiac failure)
Note:  Risk factors for TLS risk are not unique to idasanutlin or venetoclax and 
are multifactorial (i.e., WBC count 25,000/mm3, serum uric acid7.5 mg/dL, 
and LDH4ULN). 

Correct pre-existing hyperuricemia, hyperkalemia, hyperphosphatemia, or 
hypocalcemia
Prophylactic IV hydration and administration of uric acid reducing agents is permitted 
according to patient's TLS risk factors and the investigator’s clinical judgment.
For patients with leukemia, the following guidance should be followed for the first dose in 
Cycle 1:

Per the exclusion criterion, WBC counts should be 50 109/L prior to starting 
therapy.  HU or leukapheresis is allowed to meet this criterion.  HU must be 
discontinued at least 24 hours prior to initiating study treatment.

Hospitalization is required until completion of idasanutlin per Section 5.1.5.3.

Uric acid reducing agent (such as allopurinol) is required, preferably starting 1 day 
before dosing of study therapy

TLS chemistry (calcium, phosphorus, BUN (or urea), creatinine, potassium, uric 
acid) (Day 0 [pre-dose and 4, 8, and 24 hours postdose]).  
See Section 5.1.5.4 for additional information on TLS prophylaxis and monitoring 
plan.


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4.3.3.3
Infections
Anti-PCP prophylaxis is required in all patients, according to local/institutional guidelines.  
Trimethoprim is NOT a permitted therapy.
Anti-fungal and anti-bacterial prophylaxis is required in neutropenic patients with 
leukemia unless waived by the Medical Monitor, and is recommended in neutropenic 
patients with solid tumors.
Ciprofloxacin or other appropriate antibiotic prophylaxis for neutropenic patients should 
be administered according to local/institutional guidelines from Day 1 until neutrophil 
recovery or until IV antibiotic treatment is administered (whichever occurs first). 
Fungal prophylaxis for neutropenic patients should be administered per institutional 
standard and per guidance below from Day 1 until neutrophil recovery (sustained 
neutrophil count 0.5 g/L or until therapeutic antifungal therapy started) or according to 
local/institutional guidelines.  Fluconazole is permitted, but patients receiving venetoclax 
should receive 50% dose reduction of venetoclax, as fluconazole is a moderate CYP3A 
inhibitor.  Echinocandins (e.g., caspofungin, micafungin) are permitted.  Strong CYP3A 
inhibitors, including voriconazole and posaconazole are permitted as prophylaxis.
However, patients receiving venetoclax require a 4-fold venetoclax dose reduction when 
receiving strong CYP3A4 inhibitors, such as voriconazole, and a 6-fold venetoclax dose 
reduction specifically for posaconazole. For further guidance on prohibited or allowed 
concomitant medications please refer to Section 4.4, Table 3, and Table 4.


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Table 2
Prophylactic Medication
Timepoint
Patients Requiring Medication
Medication
Administration
Cycle 1, 
Day 1
All patients
Anti-diarrheal a
All neutropenic patients with leukemia; 
recommended in neutropenic patients 
with solid tumors
Anti-fungal c
From Day 1 until neutrophil 
recovery
All neutropenic patients with leukemia
(unless waived by the Medical 
Monitor); recommended in neutropenic 
patients with solid tumors
Ciprofloxacin or other appropriate antibiotic per 
local/institutional guidelines
From Day 1 until neutrophil 
recovery or until IV antibiotic 
treatment is administered 
(whichever occurs first)
Patients with leukemia 
Uric acid reducing agent (such as allopurinol), 
along with IV hydration
Required for patients with leukemia; 
recommended for other patients at risk for TLS
Should be initiated 1 day before 
administration of study drug
All patients
Anti-PCP therapy per institutional guidelines d
Continuous while on study therapy.
All cycles, 
Days 15 
All patients
5-HT3-receptor antagonist b
Administer at least 3060 minutes 
prior to study drug administration
All cycles, 
Day 6
Solid tumor patients receiving 
idasanutlin and chemotherapy
G-CSF per institutional guidelines


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Table 2
Prophylactic Medication (cont.)
IRRinfusion-related reaction; TLStumor lysis syndrome.
a Treat with prophylactic anti-diarrheal based on patient age and local institutional practice, unless waived by Medical Monitor.  Loperamide 
(per local dosing standard) is recommended therapy in patients if permitted according to the regional label or if consistent with institutional 
standard. 
b For example, ondansetron, granisetron, or palonosetron.  Administer 5-HT3-receptor antagonist if permitted according to local institutional 
practice based on the patient’s age.
c Fluconazole is permitted, but patients receiving venetoclax should receive 50% dose reduction of venetoclax, as fluconazole is a moderate 
CYP3A inhibitor. Echinocandins (e.g., caspofungin, micafungin) are permitted.  Strong CYP3A inhibitors, including voriconazole and 
posaconazole, are permitted as prophylaxis. However, patients receiving venetoclax require a 4-fold venetoclax dose reduction when receiving 
strong CYP3A4 inhibitors, such as voriconazole, and a 6-fold venetoclax dose reduction specifically for posaconazole. For further guidance on 
prohibited or allowed concomitant medications, please refer to Section 4.4, Table 3, and Table 4.
d Trimethoprim is prohibited therapy on this study.


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4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (idasanutlin, venetoclax, 
cyclophosphamide, topotecan, fludarabine, and cytarabine) will be provided by the 
Sponsor where required by local regulations.  The study site (i.e., investigator or other 
authorized personnel [e.g., mobile nurse]) is responsible for maintaining records of IMP 
delivery to the site, IMP inventory at the site, IMP use by each patient, and disposition 
or return of unused IMP, thus enabling reconciliation of all IMP received, and for 
ensuring that patients are provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions 
have been maintained during transit, either by time monitoring (shipment arrival date 
and time) or temperature monitoring, for all IMPs received and that any discrepancies 
have been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied 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 on the Drug Inventory Log.
Refer to the pharmacy manual and/or the idasanutlin and venetoclax Investigator's 
Brochure for information on IMP handling, including preparation and storage, and 
accountability. 
4.3.5
Continued Access to Idasanutlin and Venetoclax
Currently, the Sponsor does not have any plans to provide Roche IMPs (idasanutlin and 
venetoclax) or any other study treatments to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing idasanutlin and venetoclax in 


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accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL 
RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug to 30 days after final dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Palliative radiotherapy for uncontrollable pain or imminent threat to a vital organ, 
with approval by the Medical Monitor. 
The decision to continue or suspend study therapy temporarily will be made by 
the Medical Monitor.  Patients who undergo palliative radiation will not be 
evaluable for response by tumor assessments but will be assessed for 
progressive disease.

Intrathecal steroids and/or chemotherapy in patients with leukemia as specified by 
the protocol

Premedication administered as described in Section 4.3.3
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Premedication with antihistamines, 
antipyretics, and/or analgesics may be administered at the discretion of the investigator.
4.4.2
Cautionary Therapy
4.4.2.1
Medications Associated with QT Prolongation
The previous or concurrent use of medications known to be associated with QT 
prolongation is permitted in the study but should be used with caution.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) within 7 days 
orf 5 half-lives prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 


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therapy) for various time periods prior to starting study treatment, depending on the 
agent (see Section 4.1.2), and during study treatment, until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and local therapy under certain circumstances (see 
Section 4.4.1 for details)

5-Fluorocytosine should not be co-administered with cytarabine, as the therapeutic 
efficacy of 5-Fluorocytosine has been shown to be abolished during 
co-administration with this therapy

Traditional herbal or homeopathic medicines
Ingredients for such medicines have not been fully studied, and their use may 
result in unanticipated drugdrug interactions that may cause or confound 
assessment of toxicity.

Vaccination with live-attenuated vaccines

Oral or parenteral use of the following drugs during the treatment phase (see 
Table 3):
–
Strong/moderate inducers or inhibitors of CYP2C8, including gemfibrozil, which 
is also an inhibitor of UGT1A3 
–
CYP2C8 or OATP1B1/3 substrates 
–
CYP3A strong inducers

Patients receiving venetoclax will be prohibited from the following agents during the 
treatment phase (see Table 3)
–
Strong inducers of CYP3A 
–
Moderate inducers of CYP3A 

For patients receiving venetoclax, moderate or strong CYP3A inhibitors or P-gp 
inhibitors (see Table 3 and Table 4) are prohibited unless concurrent use is 
considered necessary to treat or prevent a serious medical condition and the 
following dose reduction instructions are followed:  
–
For concurrent use of moderate CYP3A inhibitors, reduce the 
cohort-designated dose of venetoclax by 50%.  No dose adjustment is needed 
for idasanutlin.  After discontinuation of the moderate CYP3A inhibitors, wait for 
3 days before venetoclax dose is increased back to the initial 
maintenance/target dose. 
–
For concurrent use of strong CYP3A inhibitors, reduce the cohort-designated 
dose of venetoclax by 4-fold.  No dose adjustment is needed for idasanutlin.  
For concurrent use of posaconazole, reduce the cohort-designated 
dose of venetoclax by 6-fold.  No dose adjustment is needed for 
idasanutlin.  
After discontinuation of CYP3A inhibitors, including posaconazole, wait 
3 days before increasing venetoclax dose back to the initial 
maintenance/target dose. 


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–
For patients who require treatment with P-gp inhibitors following venetoclax 
dose ramp-up, use the medications with caution and reduce the venetoclax 
dose by at least 50%. 

For patients receiving venetoclax, P-gp substrates are prohibited unless concurrent 
use of P-gp substrates is considered necessary to treat or prevent a serious medical 
condition.
–
For concurrent use of P-gp substrates, the P-gp substrate should be 
administered at least 6 hours before venetoclax administration.
Substrates and strong CYP2C8 inhibitors listed in Table 3 and Table 4 (except for P-gp 
substrates) must be discontinued 7 days prior to start of study treatment, while the listed 
strong inducers must be discontinued 14 days prior to start of study treatment.  All drugs 
listed in Table 3 and Table 4 may be re-initiated per protocol after the study drug 
completion/discontinuation visit.


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Table 3
List of CYP2C8, CYP3A4, or OATP1B1/3 Inhibitors, Inducers, or Substrates
CYP2C8 
Inducer
CYP2C8 
Inhibitors
CYP2C8 
Substrates
OATP1B1/3 
Substrates
Strong CYP3A4 
Inducers
Moderate 
CYP3A4
Inducers
Strong CYP3A4
Inhibitors
Moderate CYP3A4
Inhibitors
Rifampicin
Clopidogrel
Amodiaquine
Atorvastatin
Avisimbe
Bosentan
Boceprevir
Amprenavir
Deferasirox
Montelukast
Atrasentan
Carbamazepine
Efavirenz
Clarithromycin
Aprepitant
Gemfibrozil
Paclitaxel
Bosentan
Cyproterone
Etravirine
Cobicistat
Atazanavir
Quercetin
Pioglitazone
Ezetimibe
Efavirenz
Modafinil
Danoprevir/ritonavir
Cimetidine
Teriflunomide
Repaglinide
Fluvastatin
Enzalutamide
Nafcillin
Conivaptan
Ciprofloxacin
Telithromycin
Rosiglitazone
Glyburide
Etravirine
Diltiazem
Clotrimazole
Trimethoprima
Torasemide
Irinotecan
Hyperforin
Elvitegravir/ritonavir
Crizotinib
Olmesartan
Mitotane
Idelalisib
Cyclosporin
Pitavastatin
Modafinil
Indinavir
Darunavir/ritonavir
Pravastatin
Nevirapine
Itraconzole
Dronedarone
Repaglinide
Oxcarbazepine
Ketoconazole
Erythromycin
Rifampicin
Phenobarbital
Mibefradil
Fluconazole
Rosuvastatin
Phenytoin
Lopinavir/ritonavir
Fluvoxamine
Simvastatin Acid
Rifampicin
Nefazodone
Fosamprenavir
Telmisartan
St. John’s wort
Nelfinavir
Imatinib
Valsartan
Ritonavir
Isavuconazole
Paritaprevir/ritonavir
Tofisopam
Posaconazole
Verapamil
Saquinavir
Telaprevir


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Table 3
List of CYP2C8, CYP3A4, or OATP1B1/3 Inhibitors, Inducers, or Substrates (cont.)
CYP2C8 
Inducer
CYP2C8 
Inhibitors
CYP2C8 
Substrates
OATP1B1/3 
Substrates
Strong CYP3A4 
Inducers
Moderate 
CYP3A4 Inducers
Strong CYP3A4
Inhibitors
Moderate CYP3A4
Inhibitors
Telithromycin
Troleandomycin
Voriconazole
Note:  The current list may not be exhaustive.  If the concomitant medication is not included in the list, please contact the Medical Monitor for 
guidance.
a Trimethoprim is a weak CYP2C8 inhibitor; however, use is not permitted while on study treatment.


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Table 4
List of P-gp Inhibitors or Substrates
P-gp
Substrates
Inhibitors a
aliskiren
amiodarone
ambrisentan
azithromycin
colchicine
captopril
dabigatran etexilate
carvedilol
digoxin
felodipine
everolimus
propafenone
fexofenadine
quercetin
lapatinib 
quinidine
loperamide
ranolazine
maraviroc
ticagrelor
nilotinib 
ranolazine
saxagliptin
sirolimus
sitagliptin
talinolol
tolvaptan
topotecan 
a P-gp inhibitors are allowed if the patient has completed the 
venetoclax dose ramp-up period.  The appropriate dose reduction for 
venetoclax must be implemented.  See Section 4.4.3 for details. 


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4.4.4
Prohibited Food
For patients receiving venetoclax, use of the following foods is prohibited as described 
below:

Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or starfruit (potent CYP3A4 enzyme 
inhibitor) during the study and for 30 days after the final dose of study treatment.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional at the patient's home or another suitable location to improve access 
and convenience for patients participating in the study. The Sponsor will select a 
healthcare company that will be responsible for providing MN services for participating 
sites (the MN vendor). The MN vendor is responsible for ensuring that all MN 
professionals are licensed, qualified, and in good standing, as per applicable regulations, 
and that appropriate background checks have been performed. If the investigator at a 
participating site determines that MN services are appropriate for a patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient's site. MN visits will be scheduled on 
specified visit days, to allow for relevant assessments to be performed by the MN 
professional. The schedule of activities (see Appendix 1, Appendix 2, and Appendix 3) 
will specify the assessments that may be performed by an MN professional.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent, and assent when applicable, for participation in the study must 
be obtained before performing any study-related procedures (including screening 
evaluations).  Informed Consent Forms and Child's Informed Assent 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.  Re-screening following screening failure is allowed.


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4.5.2
Medical History, Concomitant Medication, and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, current cancer stage, and procedures), menstrual 
history, fertility history, and puberty history, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient in addition to 
protocol-mandated treatment within 7 days prior to initiation of study treatment until 
30 days after the final dose of study drug will be recorded.  At the time of each follow-up 
physical examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity (where 
permitted by local regulations).
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits,
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  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.
The Lansky Performance Status should be performed for patients who are 16 years 
old, and the Karnofsky Performance Status should be performed for patients who are 
16 years old.
4.5.4
Growth and Development Assessments
During the treatment period, weight will be measured at the beginning of each cycle.  
During the follow-up period, weight should be measured every 3 months.
During the treatment period, height, head circumference (until the age of 3 years), and 
Tanner stage should be measured every 3 cycles (approximately every 3 months).  
During the follow-up period, height, head circumference, and Tanner stage should be 
measured every 3 months.  Tanner staging should be performed until the patient has 
reached Tanner Stage V or the end of the study.
4.5.5
Tumor and Response Evaluations
4.5.5.1
Tumor Assessments
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Baseline tumor assessments should be performedwithin 


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28 days prior to initiation of study drug (Day 1 of Cycle 1); subsequent tumor 
assessments should be performed in accordance with the Schedule of Assessments.  
At the investigator's discretion, unscheduled tumor assessments may be performed at 
any time if progressive disease is suspected.  
Response will be assessed by the investigator on the basis of physical examinations, 
bone marrow biopsy and/or aspirate, CT scans, MRI scans, FDG-PET scans, or MIBG 
scans, as appropriate.  Tumor assessment imaging should include all areas of known 
disease.  For solid tumors including neuroblastoma, an objective response should be 
confirmed by repeat assessments 4 weeks after initial documentation.  The same 
imaging techniques and procedures used to assess disease sites at screening should be 
used throughout the study (e.g., the same contrast protocol for CT scans).  
Patients with neuroblastoma must have an MIBG scan and BMAs and BMBs done 
at least at two sites each for disease evaluation.  If the enrollment BMA and BMB tissue 
samples are negative for disease, subsequent BMA and BMB tissue samples are not 
needed.  Patients with evidence of bone marrow disease at screening require bone 
marrow evaluation with scheduled disease evaluations until they have had 
two consecutive evaluations that are negative for disease.  
Patients with other solid tumors who have a clinical suspicion of bone marrow 
involvement should also have bilateral BMAs and/or BMBs performed at screening.  
Patients who have documented bone marrow involvement at screening should have 
subsequent bone marrow evaluations performed with each response assessment until 
the first negative bone marrow evaluation.
Patients with leukemia are required to undergo bone marrow evaluation via aspiration 
(and biopsy if clinically indicated) prior to starting therapy and after Cycles 1 and 2 of 
therapy. Patients are required to undergo lumbar puncture at the same timepoints as 
bone marrow evaluations.  Subsequent bone marrow evaluations and lumbar punctures 
should be conducted based on the clinical judgment of the investigator and at any time 
that recurrent or progressive disease is suspected based on laboratory or clinical 
findings.  At baseline/screening, a BMB and BMA are required of patients.  For 
postbaseline collections, if BMA cannot be obtained or is not evaluable (e.g., dry tap or 
no spicules are obtained), then a BMB is required.
4.5.5.1.1
Timing of Leukemia Bone Marrow Aspirates and Hematology 
Assessments
Patients with leukemia will have a BMA on Day 28 (3 days) of Cycles 1 and 2 if blood 
counts have recovered sufficiently (ANC 0.5109/L, platelets 75109/L) to resume 
therapy. Patients will also have a BMA at this time if peripheral blasts are present, 
irrespective of count recovery.  


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For patients who do not have count recovery by Day 28, peripheral blood counts should
be collected weekly until ANC 0.5109/L and platelets 75109/L, up to Day 56.
A BMA should be performed once patient's counts have recovered, once peripheral 
blood blasts are present, or by Day 42, whichever occurs first. Patients who do not have 
blood count recovery by Day 42 should undergo repeat BMA prior to Day 56.
This guidance is applicable to Cycles 3 and greater, except that the investigator may 
reduce the frequency of bone marrow evaluations if considered in the patient's best 
interest.
4.5.5.2
Response Criteria
All tumors will be evaluated for disease response and progressive disease according to
the following criteria:

Neuroblastoma:  INRC

Other solid tumors: RECIST v1.1

Leukemia (morphologic response): per standard criteria outlined in Appendix 7 and
Appendix 8

Leukemia (MRD-negative response): per flow cytometry results, defined as the 
percentage of patients who achieve MRD levels 0.01% by the end of two cycles
Patients who enroll with evaluable but not measurable disease will have a modified 
response assessment.  For such patients, PR cannot be determined; therefore, 
response will be limited to CR, SD, or progressive disease.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Assessments that require blood draws should be monitored closely to ensure that 
regional or institutional guidance regarding total blood volume taken for samples is 
maintained.  In situations where no regional or institutional guidance is available, no 
more than 1% of the total blood volume should be taken at one time and no more than 
3% of the total blood volume should be taken over a 30-day period (total blood volume is 
defined as 80 mL/kg).  Institutions should use micro-sampling systems to minimize the 
amount of blood drawn when able.  In situations where the total amount will exceed the 
amount stated above, clinical laboratory assessments should be prioritized.  Any
remaining blood should be sent for PK analysis followed by biomarker and PD analyses.
Laboratory tests results must meet the inclusion criteria and not meet the exclusion 
criteria at the time of screening.  If laboratory tests are performed again prior to the first 
dose, they must continue to meet the inclusion criteria and not meet the exclusion 
criteria.


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Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
blasts, and other cells)

Serum chemistry:  bicarbonate (or total carbon dioxide), sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, albumin, magnesium, phosphate, 
calcium, total bilirubin [if abnormal, fractionate sample for direct and indirect], 
alkaline phosphatase, ALT, AST, uric acid, and LDH

Creatinine clearance as clinically indicated
If radioisotope glomerular filtration rate is routinely performed at the institution 
to measure patients' creatinine clearance, this test can be used to assess renal 
function at screening, per the eligibility criteria. Otherwise, serum creatinine is 
sufficient to document renal function at screening.

Coagulation:  INR, aPTT, and PT

Pregnancy test
All females of childbearing potential will undergo a serum pregnancy test at 
screening (prior to Cycle 1) within 1 week prior to first dose.  Urine or serum 
pregnancy test will be performed prior to all subsequent cycles.

Viral serology: HIV, hepatitis B surface antigen, hepatitis B surface antibody, total 
hepatitis B core antibody, and hepatitis C antibody
If a patient is positive for hepatitis B core antibody at screening, a test for 
hepatitis B virus DNA should be performed prior to Day 1 of Cycle 1.
If a patient is positive for hepatitis C antibody at screening, a test for hepatitis C 
virus RNA should be performed prior to Day 1 of Cycle 1.
The following assessments will be conducted for patients with solid tumors or leukemia 
requiring bone marrow evaluation:

BMA:  total cells counted, absolute mature neutrophils, mature eosinophils, mature 
basophils, monocytes, lymphocytes, blasts, promyelocytes, myelocytes, 
metamyelocytes, plasma cells, pronormoblasts, normoblasts, nucleated 
erythrocytes

BMB:  leukemia histology, cellularity, percent cellularity, percent blasts, and fibrosis 
(if applicable)

For patients with leukemia:
–
Conventional cytogenetics and molecular markers from bone marrow at the 
time of diagnosis and from most recent bone marrow assessment prior to the 
start of study
–
If sites perform MRD assessments locally or collect mutational data (any 
timepoint), sites are requested to please provide the results in the eCRF.


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The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis

BMA, BMB, blood, plasma, and serum for biomarker analyses 
If a BMA is not evaluable, a BMB should be sent.

For patients with solid tumors, including neuroblastoma, tumor tissue from 
relapsed/refractory disease or from a newly collected tumor sample at 
baseline/screening for patients in the neuroblastoma cohorts for exploratory 
research on biomarkers.  Tumor tissue must have been collected from patients no 
earlier than 6 months prior to study treatment initiation and subsequent to the most 
recent anti-cancer therapy.
A representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a 
paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, 
serial sections must be submitted along with an associated pathology report 
prior to study enrollment.  If only 1014 slides are available, the patient may still 
be eligible for the study, after Medical Monitor approval has been obtained.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 20% tumor cell content that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method. Samples collected via resection, core-needle biopsy (at least three 
cores, embedded in a single paraffin block), or excisional, incisional, punch, or 
forceps biopsy are acceptable.  Fine-needle aspirations (defined as samples 
that do not preserve tissue architecture and yield cell suspension and/or 
smears), brushing, cell pellets from pleural effusions, lavages, and samples
from bones metastases are not acceptable.  
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required.  A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.
Exploratory biomarker research may include, but will not be limited to, analysis of 
somatic mutations and gene signatures associated with disease type (i.e., MLL-1
rearrangement in leukemia), apoptosis, MDM2, and p53 signaling, as well as evaluation 
of candidate biomarkers of response to idasanutlin (i.e., MIC-1) and/or venetoclax 
(Bcl-2).  Research may involve extraction of DNA, circulating tumor DNA, or RNA, 
analysis of mutations, and genomic profiling through use of comprehensive NGS.  NGS 
methods will not include whole genome sequencing (WGS) or whole exome sequencing 
(WES).  
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator may obtain an NGS report through Foundation Medicine's web portal.  
If allowed by local laws, the investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise.  The NGS report is generated for research 


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purposes and is not provided for the purpose of guiding future treatment decisions.  
Results will not be available for samples that do not meet criteria for testing.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed.

Plasma, serum, and whole blood samples collected for biomarker research will be
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

For enrolled patients, remaining archival tissue will be returned to the site upon 
request or 18 months after final closure of the study database, whichever occurs 
first.  For patients who are not enrolled, remaining archival tissue will be returned to 
the site no later than 6 weeks after eligibility determination.

Bone marrow aspirates and biopsies collected for MRD analysis and biomarker 
research will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed, or earlier depending on local regulations.
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.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.7
Clinical Outcomes AssessmentAcceptability Survey
To better understand the acceptability of idasanutlin, a survey will be administered 
immediately following administration of idasanutlin on Day 5 of Cycle 1.  Patients will be 
advised to rinse their mouths prior to taking the medication; after taking the medication, 
patients should complete the survey before rinsing or drinking water.  


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For patients who have not yet developed the cognitive ability to provide detailed 
feedback on the acceptability of a medication, the parent or guardian will complete the 
Acceptability Survey based on their observation of their child’s reaction and facial 
expression following the medication intake.  Patients able to provide feedback will 
complete the survey with reading support from their parents or the clinical staff as 
needed.  Study staff and patient’s caregiver possibly present during the assessment 
should remain neutral.  If a patient is having difficulty with selecting a score, patients 
may be asked the interview question first and then redirected to complete the 
assessment score.  Parents or caregivers will be asked about their ease of experience of 
administering the suspension at home.
The survey will document specific aspects of the acceptability of idasanutlin, including 
swallowability and palatability (Kozarewicz 2014).  The survey is required regardless of 
tablet size or whether the tablets are administered whole or dispersed in water.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1, Appendix 2, and Appendix 3), and may be 
obtained at unscheduled timepoints as indicated.
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 are 
recommended to be performed prior to other procedures scheduled at that same time 
(e.g., blood draws) and after the patient has been resting in a supine position for at least 
10 minutes.  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.
The following should be recorded in the appropriate eCRF:  heart rate, RR interval, 
QRS interval, PR duration, uncorrected QT interval, and QTcF 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 postdose 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 Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  A decision 
on study drug discontinuation should be made, as described in Section 5.1.5.1.  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).


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In case a patient presents with an episode of Grade 2 supraventricular 
arrhythmia (atrial fibrillation, atrial flutter, sinus tachycardia, etc.), an unscheduled ECG 
should be recorded and study treatment should be withheld.
4.5.9
Cardiac Function
Cardiac echocardiograms or MUGA will be performed during screening to assess
baseline cardiac function.  Studies should be performed in accordance with institutional 
guidelines.  While on study therapy, routine cardiac function monitoring will not be 
conducted except at the discretion of the investigator.  Any patient who develops clinical 
signs or symptoms suspicious of cardiac failure should undergo a cardiac function
assessment.
FS or LVEF should be determined within 28 days prior to initiation of study drug by either 
echocardiography or MUGA scan.
4.5.10
Optional Tumor Tissue Samples
For patients enrolled to solid-tumor cohorts, if deemed clinically safe and feasible, tumor 
tissue samples obtained postbaseline (e.g., on-treatment or at the time of progression) 
may be collected and submitted to the Sponsor or a designee for exploratory biomarker 
research.

Tissue amounts and requirements for postbaseline biopsies are the same as for 
mandatory baseline/screening biopsies above.

Biopsies collected at the time of progression should be performed within 28 days
(1 cycle) after progression or prior to the next anti-cancer therapy, whichever is 
sooner.  Samples collected via resection, core-needle biopsy (at least three cores
preferred), or excisional, incisional, punch, or forceps biopsy are preferred.
Samples may be used for exploratory biomarker research as described in Section 4.5.6.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.6 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses. 
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
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 biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples 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.


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Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

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
4.5.11.2
Approval by the Institutional Review Board or Ethics Committee
Collection, storage, and analysis of RBR samples 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 approval for 
RBR sampling, this section of the protocol (Section 4.5.11) will not be applicable at that 
site.
4.5.11.3
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 cancer, diseases, or drug 
safety:

Mandatory and optional leftover blood, serum, plasma, BMA, BMB, frozen tumor 
tissue and FFPE tumor tissue samples (with the exception of remaining archival 
tissue blocks, which will be returned to sites upon request) and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides), including leftover tissue samples from 
medically indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion during the course of the 
study
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods. Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may
also be explored in aggregate with data from other studies.  The availability of a larger 


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dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples 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).
4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples 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.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses 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 samples 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.
4.5.11.5
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 consent 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 samples.  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.


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In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and 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.
4.5.11.7
Monitoring and Oversight
RBR samples 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 samples 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
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy


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
Use of an anti-cancer therapy not permitted or required per protocol

Symptomatic deterioration attributed to disease progression, except in patients 
treated with single-agent idasanutlin who proceed to combination therapy per 
Section 3.1.1.1

Confirmed disease progression per investigator assessment according to response 
criteria

Any adverse event that meets permanent discontinuation instructions as described 
in Table 5
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment may be replaced at the 
discretion of the Medical Monitor.
Patients will return for a treatment discontinuation visit 28 (30) days after the final dose 
of study drug (see Appendix 1, Appendix 2, and Appendix 3).  This may be done at the 
clinical visit where clinical or radiographic progression is first noted.
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study).  
4.6.2
Patient Discontinuation from the Study
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 patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for patient discontinuation from the study should be 
documented on the appropriate eCRF.  If a patient requests to be withdrawn from the 
study, this request must be documented in the source documents and signed by the 
investigator.  Patients who withdraw from the study may be replaced.
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study or any arm thereof 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 or 
any arm thereof.  
4.6.4
Site Discontinuation
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 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Idasanutlin and venetoclax are not approved for pediatric use, and clinical development 
is ongoing in adults for different indications, including both hematologic and solid 
malignancies.  The safety plan for patients in this study is based on nonclinical data and 
clinical experience with idasanutlin and venetoclax in completed and ongoing adult 
studies.  The anticipated important safety risks for idasanutlin and venetoclax are 
outlined below.  Please refer to the respective Investigator's Brochures for a complete 
summary of safety information for both molecules. 
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 for toxicities (see 
Section 4.1.2).  In addition, patients will undergo safety monitoring throughout the study 
(see Appendix 1, Appendix 2, and Appendix 3). 
As detailed in Section 3.1, during the dose-escalation, safety run-in, and initial expansion 
cohort (Part 2), patients will be assessed for DLTs, and study treatment will be 
interrupted and subsequently modified following the occurrence of a DLT.  
Section 5.1.5.3 also outlines mandatory hospitalization periods.


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An IMC and SOC will monitor patient safety throughout the study.  The IMC will also 
provide a recommendation on the dose to be taken forward into the expansion stage 
after completion of the dose-escalation stage. 
All enrolled patients will be evaluated clinically and with standard laboratory tests before
and at regular intervals during their participation in this study. Safety evaluations will
consist of medical interviews, recording of adverse events, physical examinations, 
ECGs, and laboratory measurements (hematology, chemistry).
Finally, guidelines for managing selected adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, have been provided (see
Section 5.1.5). These guidelines apply to patients in the dose-escalation and expansion 
stages; however, the guidelines are not intended to replace clinical judgment or dictate 
care of individual patients.
5.1.1
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-tumor cancer and AML (Studies NP27872, 
NP28902, and NP28679, respectively) as described in Section 1.4.1 and in the 
Idasanutlin Investigator’s Brochure. 
Risks include GI toxicity, cytopenias, TLS, infectious complications, and electrolyte 
abnormalities.  Many of the toxicities experienced appear to be manageable with 
supportive therapies and/or reversible with discontinuation of idasanutlin.  Refer to the 
current Idasanutlin Investigator’s Brochure for details on the safety data from these 
studies and for additional information on idasanutlin warnings and precautions. 
5.1.1.1
Gastrointestinal Toxicity
GI adverse events reported in Phase I idasanutlin studies were primarily diarrhea, 
nausea, vomiting, abdominal pain, constipation, and anorexia. Diarrhea was the most 
common adverse event and was observed in 90% of patients with AML in 
Study NP28679 (mostly Grade 1 and Grade 2 in severity). Nausea and vomiting were 
also frequently reported, but to a lesser extent, and the majority of adverse events were 
Grade 1 and Grade 2. In addition to institutional guidelines, specific instructions for the 
management of GI side effects are provided in Table 5.  
Diarrhea is also a common adverse event with venetoclax and the proposed 
chemotherapy regimens; therefore, it may occur more frequently or may take longer to 
recover with combination therapy.
Before beginning study treatment, individual patients' normal bowel function should be 
established and patients should be instructed on warning signs of GI toxicity 
(e.g., bloody stools, associated fever, and dizziness).


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5.1.1.2
Cytopenias
Bone marrow toxicity may manifest as cytopenias (i.e., pancytopenia, neutropenia, 
febrile neutropenia, thrombocytopenia, and anemia). Combined effects of idasanutlin 
and venetoclax or chemotherapy on normal bone marrow progenitors are possible. 
Study NP27872 evaluating idasanutlin in patients with solid tumors has shown possible 
exposure-dependent neutropenia and thrombocytopenia. These can be reversible and 
monitorable. In patients with leukemia who are neutropenic and thrombocytopenic as 
part of their disease process at baseline, elimination of leukemic blasts is essential for 
normal marrow recovery.  Idasanutlin was associated with myelosuppression in AML
Study NP28679, but normal marrow recovery was observed in patients showing a 
clinical response. In patients with leukemia, drug-induced myelosuppression is expected 
during idasanutlin treatment, and idasanutlin administered in combination with 
venetoclax may prolong the aplasia window. In Study NP28679, the time to platelet and 
neutrophil recovery were highly variable, and the mean time to recovery for platelet and 
leukocyte counts (Kaplan-Meier estimates) were 34 days in patients who responded to 
idasanutlin and cytarabine administered in combination. In this study, blood counts will 
be monitored closely throughout study treatment (see Appendix 1, Appendix 2, and 
Appendix 3). 
5.1.1.3
Tumor Lysis Syndrome
TLS is a potentially life-threatening metabolic disorder that occurs when tumor cells 
release their contents into the bloodstream, either spontaneously or in response to 
therapy, leading to characteristic findings of hyperuricemia, hyperkalemia, 
hyperphosphatemia, and hypocalcemia. This complication is common in patients with 
acute leukemia.  To date across all idasanutlin studies, the overall incidence of TLS is 
1.7%, with all cases occurring in the AML setting. The large majority of cases were 
Grade 3 or above (although by definition, TLS should be at least a Grade 3 event). TLS
is also an important identified risk for venetoclax, although this has primarily been 
observed in CLL and mantle cell lymphoma (see Section 5.1.2.1).
5.1.1.4
Infections
Infections of various types (including fatal fungal infections) have occurred in patients 
treated with idasanutlin, most commonly in the AML setting (Studies NP28679 
and WO29519). AML itself is associated with impaired immune function and higher 
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. Infectious diarrhea, in particular C. difficile infection, was reported in 
approximately 10% of patients with AML administered idasanutlin in Study NP28679, 
including 1 fatal case of C. difficile infection.  There were 13 deaths associated with 
infectious processes in Phase I patients with relapsed or refractory AML treated with 
idasanutlin (either monotherapy or combination therapy).  The deaths were attributed to 
the following causes: sepsis (5 patients), pneumonia (3 patients), neutropenic sepsis 
(2 patients), and C. difficile infection, neutropenic colitis, and scedosporium infection 
(1 patient each). Infections are also a risk with venetoclax and the proposed 


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chemotherapy treatments; therefore, patients may be at greater risk of developing 
infections when treated with idasanutlin in combination with venetoclax or chemotherapy 
compared to each treatment alone.
For additional information on risks of infection, refer to the current Idasanutlin 
Investigator's Brochure.
5.1.1.5
Electrolyte Disorders
Hypokalemia, hypophosphatemia, and hypomagnesemia were commonly observed in 
patients treated with idasanutlin. In addition to institutional guidelines, electrolytes 
should be monitored during treatment, and electrolyte disorders should be treated 
according to institutional guidelines.
5.1.1.6
Testicular Toxicity
In studies in juvenile animals (rats), there were adverse effects on the male reproductive 
organs, including unpalpable testes and lower testicular weight, at doses of idasanutlin
10/50 mg/kg/day (doses of the two treatment cycles of 10 days each; from Days 716
post partum and from Days 3544 post partum, with 18 days off treatment in between).  
Seminiferous tubular degeneration/atrophy was seen at 30/200 mg/kg/day at the end of 
the treatment period, and at 10/50 mg/kg/day at the end of the recovery period (only 
considered adverse at 15/100 mg/kg/day). Males given 30/200 mg/kg/day showed 
delayed sexual development, reduced fertility after mating, and decreased sperm counts 
and motility. The findings in testes did not reverse after the 13-week recovery period
and are considered an on-target effect on dividing Sertoli cells that express high levels of 
MDM2 in the developing testis.
Due to the risk of testicular toxicity, male patients considering preservation of fertility 
should bank sperm before treatment with idasanutlin and should agree to refrain from 
donating sperm during the treatment period and for at least 90 days after the last dose of 
idasanutlin.
5.1.1.7
Other Adverse Events
Other adverse events commonly reported with idasanutlin include fatigue/asthenia, 
pyrexia, peripheral edema, mucosal inflammation, headache, dyspnea, dizziness, and 
chills.  These adverse events have been of mild severity and controllable with 
symptomatic treatment and/or nutritional support.
5.1.2
Risks Associated with Venetoclax
Information related to venetoclax-associated risks is based mainly on review of data 
from Phase IIII studies (see the Venetoclax Investigator’s Brochure) in CLL and 
Phase III data in AML (Studies M14-212, M14-358, GH29914, and M14-387).  
Venetoclax is generally well tolerated, and toxicities appear to be mostly manageable 
and/or reversible.  Risks include tumor lysis syndrome, infectious complications, 


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cytopenias, effects on fertility, treatment-emergent malignancies (second primary 
malignancies), and food effect.
There is currently limited data on the use of venetoclax in pediatric patients.  
Study M13-833 is an ongoing study investigating the use of venetoclax in pediatric and 
young adult patients with relapsed or refractory malignancies.  No new safety signals 
have been identified from review of the available data.  The most commonly reported 
events included febrile neutropenia, vomiting, and diarrhea.
Refer to the current Venetoclax Investigator’s Brochure for details on the safety data 
from these studies and for additional information on venetoclax warnings and 
precautions. 
5.1.2.1
Tumor Lysis Syndrome
Tumor lysis syndrome is an important identified risk for venetoclax in oncology studies, 
especially in CLL and mantle cell lymphoma.  The available data suggest that in 
indications other than CLL or mantle cell lymphoma, the risk of TLS is low but present.
To date, the principal adverse reaction associated with venetoclax in the single-agent 
Phase I dose-escalation Study M12-175 of CLL has been tumor lysis syndrome 
(primarily, but not exclusively related to, the first dose). These include cases of tumor 
lysis syndrome that have led to clinical sequelae including death in 2 patients. Among 
the non-chronic lymphocytic leukemia studies, 6 patients with NHL experienced 
Grade 34 adverse events of laboratory tumor lysis syndrome. Although several events 
of hyperphosphatemia and two events of rising potassium have been observed in 
relapsed or refractory AML study (Study M14-212), no patients experienced tumor lysis 
syndrome during administration of venetoclax.  Safety data from 94 patients treated on 
three venetoclax studies in AML (M14-212, M14-358, M14-387) demonstrated no events 
of clinical tumor lysis syndrome.  Five events of laboratory TLS have been reported 
across all studies of AML, including two events (one in Study M14-212, one in 
Study M14-387) that occurred after the patients had discontinued venetoclax and started 
another line of therapy.  The remaining three events were protocol-defined laboratory 
TLS that occurred among the 92 patients in Study M14-387 during treatment with 
venetoclax in combination with low dose cytarabine.  All three cases of laboratory TLS 
were transient and managed with standard-of-care measures.  No events of TLS were 
reported in combination Study M14-358 (venetoclax plus hypomethylating agents).
Because of the known background risk of tumor lysis syndrome in this study population, 
patients in the study are being actively monitored and managed to prevent potential 
tumor lysis syndrome, and dose ramp-up is implemented (see Section 5.1.5.4 for tumor 
lysis syndrome prophylaxis and monitoring plan).


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5.1.2.2
Neutropenia
Neutropenia is an important identified risk for venetoclax, specifically in chronic 
lymphocytic leukemia. Clinical data from the oncology studies suggest that the 
neutropenia adverse events are observed among patients who receive venetoclax as a 
single agent or in combination with other therapeutic agents, with slightly higher 
frequency observed in some combination studies. Serious adverse events of 
neutropenia or neutropenia events that lead to discontinuations are few across the entire 
venetoclax oncology program. For the oncology studies, neutropenia management 
guidelines are provided in the protocol. Granulocyte colony stimulating factors can be 
used for supportive measures; however, the guidance for their use in non-chronic 
lymphocytic leukemia indications, especially in AML, is per routine local oncology 
practice, as well as protocol-specific.
5.1.2.3
Infections
Serious infections are an important identified risk for venetoclax.  Most common 
infections reported with venetoclax include pneumonia, sepsis, upper respiratory tract 
infections, and urinary tract infections.  Fatalities resulting from pneumonia and sepsis 
have been reported in patients receiving venetoclax.  Infections of various types have 
occurred in patients with AML in the completed M14-212 study and in ongoing studies 
M14-358 and M14-387.  AML itself is associated with impaired immune function and 
increased infections, and it is unclear whether or how much the incidence could be 
increased owing to venetoclax treatment.
See Section 5.1.5.4 and Table 5 for management of infections.
5.1.2.4
Cytopenias
Anemia has been reported with slightly higher frequency in some oncology studies in 
which venetoclax is combined with other chemotherapeutic agents; however, most of the 
events were non-serious and confounded by disease factors and prior therapies. The 
dataset in non-chronic lymphocytic leukemia indications is small.
Thrombocytopenia adverse events have been reported in oncology studies, with slightly 
higher frequency in studies in which venetoclax is combined with other 
chemotherapeutic agents. However, most of the events were non-serious and 
assessment of these events is confounded by the patients' underlying disease state, 
prior therapies, and preexisting thrombocytopenia, including autoimmune 
thrombocytopenia in several patients. The dataset in non-chronic lymphocytic leukemia 
indications is small.
Lymphopenia has been observed in nonclinical studies. Although opportunistic infections 
have been reported in the clinical program, data are confounded by patients' underlying 
disease and prior therapies. In oncology studies, anti-infective prophylaxis should be 
implemented as clinically indicated, including appropriate prophylaxis for viral, fungal, 
bacterial, or pneumocystis carinii pneumonia infections.


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See Section 5.1.5.4 and Table 5 for management of cytopenias.
5.1.2.5
Effects on Fertility and Reproductive Toxicity
There were no effects of venetoclax on female or male mouse fertility; however, a risk to 
human male fertility exists based on the testicular toxicity (germ cell depletion) observed 
at all dose levels in the repeat-dose dog studies. Reversibility of this finding has not 
been demonstrated. It is not known whether the dog testicular findings translate to 
humans. Male patients should be instructed to consider sperm banking before treatment 
with venetoclax if they are considering preservation of fertility.
In embryo-fetal development studies, venetoclax was administered to pregnant mice and 
rabbits during the respective periods of organogenesis. In pregnant mice, venetoclax 
was associated with increased post-implantation loss and decreased fetal body weight at 
150 mg/kg/day (approximately 1.2 times the human AUC exposure at the 400-mg 
human dose). No fetal toxicity was observed in rabbits up to the highest dose tested 
(approximately 0.2 times the human AUC exposure at the-400 mg human dose).
Due to the risk of decreased spermatogenesis, male patients considering preservation of 
fertility should bank sperm before treatment with venetoclax and should agree to refrain 
from donating sperm during the treatment period and for at least 90 days after the last 
dose of venetoclax.
5.1.2.6
Treatment-Emergent Malignancies (Second Primary Malignancies)
Events of second primary malignancies have been reported across the venetoclax
oncology program. No pattern has been observed. Because venetoclax is being 
evaluated in patients with relapsed or refractory disease who had previously been 
treated with various cytotoxic agents, second primary malignancies are closely 
monitored.  Second primary malignancy is an important potential risk for venetoclax.
5.1.2.7
Food Effect
Administration with a low-fat meal increased venetoclax exposure by approximately 
3.4-fold and administration with a high-fat meal increased venetoclax exposure 
by 5.1- to 5.3-fold compared with fasting conditions.  Oral venetoclax should be taken 
with water within 30 minutes of completion of a meal.  The tablets for oral suspension 
should be taken within 30 minutes after completion of any meal.
5.1.3
Risks Associated with Chemotherapy
5.1.3.1
Risks with Cyclophosphamide and Topotecan
The most common risks with cyclophosphamide treatment include infections, 
myelosuppression (including anemia, [febrile] neutropenia, leukopenia, and 
thrombocytopenia), immunosuppression, and urinary/renal toxicity.  Cyclophosphamide 
may also have effects on fertility in both males and females, and men should be 
informed about sperm preservation prior to starting treatment.


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The most common risks with topotecan treatment include infections, myelosuppression 
(including anemia, [febrile] neutropenia, leukopenia, and thrombocytopenia), and 
GI effects (including diarrhea, vomiting, and nausea).  Use of granulocyte colony 
stimulating factors is recommended for patients who are receiving the combination of 
idasanutlin and cyclophosphamide/topotecan per routine local practice.
In neuroblastoma, the combination of cyclophosphamide and topotecan has been shown 
to be tolerable in children with no unexpected significant toxicities.  The most common 
toxicities were infections, neutropenia, and thrombocytopenia (London et al. 2010).
5.1.3.2
Risks with Fludarabine and Cytarabine 
The most common risks with fludarabine treatment include myelosuppression (including 
neutropenia, anemia, and thrombocytopenia), infections, and GI effects (including 
diarrhea, vomiting, and nausea).  Fludarabine also has the potential to cause fetal harm.
The most common risks with cytarabine treatment include infections, myelosuppression 
(including anemia, leukopenia, and thrombocytopenia), GI effects (including diarrhea, 
vomiting, and nausea) and abnormal hepatic function.
In pediatric patients with AML, the combination of fludarabine and cytarabine has been 
shown to be tolerable with the most common toxicities being hematologic (including 
thrombocytopenia, neutropenia, and anemia), infections, fever, and nausea (Kaspers 
et al. 2013).
5.1.4
Risk of Overlapping Toxicities
The likely potential overlapping toxicities for the combination idasanutlin and venetoclax 
are primarily hematologic, including partial to complete decrease in lymphocyte counts 
and/or total WBC depletion and decreased red cell mass. Rapid, marked depletion of 
WBCs (total lymphocytes for venetoclax) could lead to increased cases of tumor lysis 
syndrome and infection, and recovery of normal WBC counts may require a prolonged 
period without treatment. In addition, idasanutlin reduced WBC counts, most severely 
reducing neutrophils. The combination of venetoclax and idasanutlin could therefore 
cause overlapping toxicities to WBC counts, concomitant immunosuppression, increase 
susceptibility to infections, and prolong recovery time.
Other potential overlapping toxicities for the combination are GI toxicities, including 
diarrhea and nausea/vomiting.
There is the potential for the venetoclaxidasanutlin combination to cause overlapping 
reproductive and embryo-fetal toxicities (see contraception requirements in 
Section 4.1.1). 


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Similarly, the likely potential overlapping toxicities for the combination of idasanutlin and 
the chemotherapy regimens are primarily hematologic, GI toxicity, and infections.  
A robust risk minimization plan is in place to monitor and mitigate these risks.
All above toxicities are expected to be clinically manageable in this clinical trial, with the 
potential benefit to the patient outweighing the risk.
5.1.5
Management of Patients Who Experience Adverse Events
5.1.5.1
Dose Modifications
Guidelines for management of specific adverse events are outlined in Table 5. 
Additional guidelines are provided in the subsections below.
Reasons for dose modifications or delays to the start of the next cycle, the supportive 
measures taken, and the outcome will be documented in the patient's chart and 
recorded in the eCRF.
As a rule, all study treatment should be held and resumed together to remain 
synchronized when toxicity resulting from any component of the regimen occurs. Missed 
doses of study treatment cannot be administered at a later timepoint in the case of 
treatment interruption.
Please refer to Section 3.1.1.3 for details of idasanutlin dose reductions or withdrawals 
required as a result of defined DLTs during the initial dose escalation and safety run-in 
stages of the study.
The dose of idasanutlin can be reduced by 20% up to two times (or by 50% once) for 
management of drug-related toxicities (not including idasanutlin dose reductions that 
occur when transitioning from single agent idasanutlin to combination regimens or 
after morphologic CR/CRp/CRi is achieved).  If further dose reduction is indicated after 
two dose reductions, the patient must discontinue study therapy unless treatment 
continuation/dose reduction is approved by the Medical Monitor.  After dose reduction, 
idasanutlin may be re-escalated by a maximum of one dose level at the investigator's 
discretion, provided there are no safety concerns.
If the investigator views that therapeutic toxicity warrants dose modification of 
venetoclax, fludarabine, cytarabine, cyclophosphamide, topotecan, or IT therapy, the 
investigator must consult the Medical Monitor for further guidance, unless specific dose 
modification guidance is provided elsewhere in this protocol. 
5.1.5.2
Treatment Interruption
Please refer to Section 3.1.1 for details of dose interruption and re-treatment following 
DLTs during the dose-escalation phase. 
Investigators are permitted to suspend treatment with idasanutlin, venetoclax, or other 
required chemotherapy agents in patients who experience toxicity considered to be 


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related to study therapy.  All treatment related toxicities should be resolved to Grade 1 
or to baseline grade prior to beginning the next cycle.  Patients are allowed a maximum 
of an additional 28 days (up until Day 56) for recovery of toxicities to Grade 1 or the 
baseline grade.  In the event that a non-hematologic toxicity occurs prior to the start of a 
subsequent cycle until Day 56, the case may be discussed with the Medical Monitor or 
designee, who may allow an additional recovery period.  If study therapy has been 
withheld beyond Day 56 because of toxicity, the patient should be discontinued from 
study therapy, unless resumption of treatment is approved following investigator 
discussion with the Medical Monitor.  Study therapy may be suspended for reasons 
other than toxicity (e.g., surgical procedures) with Medical Monitor approval.  The 
investigator and the Medical Monitor will determine the acceptable length of treatment 
interruption.  
The requirement for the minimum criteria for starting next cycle of therapy:

Absolute neutrophil count
–
Solid tumors, 0.75109/L
–
Leukemia, 0.5109/L

Platelet count of 75109/L (exceptions apply for patients with leukemia; see 
Table 5)
If blood count recovery is delayed beyond Day 42, the patient will receive therapy with 
idasanutlin at a 50% dose reduction.  Further dose reduction guidance for hematologic 
toxicity specific to diseases is provided in Table 5.
5.1.5.3
Hospitalization Requirements
The following patients are required to be hospitalized:

During the dose-escalation phase, the first 3 patients must be hospitalized for 
24 hours after receiving the first dose of idasanutlin to monitor for diarrhea.  
Following review of the first 3 patients, subsequent patients may be dosed without 
this requirement for hospitalization.

Patients with leukemia are required to be hospitalized in Cycle 1 at least until the 
Day 5 dose of idasanutlin has been administered, because of the risk of tumor lysis 
syndrome (see Section 5.1.1.3 for background and Table 5 for management 
guidelines). 

Patients with neuroblastoma receiving venetoclax are required to be hospitalized 
during the ramp-up phase (Days 1 and 2) because of the risk of tumor lysis 
syndrome (see Section 5.1.2.1 for background and Table 5 for management 
guidelines).
Investigators should otherwise follow institutional practice, clinical judgment, and 
recommendations in Table 5 to determine situations warranting hospitalization.  Note 
that hospitalization required for observation mandated either by the study protocol or 


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institutional practice would not be considered a serious adverse event (see 
Section 5.3.5.9).
5.1.5.4
Management Guidelines for Specific Adverse Events
Any toxicities associated with or possibly associated with study treatment should be 
managed with symptomatic treatment, dose interruptions (maximum allowable length of 
treatment interruption is 28 days), and/or dose reductions. The decision to extend the 
dose delay will be made on the basis of the investigator's assessment of ongoing clinical 
benefit and in consultation with the Medical Monitor.
Guidelines for management of specific adverse events are outlined in Table 5. 


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events
Event
Action to Be Taken
Diarrhea Grade 12

Rule out other or concomitant causes, including medications (e.g., stool softeners, laxatives, antacids), 
infection by C. difficile, malabsorption/lactose intolerance, fecal impaction, and dietary supplements high 
in fiber.

Monitor electrolytes closely and correct as appropriate.

Implement the following dietary modifications for patient:
–
Stop all lactose-containing products and eat small meals.
–
Encourage bland diet.
Encourage adequate hydration.

Implement anti-diarrheal therapy based on age and local institutional practice.  Loperamide treatment 
(per local dosing standard) is recommended therapy in patients if permitted according to the regional 
label or if consistent with institutional standard.

If event persists after 4872 hours despite maximal supportive care, consider second line anti-diarrheal 
agents, if applicable.

No change in study drug dosing for Grade 2 diarrhea, patients should receive maximal supportive care 
as described above.
Diarrhea Grade 3+

Provide maximal supportive care as described above.

If Grade 3 diarrhea persists despite adequate supportive care, hold idasanutlin (and, if applicable, 
venetoclax) until diarrhea improves to Grade 1. 

If no improvement is observed within 24 hours despite best supportive care and anti-diarrheal treatment 
(if permitted based on patient's age), test for C. difficile.  If bowel movement characteristics improve to 
baseline or Grade 1 within 28 days, restart study drug, with idasanutlin at a 50% dose reduction (or, if 
applicable, venetoclax reduced by 1 dose level), with continued supportive care or prophylaxis.  If the 
diarrhea is confirmed to be infectious on the basis of results from the stool culture, study treatment may 
be resumed at the same dose level if approved by the Medical Monitor.

If bowel movement characteristics have NOT improved to Grade 1 or baseline with maximal 
supportive care by 28 days, permanently discontinue study therapy.

If Grade 3 diarrhea recurs despite supportive care and idasanutlin or venetoclax dose reduction, 
permanently discontinue all study therapy.


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
Event
Action to Be Taken
Vomiting

Administer rescue medication according to standard institutional practice. 
Caution:  
o
For patients receiving venetoclax, only administer Aprepitant (Emend® Oral) if medically 
necessary and with 50% venetoclax dose reduction, as it is a moderate CYP3A inhibitor.
o
Avoid agents such as metoclopramide, which may stimulate GI motility.

Re-dosing of study treatment after vomiting:
–
If vomiting occurs within 15 minutes of administering idasanutlin and/or venetoclax and all expelled 
tablets are still intact (if applicable), another dose may be administered, and the second dose must 
be recorded in the drug log.  Otherwise, no replacement dose is to be administered.
Tumor lysis syndrome

Monitor clinical chemistry for signs or symptoms of TLS according to local institutional practice. 

Administer recombinant urate oxidase (i.e., rasburicase) for hyperuricemia per institutional practice if 
available and not otherwise contraindicated.

Withhold study treatment and consult Medical Monitor if any of the following are observed:
–
Potassium 7.0 mmol/L and/or symptoms of hyperkalemia (e.g., muscle cramps, arrhythmias, 
paresthesia, and nausea)
–
Serum uric acid (SUA) 10 mg/dL (595 mol/L) or SUA 8.0 mg/dL (476 mol/L) with a 25% 
increase and a creatinine increase 0.3 mg/dL from baseline
–
Nephrology assessment warrants initiating dialysis


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
Event
Action to Be Taken
Tumor lysis syndrome 
(cont.) 

Permanently discontinue study treatment in the case of Grade 4 events.

Ensure appropriate hydration, as strongly recommended for all patients especially patients considered 
at risk.

Correct relevant clinical chemistry abnormalities promptly.

Maintain a low threshold for treatment with IV fluids and consideration of uric acid reducing agents.

If all laboratory and clinical signs of TLS are stable for at least 24 hours, study treatment may be 
restarted following the below guidelines, which are based on the presentation of the event:
–
For clinical TLS, defined as laboratory TLS with clinical consequences such as acute renal failure, 
cardiac arrhythmias, seizures, idasanutlin and venetoclax may be resumed at a reduced dose as 
described below: 
o
The dose of idasanutlin can be reduced by 20% up to two times (or by 50% once) for 
management of drug-related toxicities (see Section 5.1.5.1).
o
The dose of venetoclax should be reduced by 50%. 
–
For laboratory TLS that is transient, lasting 48 hours, restart study treatment at the same dose.
–
For laboratory TLS that lasts longer than 48 hours, idasanutlin and venetoclax may be resumed at 
a reduced dose as described below:
o
The dose of idasanutlin can be reduced by 20% up to two times (or by 50% once) for 
management of drug-related toxicities (see Section 5.1.5.1).
o
The dose of venetoclax should be reduced by 50%. 

TLS related abnormalities should be managed per institutional guidelines
LFT elevations: Grade 1 
or 2

No action required.


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
LFT elevations: Grade 3
(5.020.0ULN) 

For Grade 3 AST/ALT elevation, study treatment may continue without interruption and/or dose 
reduction at the discretion of the investigator per institutional practice.  LFTs should be monitored every 
3 days until return to baseline values.

If duration of Grade 3 AST/ALT elevation 3 days, hold idasanutlin (and venetoclax, if applicable) until 
levels resolve to Grade 1.
–
For patients with baseline elevation of AST/ALT due to metastasis or leukemic infiltrate, hold 
idasanutlin (and venetoclax if applicable) if AST/ALT are 5to <10baseline for 3 days, or for 
any AST/ALT above 10 baseline, until levels resolved to baseline. 
–
Venetoclax and idasanutlin may be resumed at the current dose or at a dose reduction at the 
discretion of the investigator and after discussion with the Medical Monitor.

Discontinue study drugs permanently if Hy's Law criteria (defined in Section 5.3.5.5) are met or 
AST/ALT do not resolve to Grade 1 or baseline) within 28 days.
LFT elevations: Grade 4
(20ULN)

Hold study drugs until levels return to Grade 1.  If study drug is resumed: Resume venetoclax and 
idasanutlin at the reduced dose (please refer to guidance in Section 3.1.1.4) at the discretion of the 
investigator and after discussion with the Medical Monitor.

Permanently discontinue study drugs if Hy's Law criteria (defined in Section 5.3.5.5) are met, AST/ALT 
do not resolve to Grade 1 or baseline within 28 days, or if Grade 4 AST/ALT recurs.


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
Cytopenias
Patients with Solid Tumors: 
If any of the following adverse events occur (whether as single agent or in combination), reduce idasanutlin 
(and, if applicable, topotecan/cyclophosphamide or venetoclax) by at least 20% for the following cycle:

Grade 4 neutropenia lasting at least 7 days
Treatment with cytokines is recommended per routine local practice.

Grade 4 anemia

Thrombocytopenia Grade 4 (i.e., platelet count 25.0 109/L) lasting at least 14 days and assessed on 
at least 2 separate days or requiring at least 2 platelet transfusion on separate days

Delay in starting Cycle 2 beyond Day 28 due to slow recovery from thrombocytopenia (platelet 
count < 75 109/L) or neutrophil count 0.75 109/L
Patients with delayed blood count recovery beyond Day 42 should undergo 50% idasanutlin dose reduction.  
Patients with delayed blood count recovery beyond Day 56 should discontinue study therapy.


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
Event
Action to Be Taken
Cytopenias (cont.)
Patients with Leukemia:

If blood counts have not recovered (ANC 0.5 109/L, platelets 75 109/L) by Day 28, interrupt 
dosing with venetoclax (if applicable) to allow for count recovery.  

If blood count recovery is delayed by 42 days (between Day 42 and Day 56), administer idasanutlin 
at a 50% dose reduction for the next cycle. 
–
Patients whose ANC is 0.5 109/L but who have not recovered platelet counts may start therapy 
at Day 56. 
–
If ANC 0.5 109/L on Day 56, discontinue patient from treatment. 
Growth factors will be permitted for neutropenic sepsis according to local practice, and patients will be 
monitored and treated promptly in case of infections.  Dose interruptions or reductions will be allowed based 
on toxicity.

In cases of fever in neutropenic patients:  Consider a medical emergency.  Administer initial doses of 
antibacterial therapy within 1 hour of triage for febrile neutropenic patients (Grade 3 and higher) 
(Flowers et al. 2013).
Refer to institutional and published guidelines for optimal management of febrile neutropenia for 18 year 
olds (Flowers et al. 2013; de Naurois et al. 2010) and 18 year olds (Lehrnbecher et al. 2017).
Follow the below recommended transfusion thresholds for all patients:

Prophylactic platelet transfusion is recommended when platelet counts is 10 109/L, and therapeutic 
transfusions are recommended when clinically indicated (any platelet value in the presence of 
hemorrhagic symptoms).

In patients with HLA sensitization, administer HLA-compatible platelet transfusions.

Packed red blood cell transfusion is recommended if hemoglobin 7 g/dL (or 9 g/dL in patients with 
documented cardiac insufficiency) or if patient has symptomatic anemia (e.g., profuse asthenia).


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Table 5
Guidelines for Management of Patients Who Experience Adverse Events (cont.)
Event
Action to Be Taken
Infections
Patients should be closely monitored for infections and prompt therapy will be instituted, as necessary.  Due 
to the high incidence of diarrhea, Clostridium difficile infection (CDI) may occur undetected (refer to above 
diarrhea guidance for recommended CDI testing).  CDI once confirmed should be treated as per standard 
institutional practice.
Other Grade 3 
non-hematologic 
adverse events or 
Grade 4 hematologic 
adverse events 
considered to be related 
to study treatment

Do not administer study treatment until recovery to Grade 1.  Resume idasanutlin and venetoclax at a 
reduced dose level.

If patient experiences two episodes of the toxicity, or the toxicity persists for 14 days despite adequate 
supportive care, discontinue study treatment permanently.
Note:  A hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia.
AE adverse event; CDI Clostridium difficile infection; GI gastrointestinal; HLA human leukocyte antigen; TLS tumor lysis 
syndrome; ULN upper limit of normal.


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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, 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 5.4.1.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, 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) (see Sections 5.3.5.9 and 
5.3.5.10 for more information)

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 drug

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)


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
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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).
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 
are as follows:

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 drug, 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 the study drug is suspected.

Any tumor lysis syndrome (per Howard criteria, see Appendix 12)

Febrile neutropenia (Grade3)

Thrombocytopenia (Grade3 if associated with hemorrhage or bleeding)

Diarrhea (Grade2)

Infections (Grade3)

C. difficile infection (Grade2)

Mucosal inflammation (Grade 3)


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5.2.4
Dose-Limiting Toxicities (Immediately Reportable to the Sponsor)
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.1.3, 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).
5.3
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 5.3.5.105.6.  The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4).
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 drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications, or the use of mandatory 
prophylactic medications) should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after 
completion of the last treatment cycle, with the following exception:

For patients with AML, all adverse events up to 56 days after the last dose of study 
treatment should be reported 
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?" 


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 6
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 (v5.0), 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 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 7):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
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
Table 7
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
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
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 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
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 gastrointestinal 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.
5.3.5.3
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 (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.  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.
5.3.5.4
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)


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
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).
5.3.5.5
Abnormal Liver Function Tests
The finding of an elevated ALT/ 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/ AST 3baseline value in combination with total bilirubin 
2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT/ 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).


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5.3.5.6
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 cancer should be recorded on the Death Attributed 
to Progressive Disease eCRF.  All other deaths that occur during the adverse event 
reporting period, regardless of relationship to study drug, 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
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.
5.3.5.7
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").
5.3.5.8
Lack of Efficacy or Worsening of AML, ALL, or Solid-Tumor Cancer
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 applicable response assessments (see 
Appendix 5Appendix 8 for details).  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 


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uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.9
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

Hospitalization for observation as per institutional practice following administration of 
study treatment

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

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
5.3.5.10
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 or qualifies as an adverse event of special interest, 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 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 and venetoclax, regardless 
of whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

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.


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
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.
5.3.5.11
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) or 
observer-reported outcome (ObsRO) data by the Sponsor, and safety analyses will not 
be performed using PRO or ObsRO data.  Sites are not expected to review the PRO or 
ObsRO data for adverse events.
5.3.5.12
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.


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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 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

DLTs during the DLT assessment window (defined in Section 5.2.4; see 
Section 5.4.2 for details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Medical device complaints (see Section 5.4.4 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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)
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, 


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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 Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial 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.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported 30 days after the final dose of study drug for patients with solid 
tumors or ALL, and 56 days after the final dose of study drug for patients with AML. 
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 paper Clinical Trial 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 6 weeks after the final dose 
of idasanutlin or 30 days after the last dose of venetoclax after the final 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 through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 6 weeks after the final dose of idasanutlin, 30 days after the final dose of 
venetoclax, 12 months after final treatment for patients receiving 
cyclophosphamide/topotecan (or longer if required according to national prescribing 
information), 6 months after final treatment for patients receiving FLA (or longer if 


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required according to national prescribing information), or in accordance with national
prescribing information guidance regarding abstinence, contraception, and egg donation 
for any non-Investigational Medicinal Products listed in Section 4.3.  A paper 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 drug 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.  
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 
90 days after the final dose of idasanutlin, 12 months after final treatment with 
cyclophosphamide/topotecan (or longer if required according to national prescribing 
information), 6 months after final treatment with fludarabine (or longer if required 
according to national prescribing information), or in accordance with national prescribing 
information guidance regarding abstinence, contraception, and sperm donation for any 
non-Investigational Medicinal Products listed in Section 4.3.  The investigator should 
report the pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit 
the form 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 drug.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it 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
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 


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and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity 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).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug 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 Medical Device Complaints
In this study, the idasanutlin oral dispenser (syringe) is considered a medical device.  
The investigator must report all medical device complaints to the Sponsor.  The 
investigator should document as much information as possible on the IMP Deviation 
Form, including the product batch number, and forward the form to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event) (refer to the 
pharmacy manual for further details).  If the medical device results in an adverse event 
to the study patient, the event must be reported on the Adverse Event eCRF and 
submitted through the EDC system.  If the event is serious, the Adverse Event eCRF 
must be completed immediately (i.e., no more than 24 hours after learning of the event), 
as outlined in Section 5.4.2.
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 drug or trial-related procedures 
until a final outcome can be reported.
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.


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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, email, 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 30 days after the last 
dose of study drug for patients with solid tumors or ALL, and 56 days after the last dose 
of study drug for patients with AML), all deaths, regardless of cause, should be reported 
on the Survival Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
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.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Idasanutlin Investigator's Brochure

Venetoclax Investigator's Brochure

Cyclophosphamide SmPC

Topotecan SmPC

Fludarabine SmPC

Cytarabine SmPC


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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
For purposes of analysis, the following populations are defined below:

Intent-to-treat (ITT) population:  All enrolled patients in the study, regardless of 
whether they were dosed 
All other populations will be a subset of the ITT population.

Safety evaluable (SE) population: All patients who received any amount of the 
study treatment, whether prematurely withdrawn from the study or not

DLT-evaluable (DE) population:  All patients enrolled in Part 1 and Part 2 who either 
have completed at least 80% of the prescribed dose of idasanutlin and the DLT 
observation window in Cycle 1 OR have experienced a DLT in Cycle 1 of the dose-
escalation phase

PK population:  All patients who have received at least one dose of study treatment 
and who have data from at least one postdose sample
Patients will be excluded from the PK analysis population if they significantly 
violate the inclusion or exclusion criteria or deviate significantly from the 
protocol, or if data are unavailable or incomplete, which may influence the PK 
analysis.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size for the dose-escalation phase of this study is based on the 
mCRM-EWOC design.  The study will enroll approximately 924 DLT-evaluable patients 
in dose escalation to reach the MTD/MAD and approximately 39 patients in each cohort 
in the safety run-in phase to reach RP2D.  Explicit power and type I error considerations 
are not factored into the design of the MTD/MAD or RP2D determination, as the 
dose-escalation and safety run-in phases are designed to obtain preliminary safety and 
PK information for the study drug.
An early response assessment (Gate 1B), will be performed for the neuroblastoma 
cohorts at the end of Study Part 1b after six patients have been treated at the RP2D for 
the combination.  Additional response assessments of patients enrolled in Part 2 (also 
including patients treated at the RP2D in Part 1b for the neuroblastoma cohorts) (Gate 
2) and of patients enrolled in Part 2 and Part 3 (again including patients treated at the 
RP2D in Part 1b for the neuroblastoma cohort) (Gate 3) are planned in order to make a 
preliminary assessment of the efficacy of the study drug.


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At least 50% of patients with TP53 wild-type tumors treated at the RP2D in Study 
Part 1b for the neuroblastoma cohorts (Gate 1b) must have an observed objective 
response prior to advancing to the next phase of the study.  If this benchmark is not 
reached, the cohort will be discontinued for futility.  The minimum number of patients in 
the response assessment at Gate 2 and the minimum number of responders required for 
advancement to the additional response assessment (Part 3) are presented by tumor 
type in Table 8, taking into account historical control ORRs for neuroblastoma and CRR 
for leukemias.  For neuroblastoma and AML, up to one combination regimen may
advance to Part 3 for each tumor type, taking into account the preliminary efficacy
(i.e., response criteria in Table 8), safety, biomarker data, and enrollment feasibility. The 
ALL cohort will be considered for expansion similarly, if either morphologic response or 
MRD-negative response criteria are met.
The sample size and minimum number of responders for the additional response 
assessment for each tumor type cohort were determined based on 90% confidence 
interval (CI) for the appropriate response rate parameter for each disease cohort.  Part 3
of this trial will be able to detect a large benefit of the idasanutlin in combination with 
chemotherapy or venetoclax in terms of the appropriate response rate for the disease.  
For example, an observed response rate of 45% in 40 patients with neuroblastoma will 
have a 90% confidence interval excluding the 32% historical response rate.  Similarly, an 
observed CRR of 53% in 30 patients with ALL will have a 90% confidence interval 
excluding 40%. 


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Table 8
Sample Size for Initial and Additional Response Assessment
Tumor Type
Response
Assessment
Control 
CRR/ORR
Initial Response Assessment (Part 2)
Additional Response Assessment
(Parts 2 and 3)
Minimum No. of 
Patients Enrolled
Minimum No. of Responders Needed
for Tumor Type Cohort Expansion
No. of Patients Enrolled a
NBL
INRC
32% b
10c
5
40
AML
AML d
55% e
10
7
35
ALL f
ALL 
(morphologic 
response)
40% g
10
6
30
ALL 
(MRD-negative 
response) h
20% i
10
4
30
ALLacute lymphocytic leukemia: AMLacute myeloid leukemia; CRRcomplete remission rate; FLAG Fludarabine, cytarabine, and 
G-CSF; INRCInternational Neuroblastoma Response Criteria; MRD minimal residual disease; NBLneuroblastoma; No. number; 
ORRoverall response rate.
a Includes patients from initial response assessment.
b London et al. 2010 (TOPO/CTX vs. TOPO).
c including patients treated in Part 1b at RP2D.
d See Appendix 7.
e
Kaspers et al. 2013 (combination FLAG).
f
ALL cohort considered for expansion if either morphologic response or MRD-negative response criteria are met.
g Ko et al. 2010; Messinger 2012; Bertaina 2017.
h MRD negative defined as <0.01% blasts in the bone marrow detected by nucleic acid-based methods, such as next-generation sequencing.
i
von Stackelberg 2016.


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6.2
SUMMARIES OF CONDUCT OF STUDY
All major protocol deviations will be captured. The number of patients who enroll, 
discontinue, or complete the study will be summarized.  Reasons for premature study 
discontinuation will be listed and summarized.  Enrollment and major protocol deviations 
will be listed and evaluated for their potential effects on the interpretation of study 
results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographics and baseline characteristics, including age, sex, race/ethnicity, medical 
history, and prior cancer treatment, will be summarized overall and by each cohort type. 
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile, 
and range) will be presented for continuous variables, and proportions will be presented 
for categorical variables. 
All demographic and baseline characteristics analyses will be based on the ITT 
population.
6.4
SAFETY ANALYSES
Safety will be characterized by incidence of adverse events and DLTs, as well as 
change from baseline in ECG parameters and clinical laboratory results. Study 
treatment exposure (such as treatment duration, total dose received, and number of 
cycles and dose modifications) will be summarized with descriptive statistics.
All safety analyses will be based on the SE population. 
Incidence and nature of DLTs assessed during the first cycle of study treatment will be 
summarized using descriptive statistics.  All DLT analyses will be based on the 
DE population.  
6.4.1
Primary Safety Model (mCRM-EWOC) for Single-Agent Dose Finding
An mCRM-EWOC model will be utilized to inform decision-making regarding the MTD of 
idasanutlin in Study Part Ia.  The MTD is defined as the dose that maximizes the 
posterior probability of a DLT being in the targeted toxicity interval of 20%35%, while 
controlling the probability of a DLT being in the excessive toxicity interval of 35%100% 
to be 25%. 
The mCRM-EWOC model will adaptively estimate the MTD after gathering cumulative 
DLT data including newly completed cohorts and calculate a recommended next dose 
for the next cohort. The mCRM-EWOC design parameters and operating characters are 
described in Appendix 11.


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6.5
PHARMACOKINETIC ANALYSES
Standard non-compartmental analysis will be applied for calculating PK parameters and 
population methods may be considered. 
Analyses will be carried out on the PK analysis population. All PK parameters will be 
presented by listings and descriptive summary statistics (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum) separately by disease cohorts 
and sub-grouped by drug combinations, when applicable.
Individual and mean serum idasanutlin (and M4 metabolite RO6802287, where relevant)
concentration versus time data will be tabulated and plotted by dose-level in 
dose-escalation phase and by drug combination and disease cohorts in later phases of 
the study. Graphical displays of PK data will also be provided. The PK of idasanutlin 
(and M4 metabolite RO6802287, where relevant) will be summarized by estimating total 
exposure (AUC), maximum concentration (Cmax), minimum concentration (Cmin), total 
clearance, volume of distribution at steady-state (Vss), and t1/2 when available data 
permits. Estimates for these parameters will be tabulated and summarized. Inter-
patient variability and drug accumulation will be evaluated.
6.6
EFFICACY ANALYSES
All efficacy analyses will be performed on SE population.   
Interim response assessments will be performed in centrally-confirmed TP53 wild-type 
patients from each tumor type and combination following Part 1b of the neuroblastoma 
cohorts and Part 2 for all cohorts.  The IMC-SOC will review the safety and efficacy data 
and recommend whether to expand or stop further enrollment for a tumor type and 
combination. 
Tumor response data will be reported using descriptive statistics. The exact binomial 
CIs will be calculated using Clopper-Pearson method. 
6.6.1
Primary Efficacy Endpoints
The primary endpoint for efficacy in neuroblastoma is ORR in patients with TP53 WT 
tumors (see Section 2.3.1).  Patients with no postbaseline tumor assessments will be 
counted as non-responders.  The ORR and its 95% CI will be calculated for patients 
enrolled in Part 1b (neuroblastoma cohorts only), Part 2, and Part 3 by combination 
regimen.  
The primary endpoint for efficacy in AML is CRR in patients with TP53 WT tumors (see 
Section 2.3.1).  Patients with no postbaseline tumor assessments will be counted as 
non-responders.  The CRR and 95% CI will be calculated by combination regimen.
The co-primary endpoints for efficacy in ALL are CRR and MRD-negative rate in patients 
with TP53 WT tumors (see Section 2.3.1).  Patients with no postbaseline tumor 


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assessments will be counted as non-responders in the CRR analysis and MRD-positive 
patients in the MRD-negative rate analysis, respectively.  The CRR and MRD-negative 
rate, and their corresponding 95% CI will be calculated.
6.6.2
Secondary Efficacy Endpoints
6.6.2.1
Solid Tumors including Neuroblastoma
CBR, DOR, PFS, and OS are defined in Section 2.3.2 and will be calculated in patients 
with TP53 WT tumors in Part 1b, Part 2, and Part 3, by combination regimen.
DOR will be calculated for patients who achieve an objective response.  Data for 
patients without disease progression or death will be censored at the date of the last 
tumor assessment at which the patient was known to be progression-free or, if no tumor 
assessment is performed after the baseline visit, at the date of initiation of study drug.  
The Kaplan-Meier approach will be used to estimate median DOR.  The 95% CI of the 
median DOR will be estimated using Brookmeyer and Crowley method.
For PFS calculation, data for patients without disease progression or death will be 
censored at the date of the last tumor assessment at which the patient was known to be 
progression-free or, if no tumor assessment is performed after the baseline visit, at the 
date of initiation of study drug.  The Kaplan-Meier approach will be used to estimate 
median DOR.  The 95% CI of the median DOR will be estimated using Brookmeyer and 
Crowley method.
ORR and its 95% CI will be calculated for all patients and by dose level in Part 1, as well 
as in patients in Part 2 and Part 3 regardless of their tumors’ TP53 mutation status. 
6.6.2.2
Leukemias
Rate of patients receiving transplant after study treatment, OS, and CRR will be 
calculated in patients with TP53 WT tumors, by tumor type and combination regimen.
DOR and EFS are defined in Section 2.3.2 and will be calculated in patients with TP53 
WT tumors, by tumor type and combination regimen.
MRD-negative rate and its 95% CI will be calculated for patients with TP53 WT AML by 
combination regimen.
CRR and its 95% CI will be calculated for all patients by tumor type and combination 
regimen, regardless of their tumors' TP53 mutation status.  
6.7
BIOMARKER ANALYSES
Exploratory biomarker analyses may be performed in an effort to better understand 
response to idasanutlin as a single agent or in combination with chemotherapy or 
venetoclax at a molecular level and identify potential mechanisms of resistance.  These 
analyses will be descriptive and exploratory in nature and results will be presented in a 


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separate report.  The potential exploratory biomarker assessments for this study 
requiring statistical considerations may include, but will not be limited to, the following:

Alterations in DNA and RNA, including DNA mutational status (such as TP53
mutations), RNA expression levels (such as Bcl-2 and MDM2 transcripts), and DNA 
copy number may be assessed on pre-study, on-study, and end-of-study tissue 
samples and/or BMAs to better understand molecular mechanisms of response and 
resistance.

Analysis of serum samples for MIC-1 protein levels by ELISA

Analysis of ctDNA from plasma isolated from peripheral blood for potential 
blood-based biomarkers including, but not limited to, TP53 mutations
6.8
HEALTH STATUS UTILITY ANALYSIS
Analyses will be descriptive, enumerating the number of patients that selected each 
answer choice.
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.
Acceptability survey data will be collected on paper questionnaires.  The data from the 
questionnaires will be entered into the EDC system by site staff.
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.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review 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 into 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 and review, 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 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.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO, Clin RO, and ObsRO data 
(if applicable), Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by 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.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
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 applicable 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. 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) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile 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.  


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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.
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 


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also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
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. 
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 exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine). The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.6).
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.
Study data, which may include data on genomic mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6).


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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 (see definition of end of 
study in Section 3.2).
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.
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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data 
and implement plans for evaluating and controlling these risks.  Risk evaluation and 
control included the selection of risk-based parameters (e.g., adverse event rate, protocol 
deviation rate) and the establishment of quality tolerance limits for these parameters. 
Detection of deviations from quality tolerance limits will trigger an evaluation to 
determine if action is needed.  Details on the establishment and monitoring of quality 
tolerance limits will be provided in a Quality Tolerance Limit Management Plan.
9.4
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 


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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 1020 sites globally will participate to enroll approximately 183 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An IMC and an SOC will be employed to monitor and evaluate patient safety throughout 
the study.  
9.6
DISSEMINATION 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, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study(see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 Clinical Study Report.  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, 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.


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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.
9.7
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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Appendix 1:
Schedule of Activities for Patients with Solid Tumors (Single-Agent Dose-Escalation Cohort)
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
167/Protocol GO40871, Version 4
c
Patients are expected to complete all follow up investigations unless return visits to the study site are considered onerous for the patient (due to distance from 
the site, health status, etc.) in the opinion of the investigator; such patients will be followed for survival only.  Long-term follow up information will be collected 
every 3 months until death or end of study, whichever occurs first.
d
The visit window for each visit is 3 days, with the exception of PK samples on Days 2 and 5 of Cycle 1. The window for continuing to the next cycle is 
3 days, for study treatment discontinuation visit is 30 days, and for follow-up is 1 month.
e
All assessments should be completed prior to dosing, with the exception of certain  PK assessments outlined in Appendix 4.
f
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days before initiation of 
study treatment.
g
During the treatment period, weight will be measured at the beginning of each cycle.  During the follow-up period, weight should be measured every 3 months.  
Height, head circumference (until the age of 3 years), and Tanner stage should be measured every three cycles (approximately every 3 months).  During the 
follow up period, height, head circumference, and Tanner stage should be measured every 3 months.  Tanner staging should be performed until the patient has 
reached Tanner Stage V.
h
Assessments to be obtained every 3 months (i.e., every 3 cycles). 
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.
j
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits or as clinically indicated.  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.
k
The Lansky Performance Status should be performed for patients who are 16 years old, and the Karnofsky Performance Status should be performed for 
patients who are 16 years old.
l
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from 7 days prior to initiation of study drug until 30 days after the final dose of study drug.
m After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be 
reported.  After initiation of study drug, all adverse events will be reported 30 days after completion of the last treatment cycle.  After this period, all deaths, 
regardless of cause, should be reported on the Long-Term Survival eCRF.  In addition, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).
n
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, blasts, and other cells).
o
Weekly thereafter until able to start next cycle.
p
Can be omitted for patients who continue with single-agent idasanutlin (i.e. do not combine with chemotherapy) unless clinically indicated in investigator’s 
judgement.


Appendix 1:
Schedule of Activities for Patients with Solid Tumors (Single-Agent Dose-Escalation Cohort)
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
168/Protocol GO40871, Version 4
q
Chemistry panel (serum) includes bicarbonate (or total carbon dioxide), sodium, potassium, chloride, glucose, BUN or urea, creatinine, albumin, phosphate, 
calcium, total bilirubin [if abnormal, fractionate sample for direct and indirect], alkaline phosphatase, ALT, AST, uric acid, and LDH.
r
Viral serology includes hepatitis B surface antigen, hepatitis B surface antibody, total hepatitis B core antibody, hepatitis C antibody, and HIV.
s
All females of childbearing potential will have a serum pregnancy test at screening within 1 week prior to first dose.  Urine or serum pregnancy tests will be 
performed at specified subsequent visits.  
t
If clinically feasible and safe, patients are encouraged to provide an optional on-treatment tissue biopsy for biomarker assessments at Day 15 of Cycle 1 (or on 
Day 22 of Cycle 1, if not provided on Day 15).  Similarly, at the time of progression and at the study discontinuation visit, if clinically feasible and safe, patients 
are also encouraged to provide an end-of-treatment biopsy.






Appendix 2:
Schedule of Activites for Patients with Neuroblastoma (Study Parts 1b, 2, and 3)
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
171/Protocol GO40871, Version 4
c
Patients are expected to complete all follow up investigations unless return visits to the study site are considered onerous for the patient (due to distance from 
the site, health status, etc.) in the opinion of the investigator; such patients will be followed for survival only. Long-term follow up information will be collected 
every 3 months until death or end of study, whichever occurs first.
d
The visit window for each visit is 3 days, with the exception of PK samples on Days 2 and 5 of Cycle 1. The window for continuing to the next cycle is 3 days, 
for study treatment discontinuation visit is 30 days, and for follow-up is 1 month.
e
All assessments at should be completed prior to dosing, with the exception of certain PK assessments outlined in Appendix 4.
f
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days before initiation of 
study treatment.
g
During the treatment period, weight will be measured at the beginning of each cycle.  During the follow-up period, weight should be measured every 3 months.  
Height, head circumference (until the age of 3 years), and Tanner stage should be measured every three cycles (approximately every 3 months).  During the 
follow up period, height, head circumference, and Tanner stage should be measured every 3 months.  Tanner staging should be performed until the patient has 
reached Tanner Stage V.
h
Assessments to be obtained every 3 months (i.e., every 3 cycles). 
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.
j
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits or as clinically indicated.  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.
k
The Lansky Performance Status should be performed for patients who are16 years old, and the Karnofsky Performance Status should be performed for 
patients who are 16 years old.
l
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from 7 days prior to initiation of study drug until 30 days after the final dose of study drug.
m After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be 
reported.  After initiation of study drug, all adverse events will be reported until until 30 days after completion of the last treatment cycle. After this period, all 
deaths, regardless of cause, should be reported on the Long-Term Survival eCRF.  In addition, the Sponsor should be notified if the investigator becomes aware 
of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).
n
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, blasts, and other cells).
o
Weekly thereafter until able to start next cycle.
p
Chemistry panel (serum) includes bicarbonate (or total carbon dioxide), sodium, potassium, chloride, glucose, BUN or urea, creatinine, albumin, phosphate, 
calcium, total bilirubin [if abnormal, fractionate sample for direct and indirect], alkaline phosphatase, ALT, AST, uric acid, and LDH.


Appendix 2:
Schedule of Activites for Patients with Neuroblastoma (Study Parts 1b, 2, and 3)
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
172/Protocol GO40871, Version 4
q
Viral serology includes hepatitis B surface antigen, hepatitis B surface antibody, total hepatitis B core antibody, hepatitis C antibody, and HIV.
r
All females of childbearing potential will have a serum pregnancy test at screening within 1 week prior to first dose.  Urine or serum pregnancy tests will be 
performed at specified subsequent visit.
s
If clinically feasible and safe, patients are encouraged to provide an optional on-treatment tissue biopsy for biomarker assessments at Day 15 of Cycle 1 (or on 
Day 22 of Cycle 1, if not provided on Day 15).  Similarly, at the time of progression and at the study discontinuation visit, if clinically feasible and safe, patients 
are also encouraged to provide an end-of-treatment biopsy.
t
Applicable for patients combining with venetoclax only. TLS chemistry includes calcium, phosphorus, BUN (or urea), creatinine, potassium, uric acid on 
Cycle 1, Day 1 predose and at 4, 8, and 24 hours postdose.






Appendix 3:
Schedule of Activites for Patients with ALL and AML
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
175/Protocol GO40871, Version 4
g
During the treatment period, weight will be measured at the beginning of each cycle.  During the follow-up period, weight should be measured every 3 months.  
Height, head circumference (until the age of 3 years), and Tanner stage should be measured every three cycles (approximately every 3 months).  During the 
follow up period, height, head circumference, and Tanner stage should be measured every 3 months.  Tanner staging should be performed until the patient has 
reached Tanner Stage V.
h
Assessments to be obtained every 3 months (i.e., every 3 cycles). 
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, 
and neurologic systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.
j
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits or as clinically indicated.  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.
k
The Lansky Performance Status should be performed for patients who are 16 years old, and the Karnofsky Performance Status should be performed for 
patients who are 16years old.
l
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from 7 days prior to initiation of study drug until 30 days after the final dose of study drug.
m After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention should be 
reported.  After initiation of study drug, all adverse events will be reported until until 30 days after completion of the last treatment cycle, with the following 
exception: For patients with AML, all adverse events up to 56 days after the last dose of study treatment should be reported. After this period, all deaths, 
regardless of cause, should be reported on the Long-Term Survival eCRF.  In addition, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).
n
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, blasts, and other cells).
o
Weekly thereafter until able to start next cycle.
p
Chemistry panel (serum) includes bicarbonate (or total carbon dioxide), sodium, potassium, chloride, glucose, BUN or urea, creatinine, albumin, phosphate, 
calcium, total bilirubin [if abnormal, fractionate sample for direct and indirect], alkaline phosphatase, ALT, AST, uric acid, and LDH. On Day 1 of Cycle 1, 
chemistry must be collected pre-dose and 4, 8 and 24 hours post-dose due to the risk of tumor lysis syndrome. Pre-dose chemistry results must be reviewed 
before dosing.
q
Viral serology includes hepatitis B surface antigen, hepatitis B surface antibody, total hepatitis B core antibody, hepatitis C antibody, and HIV.
r
All females of childbearing potential will have a serum pregnancy test at screening within 1 week prior to first dose. Urine or serum pregnancy tests will be 
performed at specified subsequent visits.  


Appendix 3:
Schedule of Activites for Patients with ALL and AML
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
176/Protocol GO40871, Version 4
s
BMA for MRD should be collected at any timepoint during the study at which BMA and/or BMB is collected as part of hematological response assessments. 
BMA collections in Cycle1 and Cycle 2 are mandatory as per the specific instructions detailed in Section 4.5.5.1.1. If any MRD assessments are done locally, 
record this information in the eCRF.
t
TLS chemistry includes calcium, phosphorus, BUN (or urea), creatinine, potassium, uric acid on Cycle 1, Day 1 predose and at 4, 8, and 24 hours postdose.
u
Assessments will take place every two cycles after Cycle 2.
v
If BMA cannot be obtained or is not evaluable (e.g., dry tap or no spicules are obtained), both BMB and blood collection are required.












Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
182/Protocol GO40871, Version 4
Appendix 6
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 (Eisenhauer et al. 2009) are presented below, with slight modifications and 
the addition of explanatory text as needed for clarity.
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  See also notes below on "Baseline 
Documentation of Target and Non-Target Lesions" for information on lymph node 
measurement.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.


Appendix 6:
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
183/Protocol GO40871, Version 4
Bone Lesions:

Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques for measuring bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.


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Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 


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of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”


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In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met, since a normal lymph node is defined as having a short axis 
of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.


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
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore be extremely rare.


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Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.


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Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
Table 1
Timepoint Response:  Patients with Target Lesions (with or without 
Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.


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Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint (see Table 3).  If only a subset of lesion measurements are 
made at an assessment, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.
Table 3
Best Overall Response When Confirmation Is Required
Overall Response 
at First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
PR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
NE
NE
NE
CR complete response; NE not evaluable; PD progressive disease; PR partial 
response; SD stable disease.


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Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient had PR, not CR, 
at the first timepoint.  Under these circumstances, the original CR should be changed to PR 
and the best response is PR.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.










Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
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Appendix 9
Lansky Performance Status Scale (Patients 16 years of age)
Score
Description
100
Fully active; normal
90
Minor restrictions in physically strenuous activity
80
Active but tires more quickly
70
Both greater restriction of and less time spent in play activity
60
Up and around, but minimal active play; keeps busy with 
quieter activities
50
Gets dressed, but lies around much of the day; no active play; 
able to participate in all quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed


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Appendix 10
Karnofsky Performance Status Scale (Patients 16 years of age)
Score
Description
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of 
disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active 
work
60
Requires occasional assistance, but is able to care for most of 
his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated; death not 
imminent
20
Very sick; hospitalization indicated; death not imminent
10
Moribund; fatal processes progressing rapidly


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Appendix 11
Modified Continual Reassessment Method of Escalation with 
Overdose Control Design
Details of the modified continual reassessment method of escalation with overdose 
control (mCRM-EWOC) design used in the study are descripted in this appendix.
In addition, the design operating characteristics are evaluated through comprehensive 
simulations in this section. In this study, the maximum tolerated dose (MTD) is defined 
as the dose maximizing the posterior probability that the dose-limiting toxicity (DLT) rate 
belongs to [0.20, 0.35], while keeping the probability of overdose below 0.25. 
Calculations are done using R package crmPack 0.2.7 (https://cran.r-
project.org/web/packages/crmPack/index.html). 
Dose-Response Model 
The probability of DLTs over doses (dose-DLT response curve) will be described by a 
two-parameter logistic regression model: 
where p(d) stands for the DLT rates under a dose level d, and d* is set to 20 mg/kg 
(i.e., 4 mg/kg QD5 days per cycle) in the study as the reference dose. Thus, the 
dose-DLT response curve follows a sigmoidal shape and can be flexibly adjusted by a 
parameter. 
It is common to assume such a sigmoidal curve since usually the DLT rate increases 
monotonically while dose levels go up, but not in a linear way because it has a minimal 
level 0 and will reach a plateau when dose is very high. It is anticipated that idasanutlin 
would have a similar dose-DLT relationship.
Prior setting 
In particular, a moderately informative prior is chosen for the log logistic models 
parameters. The parameters of this prior distribution θ are estimated from a posterior 
distribution utilizing DLT data collected from Study NP27872, which was a Phase I 
dose-escalation study for idasanutlin in adult patients with advanced malignancies 
except leukemia. Data were available from 30 DLT-evaluable patients on Schedule B 
(QD dosing5 days per cycle) portion of this Phase I study.  The MBP formulation was 
used and the tested dose levels ranged from 500 mg to 6000 mg per cycle with DLT 
distribution as follows: 3 of 10 patients experiencing DLTs at 3000 mg, 6 of 9 patients at 
4000 mg, 2 of 3 patients at 4800 mg, 1 of 2 patients at 5000 mg, and 2 of 3 patients at 
6000 mg. The RP2D was 2500 mg MBP (500 mg QD5 days), which is considered 
equivalent to 1250 mg SDP formulation (see Figure 1).  


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The posterior distribution of the log logistic model using this DLT data from the adult 
population was estimated based on mCRM. The mCRM design includes a statistical 
model to describe the DLT-dose relationship by a DLT-dose response curve. 
Figure 1DLT Distribution at Different Dose Levels of Idasanutlin from 
Study NP27872
DLT dose-limiting toxicity.


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Control Design 
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Figure 2Posterior Distribution of the Dose-DLT Response Curve according to 
Patient DLT data from Study NP27872 in Adult Population
DLT dose-limiting toxicity; RP2DRecommended Phase 2 Dose; SDPsolid dispersion 
powder.
The parameters of the log logistic model are listed below based on estimation from 
Study NP27872: 
 = (−0.41709244
−0.09044227)
Σ = 0.133065782
0.002678115
0.002678115
0.001752474
This prior will be informative as illustrated by the relatively narrow confidence bands.
In order to have a less informative prior, the variance is artificially increased by 
multiplying the covariance matrix by a factor of 6. This factor is chosen to be the factor 
such that the desired maximum increments (50%) are reached (a smaller factor leads to 
smaller increments because of the high prior toxicity curve and a larger factor leads to 


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Control Design 
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larger increments because of the higher variability of the posterior estimates). The 
parameters of the prior are listed below:
 = (−0.41709244
−0.09044227)
Σ = 0.79839469
0.01606869
0.01606869
0.01051484
The prior distribution displayed in Figure 3 assumes: it would be unlikely that a 3-mg/kg
dose (0.6 mg/kg QD5 days per cycle) corresponds to a 35% or higher DLT rate, and a 
30-mg/kg dose (6 mg/kg QD x5 days per cycle) corresponds to a 15% or lower DLT rate. 
Figure 3Prior Distribution of the mCRM-EWOC Design for Study GO40871
DLT dose-limiting toxicity; mCRM-EWOCmodified continual reassessment method of
escalation with overdose control; RP2D Recommended Phase 2 Dose; SDP solid dispersion 
powder.
Cohort size 
At least 3 patients will be enrolled in each cohort, which, if required, may be expanded 
with additional patients in order to collect additional data on pharmacokinetics, 
pharmacodynamics, or safety. If 2 of 3 patients in a cohort (or 2 of 2 patients in a cohort 
if the third one become non-evaluable) already experienced DLT, no further expansion 
will be done. See details in Section 3.1.
Maximum Allowable Dose Increments 


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The maximum allowable dose increment is 50%.
Next Dose Selection 
The selection dose for the next cohort will be guided by the mCRM-EWOC model, 
subject to clinical judgment and mandated safety constraints that limit the size of 
maximum allowable dose increments. Clinical judgment always overrides model 
estimates in the selection of the next dose. The Sponsor, in consultation with the 
investigators, can modify the dose to be used in the next cohort of patients as deemed 
appropriate at any time during the trial. 
mCRM-EWOC Stopping rules 
The dose-escalation trial will continue until the RP2D has been determined or the 
following pre-specified precision rules have been fulfilled: 

At least 6 subjects have been observed at a dose close to MTD (i.e., a dose within a 
20% range of the estimated MTD). 

The maximal posterior probability of a dose being in the target DLT range is above 
40%.
The Sponsor in consultation with the investigators may decide to stop the escalation 
prior to above stopping criteria being met if an RP2D has been determined. Also, based 
on clinical judgement and after discussion and agreement by IMC-SOC, dose escalation 
may continue despite meeting stopping rule criteria. 
The mCRM-EWOC Algorithm 
Patients in the first cohort will be treated with the starting dose of 10 mg/kg (2 mg/kg 
QD5 days per cycle), as recommended by PBPK modeling. Prior to opening a new 
cohort, the available DLT data will be used to update the mCRM-EWOC model through 
a Bayesian approach. That is, the posterior probability of parameter θ from the logistic 
model will be estimated by using the DLT data from all patients in DLT-evaluable 
population. A recommended dose, dr, for the next cohort will be calculated using the 
updated mCRM-EWOC model, i.e., P(dr)overdose < 25% and dr = min(drmax, max{di: P(p(di)
∈[0.2,0.35])}) where drmax is the highest next dose which subjects to the maximal 
increment rule. 
Patients in the next cohort will be treated at the dose recommended by such an 
algorithm (possibly adjusted based on clinical judgment). This process is repeated until 
the stopping criterion is met.
Hypothetical trials 
Several hypothetical trials are reported here to illustrate the behavior of the design in 
specific situations. 


Appendix 11: Modified Continual Reassessment Method of Escalation with Overdose 
Control Design 
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
203/Protocol GO40871, Version 4
The first scenario illustrates how dose will be escalated assuming no DLTs are 
observed. The mCRM-EWOC model considered doses under a dose grid from 0 to 
30 mg/kg (6 mg/kg QD5 days per cycle) by every 1 mg/kg (0.2 mg/kg QD5 days per 
cycle). The same dose grid applies in the simulation study. 
Table 1 shows the different levels suggested by the mCRM-EWOC design. The results 
show that, in the absence of observed DLTs, the design will reach high doses based in 
3 cohorts but also that the increments are 50% or below to protect the safety of patients. 
Table 1
Simulated Dose Escalation Path in Absence of Observed 
Dose-Limiting Toxicities
Cohort
Dose (mg/kg)
Next Dose (mg/kg)
Increment
1
10
15
50%
2
15
22
47%
3
22
30
36%
Besides the impact on dose-escalation of the occurrence of a first DLT is examined, 
i.e., for cohorts of 3 subjects, all possible DLT frequencies (1 to 3) are examined 
assuming that no DLTs occur until the given dose for demonstration purpose. The 
recommended next doses suggested by the design after the DLTs are reported in the 
following table. Assuming that no DLTs are observed at this reduced dose, the dose 
suggested after the reduced dose is also computed. 
The results show that the design will adequately adapt the dose in the presence of 
observed DLTs.
Table 2
Impacts on Dose-Escalation of the Occurrence of First Dose-Limiting 
Toxicities (Cohort of 3 Patients)
First DLT 
at Dose 
(mg/kg)
DLTs/Cohort Size
Next Dose 
(mg/kg)
Increment
Dose after the Next 
Cohort (mg/kg)
10
1/3
9
10%
13
2/3
5
50%
7
3/3
3
70%
4
15
1/3
15
0%
19
2/3
10
33%
13
3/3
7
53%
9
22
1/3
20
9%
28
2/3
16
27%
18
3/3
11
50%
14
DLT dose-limiting toxicity. 


Appendix 11: Modified Continual Reassessment Method of Escalation with Overdose 
Control Design 
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
204/Protocol GO40871, Version 4
Simulations 
A simulation study is conducted to evaluate the operating characteristics (sample size, 
estimated MTD, number of patients treated for overdose, etc.) for the chosen design 
parameters (priors, reference dose, stopping rules). For evaluation purposes, a 
maximum sample size of approximately 24 is used in the simulation. 
Scenarios with different toxicity profiles are simulated with hypothetical MTDs from
7 mg/kg (low MTD) to around 20 mg/kg (illustrating a scenario for which a high MTD are 
expected). The starting dose is 10 mg/kg, which is marked by the vertical line in 
Figure 4 in this appendix. The 20% and 35% DLT range is marked by the blue area in 
Figure 4 in this appendix.
Figure 4
"True" Scenarios Used for Simulations
DLT dose limiting toxicity. 
Each scenario uses 1000 simulated trials, analyzed by generating a Markov chain Monte 
Carlo (MCMC) algorithm for 10000 iterations following a 1000-iteration burn-in period.  
Every one out of 2 iterations are saved after the burn-in (i.e., step2).  Random manual 
checks revealed no significant MCMC convergence issues using standard convergence 
diagnostics.


Appendix 11: Modified Continual Reassessment Method of Escalation with Overdose 
Control Design 
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
205/Protocol GO40871, Version 4
The design is evaluated using the following criteria: the MTD chosen, the number of 
subjects treated at doses higher than the MTD, and the sample size of the trials.  The 
following table demonstrates the simulation study result.
According to the simulation study, overall approximate 1214 DLT-evaluable patients will 
be needed to reach to the MTD.  The number of patients who may be treated above 
doses with 35% DLT rate is below 7 on average depending on the MTD.  The most often 
selected MTD according to the mCRM-EWCO are all located within or very near the true 
target dose range.  Overall, the mCRM-EWOC design has a relatively good performance 
in terms of controlling the safety and identifying MTD efficiently (Table 3 in this 
appendix).


Appendix 11: Modified Continual Reassessment Method of Escalation with Overdose Control Design 
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
206/Protocol GO40871, Version 4
Table 3
Operating Characteristics of the mCRM-EWOC Design with Respect to the Chosen Scenarios
Scenarios
Target Dose Range 
From the "True" 
Scenario (mg/kg)
Overall 
Number of 
Patients a
Number of 
Patients Treated 
Above Target 
Toxicity Interval a
Doses 
Selected as 
MTD 
(mg/kg) a
True Toxicity at 
Doses Selected 
as MTD a
Dose Most 
Often 
Selected as 
MTD (mg/kg)
Fitted Toxicity 
Rate at Dose 
Most Often 
Selected a
1
1822
14 (12, 18)
2 (0, 6)
19 (14, 25)
24% (10%, 45%)
20
30% (22%, 35%)
2
1419
13 (9, 18)
2 (0, 6)
15 (10, 21)
24% (10%, 41%)
14
30% (20%, 34%)
3
1015
11 (9, 15)
3 (0, 9)
12 (9, 17)
26% (17%, 42%)
9
20% (16%, 28%)
4
811
11 (6, 15)
3 (0, 6)
10 (7, 14)
29% (17%, 45%)
9
30% (19%, 33%)
5
69
12 (6, 15)
7 (3, 9)
8 (5, 12)
32% (15%, 50%)
9
30% (22%, 40%)
mCRM-EWOCModified Continual Reassessment Method of Escalation with Overdose Control; MTD maximum tolerated dose.
a Values in the table are means, followed by 10% and 90% quantile.


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
207/Protocol GO40871, Version 4
Appendix 12
Howard Definition and Classification of Tumor Lysis Syndrome 
Definitions of Laboratory and Clinical Tumor Lysis Syndrome a
Metabolic
Abnormality
Criteria for Classification of Laboratory 
Tumor Lysis Syndrome
Criteria for Classification of Clinical
Tumor Lysis Syndrome
Hyperuricemia Uric 
acid 8.0 mg/dL
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
Hyperphosphatemia
Phosphorus 4.5 mg/dL (1.5 mmol/L) 
in adults or 6.5 mg/dL (2.1 mmol/L) in 
children
Hyperkalemia
Potassium 6.0 mmol/L
Cardiac dysrhythmia or sudden 
death probably or definitely 
caused by hyperkalemia
Hypocalcemia
Corrected calcium 7.0 mg/dL
(1.75 mmol/L) or ionized 
calcium 1.12 (0.3 mmol/L) b
Cardiac dysrhythmia, sudden 
death, seizure, 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 in the serum creatinine 
level of 0.3 mg/dL (26.5 mol/L) 
(or a single value 1.5 times the 
upper limit of the age-appropriate 
normal range if no baseline 
creatinine measurement is 
available) or the presence of 
oliguria, defined as an average 
urine output of 0.5 mL/kg/hours 
for 6 hours
a In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present 
during the same 24-hour period within 3 days before the start of therapy or up to 7 days 
afterward.  Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis 
syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
b The corrected calcium level in milligrams per deciliter measured calcium level in milligrams 
per deciliter 0.8(4albumin in grams per deciliter).
c Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dL 
(26.5 mol/L) or a period of oliguria lasting 6 hours or more.  By definition, if acute kidney 
injury is present, the patient has clinical tumor lysis syndrome.  Data about acute kidney injury 
are from Levin et al. (2007).
REFERENCES
Table copied from: Howard SC, Jones P, Pui CH. The tumor lysis syndrome. N Engl J Med 
2011;364:184454.
Levin A, Warnock DG, Mehta RL, et al. Improving outcomes from acute kidney injury: report of an 
initiative. Am J Kidney Dis 2007;50:14.


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
208/Protocol GO40871, Version 4
Appendix 13
Acceptability Survey for Patients
Instructions:  Please answer the questions below to help us understand your 
experience with the study medication (idasanutlin).  For questions with a face, indicate 
which of the faces best matches how you felt about the medication.
For children who cannot read yet, parents or caregiver, please help us understand 
your child’s experience with the medication.  Invite your child to look at the cartoon, ask 
him or her the questions, and record his or her answer.  If your child cannot answer the 
question, please leave the question blank.
1.
How did you take the medication?
As a tablet (pill)
         
As a suspension (pills dissolved in water)          
For children who cannot answer for themselves, parents or caregiver, please go 
directly to Questions 8 and 9.
2.
How much did you like the taste of the medication?





Really Bad
Bad
Not sure
Good
Really Good
3.
What was the taste of the medication?
Bitter          
Sweet
         
Sour             
Salty        
Acceptability Survey for Patients, Version 1 (dated December 2018)


Appendix 13: Acceptability Survey for Patients
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
209/Protocol GO40871, Version 4
4.
How much did you like the feeling of the medication in your mouth?





Really Bad
Bad
Not sure
Good
Really Good
5.
How difficult was it to swallow the medication?





Really Bad
Bad
Not sure
Good
Really Good
6.
After the medication was not in your mouth anymore, could you still taste the 
medication?
Yes
No
7.
What was the taste you had in your mouth after the medication was gone?
Bitter          
Sweet
         
Sour             
Salty        
For parent or caregiver of children who cannot answer for themselves: 
8.
At any time did you have a problem in giving the medication to your child because 
he or she refused to take it? 
Yes
No
Acceptability Survey for Patients, Version 1 (dated December 2018)


Appendix 13: Acceptability Survey for Patients
Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
210/Protocol GO40871, Version 4
9.
At any time did you have a problem in giving the planned dose of the medication to 
your child because he or she threw it up? 
Yes
No
Additional questions for participants receiving and caregivers administering 
suspension (tablets dispersed in water):
Instructions:  Please answer the questions below to help us understand your 
experience giving the study medication (idasanutlin). 
10. How easy or difficult was it to fill the medication dispenser (syringe) with water?
Very easy
Somewhat easy
Somewhat difficult
Very difficult
11. Did all of the tablets dissolve completely in the water?
Yes
No
12. Were there any undissolved tablets left in the syringe?
Yes
No
Thank You
Acceptability Survey for Patients, Version 1 (dated December 2018)


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
211/Protocol GO40871, Version 4
Appendix 14
Age and Weight Adjusted Adult-Equivalent Venetoclax Dosing Table
For 2 Years
For2 Years
Dose Groups:     
Age
2-day Ramp-up
(Solid Tumors)
3-Day Ramp-up
(Hematologic Malignancies)
Dose Groups:  
Weight
2-day Ramp-up
(Solid Tumors)
3-Day Ramp-up
(Hematologic Malignancies)
Day 1
Day 2
& On
Day 1
Day 2
Day 3
& On
Day 1
Day 2
& On
Day 1
Day 2
Day 3 
& On
400 mg Adult Equivalent Dose
newborn to 1 month
2.5 a
5 a
2.5 a
2.5 a
5 a
10 to 20 Kg
60
120
30
60
120
1 to 3 months
5 a
10
2.5 a
5 a
10
20 to 30 Kg
80
170
40
80
170
3 to 6 months
10
25
5 a
10
25
30 to 45 Kg
120
250
60
120
250
6 months to 1 year
25
50
10
25
50
45 Kg
200
400
100
200
400
1 to 2 years
30
75
20
40
75
600 mg Adult Equivalent Dose
newborn to 1 month
2.5 a
7.5 a
2.5 a
2.5 a
7.5 a
10 to 20 Kg
80
150
40
80
150
1 to 3 months
10
20
5
10
20
20 to 30 Kg
120
250
50
120
250
3 to 6 months
20
40
10
20
40
30 to 45 Kg
170
350
80
170
350
6 months to 1 year
30
75
20
40
75
45 Kg
300
600
150
300
600
1 to 2 years
60
120
30
60
120
a Dose can only be administered using the 2.5 mg tablet for oral suspension formulation.


Idasanutlin and Venetoclax—F. Hoffmann-La Roche Ltd
212/Protocol GO40871, Version 4
Appendix 15
Dosing Tables for Intrathecal Therapy
AML: CNS negative
Age
Cytarabine
1 year
20 mg
12 years
30 mg
23 years
50 mg
3 years
70 mg
ALL: CNS negative
Age
Methotrexate
1 year
6 mg
12 years
8 mg
23 years
10 mg
3 years
12 mg
AML and ALL: CNS positive or post-traumatic lumbar puncture
Age
Methotrexate
Cytarabine
Hydrocortisone
1 year
6 mg
18 mg
12 mg
12 years
8 mg
24 mg
16 mg
23 years
10 mg
30 mg
20 mg
3 years
12 mg
36 mg
24 mg