Clinical trial NCT03850535
Conditions: Acute Myeloid Leukemia
Keywords: AML
Sponsor: Hoffmann-La Roche
Start date: 2019-03-25; Completion date: 2020-09-10
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin when it is given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance for treating participants with acute myeloid leukemia (AML).

Detailed description:

Arms: arm 1: Participants with newly diagnosed, previously untreated, favorable or intermediate risk AML (according to European LeukemiaNet \[ELN\] 2017 criteria) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin. arm 2: Participants who are idasanutlin treatment-naive, had received induction and chemotherapy consolidation for AML outside of the study, and were in minimal residual disease (MRD)-positive remission after induction will be enrolled in this cohort to receive maintenance treatment with single-agent idasanutlin. arm 3: Participants with newly diagnosed, previously untreated, favorable or intermediate risk AML (according to ELN 2017 criteria) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin (at the recommended Phase 2 dose) plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin. arm 4: Participants with newly diagnosed, previously untreated, high-risk AML (defined as adverse risk according to ELN 2017 criteria, and secondary AML) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin (at the recommended Phase 2 dose) plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin.
Interventions: intervention 1: Idasanutlin intervention 2: Cytarabine intervention 3: Daunorubicin intervention 4: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)
Intervention descriptions: intervention 1: Participants will self-administer idasanutlin tablets by mouth (PO) once daily (QD) for 5 days of each 28-day treatment cycle for up to 2 cycles of induction, up to 4 cycles of consolidation, and 12 cycles of maintenance, according to the study's protocol. intervention 2: Cytarabine will be administered for 7 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 200 milligrams per meter squared (mg/m\^2) of body surface area, once daily (QD) by intravenous (IV) infusion. At the investigator's discretion, cytarabine will also be administered as part of chemotherapy consolidation at a dose of 1.5 g/m\^2 QD as IV infusion for 5 days of each 28-day cycle and for up to 4 cycles of treatment. intervention 3: Daunorubicin will be administered for 3 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 60 mg/m\^2 QD as IV infusion. intervention 4: After induction treatment, participants who achieve remission will either receive chemotherapy consolidation treatment or undergo Allo-HSCT (as per local guidelines) at the investigator's discretion.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase Ib/II Study Evaluating the Safety and Efficacy of Idasanutlin 
in Combination With Cytarabine and Daunorubicin in Patients Newly 
Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and 
Efficacy of Idasanutlin in the Maintenance of First AML Complete 
Remission 
NCT Number: NCT03850535 
Document Date: Protocol Version 1: 31-October-2018 
 
 


FINAL PROTOCOL 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—F. Hoffmann-La Roche Ltd 
Protocol GO40800, Version 1 
PROTOCOL 
TITLE: 
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF IDASANUTLIN IN 
COMBINATION WITH CYTARABINE AND 
DAUNORUBICIN IN PATIENTS NEWLY 
DIAGNOSED WITH ACUTE MYELOID LEUKEMIA 
(AML) AND THE SAFETY AND EFFICACY OF 
IDASANUTLIN IN THE MAINTENANCE OF FIRST 
AML COMPLETE REMISSION 
PROTOCOL NUMBER: GO40800 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2018-002964-25 
IND NUMBER: 
117005 
TEST PRODUCTS: 
Idasanutlin (RO5503781), cytarabine, and 
daunorubicin 
MEDICAL MONITOR: 
, Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
See electronic date stamp below.
 
31-Oct-2018 14:34:15
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Idasanutlin—F. Hoffmann-La Roche Ltd
2/Protocol GO40800, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 22
1.1
Background on Front-Line Acute Myeloid 
Leukemia............................................................................... 22
1.2
Background on Idasanutlin .................................................... 23
1.2.1
Clinical Studies with Idasanutlin ............................................ 23
1.2.2
Idasanutlin in AML................................................................. 24
1.3
Study Rationale and BenefitRisk Assessment..................... 24
2.
OBJECTIVES AND ENDPOINTS ............................................................... 25
2.1
Safety Objectives................................................................... 26
2.2
Efficacy Objectives ................................................................ 26
2.2.1
Primary Efficacy Objective..................................................... 27
2.2.2
Secondary Efficacy Objectives .............................................. 27
2.2.3
Exploratory Efficacy Objectives ............................................. 28
2.3
Pharmacokinetic Objectives .................................................. 28
2.4
Biomarker Objective .............................................................. 29
2.5
Health Status Utility Objective ............................................... 29
3.
STUDY DESIGN......................................................................................... 29
3.1
Description of the Study......................................................... 29
3.1.1
Overview of Study ................................................................. 29
3.1.2
Dose-Escalation Phase ......................................................... 31
3.1.2.1
Definition of DLT.................................................................... 32
3.1.2.2
Treatment Regimens and Dose-Escalation Rules................. 32
3.1.2.3
Use of mCRM for Dose and MTD Determination................... 34
3.1.3
Post-Consolidation Phase and Expansion Phase.................. 37
3.1.4
Post-Treatment Follow-Up and Survival Follow-
Up.......................................................................................... 39
3.2
End of Study and Length of Study......................................... 40
3.3
Rationale for Study Design.................................................... 40
3.3.1
Rationale for Idasanutlin Dose and Schedule........................ 40


Idasanutlin—F. Hoffmann-La Roche Ltd
3/Protocol GO40800, Version 1
3.3.2
Rationale for Study Population .............................................. 40
3.3.3
Rationale for Population PK/Pharmacodynamic 
Analysis ................................................................................. 41
3.3.4
Rationale for Biomarker Assessments................................... 41
3.3.4.1
AML-Associated Mutations, MDM2 Protein 
Expression, MIC-1 Secretion and Gene 
Expression............................................................................. 42
3.3.4.2
MRD Assessment.................................................................. 42
3.3.5
Rationale for Patient-Reported Outcomes............................. 42
4.
MATERIALS AND METHODS .................................................................... 43
4.1
Patients.................................................................................. 43
4.1.1
Inclusion Criteria.................................................................... 43
4.1.1.1
Inclusion Criteria for All Study Phases................................... 43
4.1.1.2
Inclusion Criteria for Patients in the Dose-
Escalation and Expansion Phases ........................................ 45
4.1.1.3
Inclusion Criteria for Patients in the Post-
Consolidation Phase.............................................................. 45
4.1.2
Exclusion Criteria................................................................... 45
4.1.2.1
Exclusion Criteria for All Study Phases.................................. 45
4.1.2.2
Exclusion Criteria for Patients in the Phase Ib 
Dose-Escalation Phase Only................................................. 47
4.1.2.3
Exclusion Criteria for Patients in Phase Ib Post-
Consolidation Phase Only ..................................................... 47
4.1.2.4
Exclusion Criteria for Patients in the Dose-
Escalation Phase and Patients in the 
Favorable/IntermediateRisk Cohort of the 
Expansion Phase Only .......................................................... 47
4.2
Method of Treatment Assignment.......................................... 47
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 48
4.3.1
Formulation, Packaging, and Handling.................................. 48
4.3.1.1
Idasanutlin ............................................................................. 48
4.3.1.2
Cytarabine ............................................................................. 48
4.3.1.3
Daunorubicin ......................................................................... 48
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 48


Idasanutlin—F. Hoffmann-La Roche Ltd
4/Protocol GO40800, Version 1
4.3.2.1
Idasanutlin ............................................................................. 49
4.3.2.2
Cytarabine ............................................................................. 49
4.3.2.3
Daunorubicin ......................................................................... 49
4.3.2.4
Premedication........................................................................ 50
4.3.3
Investigational Medicinal Product Accountability ................... 50
4.3.4
Continued Access to Idasanutlin ........................................... 51
4.4
Concomitant Therapy ............................................................ 51
4.4.1
Permitted Therapy................................................................. 51
4.4.2
Prohibited Therapy ................................................................ 51
4.5
Study Assessments ............................................................... 53
4.5.1
Informed Consent Forms and Screening Log........................ 53
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 54
4.5.3
Physical Examinations........................................................... 54
4.5.4
Performance Status............................................................... 55
4.5.5
Vital Signs.............................................................................. 55
4.5.6
Tumor and Response Evaluations......................................... 55
4.5.7
Laboratory Assessments ....................................................... 56
4.5.8
Mandatory Samples for Pharmacokinetic, 
Pharmacodynamic Biomarker, and Exploratory 
Biomarker Analyses............................................................... 57
4.5.8.1
MRD Assessments for Patients in the Post-
Consolidation Phase.............................................................. 57
4.5.8.2
Pharmacokinetic Analyses..................................................... 57
4.5.8.3
Pharmacodynamic and Exploratory Biomarkers.................... 58
4.5.8.4
Clinical Genotyping................................................................ 59
4.5.8.5
Bone Marrow ......................................................................... 59
4.5.9
Electrocardiograms................................................................ 60
4.5.10
Patient-Reported Outcomes .................................................. 61
4.5.10.1
FACIT-Fatigue....................................................................... 61
4.5.10.2
EORTC QLQ-C30.................................................................. 61
4.5.10.3
EORTC Item Library .............................................................. 62
4.5.10.4
PRO-CTCAE ......................................................................... 62
4.5.10.5
EQ-5D-5L .............................................................................. 62


Idasanutlin—F. Hoffmann-La Roche Ltd
5/Protocol GO40800, Version 1
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 62
4.5.11.1
Overview of the Research Biosample Repository.................. 62
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 63
4.5.11.3
Sample Collection.................................................................. 63
4.5.11.4
Confidentiality........................................................................ 64
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 64
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 65
4.5.11.7
Monitoring and Oversight....................................................... 65
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 65
4.6.1
Study Treatment Discontinuation........................................... 65
4.6.2
Patient Discontinuation from Study........................................ 66
4.6.3
Study Discontinuation............................................................ 66
4.6.4
Site Discontinuation............................................................... 67
5.
ASSESSMENT OF SAFETY....................................................................... 67
5.1
Safety Plan ............................................................................ 67
5.1.1
Safety Risks of Idasanutlin, Cytarabine, and 
Daunorubicin in Leukemia ..................................................... 67
5.1.1.1
Gastrointestinal Toxicity......................................................... 68
5.1.1.2
Cytopenias............................................................................. 68
5.1.1.3
Tumor Lysis Syndrome.......................................................... 68
5.1.1.4
Infections ............................................................................... 68
5.1.1.5
Electrolyte Disorders ............................................................. 69
5.1.1.6
Other Adverse Events............................................................ 69
5.1.2
Risk of Overlapping Toxicities ............................................... 69
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 70
5.1.3.1
Toxicities during Induction and Consolidation 
Treatment .............................................................................. 71
5.1.3.2
Toxicities during Maintenance Treatment.............................. 76
5.2
Safety Parameters and Definitions ........................................ 76


Idasanutlin—F. Hoffmann-La Roche Ltd
6/Protocol GO40800, Version 1
5.2.1
Adverse Events ..................................................................... 76
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 77
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 78
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78
5.3.1
Adverse Event Reporting Period ........................................... 79
5.3.1.1
Adverse Events Associated with Allo-HSCT.......................... 79
5.3.2
Eliciting Adverse Event Information....................................... 79
5.3.3
Assessment of Severity of Adverse Events ........................... 79
5.3.4
Assessment of Causality of Adverse Events ......................... 80
5.3.5
Procedures for Recording Adverse Events............................ 81
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 81
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 81
5.3.5.3
Persistent or Recurrent Adverse Events................................ 81
5.3.5.4
Abnormal Laboratory Values ................................................. 82
5.3.5.5
Abnormal Vital Sign Values ................................................... 83
5.3.5.6
Abnormal Liver Function Tests.............................................. 83
5.3.5.7
Deaths ................................................................................... 84
5.3.5.8
Preexisting Medical Conditions.............................................. 84
5.3.5.9
Lack of Efficacy or Worsening of Acute Myeloid 
Leukemia............................................................................... 84
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 84
5.3.5.11
Patient-Reported Outcome Data ........................................... 85
5.3.5.12
Safety Biomarker Data........................................................... 85
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 86
5.4.1
Emergency Medical Contacts................................................ 86
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 87
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 87
5.4.2.2
Events That Occur after Study Drug Initiation........................ 87
5.4.3
Reporting Requirements for Pregnancies.............................. 87


Idasanutlin—F. Hoffmann-La Roche Ltd
7/Protocol GO40800, Version 1
5.4.3.1
Pregnancies in Female Patients............................................ 87
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 88
5.4.3.3
Abortions ............................................................................... 88
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 88
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 89
5.5
Follow-Up of Patients after Adverse Events .......................... 91
5.5.1
Investigator Follow-Up........................................................... 91
5.5.2
Sponsor Follow-Up ................................................................ 91
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 91
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 91
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 92
6.1
Determination of Sample Size ............................................... 92
6.2
Summaries of Patients Characteristics.................................. 93
6.3
Efficacy Analyses .................................................................. 94
6.3.1
Primary Efficacy Endpoint...................................................... 94
6.3.2
Secondary Efficacy Endpoints............................................... 94
6.3.3
Exploratory Efficacy Endpoints.............................................. 96
6.4
Safety Analyses..................................................................... 96
6.5
PK Analyses .......................................................................... 97
6.6
Biomarker Analyses............................................................... 97
6.7
Health Status Utility Analyses................................................ 97
6.8
Interim Analyses .................................................................... 97
7.
DATA COLLECTION AND MANAGEMENT ............................................... 98
7.1
Data Quality Assurance......................................................... 98
7.2
Electronic Case Report Forms............................................... 98
7.3
Source Data Documentation.................................................. 98
7.4
Use of Computerized Systems .............................................. 99
7.5
Retention of Records............................................................. 99
8.
ETHICAL CONSIDERATIONS.................................................................... 99


Idasanutlin—F. Hoffmann-La Roche Ltd
8/Protocol GO40800, Version 1
8.1
Compliance with Laws and Regulations ................................ 99
8.2
Informed Consent................................................................ 100
8.3
Institutional Review Board or Ethics Committee.................. 101
8.4
Confidentiality...................................................................... 101
8.5
Financial Disclosure ............................................................ 102
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 102
9.1
Study Documentation .......................................................... 102
9.2
Protocol Deviations.............................................................. 102
9.3
Site Inspections ................................................................... 103
9.4
Administrative Structure....................................................... 103
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 103
9.6
Protocol Amendments ......................................................... 104
REFERENCES................................................................................................. 105
LIST OF TABLES
Table 1
Treatment during the Dose-Escalation Phase............................. 34
Table 2
Hypothetical Trial Realizations (Cohort Size3).......................... 37
Table 3
Post-Consolidation and Expansion Cohorts................................ 38
Table 4
Treatment for Expansion Phase (Favorable/Intermediate-
Risk and High-Risk Cohorts)....................................................... 39
Table 5
Treatment for Post-Consolidation Phase .................................... 39
Table 6
Premedication............................................................................. 50
Table 7
Overlapping Toxicities Grade 3: Idasanutlin, Cytarabine, 
and Daunorubicin........................................................................ 70
Table 8
Idasanutlin Dose-Reduction Steps.............................................. 71
Table 9
Guidelines for Management of Idasanutlin-Related 
Hematologic Toxicities in Induction and Consolidation 
Treatment.................................................................................... 72
Table 10
Guidelines for Management of Idasanutlin-Related
Gastrointestinal Toxicities in Induction and Consolidation .......... 73
Table 11
Guidelines for Management of Idasanutlin-Related Non-
Hematologic Toxicities in Induction and Consolidation ............... 74
Table 12
Guidelines for Management of Toxicities That Occur during 
Maintenance ............................................................................... 76
Table 13
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 80


Idasanutlin—F. Hoffmann-La Roche Ltd
9/Protocol GO40800, Version 1
Table 14
Potential 90% CI for the True Probability of Achieving 
Complete Response at the End of Induction for N20 in 
High-Risk Patients ...................................................................... 93
Table 15
Potential 90% CI for the True Probability of Achieving 
Complete Response at End of Induction/Consolidation for 
N20 in Favorable/IntermediateRisk Patients........................... 93
LIST OF FIGURES
Figure 1
Regulation of p53 Stability and Activity by MDM2....................... 23
Figure 2
Study Schema............................................................................. 30
Figure 3
Induction, Consolidation, and Maintenance Phases ................... 31
Figure 4
Selected Prior Distribution with 95% Credible Interval................ 36
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 109
Appendix 2
Schedule of Pharmacokinetic and PD Biomarker Samples ...... 122
Appendix 3
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 126
Appendix 4
Howard Definition and Classification of Tumor Lysis 
Syndrome ................................................................................. 127
Appendix 5
Toxicity Management Guidelines.............................................. 129
Appendix 6
Calculation of Creatinine Clearance Using the Modified 
Cockcroft-Gault Formula........................................................... 136
Appendix 7
Classification of Acute Myeloid Leukemia (World Health 
Organization, 2016 revision) ..................................................... 137
Appendix 8
European LeukemiaNet Standardization Reporting System ..... 139
Appendix 9
Mosteller and Dubois Calculation for Body Surface Area 
(BSA) ........................................................................................ 141
Appendix 10
New York Heart Association Functional Classification.............. 142
Appendix 11
Fridericia’s Formula for Corrected QT interval .......................... 143
Appendix 12
FACIT-Fatigue .......................................................................... 144
Appendix 13
EORTC QLQ-C30 (Selected Scales)........................................ 145
Appendix 14
EORTC Item Library Symptoms................................................ 146
Appendix 15
Patient-Reported Outcomes Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) ........................................... 147
Appendix 16
EQ-5D-5L.................................................................................. 148
Appendix 17
Prohibited Medications.............................................................. 151
Appendix 18
Modified Continual Reassessment Method Simulations ........... 153
Appendix 19
Response Criteria for Acute Myeloid Leukemia ........................ 160


Idasanutlin—F. Hoffmann-La Roche Ltd
10/Protocol GO40800, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY 
AND EFFICACY OF IDASANUTLIN IN 
COMBINATION WITH CYTARABINE AND 
DAUNORUBICIN IN PATIENTS NEWLY 
DIAGNOSED WITH ACUTE MYELOID LEUKEMIA 
(AML) AND THE SAFETY AND EFFICACY OF 
IDASANUTLIN IN THE MAINTENANCE OF FIRST
AML COMPLETE REMISSION
PROTOCOL NUMBER:
GO40800
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-002964-25
IND NUMBER:
117005
TEST PRODUCTS:
Idasanutlin (RO5503781), cytarabine, and 
daunorubicin
MEDICAL MONITOR:
, 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 as instructed by your local study monitor.


Idasanutlin—F. Hoffmann-La Roche Ltd
11/Protocol GO40800, Version 1
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II STUDY EVALUATING THE SAFETY AND 
EFFICACY OF IDASANUTLIN IN COMBINATION WITH 
CYTARABINE AND DAUNORUBICIN IN PATIENTS NEWLY 
DIAGNOSED WITH ACUTE MYELOID LEUKEMIA (AML) AND THE 
SAFETY AND EFFICACY OF IDASANUTLIN IN THE 
MAINTENANCE OF FIRST AML COMPLETE REMISSION
PROTOCOL NUMBER:
GO40800
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-002964-25
IND NUMBER:
117005
TEST PRODUCTS:
Idasanutlin (RO5503781), cytarabine, and daunorubicin
PHASE:
Phase Ib/II
INDICATION:
Acute myeloid leukemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin in the following 
groups:

Idasanutlin in combination with cytarabine and daunorubicin (73 regimen) in induction,
idasanutlin in combination with cytarabine in consolidation, and single-agent idasanutlin in 
maintenance in patients with newly diagnosed, previously untreated acute myeloid leukemia 
(AML)

Idasanutlin as a single agent in maintenance for idasanutlin treatmentnaive patients who 
received induction and chemotherapy consolidation for AML outside the study and had 
minimum residual disease (MRD)-positive complete remission (CR) after induction
The safety objectives for this study are as follows:

To determine the recommended Phase II dose (RP2D) for idasanutlin when given in 
combination with cytarabine and daunorubicin during the dose-escalation phase on the 
basis of the following endpoint:

Incidence of dose-limiting toxicities (DLTs) during the first cycle of study treatment

To evaluate the safety and tolerability of idasanutlin when given in combination with 
cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, 
and as a single agent in maintenance on the basis of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in ECG parameters

Change from baseline in targeted clinical laboratory test results


Idasanutlin—F. Hoffmann-La Roche Ltd
12/Protocol GO40800, Version 1

To compare the differences in patient-reported treatment-related symptoms

Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of symptomatic treatment toxicities (nausea, vomiting, and diarrhea), as 
assessed through use of the NCI Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events (PRO-CTCAE)

Change from baseline in symptomatic treatment toxicities, as assessed through use of 
the PRO-CTCAE
The primary efficacy objective for this study is to evaluate the efficacy of idasanutlin when given 
in combination with cytarabine and daunorubicin as induction treatment, on the basis of the 
following endpoint:

Proportion of patients with a CR at the end of induction treatment
The secondary objective for this study is to evaluate the efficacy of idasanutlin when given in 
combination with cytarabine and daunorubicin as induction treatment, in combination with 
cytarabine as consolidation treatment, and/or as a single agent during maintenance treatment,
on the basis of the following endpoints, which will be analyzed in patients enrolled during 
specified phases:
Dose-escalation or expansion phase

Proportion of patients with a CR, complete remission with incomplete blood count recovery 
(CRi), or complete remission with incomplete platelet count recovery (CRp) at the end of 
induction treatment

Proportion of patients with a CR or complete remission with partial hematologic recovery 
(CRh) at the end of induction treatment

Proportion of patients with a negative MRD status at the end of induction treatment 

EFS, defined as the time from initiation of study treatment to treatment failure (failure to 
achieve CR, CRi, CRp, or CRh), hematologic relapse, or death from any cause, whichever 
occurs first

OS, defined as the time from initiation of study treatment to death from any cause

RFS in patients who achieve remission (CR, CRi, CRp, or CRh), defined as the time from 
remission to the date of hematologic relapse or death from any cause, whichever occurs 
first
Post-consolidation phase

Proportion of patients converting from MRD-positive to MRD-negative status at any time 

EFS, defined as the time from initiation of induction treatment (prior to study entry) to 
hematologic relapse or death from any cause, whichever occurs first

OS, defined as the time from remission (prior to study entry) to death from any cause

RFS in patients who achieved remission (CR, CRi, CRp, or CRh), defined as the time from 
remission (prior to study entry) to the date of hematologic relapse or death from any cause, 
whichever occurs first
All phases

Change from baseline in patient-reported disease-related symptoms and health-related 
quality of life at specified timepoints, as assessed through use of the Functional
Assessment of Chronic Illness Therapy (FACIT)-Fatigue, European Organisation for 
Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (EORTC 
QLQ-C30) (selected scales), and European Organisation for Research and Treatment of 
Cancer (EORTC) Item Library (selected symptoms)
The exploratory efficacy objectives for this study are as follows:

Primary and secondary endpoints (defined above) in the subset of patients with 
wild-type p53

MRD response over time (i.e., during induction, consolidation, and maintenance)


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
Time to MRD-negative status, defined as time from initiation of treatment to confirmation of 
negative MRD status
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the PK profiles of idasanutlin (and its metabolites, if appropriate), 
cytarabine, and daunorubicin on the basis of the following endpoint:

Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, and 
daunorubicin at specified timepoints

To assess potential PK interactions among idasanutlin, cytarabine, and daunorubicin on the 
basis of the following endpoint:

Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, and 
daunorubicin at specified timepoints
The exploratory PK objective for this study is to evaluate potential relationships between drug 
exposure and the efficacy and safety of idasanutlin, cytarabine, and daunorubicin on the basis 
of the following endpoints:

Relationship between plasma concentration or PK parameters for each drug (idasanutlin, 
cytarabine, and daunorubicin) and efficacy endpoints

Relationship between plasma concentration or PK parameters for each drug (idasanutlin, 
cytarabine, and daunorubicin) and safety endpoints
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to study treatment (i.e., predictive biomarkers), are associated with acquired 
resistance to study treatment, are associated with susceptibility to developing adverse events, 
can provide evidence of study treatment activity (i.e., pharmacodynamic biomarkers), can 
contribute to improvement of diagnostic assays, or can increase the knowledge and 
understanding of disease biology, drug safety, or study treatment mechanism of action, on the 
basis of the following endpoint:

Relationship between biomarkers in blood or bone marrow and efficacy, safety, PK, or other 
biomarker endpoints
The health status utility objective for this study is to evaluate health status utility scores of 
patients treated with idasanutlin on the basis of the following endpoint:

Change from baseline in EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
index-based and visual analogue scale scores at specified timepoints
Study Design
Description of Study
This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, efficacy, 
and pharmacokinetics of idasanutlin when given in combination with cytarabine and 
daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent 
in maintenance.  
The study will include an initial dose-escalation phase designed to determine the RP2D for 
idasanutlin when given in combination with cytarabine and daunorubicin in induction. The dose-
escalation phase includes patients with newly diagnosed, previously untreated AML who have 
favorable or intermediate risk to maximize accumulated safety data on consolidation by 
minimizing the number of patients moving to allogenic hematopoietic stem cell transplant 
(allo-HSCT) instead of systemic consolidation.  A post-consolidation phase, run in parallel to the 
dose-escalation phase, includes idasanutlin treatmentnaive patients who received induction 
and chemotherapy consolidation for AML outside the study and had MRD-positive remission 
after induction.  Patients enrolled in the post-consolidation phase will be treated with idasanutlin 
at a set dose of 150 mg.  An expansion phase, to be conducted after completion of the 
dose-escalation phase, includes two distinct cohorts of patients with newly diagnosed, 
previously untreated AML:  patients with favorable or intermediate risk and patients with high 
risk.  High risk is defined as patients with adverse risk or secondary AML (i.e., AML evolving 


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from antecedent hematologic disorder [AHD]).  Patients enrolled in the expansion phase will be 
treated with induction therapy consisting of idasanutlin at the RP2D in combination with 
cytarabine and daunorubicin.  After completion of induction therapy, patients enrolled in the 
dose-escalation phase or expansion phase will receive idasanutlin in combination with 
cytarabine in consolidation, followed by single-agent idasanutlin in maintenance.
Number of Patients
Approximately 80 patients (915 patients in the dose-escalation phase, 30 patients in the 
post-consolidation phase, and 40 patients in the expansion phase) are expected to be enrolled 
in this study at approximately 20 investigational sites worldwide.  Given the nature of the dose 
escalation, the number of patients enrolled may vary. 
Target Population
Inclusion Criteria
For all study cohorts, patients must meet the following inclusion criteria for enrollment in the 
study:

Signed Informed Consent Form

Age 18 years old

Eastern Cooperative Oncology Group performance status 2

Adequate hepatic function, as assessed by the following:
Serum total bilirubin 1.5institutional upper limit of normal (ULN), unless resulting 
from hemolysis, Gilbert syndrome, or liver infiltration with leukemia (up to 3ULN)
AST or ALT 3institutional ULN (or 5upper limit of institutional laboratory 
reference range if liver infiltration with leukemia)

Adequate renal function assessed by serum creatinine within reference laboratory ranges or
creatinine clearance (by Cockcroft-Gault formula) 50 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 6 months after the final dose of 
study drug. Women must refrain from donating eggs during this same period.
A woman 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 has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study 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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for 6 months after the final dose of study drug.  Men must refrain 
from donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period and for 6 months after the final dose of study drug to avoid 
exposing the embryo.


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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.

Ability to understand and willingness to sign a written informed consent form and comply 
with all study requirements including completion of patient-reported questionnaires
Inclusion Criteria for Patients in the Dose-Escalation and Expansion Phases
Patients in the dose-escalation and expansion cohorts must meet the following inclusion 
criterion for enrollment in the study:

Documented/confirmed newly diagnosed AML not previously treated according to WHO
Inclusion Criteria for Patients in the Post-Consolidation Phase:
Patients in the post-consolidation cohort must meet the following inclusion criterion for 
enrollment in the study:

Documented/confirmed AML according to WHO in remission after induction, within 21 days 
of end of last chemotherapy consolidation cycle and were MRD positive at end of induction 
as per local laboratory assessment (validated quantitative AML specific MRD assessment 
with a 0.1% threshold)  
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry in any part of 
the study:

Clinical evidence of CNS leukemia

Any Grade 2 non-hematological toxicities prior to starting therapy (except fatigue, anorexia, 
and alopecia).

Current treatment with any other investigational or commercial agents or therapies 
administered with the intention to treat their malignancy with the exception of hydroxyurea 
(HU) or 6-mercaptopurine (6-MP).  
HU and 6-MP must be discontinued at least 24 hours before initiation of study 
treatment.

Treatment-related AML

Acute promyelocytic leukemia

History of other malignancy that could affect compliance with the protocol or interpretation
of results, with the exception of the following:
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in 
situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-grade, 
early-stage localized prostate cancer
Any previously treated malignancy that has been in remission without treatment for 
2 years prior to enrollment

Any severe and/or uncontrolled medical conditions or other conditions that could affect their 
participation in the study, impair the ability of the investigator to evaluate the patient, or 
impair the patient’s ability to complete the study such as the following:
Unstable angina, symptomatic or otherwise uncontrolled arrhythmia (does not include 
stable, lone atrial fibrillation), uncontrolled hypertension, symptomatic congestive heart 
failure (New York Heart Association Class III and IV cardiac), myocardial infarction 
6 months prior to first study treatment, and cerebrovascular accidents 6 months 
before study treatment start
Unstable seizure disorders

Echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan showing ejection 
fraction 40%


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
Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized 
by this study treatment, such as hereditary coagulation disorders, insulin-dependent 
diabetes mellitus not optimally controlled with medical management (e.g., presence of 
ketoacidosis), or active GI conditions affecting absorption

Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk 
to the patient upon the induction of neutropenia, that is, patients who are or should be on 
antimicrobial agents for the treatment of active infection such as the following:
Fungal infection with visceral involvement, other than mucosal candidiasis, with less 
than 2 weeks of appropriate systemic antifungal therapy
Bacterial infection with positive cultures in the 7 days prior to dosing
Patients who have received less than 5 days of appropriate therapeutic antibiotic 
therapy for an identified infection
Neutropenic fever that is considered infection related within 72 hours prior to dosing
History of symptomatic C. difficile infection that required treatment within 1 month prior 
to dosing.
Upon clinical response to C. difficile treatment, the stool consistency and frequency 
must have returned to normal.

Febrile patients within 72 hours of study treatment initiation

Patients with a history of active or chronic infectious hepatitis unless serology demonstrates 
clearance of infection

Patients unable to interrupt treatment with moderate to strong CYP2C8 inducers and 
inhibitors (including gemfibrozil, which is also an inhibitor of UGT1A3), CYP2C8 or 
OATP1B1/3 substrates, or strong CYP3A4 inducers during the treatment phase.
These agents must be discontinued 7−14 days prior to the start of study.

Patients unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-
platelet agents (e.g., warfarin, chronic daily treatment with aspirin [325 mg/day], 
clopidogrel, dabigatran, apixaban, rivaroxaban, or subcutaneous [SC] anticoagulant 
prophylaxis) during the treatment phase.  These agents must be discontinued 7 days (or 
5 half-lives) prior to the start of study medication  

Patients who have a history of clinically significant liver cirrhosis (e.g., ChildPugh class B 
and C)

Patients with extramedullary AML with no evidence of systemic involvement

Pregnant or breastfeeding patients

Known history of HIV-positive status
For patients with unknown HIV status, HIV testing must be performed at screening if 
not in contradiction with local legislation.

Patients who might refuse to receive blood products and/or have a hypersensitivity to blood 
products

Prior treatment with an MDM2 antagonist

Patients with clinically relevant QTc prolongation (QT interval corrected using Fridericia’s
formula 480 ms), a family history of long QT syndrome
Exclusion Criteria for Patients in the Phase Ib Dose-Escalation Phase Only
Patients who meet any of the following exclusion criterion will be excluded from enrollment in 
the dose-escalation cohort in any part of the study:

Adverse risk patients as per Europe LeukemiaNet 2017 
Exclusion Criteria for Patients in Phase Ib Post-Consolidation Phase Only
Patients who meet any of the following exclusion criterion will be excluded from enrollment in 
the dose-escalation cohort in any part of the study:

Any Grade 2 hematologic adverse events prior to starting therapy


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
Previous HSCT
Exclusion Criteria for Patients in the Dose-Escalation Phase and Patients in the 
Favorable/Intermediate-Risk Cohort of the Expansion Phase Only
Patients who meet any of the following exclusion criterion will be excluded from the 
dose-escalation phase and the favorable/intermediate-risk cohort of the expansion phase:

Secondary AML defined as AML evolving from AHD
End of Study
The end of this study is defined as the date when the last patient, last visit occurs.  Patients will 
be followed up to 2 years after last patient is enrolled or all patients have died, whichever occurs 
first.  
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 6 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Idasanutlin:  Patients will self-administer idasanutlin tablets by mouth each day in the morning 
according to the schedule of activities.
On days when idasanutlin is given in combination with chemotherapy, idasanutlin should be 
administered first.  During consolidation when idasanutlin is given in combination with 
cytarabine, idasanutlin should be administered first.  
Cytarabine:  Cytarabine will be administered in the first cycle of induction at a dose of 
200 mg/m2 daily by IV for 7 days, immediately after the corresponding dose of idasanutlin. 
Dose and regimen can be lowered per investigator choice in the second induction cycle
Cytarabine will be administered in consolidation at a dose of 1.5 g/m2 once a day (QD) for 
5 days as an IV infusion over a minimum of 3 hours, immediately after corresponding dose of 
idasanutlin.  
The dose of cytarabine should be calculated based on a body weight measurement within 
2 days of the first day of each cycle.
Daunorubicin:  Daunorubicin will be administered in induction at a dose of 60 mg/m2 QD for 
3 days as IV infusion, immediately after the corresponding dose of idasanutlin.  Dose and 
regimen can be lowered per investigator choice in the second induction cycle.
The dose of daunorubicin should be calculated based on a body weight measurement within 
2 days of the first day of each cycle.
Statistical Methods
Primary Analysis
The primary efficacy analysis will be the estimation of the proportion of patients with a CR at the 
end of induction treatment.
Determination of Sample Size  
Dose finding will be conducted during the dose-escalation phase of this study.  The estimated 
sample size follows from the dose-escalation rules for a modified continuous reassessment 
method (mCRM) algorithm.  It is anticipated that enrollment of up to five cohorts of 36 patients 
each, for a total of 915 evaluable patients, will be required to establish the RP2D during the 
dose-escalation phase.  Assuming 5 not-evaluable patients; the expected maximum sample 
size will be approximately 20 patients.
Approximately 40 patients (20 favorable/intermediaterisk patients and 20 high-risk patients in 
two separate cohorts) will be enrolled during the expansion phase.  A sample size of 20 patients 
in the high-risk cohort is deemed sufficient to provide adequate precision for the point estimate 
and for the lower end of the 90% CI to rule out a clinically uninteresting probability of response 
of 50% with an observed CR proportion of 70%.  Depending on the proportions of patients 
with adverse risk or secondary AML enrolled, a CR proportion up to 50%55% is expected for 
high-risk patients under current 73 standard of care.


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Interim Analyses
Optional interim safety and/or efficacy data review may be carried out by an internal monitoring 
committee (IMC) that includes Sponsor members at the discretion of the Medical Monitor. The 
decision to conduct such an analysis and the corresponding timing will be documented in the 
Sponsor's trial master file prior to the conduct of the interim analysis.  In particular, given the 
hypothesis-generating nature of this study, the Sponsor may choose to conduct interim efficacy 
analyses for early stopping (futility) by using observed proportion of patients achieving complete 
response (e.g., predictive probability that this trial will have a positive outcome if carried out to 
completion based on historical control data available at the time of analysis).


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
6-MP
6-mercaptopurine
73
7 days of cytarabine and 3 days of daunorubicin
AHD
antecedent hematologic disorder
allo-HSCT
allogenic hematopoietic stem cell transplant
AML
acute myeloid leukemia
APL
acute promyelocytic leukemia
AUC
area under the concentrationtime curve
AUC0-
area under the concentrationtime curve during one dosing interval
AUC0-24h
area under the concentrationtime curve during a 24 hour dosing 
interval
BID
twice a day
BSA
body surface area
CL
total clearance of drug
CL/F
apparent clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum concentration observed
CR
complete remission
CRi
complete remission with incomplete blood count recovery
CRh
complete remission with partial hematologic recovery
CRp
complete remission with incomplete platelet count recovery
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLS
clinical tumor lysis syndrome
Ctrough
steady-state concentration at the end of a dosing interval (i.e., just prior 
to next drug administration)
CYP
cytochrome P450
DDI
drugdrug interaction
DLT
dose-limiting toxicity
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
EFS
event-free survival
ELN
European LeukemiaNet


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Abbreviation
Definition
EORTC QLQ-C30
European Organisation for the Research and Treatment of Cancer 
Quality-of-Life Questionnaire, Core 30
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
FACIT
Functional Assessment of Chronic Illness Therapy
GI
gastrointestinal
HIPPA
Health Insurance Portability and Accountability Act
HMRA
hematologic malignancy response assessment
HRQoL
health-related quality of life
HSCT
hematopoietic stem cell transplant
HU
hydroxyurea
ICH
International Council on Harmonisation
IDCC
independent Data Coordinating Center
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LFS
leukemia-free survival
LPLV
last patient, last visit
mCRM
modified continual reassessment method
MDM2
murine double minute 2
MIC-1
macrophage inhibitory cytokine-1
MLFS
morphologic leukemia-free state
MRD
minimal residual disease
MTD
maximum tolerated dose
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5
NGS
next-generation sequencing
NIMP
non-investigational medicinal product
OATP
organic anion-transporting polypeptide
OS
overall survival
PK
pharmacokinetic
PO
orally
PR
partial remission
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcomes Common Terminology Criteria for Adverse 
Events
QD
once a day


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Abbreviation
Definition
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
relapse-free survival
RP2D
recommended Phase II dose
R/R
relapsed or refractory
TLS
tumor lysis syndrome
ULN
upper limit of normal
VAS
visual analogue scale


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1.
BACKGROUND
1.1
BACKGROUND ON FRONT-LINE ACUTE MYELOID LEUKEMIA
Acute myeloid leukemia (AML) is an aggressive malignancy arising from hematopoietic 
progenitor cells in the bone marrow and is characterized by accumulation of blasts that 
fail to mature and differentiate.  It is the most common form of acute leukemia in adults, 
with a median age of 67 years at diagnosis (Howlader et al. 2014).  
The yearly incidence of AML in European adults is 58 cases per 100,000 individuals,
with a steep increase in the population aged over 70 years, where the incidence reaches 
15–25 cases per 100,000 individuals per annum (Fey and Buske 2013).  Approximately 
20,000 patients were diagnosed with AML with greater than 10,000 AML patient deaths 
in the United States during 2015 (Siegel et al. 2015).  
Specific genetic markers have been shown to correlate with prognosis (Döhner et al. 
2017) and therefore are the basis of risk classification in AML, which drives the 
treatment strategy (see Appendix 7). Development of targeted therapies in the past 
2 years led to recent approvals (FLT3 inhibitors, IDH inhibitors) (Döhner et al. 2017) but 
only for a subset of patients, and for the majority of patients the treatments have not 
changed in decades. Patients fit for intensive chemotherapy receive up to 2 cycles of 
induction followed by a consolidation phase with cytarabine-based regimen or 
hematopoietic stem cell transplant (HSCT); unfit patients receive a low-intensity regimen 
given in consecutive cycles. A major field of research has included a maintenance 
phase, but no conclusive data have yet shown clinical benefit.
Intensive treatment of de novo AML in adults using standard cytarabine- and 
anthracyclinebased chemotherapy induction regimens achieves complete remission 
(CR) proportions ranging from 50% to 80% (Estey 2001; Appelbaum et al. 2006).  
Nonetheless, 60%70% of patients under the age of 60 years who achieve a CR will 
relapse, and only less than 20% of elderly patients are long-term survivors 
(Burnett et al. 2011).  Secondary AML (s-AML) includes patients with a history of an 
antecedent hematologic disorder (AHD), such as myelodysplastic syndrome or 
myeloproliferative neoplasms, whose disease has progressed to AML.  s-AML accounts 
for 10%20% of AML and is associated with poor outcomes (Granfeldt Østgård et al. 
2015; Hulegardh et al 2015; Zeichner and Arellano 2015).  Survival after relapse in 
patients with AML is poor, especially in elderly patients.  
Although some patients with AML benefit from chemotherapy-based regimens, these 
therapies are rarely curative.  There continues to be an unmet need for novel treatments 
that can significantly extend overall survival (OS).  The use of therapies that specifically 
target signaling pathways known to be dysregulated or aberrant in AML may improve 
outcomes in AML.


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1.2
BACKGROUND ON IDASANUTLIN
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, including 
lymphoma cells, to the compound leads to a dose-dependent accumulation of p53 
protein and activation of its transcriptional targets and the p53 pathway. As a result, 
cancer cells undergo a cell-cycle block during G1 and G2 phases followed by apoptosis 
in vitro and in vivo (see Figure 1) (Ding et al. 2013). 
See the Idasanutlin Investigator's Brochure for additional details on nonclinical and 
clinical studies.
Figure 1
Regulation of p53 Stability and Activity by MDM2 
BAXBCL-2associated X protein; BCL-2B-cell lymphoma 2 protein; CDKcyclin-dependent 
kinase; Cyto Ccytochrome C; G1Growth 1/Gap 1 phase; G2Growth 2/Gap 2 phase; 
Mmitosis; MDM2murine double minute 2; NOXAphorbol-12-myristate-13-acetateinduced 
protein 1; p21cyclin-dependent kinase inhibitor 1A (CDKN1A, CIP1); PUMAp53 upregulated 
modulator of apoptosis; Ssynthesis phase.
1.2.1
Clinical Studies with Idasanutlin
Idasanutlin was investigated in patients with solid tumors (Phase I Studies NP27872, 
NP28902, and NP29910) and in patients with AML (Phase I Study NP28679).  It is 
currently being developed in patients with relapsed or refractory (R/R) AML in a Phase III 
study (WO29519), exploring the combination of cytarabine and idasanutlin in fit patients.
In parallel, the Phase Ib/II study GH29914 is exploring the combination of idasanutlin
and venetoclax in a chemotherapy-free regimen in unfit patients with R/R AML.  
Exploration of idasanutlin in combination with obinutuzumab and rituximab, with or 
without venetoclax, in patients with non-Hodgkin lymphoma (NHL) (Phase Ib/II


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Studies BH29812 and BH39147) are ongoing as well as the bioequivalence study 
NP39051 in patients with solid tumors and a Phase I/II, single-agent study in patients 
with polycythemia vera. See the Idasanutlin Investigator's Brochure for additional details 
on clinical studies.
1.2.2
Idasanutlin in AML
All patients in the Phase I/Ib study NP28679 (n122) have experienced at least one 
adverse event.  The most common adverse events across the study groups were from 
the gastrointestinal (GI) disorders system organ class; in particular, patients experienced 
diarrhea and nausea, and to a lesser extent, vomiting.  These events were also the most 
common adverse events considered by investigators to be related to study treatment.  
Serious adverse events occurred in 71 of 122 patients during the study; the most 
common were infectious and hematologic events.  Infectious adverse events were more 
common for patients with AML compared with patients with solid tumors (Studies 
NP27872 and NP28902).  The most frequent serious adverse events that were 
considered by investigators to be related to study treatment (febrile neutropenia and
sepsis) occurred in 25 of the 71 patients.
Although the maximum tolerated dose (MTD) was not reached in a formal manner for 
the 56 patients with AML during dose escalation, the clinical experience for patients 
treated at 800 mg twice a day (BID) was evaluated by investigators as not tolerable for 
those patients, primarily due to GI adverse events (mainly diarrhea) and bone marrow 
failure (a dose-limiting toxicity [DLT]), and the 600 mg BID dose was therefore selected 
as the recommended Phase II dose (RP2D).
In a Phase Ib/II study (GH29914) in elderly unfit patients with R/R AML, 34 patients had 
received combination therapy with venetoclax (daily dosing) and idasanutlin (Days 15) 
as of cutoff date of 6 April 2018. As of this date, the most frequent adverse events in the 
venetoclax plus idasanutlin arm were GI toxicities (diarrhea, nausea, and vomiting) and 
hematologic toxicities (neutropenia and thrombocytopenia). The most frequent 
Grade 3 adverse events in the venetoclax plus idasanutlin arm were febrile neutropenia, 
neutropenia, thrombocytopenia, and anemia. 
The Phase III study WO29519 in patients with R/R AML fit for intensive chemotherapy is 
designed to compare 300 mg idasanutlin (adjusted for formulation differences) BID plus 
1 g/m2 cytarabine with placebo plus 1 g/m2 cytarabine.  This study is currently ongoing.
For further details on clinical studies, please refer to the Idasanutlin Investigator’s 
Brochure.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Patients newly diagnosed with AML and treated with standard induction chemotherapy 
(such as cytarabine on Days 17 plus daunorubicin on Days 13 [73 regimen]) will 
achieve a CR rate of 50%80%, depending on their risk classification. Nevertheless, a 


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vast majority of patients will relapse within months and OS in patients with AML remains
poor (Döhner et al. 2017). Improvement of the CR rate at end of induction and
sustainability of the response through consolidation to achieve deeper and more durable 
remissions remains a high unmet need. Furthermore, the role of maintenance treatment 
to prevent relapse remains to be assessed.  This study will combine idasanutlin with 
cytarabine and daunorubicin in induction and idasanutlin with cytarabine in consolidation
followed by single-agent idasanutlin as maintenance. One additional cohort will
investigate the benefit of single-agent idasanutlin as maintenance therapy in idasanutlin
treatmentnaive patients who were minimal residual disease (MRD) positive at end of 
induction. Those patients are known to have a higher rate of relapse (Jongen-Lavrencic 
et al. 2018).
Cytarabine and daunorubicin are both myelosuppressive and, as such, have an 
overlapping toxicity profile with idasanutlin.  In the AML population, this combination 
appears nevertheless desirable because the additive effect might lead to increased 
clearance of blasts and deeper responses for the combination treatment.
Comorbidities and characteristics such as older age, frailty, and presence of prolonged 
cytopenias prior to study initiation are common among patients with AML.  The induction 
and consolidation treatment proposed in this study is anticipated to lead to cytopenias,
rendering patients susceptible to infections. To reduce the risk to patients enrolled, this 
study will rely on stringent enrollment criteria for performance status, diligent clinical 
observation, and management (for detailed information on toxicity management 
guidelines, please refer to Appendix 5), and pharmacovigilance.  Doses for 73 
chemotherapy in induction and cytarabine in consolidation have been chosen in 
accordance to standard clinical practices and aim to minimize combination toxicities.
A maintenance phase will be investigated in this study in both idasanutlin predosed 
patients and idasanutlin treatmentnaive patients with the goal to decrease relapse rate 
following consolidation hence improving OS in all comers (regardless of cytogenetic risk). 
Idasanutlin will be given as single agent every month for a year.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin in the 
following groups:

Idasanutlin in combination with cytarabine and daunorubicin (73 regimen) in 
induction, idasanutlin in combination with cytarabine in consolidation, and 
single-agent idasanutlin in maintenance in patients with newly diagnosed, previously 
untreated AML

Idasanutlin as a single agent in maintenance for idasanutlin treatmentnaive 
patients who received induction and chemotherapy consolidation for AML outside 
the study and had MRD-positive remission after induction


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This study is composed of a dose-escalation phase, an expansion phase, and a 
post-consolidation phase (see Figure 2).
Specific objectives and corresponding endpoints for the study are outlined below.
In this study, "study treatment" refers to the protocol-mandated treatments under study 
(i.e., idasanutlin, cytarabine, and daunorubicin).
2.1
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To determine the RP2D for idasanutlin when given in combination with cytarabine 
and daunorubicin during the dose-escalation phase on the basis of the following 
endpoint:

Incidence of DLTs during the first cycle of study treatment

To evaluate the safety and tolerability of idasanutlin when given in combination with 
cytarabine and daunorubicin in induction, in combination with cytarabine in
consolidation, and as a single agent in maintenance on the basis of the following 
endpoints:

Incidence and severity of adverse events, including DLTs, with severity 
determined according to National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in ECG parameters

Change from baseline in targeted clinical laboratory test results

To compare the differences in patient-reported treatment-related symptoms

Presence, frequency of occurrence, severity, and/or degree of interference with 
daily function of symptomatic treatment toxicities (nausea, vomiting, and 
diarrhea), as assessed through use of the NCI Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Change from baseline in symptomatic treatment toxicities, as assessed through 
use of the PRO-CTCAE
2.2
EFFICACY OBJECTIVES
Response is determined by the investigator according to European LeukemiaNet (ELN) 
and additional response criteria for AML (see Appendix 19).
Efficacy will be evaluated in patients enrolled in the expansion phase and the 
post-consolidation phase but will also be assessed for patients enrolled in the 
dose-escalation phase.  Data from patients who were treated at the RP2D during the 
dose-escalation phase will be pooled with data from the corresponding cohort of the 
expansion phase (favorable/intermediaterisk patients; see Section 3.1.1).  


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2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of idasanutlin 
when given in combination with cytarabine and daunorubicin as induction treatment, on 
the basis of the following endpoint:

Proportion of patients with a CR at the end of induction treatment
2.2.2
Secondary Efficacy Objectives
The secondary objective for this study is to evaluate the efficacy of idasanutlin when 
given in combination with cytarabine and daunorubicin as induction treatment, in 
combination with cytarabine as consolidation treatment, and/or as a single agent during 
maintenance treatment, on the basis of the following endpoints, which will be analyzed in 
patients enrolled during specified phases:
Dose-escalation or expansion phase

Proportion of patients with a CR, complete remission with incomplete blood count 
recovery (CRi), or complete remission with incomplete platelet count recovery (CRp)
at the end of induction treatment

Proportion of patients with a CR or complete remission with partial hematologic 
recovery (CRh) at the end of induction treatment

Proportion of patients with a negative MRD status at the end of induction treatment 

EFS, defined as the time from initiation of study treatment to treatment failure 
(failure to achieve CR, CRi, CRp, or CRh), hematologic relapse, or death from any 
cause, whichever occurs first

OS, defined as the time from initiation of study treatment to death from any cause

RFS in patients who achieve remission (CR, CRi, CRp, or CRh), defined as the time 
from remission to the date of hematologic relapse or death from any cause, 
whichever occurs first
Post-consolidation phase

Proportion of patients converting from MRD-positive to MRD-negative status at any 
time

EFS, defined as the time from initiation of induction treatment (prior to study entry) 
to hematologic relapse or death from any cause, whichever occurs first

OS, defined as the time from remission (prior to study entry) to death from any 
cause

RFS in patients who achieved remission (CR, CRi, CRp, or CRh), defined as the 
time from remission (prior to study entry) to the date of hematologic relapse or death 
from any cause, whichever occurs first


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All phases

Change from baseline in patient-reported disease-related symptoms and 
health-related quality of life at specified timepoints, as assessed through use of the 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, European 
Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire, 
Core 30 (EORTC QLQ-C30) (selected scales), and European Organisation for 
Research and Treatment of Cancer (EORTC) Item Library (selected symptoms)
2.2.3
Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are as follows:

Primary and secondary endpoints (defined above) in the subset of patients with 
wild-type p53

MRD response over time (i.e., during induction, consolidation, and maintenance)

Time to MRD-negative status, defined as time from initiation of treatment to 
confirmation of negative MRD status
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives for this study are as follows:

To characterize the PK profiles of idasanutlin (and its metabolites, if appropriate), 
cytarabine, and daunorubicin on the basis of the following endpoint:
Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, 
and daunorubicin at specified timepoints

To assess potential PK interactions among idasanutlin, cytarabine, and 
daunorubicin on the basis of the following endpoint:
Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, 
and daunorubicin at specified timepoints
The exploratory PK objective for this study is to evaluate potential relationships between 
drug exposure and the efficacy and safety of idasanutlin, cytarabine, and daunorubicin 
on the basis of the following endpoints:

Relationship between plasma concentration or PK parameters for each drug 
(idasanutlin, cytarabine, and daunorubicin) and efficacy endpoints

Relationship between plasma concentration or PK parameters for each drug 
(idasanutlin, cytarabine, and daunorubicin) and safety endpoints


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2.4
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to study treatment (i.e., predictive biomarkers), are associated 
with acquired resistance to study treatment, are associated with susceptibility to 
developing adverse events, can provide evidence of study treatment activity (i.e., 
pharmacodynamic biomarkers), can contribute to improvement of diagnostic assays, or 
can increase the knowledge and understanding of disease biology, drug safety, or study 
treatment mechanism of action, on the basis of the following endpoint:

Relationship between biomarkers in blood or bone marrow (listed in Section 4.5.8)
and efficacy, safety, PK, or other biomarker endpoints
2.5
HEALTH STATUS UTILITY OBJECTIVE
The health status utility objective for this study is to evaluate health status utility scores 
of patients treated with idasanutlin on the basis of the following endpoint:

Change from baseline in EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) 
index-based and visual analogue scale (VAS) scores at specified timepoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study
This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, 
efficacy, and pharmacokinetics of idasanutlin when given in combination with cytarabine 
and daunorubicin in induction, in combination with cytarabine in consolidation, and as a 
single agent in maintenance. 
The study will include an initial dose-escalation phase designed to determine the RP2D 
for idasanutlin when given in combination with cytarabine and daunorubicin in induction. 
The dose-escalation phase includes patients with newly diagnosed, previously untreated 
AML who have favorable or intermediate risk (see Appendix 8) to maximize accumulated 
safety data on consolidation by minimizing the number of patients moving to allogenic 
hematopoietic stem cell transplant (allo-HSCT) instead of systemic consolidation. A 
post-consolidation phase, run in parallel to the dose-escalation phase, includes 
idasanutlin treatmentnaive patients who received induction and chemotherapy 
consolidation for AML outside the study and had MRD-positive remission after induction.  
Patients enrolled in the post-consolidation phase will be treated with idasanutlin at a set 
dose of 150 mg (see Figure 2). An expansion phase, to be conducted after completion 
of the dose-escalation phase, includes two distinct cohorts of patients with newly 
diagnosed, previously untreated AML:  patients with favorable or intermediate risk and 
patients with high risk (see Figure 2). High risk is defined as patients with adverse risk 
or secondary AML (i.e., AML evolving from AHD). Patients enrolled in the expansion 
phase will be treated with induction therapy consisting of idasanutlin at the RP2D in 
combination with cytarabine and daunorubicin. After completion of induction therapy, 




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The Sponsor may decide to delay or suspend enrollment within a given treatment cohort
or a cohort may be expanded to include more patients based on safety and efficacy. 
New experimental arms may be added during the study by amending the protocol.
3.1.2
Dose-Escalation Phase
All patients in the dose-escalation phase will undergo the treatment sequence of 
induction, consolidation, and maintenance (see Figure 3). The purpose of the dose-
escalation phase is to identify the RP2D for idasanutlin when combined with fixed doses 
of cytarabine and daunorubicin in induction. The dose-escalation phase will also allow 
identifying the idasanutlin dose to be used in consolidation based on all available safety 
data. The consolidation dose will match the induction dose unless prevented by 
unacceptable toxicities. As a result, there could be two different idasanutlin doses in 
induction and consolidation.
The RP2D will be based on the MTD of idasanutlin when combined with fixed doses of 
200 mg/m2/day on Days 17 of cytarabine and 60 mg/m2/day of daunorubicin on 
Days 13 but will also take into account all safety data during treatment.
Figure 3
Induction, Consolidation, and Maintenance Phases
737 days of cytarabine plus 3 days of daunorubicin; allo-HSCTallogenic 
hematopoietic stem cell transplant; iDACintermediate dose cytarabine.
A minimum of 9 patients and a maximum of approximately 15 evaluable patients will be 
enrolled during the dose-escalation phase.  Cohorts of 36 patients each will be treated 
at escalating doses of idasanutlin (starting at 200 mg) in accordance with the treatment 
regimens and dose-escalation rules described in Section 3.1.2.2.
A Bayesian modified continual reassessment method (mCRM) (see Section 3.1.2.3) is
planned to guide the dose-escalation phase to determine the MTD that achieves the 
efficacious exposure observed.  The principle underlying this trial design is the 
assessment of the dosetoxicity relationship in a safe and efficient manner, allowing for 
enrollment of patients at subsequent dose levels and/or defining the MTD with robust 
data. 


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Patients will be closely monitored for adverse events during the DLT assessment
window, defined as the first induction cycle. Adverse events meeting the criteria for DLT, 
as defined in Section 3.1.2.1, will be reported to the Sponsor within 24 hours (see 
Section 5.3.1).
Patients experiencing a DLT during the DLT window (first induction cycle) may continue 
treatment after consultation with the Medical Monitor based on safety, tolerability, and 
clinical benefit.
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and MTD assessments and will be replaced by an additional patient at that 
same dose level.  Patients who miss more than one dose of idasanutlin, cytarabine, or 
daunorubicin during the DLT assessment window for reasons other than a DLT will also 
be considered non-evaluable and will be replaced.  
Additional cohorts may be added following the Sponsor’s decision to explore 
idasanutlin’s therapeutic advantage (e.g., change of regimen).  The decision for opening 
such cohorts will be based on available safety and tolerability data.  
3.1.2.1
Definition of DLT
In this study, a DLT is defined as at least one of the following events occurring during the 
first induction cycle of treatment and assessed by the investigator as clearly not 
attributable to the patient’s underlying disease or concurrent medications:

Any Grade 5 adverse event unless unequivocally due to the underlying malignancy 
or extraneous causes

Any clinically significant, non-hematologic adverse event Grade 3 unless clearly 
unrelated to the treatment (except GI toxicity, fatigue, anorexia, and alopecia)

GI toxicity: nausea, vomiting and/or diarrhea if Grade 3 severity despite adequate 
supportive care measures (72 hours of treatment, requiring tube feeding, total 
parenteral nutrition, or requiring or prolonging hospitalization) which is attributable to 
study treatment

Grade 3 AST or ALT toxicity lasting for 7 days, or Grade 4 lasting for any duration 
of time not attributable to disease progression

Prolonged myelosuppression: hypocellular (5% cellularity) bone marrow without 
evidence of leukemia, lasting 28 days from first observation (i.e., the first 
post-treatment bone marrow examination showing 5% cellularity or aplasia
[Kantarjian et al. 2007]) 
Other toxicities that are considered clinically relevant and related to study treatment as 
determined by the investigator and the Medical Monitor may also be considered DLTs.
3.1.2.2
Treatment Regimens and Dose-Escalation Rules
During this first dose-escalation phase, patients will be enrolled as described below.


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Three patients will initially be enrolled in each dose cohort, and up to an additional 
3 patients can be enrolled in a cohort at the Sponsor’s discretion.  A minimum of 
3 patients enrolled in a cohort must complete at least the first induction cycle (i.e., the 
DLT assessment window) before enrollment commences in the next cohort(s).  
Intra-patient dose escalation is not permitted with the exception of the maintenance dose,
which can be increased to 200 mg on the basis of safety, tolerability and clinical benefit
and after consultation with the Medical Monitor (see Table 1). 
Enrollment will begin in Cohort 1 in which patients will be treated at idasanutlin starting 
doses of 200 mg once a day (QD) on Days 15 in the induction cycle(s) given in 
combination with cytarabine 200 mg/m2 on Days 17 and daunorubicin 60 mg/m2 on 
Days 13 (see Table 1 for details on treatment regimens). 
If safety and tolerability in the first cycle allow (the DLT assessment window), the next 
cohort will be enrolled.  Patients in this cohort will receive an escalated dose of 
idasanutlin (see Table 2).
During the dose-escalation phase, study treatment will be administered as outlined in 
Table 1. Patients who achieve remission (CR, CRi, CRp, or CRh) after up to 2 induction
cycles will receive chemotherapy consolidation treatment up to 4 cycles or allo-HSCT 
consolidation at the investigator's discretion.  Patients who achieved a confirmed
remission at the end of chemotherapy consolidation or allo-HSCT or who underwent 
allo-HSCT in MLFS after induction (see definition of MLFS in Appendix 19) will receive 
maintenance treatment for 12 cycles (see Table 1). In cases where the patient receives 
allo-HSCT consolidation, maintenance should start within 90 days of the transplant and 
a full pre-transplant hematologic response assessment must be provided if the 
transplant is performed more than 4 weeks after end of induction. Patients receiving 
chemotherapy consolidation should start maintenance right after completion of the 
consolidation. On the basis of safety, tolerability, and clinical benefit and after 
consultation with the Medical Monitor, patients may be allowed to continue maintenance 
at the same dose beyond 12 cycles. All patients will be followed for disease progression 
and survival.  The dose for idasanutlin in consolidation will be determined by the 
Sponsor upon review of all available safety, PK, pharmacodynamic, and efficacy data.  
The dose for consolidation will not exceed the dose the patient received during induction.
After the last patient in each cohort has completed the DLT assessment window (first 
induction cycle), the Sponsor will evaluate the next dose recommended according to the 
mCRM (see Section 3.1.2.3) and determine doses for the subsequent cohort(s), taking 
into account relevant demographic, adverse event, laboratory, dose administration, and 
PK (if available) data.  At each dose-escalation step, the dose may be escalated or 
de-escalated, or an additional cohort at the same dose level may be enrolled.


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On the basis of review of real-time safety data from this study and all available data from 
other studies in the program, dose escalation may be halted or modified by the Sponsor 
as deemed appropriate.
Although the DLT assessment window is defined as the first induction cycle, cumulative 
toxicities occurring beyond the first cycle may be considered when determining the MTD 
for idasanutlin. At the end of the dose-escalation phase, the idasanutlin RP2D in 
combination with cytarabine and daunorubicin will be decided.   
Table 1
Treatment during the Dose-Escalation Phase
Cycles
Drug Regimens
Induction
Up to 2 cycles a

Cytarabine 200 mg/m2 IV on Days 17

Daunorubicin 60 mg/m2 IV on Days 13

Idasanutlin TBD QD (starting dose 
200 mg) orally on Days 15
Chemotherapy consolidation or 
allo-HSCT (per investigator discretion):
Chemotherapy
Up to 4 cycles

Cytarabine 1.5 g/m2 IV on Days 15 
administered over 3 hours

Idasanutlin TBD b QD orally on Days 15
Allo-HSCT

As per local guidelines
Maintenance
Cycles 112 c

Idasanutlin 150 mg QD orally on 
Days 15 d
allo-HSCT allogenic hematopoietic stem cell transplant; QDonce a day; TBDto be 
determined.
a Cytarabine/daunorubicin doses/regimen can be lowered in the second cycle as per site 
guidelines.
b Dose in consolidation will be determined by the Sponsor after determination of all 
available data.  It will not exceed induction dose.
c On the basis of safety, tolerability, and clinical benefit and after consultation with the 
Medical Monitor, intra-patient escalation may be allowed to 200 mg.
d On the basis of safety, tolerability, and clinical benefit and after consultation with the 
Medical Monitor, patient may be allowed to continue maintenance at the same dose 
within past the 12 cycles
3.1.2.3
Use of mCRM for Dose and MTD Determination
The dose escalation will employ a mCRM with overdose control design in order to define 
the MTD and/or the recommended dose for subsequent cohorts.
The design is based on the primary safety variable, that is, the occurrence of a DLT. 
The MTD is defined as the dose that maximizes the probability of a DLT being in the 
targeted toxicity interval of 25%35%, subject to the probability of the DLT being in the 


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excessive toxicity interval of 35%100% being 35%. Simulations of the designs under 
various scenarios of true toxicity are presented in Appendix 18.  
Patients within a phase will be enrolled in cohorts of at least 3 patients each, which, if 
required, can be expanded with additional patients. Each patient will be observed over 
1 cycle of treatment for DLT assessment. After the last patient in each cohort has 
completed the first cycle of the observation period, the next dose recommended by the 
mCRM design will be evaluated and that analysis will support the dose decision for the 
subsequent cohort. At each dose-escalation step, the dose can be escalated, the dose 
can be de-escalated, or an additional cohort at the same dose level can be enrolled. The 
idasanutlin starting dose will be 200 mg QD on Days 15, and maximum allowable 
increments for the highest dose already tested will not exceed 150 mg, with a minimum 
increment of 50 mg.  In addition, the dose of idasanutlin will not be escalated above 
800 mg QD. The selection of the next dose will be subject to clinical judgment and 
mandated safety constraints that limit the size of the dose increments.  Clinical judgment 
will always override mCRM recommendations in the dose-selection process.
Dose escalation will stop when the maximum allowed sample size, approximatively 
15 evaluable patients, has been reached or if there is enough confidence in the 
prediction of the MTD (e.g., at least 6 patients have been recruited at the MTD dose and 
there is a 40% probability of having a DLT rate of 25%35%).
The dosetoxicity relationship is described by a two-parameter logistic regression model:
	
(
∗) =  + (
∗)      
In this model,  and  are model parameters and 
(
∗) is the probability of 
experiencing a DLT at a dose 
∗, where 
∗=

 being the normalized dose using the 
reference dose dR300 mg.
In order to define the prior distributions (priors) for the parameters of the model, the 
Sponsor's clinical team completed Bayesian prior elicitation to reach a consensus on the 
following questions, based on expert knowledge and previous idasanutlin data (e.g.,
Studies NP27872 and BH29812):

What is the (low) probability that the DLT rate for the lowest-tested dose (200 mg) is 
above a threshold of 30%? 

What is the (low) probability that the DLT rate for the highest potentially tested dose 
(800 mg) is below a threshold of 30%?
These probabilities reflecting the prior knowledge of dose toxicity were chosen by the 
team to be 40% and 25%, respectively, for the first and second questions. Of note, a 
lower or a higher probability would reflect respectively more or less prior knowledge that 
is borrowed by the model.


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As a consequence of this choice, the following prior was defined:

 ~ −0.797
0.995 $ , 1.699
0.280
0.280
1.076$
A visual representation of the prior is shown in Figure 4.
Figure 4
Selected Prior Distribution with 95% Credible Interval
DLT dose-limiting toxicity.
Consider the various hypothetical trial realizations. If 3 patients are given the starting 
dose of 200 mg and none develop a DLT, then the next mCRM dose recommendation is 
350 mg. Afterward the mCRM recommendations are 450 and 600 mg if the next cohorts 
of 3 patients also have no DLT observed each time. 
If DLTs are observed, the next recommended dose is (almost) equal to or lower than the 
current dose. Specifically, if the first cohort is at 200 mg QD with 3 patients when one
DLT is observed, then the dose recommended for the second cohort is again 200 mg
QD. If the first DLTs are observed in the second cohort of 3 patients at 300 mg QD and 
none in the first cohort of 200 mg QD, the dose for the third cohort is recommended as 
300 mg QD. When two or three DLTs are observed in a cohort, a dose de-escalation is 
always recommended by the model (even if no DLTs were observed in previous cohorts).
A summary of dose recommendations among same principle is provided in Table 2. Of 
note, these recommendations are subject to the constraint that the dose increase in the 
subsequent cohort cannot exceed a 50% increment of the previous cohort dose. 


 
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Table 2 
Hypothetical Trial Realizations (Cohort Size3)  
Dose (mg) at Which the First DLTs 
Were Observed (mg) 
Number of 
DLTs 
Recommended 
Next Dose (mg)
200 
0 
350 
200 
1 
200 
200 
2 
200 
200 
3 
200 
350 
0 
450 
350 
1 
300 
350 
2 
200 
350 
3 
200 
450 
0 
600 
450 
1 
450 
450 
2 
300 
450 
3 
200 
DLT  dose-limiting toxicity. 
 
The operating characteristics of the proposed mCRM were also carefully evaluated 
through the use of simulations across different scenarios, and the results are reported in 
Appendix 18.  The general conclusion is that the current design provides, with an 
assumed sample size of approximatively 15 evaluable patients, overall good 
performances in selecting the correct MTD, while at the same time limiting the potential 
amount of overdose across all scenarios. 
3.1.3 
Post-Consolidation Phase and Expansion Phase 
The post-consolidation cohort of 30 patients is designed to further assess the safety and 
efficacy of idasanutlin given as a single agent to idasanutlin treatmentnaive patients in 
a maintenance setting.  Patients will start maintenance right after consolidation 
completion. 
 
The expansion phase is designed to further assess the safety and efficacy of idasanutlin 
in combination with cytarabine and daunorubicin at its RP2D in induction and in 
combination with cytarabine in consolidation followed by a single-agent maintenance. 
The expansion phase (approximately 40 patients) is composed of two cohorts:  
20 patients with favorable or intermediate risk and 20 patients with high risk (see 
Table 3).  
All expansion patients will be enrolled and treated as described in Table 4, and patients 
in the post-consolidation cohort will receive maintenance treatment as described in 
Table 5.   


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In the expansion cohorts, patients who achieve remission after up to 2 induction cycles 
will receive chemotherapy consolidation treatment up to 4 cycles with 1.5 mg/m2
cytarabine or allo-HSCT (as per site guidelines).  Patients who achieved a confirmed
remission at the end of chemotherapy consolidation or allo-HSCT or who underwent
allo-HSCT in MLFS after induction will receive maintenance treatment for 12 cycles (see 
Table 4).
Patients receiving chemotherapy consolidation in the expansion should start 
maintenance right after consolidation completion. Patients receiving allo-HSCT 
consolidation should start within 90 days of the transplant and a full pre-transplant 
hematologic response assessment must be provided if the transplant is performed more 
than 4 weeks after end of induction.
On the basis of safety, tolerability, and clinical benefit and after consultation with the 
Medical Monitor, patients may be allowed to continue maintenance past 12 cycles.
Table 3
Post-Consolidation and Expansion Cohorts
Cohorts
Population
Post-consolidation
Idasanutlin treatmentnaive patients in 
remission who received chemotherapy 
consolidation but were MRD positive 
after induction as locally assessed
Expansion: favorable or 
intermediate risk
Favorable and intermediate risk
patients (ELN 2017; see Appendix 8)
Expansion: high risk
Adverse-risk patients (ELN 2017; see 
Appendix 8) and secondary AML 
defined as AML evolving from AHD
AHDantecedent hematologic disorder; AMLacute myeloid 
leukemia; ELNEuropean Leukemia Net; MRDminimum residual 
disease.


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Table 4
Treatment for Expansion Phase (Favorable/Intermediate-Risk and 
High-Risk Cohorts)
Cycles
Dosing Regimens
Induction
Cycles 12 a

Cytarabine 200 mg/m2 IV on Days 17

Daunorubicin 60 mg/m2 IV on Days 13

Idasanutlin RP2D QD orally on Days 15
Chemotherapy consolidation or 
allo-HSCT (per investigator discretion):
Chemotherapy
Cycles 14

Cytarabine 1.5 g/m2 IV on Days 15 over 3 hr

Idasanutlin TBD b QD orally on Days 15
Allo-HSCT
As per local guidelines
Maintenance
Cycles 112 c

Idasanutlin 150 mg QD orally on Days 15 d
HSCThematopoietic stem cell transplant; QDonce a day; RP2Drecommended Phase II dose; 
TBDto be determined.
a Cytarabine/daunorubicin doses/regimen can be lowered in the second cycle as per site 
guidelines.
b Dose in consolidation will be determined by the Sponsor after review of all available data.  It will 
not exceed induction dose.
c Based on safety, tolerability, and clinical benefit, and after consultation with the Medical Monitor, 
patients may be allowed to continue maintenance at the same dose past 12 cycles. 
d Based on safety, tolerability, and clinical benefit, and after consultation with the Medical Monitor, 
intra-patient escalation may be allowed to 200 mg.
Table 5
Treatment for Post-Consolidation Phase
Cycle
Dosing Regimen
Maintenance
Cycles 112 a

Idasanutlin 150 mg QD orally on Days 15 b
QDonce a day.
a Based on safety, tolerability, and clinical benefit and after consultation with the Medical Monitor, 
patients may be allowed to continue maintenance at the same dose past 12 cycles.
b Based on safety, tolerability, and clinical benefit and after consultation with the Medical Monitor, 
intra-patient escalation may be allowed to 200 mg.
3.1.4
Post-Treatment Follow-Up and Survival Follow-Up
Patients who complete treatment or discontinue treatment for reasons other than 
disease progression will undergo assessments (see Appendix 1) during the 
post-treatment follow-up period, which will continue until morphologic relapse or up to 
2 years, whichever occurs first.  Patients who experience morphologic relapse or were 
followed for 2 years in the post-treatment phase will be evaluated for survival status and 


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initiation of new anti-leukemia treatment until the end of the study.  Details are provided 
in the schedules of activities (see Appendix 1).
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.  
Patients will be followed up to 2 years after last patient is enrolled or all patients have 
died, whichever occurs first.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Idasanutlin Dose and Schedule
Idasanutlin dosing for this study is based on experience in both single-agent testing 
(Studies NP27872 and NP28902) in solid tumors and from the combination with 1 g/m2
cytarabine in Study NP28679 in patients with both R/R and elderly front-line AML.  The
lowest dose where responses were seen in AML was 200 mg adjusted for formulation 
differences in combination with cytarabine 1 g/m2, and as this dose has been proven 
safe and allowed for escalation (see the Idasanutlin Investigator’s Brochure), it has been 
chosen as the starting dose for idasanutlin. A lower dose of 150 mg has been chosen in 
maintenance to minimize side effects as patients in remission would not require 
aggressive treatment. This dose is below the MTD in solid tumor (see the Idasanutlin 
Investigator’s Brochure) where patients have functional bone marrow and is used in 
polycythemia vera studies over multiple cycles (see the Idasanutlin Investigator’s 
Brochure).
The QD5-day schedule was proven safe and efficacious in the Phase I AML study 
NP28679 and is investigated in the ongoing registrational R/R AML study (WO29519).  
Therefore, it was chosen also for the front-line regimen.
3.3.2
Rationale for Study Population
The dose-escalation phase includes patients with favorable or intermediate risk to 
maximize accumulated safety data on consolidation by minimizing the number of 
patients moving to HSCT instead of systemic consolidation.  
The expansion phase of the study is separated into two cohorts, patients with favorable
or intermediate and patients with high risk, on the basis of their significantly different 
relapse rates to allow a proper assessment of the benefit within all cytogenetic 
categories based on a defined sample size.
The post-consolidation cohort will enroll patients in remisssion who received 
chemotherapy consolidation for whom no transplant is foreseen, but only those who 
have been identified as MRD positive at the end of induction, and who have not been 
previously treated with idasanutlin. MRD-positive patients are known to have a higher


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risk of relapse and are in greater medical need than patients with MRD-negative status
(Jongen-Lavrencic et al. 2018). This cohort will assess the safety and benefit of 
maintenance regardless of previous treatment in idasanutlin naive patients. Additional 
cohorts might be opened to test maintenance in a post-HSCT setting or to explore 
combinations with other drugs, after amendment of the protocol.
3.3.3
Rationale for Population PK/Pharmacodynamic Analysis
Minimal blood sampling is required for conducting population pharmacokinetics analyses 
to characterize the pharmacokinetics of idasanutlin, cytarabine, and daunorubicin in 
plasma in the patient population.  The population and individual PK parameters will be 
estimated and the influence of covariates (such as ages, sex, body weight, ethnicity, and 
disease status, including organ impairments) on these parameters will be investigated in 
order to determine any subpopulations with higher- or lower-than-expected exposure.  
With these PK exposure data, the exposureresponse relationship of idasanutlin in 
combination with cytarabine and daunorubicin on efficacy measures, such as clinical
response and OS, as well as the relationship between the exposure of idasanutlin in 
combination with cytarabine and daunorubicin and the occurrence of serious adverse 
eventssuch as GI disorders, pancytopenia, neutropenia, or thrombocytopenia (i.e., 
acute versus delayed)if relevant, will be explored.  The impact of potential influential 
covariates will be investigated.  Covariates that indicate whether subpopulations may be 
at increased risk will be investigated.  
3.3.4
Rationale for Biomarker Assessments
MDM2 is overexpressed in approximately 50% of AML (Fenaux et al. 1992; Hu et al. 
1992; Wattel et al. 1994). This is believed to result in decreased levels of the tumor 
suppressor p53. Idasanutlin inhibits the interaction of MDM2 with p53, leading to 
accumulation and activation of p53 and thus inhibition of cancer cell growth and 
induction of apoptosis. 
P53 function can also be lost through mutations. However, mutations occur along the 
entire sequence of the gene and may not always be detrimental to p53 activity. The p53 
mutations status, as well as that of other mutations associated with AML biology and 
amenable to therapy is therefore important. 
Activated p53 induces or inhibits the expression of multiple genes, some of which are 
secreted (e.g., Mic-1) and may be useful as pharmacodynamic indicators of clinical 
activity of idasanutlin. Additional biomarkers related to the mechanism of action of 
idasanutlin (p53 and MDM2 activity) and disease biology may be evaluated as 
appropriate.  
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


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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.
3.3.4.1
AML-Associated Mutations, MDM2 Protein Expression, MIC-1
Secretion and Gene Expression 
The mutation status of TP53 as well as mutations of other genes with clinical relevance 
or prognostic value including FLT-3, IDH1 and IDH2 will be assessed by a sequencing 
panel. MDM2 expression in AML cells in pretreatment blood specimens in patients with 
AML will be assessed by multi-color flow cytometry. Mic-1 secretion will be analyzed by 
ELISA. Various gene expression signatures have been explored for their predictive 
value for MDM2 inhibitors. In this study, gene expression profiling is planned to clinically 
validate and explore additional signatures. 
3.3.4.2
MRD Assessment 
MRD responses are associated with improved outcomes, whereas patients who have 
MRD after induction and consolidation have a poor prognostic outcome
(Jongen-Lavrencic et al. 2018). 
MRD will be assessed as a secondary endpoint. Patients achieving remission will 
undergo additional serial MRD assessments at subsequent scheduled hematologic 
malignancy assessments (Appendix 1). 
These MRD assessments will serve as an exploratory monitoring tool to investigate the 
depth of response and afford early detection of impending relapse (before 
cytomorphologic relapse occurs) after idasanutlin therapy.  
In patients achieving remission, MRD monitoring from bone marrow aspirates will be 
prioritized over analysis of other exploratory markers.
MRD assessments can be made with the use of several technologies (e.g., by flow 
cytometry for abnormal cell phenotypes or leukemia-associated immune phenotype, by 
next-generation sequencing (NGS) of leukemia-associated mutations, or by polymerase 
chain reaction [PCR] technologies to detect AML-specific translocations or mutations).  
Recent reports suggest MRD in AML can also be assessed in cell-free DNA in plasma
(Assi et al. 2018) and blood will be collected for this purpose. 
MRD in this study will be primarily analyzed by flow cytometry. Other methods may be 
employed for orthogonal validation and exploration of the correlation of MRD detected in 
cell-free DNA with that in bone marrow aspirates.  
3.3.5
Rationale for Patient-Reported Outcomes
Symptom presentation in AML is variable with patients frequently presenting with fatigue 
and loss of appetite at the time of diagnosis. Fatigue is the most common and severe 


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symptom reported by patients, as well as the most persistent over time (Møller et al. 
2012), and is associated with decrements in health-related quality of life (HRQoL) and 
functioning (Schumacher et al. 2002; Messerer et al. 2008). 
In addition to disease-related symptoms, cancer treatments, particularly combination 
therapies, can produce significant treatment-related symptoms and impacts. Patients 
with AML in particular experience substantial HRQoL burden during treatment, 
experiencing the greatest decrements shortly after starting induction and rebounding 
thereafter (Redaelli et al. 2004; Korol et al. 2017). Research has shown that clinicians 
may underreport the incidence and severity of symptoms patients experience during 
treatment (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; Basch et al. 
2009; Basch 2010; Quinten et al. 2011; Atkinson et al. 2012). Collecting information 
about these symptoms directly from patients can provide a better understanding of 
treatment characteristics and their effects. In order to measure baseline symptoms and 
characterize symptomatic treatment toxicities from the patient perspective, patients will 
be asked to report on their experience of relevant treatment-related symptoms selected 
from the validated PRO-CTCAE item bank. On the basis of preliminary safety data, 
nausea, vomiting, and diarrhea symptoms were identified as being salient to patients'
experience of treatment with idasanutlin.
In this study, important disease- and treatment-related symptoms, as well as functioning 
will be assessed with the FACIT-Fatigue, EORTC QLQ-C30, and EORTC Item Library 
(selected symptoms), and PRO-CTCAE. The EQ-5D-5L will be administered for the 
purpose of producing health utility scores for economic modeling.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll patients with AML who meet the eligibility criteria presented below.
4.1.1
Inclusion Criteria
4.1.1.1
Inclusion Criteria for All Study Phases
For all study cohorts, patients must meet the following inclusion criteria for enrollment in 
the study:

Signed Informed Consent Form

Age 18 years old at the time of signing the Informed Consent Form

Eastern Cooperative Oncology Group (ECOG) performance status 2

Adequate hepatic function, as assessed by the following:
Serum total bilirubin 1.5institutional upper limit of normal (ULN), unless 
resulting from hemolysis, Gilbert syndrome, or liver infiltration with leukemia (up 
to 3ULN)
AST or ALT 3institutional ULN (or 5upper limit of institutional laboratory 
reference range if liver infiltration with leukemia)


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
Adequate renal function assessed by serum creatinine within reference laboratory 
ranges or creatinine clearance (by Cockcroft-Gault formula) 50 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for at least 6 months after the 
final dose of idasanutlin, cytarabine, or daunorubicin. Women must refrain from 
donating eggs during this same period.
A woman 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 has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices 
(IUDs), and copper IUDs.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study 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.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of 1% per 
year during the treatment period and for 6 months after the final dose of 
idasanutlin, cytarabine, or daunorubicin.  Men must refrain from donating sperm 
during this same period.
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 6 months after the final dose of idasanutlin, 
cytarabine, or daunorubicin to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Ability to understand and willingness to sign a written informed consent form and 
comply with all study requirements including completion of patient-reported 
questionnaires


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4.1.1.2
Inclusion Criteria for Patients in the Dose-Escalation and 
Expansion Phases
Patients in the dose-escalation and expansion cohorts must meet the following inclusion 
criterion for enrollment in the study:

Documented/confirmed newly diagnosed AML not previously treated according to 
WHO (Arber et al. 2016)
4.1.1.3
Inclusion Criteria for Patients in the Post-Consolidation Phase
Patients in the post-consolidation cohort must meet the following inclusion criterion for 
enrollment in the study:

Documented/confirmed AML according to WHO (Arber et al. 2016) in remission 
after induction, within 21 days of end of last chemotherapy consolidation cycle, and
were MRD positive at the end of induction as per local laboratory assessment
(validated quantitative AML-specific MRD assessment with a 0.1% threshold)  
4.1.2
Exclusion Criteria
4.1.2.1
Exclusion Criteria for All Study Phases
Patients who meet any of the following criteria will be excluded from study entry in any 
part of the study:

Clinical evidence of CNS leukemia

Any Grade 2 non-hematologic toxicities prior to starting therapy (except fatigue, 
anorexia, and alopecia).

Current treatment with any other investigational or commercial agents or therapies 
administered with the intention to treat their malignancy with the exception of 
hydroxyurea (HU) or 6-mercaptopurine (6-MP). 
HU and 6-MP must be discontinued at least 24 hours before initiation of study 
treatment.

Treatment-related AML

Acute promyelocytic leukemia

History of other malignancy that could affect compliance with the protocol or
interpretation of results, with the exception of the following:
Curatively treated carcinoma in situ of the cervix, good-prognosis ductal
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I
melanoma, or low-grade, early-stage localized prostate cancer
Any previously treated malignancy that has been in remission without treatment
for 2 years prior to enrollment

Any severe and/or uncontrolled medical conditions or other conditions that could 
affect their participation in the study, impair the ability of the investigator to evaluate 
the patient, or impair the patient’s ability to complete the study such as the following:
Unstable angina, symptomatic or otherwise uncontrolled arrhythmia (does not 
include stable, lone atrial fibrillation), uncontrolled hypertension, symptomatic 


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congestive heart failure (New York Heart Association Class III and IV cardiac
disease), myocardial infarction 6 months prior to first study treatment, and 
cerebrovascular accidents 6 months before study treatment start
Unstable seizure disorders

Echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan showing 
ejection fraction 40%

Non-malignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by this study treatment, such as hereditary coagulation disorders,
insulin-dependent diabetes mellitus not optimally controlled with medical 
management (e.g., presence of ketoacidosis), or active GI conditions affecting 
absorption

Infection considered by the investigator to be clinically uncontrolled or of 
unacceptable risk to the patient upon the induction of neutropenia, that is, patients 
who are or should be on antimicrobial agents for the treatment of active infection 
such as the following:
Fungal infection with visceral involvement, other than mucosal candidiasis, with 
less than 2 weeks of appropriate systemic antifungal therapy
Bacterial infection with positive cultures in the 7 days prior to dosing
Patients who have received less than 5 days of appropriate therapeutic 
antibiotic therapy for an identified infection
Neutropenic fever that is considered infection related within 72 hours prior to 
dosing
History of symptomatic C. difficile infection that required treatment within 
1 month prior to dosing.
Upon clinical response to C. difficile treatment, the stool consistency 
and frequency must have returned to normal.

Febrile patients within 72 hours of study treatment initiation (exception of 
AML-related fever)

Patients with a history of active or chronic infectious hepatitis unless serology 
demonstrates clearance of infection

Patients who are unable to interrupt treatment with moderate to strong CYP2C8 
inducers and inhibitors (including gemfibrozil, which is also an inhibitor of UGT1A3), 
CYP2C8 or OATP1B1/3 substrates, or strong CYP3A4 inducers as defined in
Appendix 17 during the treatment phase
These agents must be discontinued 7−14 days prior to the start of study 
medication per Section 4.4.2.

Patients who are unable to temporarily interrupt treatment with oral or parenteral 
anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment with 
aspirin [325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban, or 
subcutaneous [SC] anticoagulant prophylaxis) during the treatment phase  


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These agents must be discontinued 7 days (or 5 half-lives) prior to the start of 
study medication per Section 4.4.2  

Patients who have a history of clinically significant liver cirrhosis (e.g., ChildPugh 
class B and C)

Patients with extramedullary AML with no evidence of systemic involvement

Pregnant or breastfeeding patients

Known history of HIV-positive status
For patients with unknown HIV status, HIV testing must be performed at 
screening if not in contradiction with local legislation.

Patients who might refuse to receive blood products and/or have a hypersensitivity 
to blood products

Prior treatment with an MDM2 antagonist

Patients with clinically relevant QTc prolongation (QT interval corrected through use 
of Fridericia’s formula [QTcF] 480 ms), a family history of long QT syndrome
4.1.2.2
Exclusion Criteria for Patients in the Phase Ib Dose-Escalation 
Phase Only
Patients who meet the following exclusion criterion will be excluded from enrollment in 
the dose-escalation cohort in any part of the study:

Adverse risk patients as per ELN 2017 criteria (see Appendix 8)
4.1.2.3
Exclusion Criteria for Patients in Phase Ib Post-Consolidation 
Phase Only
Patients who meet any of the following exclusion criteria will be excluded from
enrollment in the dose-escalation cohort in any part of the study:

Any ongoing Grade 2 hematologic adverse events prior to starting therapy

Previous HSCT
4.1.2.4
Exclusion Criteria for Patients in the Dose-Escalation Phase 
and Patients in the Favorable/IntermediateRisk Cohort of the 
Expansion Phase Only
Patients who meet any of the following exclusion criterion will be excluded from the 
dose-escalation phase and the favorable/intermediaterisk cohort of the expansion 
phase:

Secondary AML, defined as AML evolving from AHD
4.2
METHOD OF TREATMENT ASSIGNMENT 
This Phase Ib/II, open-label, multicenter, non-randomized study evaluates the safety, 
efficacy, and pharmacokinetics of idasanutlin when given in combination with cytarabine 
and daunorubicin in induction, in combination with cytarabine in consolidation, and as a 
single agent in maintenance.  During the dose-escalation phase, patients will be 
assigned to dosing groups through use of an interactive voice or web-based response 


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system (IxRS).  During the expansion phase, all patients will be assigned to receive the 
RP2D via IxRS.  If eligible, patients will receive consolidation and maintenance treatment 
(see Section 3.1.1 for details).
Enrollment tracking will be performed through the use of the IxRS.  Prior to initiation of 
screening, study site personnel should confirm through the appropriate communication 
channel that the planned dose-escalation, expansion or post-consolidation cohort is 
open for enrollment.  After written informed consent has been obtained and preliminary 
eligibility has been established, the study site will submit documentation supporting 
eligibility to the Sponsor and obtain the Sponsor’s approval to enroll the patient.  Once 
the Sponsor reviews and approves a patient for enrollment, a patient number will be 
assigned and the patient will be enrolled via the IxRS.  The Sponsor will communicate to 
the sites impending closure of screening for a particular disease cohort.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are idasanutlin, cytarabine, 
and daunorubicin.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Idasanutlin 
Idasanutlin will be supplied by the Sponsor as film-coated tablets.  Four different dose 
strengths of 50 mg (Ro 550-3781/F17), 200 mg (Ro 550-3781/F16), 300 mg 
(Ro 550-3781/F13) were developed and optimized for use in clinical studies.  For 
information on the formulation and handling of idasanutlin, see the Idasanutlin
Investigator’s Brochure.
4.3.1.2
Cytarabine
Cytarabine will be supplied locally.  For information on the formulation, packaging, and 
handling of cytarabine, see the local prescribing information for cytarabine as used in 
standard practice.
4.3.1.3
Daunorubicin
Daunorubicin will be supplied locally.  For information on the formulation, packaging, and 
handling of daunorubicin, see the local prescribing information for daunorubicin as used 
in standard practice.
4.3.2
Study Treatment Dosage, Administration, and Compliance
Treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.4.4.


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Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.
4.3.2.1
Idasanutlin
Patients will self-administer idasanutlin tablets by mouth (PO) each day in the morning
according to the schedule of activities (see Appendix 1).
On days when idasanutlin is given in combination with chemotherapy, idasanutlin should 
be administered first. During consolidation when idasanutlin is given in combination with 
cytarabine, idasanutlin should be administered first. If vomiting occurs within 15 minutes 
of taking idasanutlin and all expelled tablets are still intact, another dose may be given,
and the second dose noted in the drug log.  Otherwise, no replacement dose is to be 
given.  In cases in which a QD dose of idasanutlin is missed or forgotten, the patient 
should take the dose as soon as possible, ensuring that the dose is taken within 8 hours 
of the missed dose.  Otherwise, the dose should not be taken.  On days when patients 
are scheduled to have blood samples collected for PK assessments, the time of each 
dose of idasanutlin will be recorded to the nearest minute.  Guidelines for dosage 
modification and treatment interruption or discontinuation for safety reasons are provided 
in Section 5.1.3.
Idasanutlin must be stored according to labeled storage conditions.
4.3.2.2
Cytarabine
Cytarabine will be administered in the first cycle of induction at a dose of 200 mg/m2 QD 
by IV for 7 days, immediately after the corresponding dose of idasanutlin. Dose and 
regimen can be lowered per investigator choice in the second induction cycle
Cytarabine will be administered in consolidation at a dose of 1.5 g/m2 QD for 5 days as 
IV infusion over a minimum of 3 hours, immediately after corresponding dose of 
idasanutlin.
The dose of cytarabine should be calculated based on a body weight measurement 
within 2 days of the first day of each cycle. To calculate body surface area (BSA) for the 
cytarabine dose, refer to Appendix 9.  
4.3.2.3
Daunorubicin
Daunorubicin will be administered in induction at a dose of 60 mg/m2 QD for 3 days as 
IV infusion, immediately after the corresponding dose of idasanutlin. Dose and regimen 
can be lowered per investigator choice in the second induction cycle.
The dose of daunorubicin should be calculated based on a body weight measurement 
within 2 days of the first day of each cycle. To calculate BSA for the daunorubicin dose, 
refer to Appendix 9.  


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4.3.2.4
Premedication
Patient must receive premedication as outlined in Table 6.  Further details are provided 
in Appendix 5.
Table 6
Premedication
Timepoints
Premedication
Administration
Induction and consolidation
All cycles
Anti-emetic medicines 
(second-generation 
anti-emetic medicines, such 
as palonosetron, 
ondansetron, or granisetron)
Mandatory prior to each 
idasanutlin dosing
Dosing as per individual drug 
prescribing information
Anti-diarrheal medicines 
(unless medically 
contraindicated) a
Mandatory prior to each 
idasanutlin dosing. 
Dosing as per individual drug 
prescribing information
Anti-fungal agents
Strongly recommended prior 
Day 1 of Cycle 1
Dosing as per individual drug 
prescribing information (until 
neutrophil count recovery 
Grade 2)
Antimicrobial medicines
Strongly recommended prior 
Day 1 of Cycle 1
Dosing as per individual drug 
prescribing information (until 
neutrophil count recovery 
Grade 2)
Maintenance
All cycles
Prophylaxis may be utilized on the basis of investigator 
discretion and patient tolerability.  
Supportive therapies, including prophylaxis for diarrhea and 
nausea, are encouraged in the maintenance phase of the 
study
a Contraindication should be recorded in the medical history or as a separate adverse event.
4.3.3
Investigational Medicinal Product Accountability
Idasanutlin, cytarabine, and daunorubicin are considered IMPs in this trial.  Idasanutlin 
that is required for completion of this study will be provided by the Sponsor.  Cytarabine 
and daunorubicin will be obtained from local sources.
The study site will acknowledge receipt of idasanutlin, using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.
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 IMP should only be returned to the Sponsor if 


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the site is unable to destroy IMP per their standard operating procedure. 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.
4.3.4
Continued Access to Idasanutlin
Currently, the Sponsor does not have any plans to provide the Roche IMP idasanutlin or 
any other study treatments or interventions to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing idasanutlin in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, and nutritional supplements) or blood product 
(e.g., RBCs and platelets) used by a patient from 28 days prior to screening up to the 
study drug completion/discontinuation visit.  All such therapies should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.  The investigator 
should instruct the patient to notify the investigator (or designee) about any new 
medications (including over-the-counter drugs and herbal/alternative medications) 
he/she takes after the start of study medication.  Patients must be instructed not to take 
any additional medications (including over-the-counter products and herbal/alternative 
medications) during the study without prior consultation with the investigator (or 
designee).
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy
4.4.2
Prohibited Therapy
Use of the following therapies (excluding protocol-specified treatments) is prohibited 
during the study:

Any anti-cancer therapy, approved or investigational, other than intrathecal CNS
prophylaxis (except during HSCT consolidation)

Hormonal therapy other than contraceptives, stable hormone-replacement therapy, 
or megestrol acetate

Biologic agents other than hematopoietic growth factors 


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MDM2 antagonists were shown in vitro to affect all types of hematopoietic progenitors, 
including megakaryocytic differentiation.  They inhibit both early and late stages of 
megakaryopoiesis, including ploidization and proplatelet formation (Mahfoudhi et al. 
2016).  As a consequence, the effect on early progenitors might induce long-lasting 
thrombocytopenia in vivo.  
Therefore, because of the potential severity and duration of thrombocytopenia induced 
by study treatment, patients in clinical need of chronic treatment with oral or parenteral 
anticoagulant/antiplatelet agents (e.g., warfarin, chronic daily treatment with aspirin 
[325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban, and systemic 
low-molecular weight heparin), or subcutaneous anticoagulant prophylaxis) are excluded 
from this study.  For patients considered eligible for the study because they are able to 
tolerate interruption of anticoagulant or antiplatelet treatment, these agents must be 
discontinued 7 days (or 5 half-lives, whichever is shorter) prior to initiating study 
treatment (except used as flushes for indwelling catheters).  After the study treatment 
completion or discontinuation visit, treatment with anticoagulant/antiplatelet agents may 
be re-initiated for patients with transfusion-independent adequate platelet levels as 
clinically indicated.  An exception can be made for patients with stable blood parameters 
in need of prophylaxis or after consultation with the Medical Monitor if use is clinically 
needed. The maintenance of anti-thrombotic treatment should be continuously 
reassessed. Sustained use over time must be clinically warranted.  
Oral or parenteral use of the following drugs will be prohibited during the treatment 
phase in order to prevent undesirable drugdrug interactions (DDIs).

Strong/moderate inducers or inhibitors of CYP2C8, including gemfibrozil, which is 
also an inhibitor of UGT1A3 (see Appendix 17, Table 1)

CYP2C8 (see substrates or OATP1B1/3 substrates (see Appendix 17, Table 3) 

Strong inducers of CYP3A4 (see Appendix 17, Table 2)
Substrates and inhibitors (Appendix 17, Table 1 and Table 3) must be discontinued 
7 days prior to start of study treatment.  
Inducers (Appendix 17, Table 1 and Table 2) must be discontinued 14 days prior to start 
of study treatment. 
Drugs listed in Appendix 17 (Table 1, Table 2, and Table 3) may be re-initiated per 
protocol after the study drug completion or discontinuation visit.  
Exception might be made upon discussion with the Medical Monitor based on the 
medical needs (such as anti-rejection drugs) and patient benefit. In such cases, 
decision will be clarified in a note to file and filed accordingly.
The above medications are not necessarily comprehensive.  Thus, the investigator 
should consult the prescribing information for any concomitant medication as well as the 


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Internet references provided below when determining whether a certain medication 
should be inhibited by the above rationale.  In addition, the investigator should contact 
the Medical Monitor if questions arise regarding medications not listed above.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf

http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.5
STUDY ASSESSMENTS 
The schedule of activities performed during the study is detailed in Appendix 1.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. Those patients who fail screening because of long
waiting times for results or study technical reasons (such as, "cohort on hold") can be 
rescreened once at a later date if deemed eligible before the screen failure.  The 
decision to rescreen individual patients will be made jointly by the Medical Monitor and 
the investigator and any other person the investigator or Medical Monitor considers 
necessary to assist with this decision.  Any such decision and the reasons for it will be 
clearly documented.  Any out-of-window assessments need to be repeated and undergo 
a complete review by the Medical Monitor. Patients deemed ineligible based on 
screening results for the following exclusion criterion will be allowed to be re-screened
once:

Infection considered by the investigator to be clinically uncontrolled or of 
unacceptable risk to the patient upon the induction of neutropenia, that is, patients 
who are or should be on antimicrobial agents for the treatment of active infection
Screening and pretreatment assessments will be performed within 14 days prior to 
Cycle 1, Day 1 unless otherwise specified. However, results of screening tests or 
examinations performed as standard of care prior to obtaining informed consent and 
within the protocol-defined window (prior to randomization/Cycle 1, Day 1) may be used 
rather than repeating required tests.  If a bone marrow aspirate cannot be obtained or is 
not evaluable, a bone marrow biopsy must be performed for AML diagnostic purposes.  
If biopsy is performed at screening, a bone marrow sample should be provided for 
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Cytogenetic and molecular risk according to ELN standardized reporting system (see
Appendix 7 and Appendix 8) must be available from initial diagnosis prior to enrolment of 
the patient to allow risk category identification.  At a minimum cytogenetic information 
allowing stratification into the two risk categories (favorable/intermediate versus adverse)
needs to be available.  Additional information on molecular markers is desirable and 
should be entered into the eCRF. 
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, 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 within 28 days prior 
to initiation of study treatment 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.
For patients enrolled in the post-consolidation cohort, all details with regards to their 
previous AML history and treatment will be collected including but not limited to dates, 
medications, regimens, and responses
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
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.
At subsequent visits (or as clinically indicated), targeted (limited, symptom-directed) 
physical examinations should be performed.  Targeted physical examinations should be 
limited to systems of primary relevance (e.g., cardiovascular and respiratory systems), 
systems associated with symptoms (newly emergent or monitored from baseline.  
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
In cases that physical examinations reveal visible manifestations of leukemia or of 
toxicities (skin involvement, rashes, etc.), additional assessments and measures (such 
as pictures and measurements) could be undertaken upon additional patient consent.


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4.5.4
Performance Status
Performance status will be measured using the ECOG performance status at baseline 
and will be assessed at regular intervals throughout the study.  Further details can be 
found in Appendix 1 and Appendix 3.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, BSA, and body 
temperature (C).  Weight will be recorded at screening and as indicated in Appendix 1.  
Height will be recorded only at screening.
4.5.6
Tumor and Response Evaluations
Hematologic malignancy response will be assessed according to ELN and additional 
response criteria for AML (see Appendix 19).
Hematologic malignancy response assessments (HMRAs) require sampling of blood and 
bone marrow on the same day as indicated (a window of 4 days is acceptable between 
the blood and bone marrow sampling).  Bone marrow aspirates are required, but if bone 
marrow biopsies are performed, the biopsy results should be provided along with the 
aspirate. Depending on the timepoint in the schedule of activities, the HMRA is 
established on the basis of blood counts only, or includes the assessment of bone 
marrow.  Patients will be considered to be in their best response state until definitive 
evidence of relapse is available from blood counts, bone marrow aspirate, or bone 
marrow biopsy.
In the event that a bone marrow aspirate or biopsy is equivocal (i.e., a recovering 
marrow), the bone marrow assessment and complete blood count should be repeated 
7 days later.  
In case disease progression/relapse is determined solely by symptomatic deterioration 
or by a hematology assessment, a bone marrow aspirate should be performed at that 
time to complete HMRA.  If a patient progresses or relapses outside of the scheduled 
visit, an unscheduled HMRA must be provided.
If a bone marrow aspirate is performed at any unscheduled timepoint during the study, 
an unscheduled HMRA must be provided. 
Please note that at the time of bone marrow sampling for HMRA, the bone marrow 
sample collected (aspirate) should also allow for further analyses (e.g., MRD by flow 
cytometry, MRD by NGS) and the amount taken should be taken into consideration.  
During the treatment period, HMRAs are to be performed and reviewed before the start 
of a new treatment cycle.  In the event that a patient has a dosing delay 7 days in 
consolidation or induction, weekly blood counts must be performed for HMRA to 


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document evidence of non-progression.  Treatment failure and relapse will lead to 
discontinuation of the study medication and patients will enter follow-up (see 
Appendix 1).  
During the follow-up of patients who remain in remission after treatment, blood will be 
required every month and a bone marrow aspirate will be required every 6 months to 
allow for HMRA until relapse.  Refer to Appendix 1 for further details.
4.5.7
Laboratory Assessments
Normal ranges for the study laboratory parameters must be submitted to the Sponsor
before the study starts. 
Samples for the following laboratory tests will be sent to the study site’s laboratory for 
analysis.

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
blasts, promyelocytes, myelocytes, metamyelocytes)  
A manual differential (including WBC) may be needed if an automated 
differential does not provide blasts.  Each differential should add up to 100% (or 
as close as possible). 

Biochemistry: procalcitonin, glucose, urea or BUN, serum creatinine, creatinine 
clearance (at screening only determined by Cockcroft-Gault Formula), AST, ALT, 
LDH, ALP, total bilirubin (and direct bilirubin where total bilirubin ULN), total protein, 
albumin, calcium, phosphorus, magnesium, sodium, potassium, bicarbonate, 
chloride, and uric acid)

Urinalysis using standard dipstick assessment (pH, protein, glucose, blood, ketones, 
and leukocytes)  
This must be supplemented with laboratory quantification of any potentially 
relevant abnormalities as deemed necessary by the investigator.

C. difficile infection at screening

Viral serology 
Hepatitis B testing includes hepatitis B surface antigen and total hepatitis B
core antibody.
Hepatitis C testing includes hepatitis C virus antibody.

Coagulation:  INR, aPTT (or PTT), and PT

Serum pregnancy test in females of child bearing potential and postmenopausal 
females with less than 1 year of amenorrhea

Bone marrow aspirate pathology report


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Total cells counted, absolute mature neutrophils, mature eosinophils, mature 
basophils, monocytes, lymphocytes, blasts, promyelocytes, myelocytes, 
metamyelocytes, plasma cells, pronormoblasts, normoblasts, and nucleated 
erythrocytes
Quantitative and validated AML-specific MRD assessment at end of induction in 
the post-consolidation cohort 

Bone marrow biopsy (leukemia histology, cellularity, percent cellularity, percent 
blasts)
4.5.8
Mandatory Samples for Pharmacokinetic, Pharmacodynamic
Biomarker, and Exploratory Biomarker Analyses
All samples listed below will be collected according to the schedule of activities outlined 
in Appendix 2.  Unscheduled PK samples matched to ECG recordings may be required 
in case any prolongation of the QTc interval or other adverse cardiac findings is 
identified (see Section 4.5.9 for details). For PK analysis, it is of utmost importance to 
record dosing and blood sampling times accurately. 
For sampling procedures, storage conditions, and shipment instructions see the 
laboratory manual(s).
4.5.8.1
MRD Assessments for Patients in the Post-Consolidation 
Phase
Patients in the post-consolidation phase with an MRD-positive remission after induction
will be enrolled after local MRD assessment with a validated quantitative AML specific 
method. In order to monitor MRD during maintenance, assessments will be performed 
at 3 monthly intervals (see Appendix 1).  
4.5.8.2
Pharmacokinetic Analyses
PK blood samples will be collected in all patients according to the sample schedule 
outlined in Appendix 2.
All PK samples will be collected from the arm (limb) that is not being used during the 
administration of IV drugs (i.e., from the alternate arm).  If IV drugs are administered via 
a central line, PK samples may be collected via the same access after completely 
flushing the line.
In case a patient experiences an adverse event without plausible clinical explanation, the 
investigator may perform an additional blood draw for unscheduled PK analysis.  Care 
should be taken to accurately record timing of blood sampling on the unscheduled PK 
sampling page of the eCRF. 
All PK blood samples may be destroyed when the analysis is complete and the 
Bioanalytical Report finalized.  Residual PK samples may be used for additional 
validation experiments as appropriate.


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4.5.8.3
Pharmacodynamic and Exploratory Biomarkers
Bone marrow and blood samples will be collected from patients for pharmacodynamic 
and exploratory biomarkers.  These samples will be tested for protein, nucleic acid, or 
other tumor cellderived biomarkers relating to the proposed mechanism of action of 
idasanutlin, disease-associated markers, or improvement of diagnostic assays.  Analysis 
to include, but are not limited to:

Sequencing of cancer-related genes including TP53  

Measurement of transcript gene expression 

Protein expression in tumor cells by flow cytometry 

MRD in bone marrow
MRD will be monitored along clinical response assessments during induction, 
consolidation and maintenance. MRD will be assessed primarily by flow 
cytometry. Subsequent confirmation may use NGS panel following AML-specific 
mutations.
This research involves extraction of DNA, or RNA, analysis of mutations and genomic 
profiling through use of NGS for a comprehensive panel of genes. Research will not be 
aimed at distinguishing germline mutations from somatic mutations.
The specimens will also be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to idasanutlin treatment, identifying biomarkers 
useful for predicting and monitoring safety, assessing pharmacodynamic effects of 
idasanutlin treatment, evaluating potential combination partners, and investigating 
mechanism of therapy resistance.  Additional markers may be measured in case a 
strong scientific rationale for these analyses develops.  On the basis continuous analysis 
of biomarker data any analysis, timepoint, or sample type not considered to be critical for 
safety may be stopped at any time if the data do not support a strong scientific 
justification to continue.  Some samples that are collected may not be analyzed.  
Furthermore, some analysis may depend on patient’s molecular status or response to 
treatment. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (Research Biosample Repository; see Section 4.5.11), 
biologic samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions:

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 blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination.


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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 germline 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.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.8.4
Clinical Genotyping
DNA will be analyzed from whole blood for polymorphisms which may predict potential 
DDI and altered metabolism (such as CYP genes) of idasanutlin.
If the sample is missed on Day 1, it can be collected at any other scheduled visit.  This 
specimen will be destroyed after analysis.  Data arising from clinical genotyping samples 
will be subject to the confidentiality standards described in Section 8.4.
4.5.8.5
Bone Marrow 
Bone marrow (i.e., aspirate and, if sampled, bone marrow biopsy for the analysis of 
biomarkers) will be collected at screening.  Bone marrow aspirate will be collected each 
time that bone marrow is required for HMRAs (see Appendix 1).  If an unscheduled bone 
marrow aspirate is being collected to assess disease state, then additional bone marrow 
aspirate should be collected for flow and biomarker analyses.  Procedures are described 
in detail in the laboratory manual(s). 

Bone marrow for MRD flow cytometry (heparin): Analysis will include determination 
of abnormal cell phenotypes by flow cytometry. After screening, the bone marrow 
for MRD flow cytometry is the priority sample.

Bone marrow sample for DNA (in ethylenediaminetetraacetic acid [EDTA]):  This is 
the priority bone marrow sample at screening. Mutation profiling, including TP53
and gene mutations, rearrangements, and fusions are commonly seen in patients
with AML. The EDTA bone marrow will potentially be used for MRD monitoring by 
sequencing  

Bone marrow (PAXgene): Analysis will include, but will not be limited to, gene 
expression analysis.
For patients who proceed to transplant, pre-transplant bone marrow samples for MRD 
and biomarkers should be obtained, when possible.  


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If sites do their own MRD assessments locally or collect mutational data, please provide 
this information in the eCRF. 
If a patient consents to optional exploratory research, the remainder of the bone marrow 
sample(s) will be stored in the RBR (see Section 4.5.11) until they are no longer needed 
or until they are exhausted.  However, the RBR storage period will be in accordance with 
the Institutional Review Board/Ethics Committee (IRB/EC)-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements).
4.5.9
Electrocardiograms
Resting 12-lead ECG recordings will be obtained in triplicate at specified timepoints, as 
outlined in the schedule of activities (see Appendix 1) and may be obtained at 
unscheduled timepoints as clinically indicated.  ECGs for each patient should be 
obtained using the same machine wherever possible.  All ECG recordings must be 
performed using a standard high-quality, high-fidelity digital electrocardiograph machine 
equipped with computer-based interval measurements.  Lead placement should be as 
consistent as possible.  ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes.  All ECGs are to be obtained prior to 
other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws) and under no conditions while the patient is receiving premedication or an IV 
infusion of study drug.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator or designee must review, sign, and date 
all ECG tracings.  Paper copies of ECG tracings will be kept as part of a patient’s 
permanent study file at the site.  The following should be recorded on the appropriate 
eCRF:  ECG abnormality (including waveform); heart rate; PQ, PR, RR, and QRS 
intervals; and QT interval and corrected QTcF interval based on the machine readings of 
the individual ECG tracings.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF. 
If at a particular post-dose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on 
two successive ECGs.  The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, co-medications known to prolong 
the QT interval, and severe bradycardia) and provide this information on the eCRF.  In 
the event a patient presents with an episode of Grade 2 supraventricular arrhythmia 
(e.g., atrial fibrillation, atrial flutter, sinus tachycardia), an unscheduled ECG should be 
reported.  Standard-of-care treatment may be instituted at the discretion of the 
investigator.  If a PK sample is not scheduled for that timepoint, an unscheduled 
idasanutlin PK sample should be obtained.  


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4.5.10
Patient-Reported Outcomes
Patient-reported outcome (PRO) data will be collected to document the treatment benefit 
and more fully characterize the safety profile of idasanutlin.  PRO data will be obtained 
through the use of the following instruments: FACIT-Fatigue, EORTC QLQ-C30
(selected scales), EORTC Item library (selected items), PRO-CTCAE (selected 
symptoms), and EQ-5D-5L. 
The questionnaires, translated into the local language as appropriate, should be 
completed in their entirety at specified time points during the study.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires need to be self-administered before the patient receives any information 
on disease status and prior to the administration of study treatment.  Completion of PRO
questionnaires should occur prior to the performance of non-PRO assessments 
whenever possible. Laboratory blood collections are permitted prior to completing the 
PRO assessments.  
Study site staff will ensure that PRO questionnaires are provided to the patients for 
completion per the schedule of activities (see Appendix 1), and before drug 
administration, site staff will confirm completion or alternatively document any reasons 
questionnaires were not completed.  Paper versions of the questionnaires will be 
administered to patients and entered into the study database by site personnel. 
4.5.10.1
FACIT-Fatigue 
The FACIT-Fatigue (Version 4) is a validated, reliable, self-report measure for use in a 
variety of conditions (Yellen et al. 1997; Cella et al. 2005; Lai et al. 2011). It consists of 
13 items that assess fatigue using a 7-day recall period. Items are scored on a 0 ("not at 
all") to 4 ("very much so") response scale (see Appendix 12).  Relevant items are 
reverse scored, and all items are summed to create total scores where higher scores are 
indicative of better functioning (i.e., less fatigue). 
4.5.10.2
EORTC QLQ-C30 
The EORTC QLQ-C30 (Version 3) is a validated, reliable, self-report measure (Aaronson 
et al. 1993; Fitzsimmons et al. 1999).  It consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, and pain), global health status/quality of 
life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) with a recall period of the previous week (see Appendix 13). Scale 
scores can be obtained for the multi-item scales.  The first 28 items are scored on a 
4-point scale that ranges from "not at all" to "very much," and the last two items are 
scored on a 7-point scale that ranges from "very poor" to "excellent." Higher scores 
indicate higher response levels (i.e., higher HRQoL, higher symptom severity).  For this 
study only the physical function (5 items), role function (2 items), and global health 
status/quality of life (2 items) will be administered to patients. 


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4.5.10.3
EORTC Item Library 
The EORTC Item Library is a database of items used in fully and partially validated 
EORTC quality-of-life questionnaires (see Appendix 14). Three items from the library 
will be used to assess disease-related symptoms relevant to patients with AML. 
Selected symptoms include headaches, dizziness, and bruising. All items are scored on 
a 4-point scale that ranges from "not at all" to "very much," with higher scores indicative 
of higher symptom severity. 
4.5.10.4
PRO-CTCAE
The PRO-CTCAE is a validated item bank that is used to characterize presence, 
frequency, severity, and interference with daily function of 78 patient-reportable 
symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 2015). The 
PRO-CTCAE contains 124 questions that are rated on either a 5-point Likert-type scale 
(frequency, severity, and interference) or dichotomously (presence/absence). Included 
treatment toxicity terms can be subjective, with or without observable components (e.g., 
vomiting and nausea, respectively) or primarily observable with subjective components 
(e.g., rash). The standard PRO-CTCAE recall period is "the past 7 days." 
A subset of three symptoms (nausea, vomiting, diarrhea) deemed most applicable to 
treatment with idasanutlin was selected for this study based on known adverse events. 
The five items assessing these symptoms will be used to characterize the patient 
experience of symptomatic adverse events (see Appendix 15).
4.5.10.5
EQ-5D-5L
The EQ-5D-5L is a validated, self-report, health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There are two 
components to the EQ-5D-5L:  a five-item health state profile that assesses mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a VAS that 
measures health state.  Published weighting systems allow for creation of a single 
composite score of the patient's health status.  It will be used in this study for informing 
pharmacoeconomic evaluations (see Appendix 16).
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
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 used to achieve 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 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 study drugs, study 
disease or other types of cancer, or drug safety:

Remaining tumor tissue samples (except for remaining blocks, which will be 
returned to the sites), bone marrow aspirate and blood samples, and any derivatives 
thereof (e.g. DNA, RNA)

Blood for serum

Blood for plasma
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations 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 will also be explored in aggregate with data from other studies.  


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The availability of a larger dataset will assist in identification and characterization of 
important biomarkers and pathways, guiding the development of new targeted agents.
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.  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:

Pregnancy

Treatment failure

Unacceptable toxicity


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The primary reason for study medication discontinuation should be documented on the 
appropriate eCRF.  Patients discontinuing study medication will be followed as per the 
schedule of activities (Appendix 1).
After the study drug completion/discontinuation visit, adverse events should be followed 
as outlined in Section 5.3.1.
Patients who discontinue study treatment will not be replaced, except as outlined below:

During the dose-escalation phase, patients who discontinue study treatment prior to 
completing the DLT assessment window for reasons other than a DLT will be 
replaced by an additional patient at that same dose level.

Patients who discontinue before having received at least one dose of each
scheduled study drugs in induction (idasanutlin, cytarabine, daunorubicin) will be 
replaced.

Patients who discontinue before having received at least one dose of idasanutlin in 
the post-consolidation cohort will be replaced.
4.6.2
Patient Discontinuation from 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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determination that it is in the best interest of the patient

Patient non-compliance (e.g., consistent failure to show up for scheduled visits)
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF. However, patients will not be 
followed for any reason after consent has been withdrawn.
If a patient withdraws consent, this request must be documented in the source 
documents and signed by the investigator.  Study personnel may use a public 
information source (e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.


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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
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
The safety plan for patients in this study is based on clinical experience with study 
treatment components in completed and ongoing studies.  The anticipated important 
safety risks of IMPs in this study (i.e., idasanutlin, cytarabine, and daunorubicin) are 
outlined below.  Please refer to the Idasanutlin Investigator’s Brochure and the local 
labels for cytarabine and daunorubicin for a complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk of toxicities (see 
Section 4.1.2).  In addition, patients will undergo adequate safety monitoring during the
study, as described in this section.  Guidelines for managing adverse events, including 
criteria for dosage modification and treatment delays or discontinuation, are provided in 
Section 5.1.3.
5.1.1
Safety Risks of Idasanutlin, Cytarabine, and Daunorubicin in 
Leukemia  
Patient well-being and safety will be protected by applying stringent exclusion criteria 
specified in Section 4.1.2, by applying the toxicity management guidelines detailed in 
Appendix 5, and through pharmacovigilance/safety monitoring of all adverse events and 
laboratory assessments and will be graded according to the NCI CTCAE v5.0 criteria.  
All treatment-emergent adverse events, whether treatment related or not, will be 
monitored to resolution or stabilization as feasible.  All serious adverse events and any 
adverse event of special interest will be reported in an expedited fashion (see 
Sections 5.2.2 and Section 5.2.3). The safety reviews will include summary tables of 
patient disposition, all adverse events, serious adverse events, deaths, adverse events 
leading to study discontinuations, adverse events of special interest, and treatment 
exposure.


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Information related to the risks associated with idasanutlin treatment is based on the 
Idasanutlin Investigator’s Brochure. Many of the toxicities experienced by patients were 
manageable with appropriate prophylaxis and supportive therapy and/or were reversible 
with discontinuation of the drug. Refer to the current Idasanutlin Investigator’s Brochure
for details on the safety data from previous studies and for additional information on 
idasanutlin warnings and precautions.  
5.1.1.1
Gastrointestinal Toxicity
The adverse GI events in the Phase I idasanutlin studies include primarily diarrhea, 
nausea, vomiting, abdominal pain, constipation, and anorexia.  Diarrhea was the most 
common adverse event observed in 90% of patients in the AML study NP28679 
(mostly Grades 1 and 2 in severity).  Nausea and vomiting were also reported in this 
study but to a lesser extent and all events were generally Grades 1 and 2.  Supportive 
therapies, including prophylaxis for diarrhea and nausea, are encouraged in this study.
In addition to institutional guidelines, specific instructions for the management of GI side 
effects are provided in Section 5.1.3.1 and Appendix 5.
5.1.1.2
Cytopenias
Cytopenias including myelosuppression are an anticipated consequence of the leukemia 
treatment proposed.  Bone marrow toxicity may manifest as cytopenias 
(i.e., pancytopenia, neutropenia, febrile neutropenia, thrombocytopenia, and anemia).  
The NP27872 study evaluating idasanutlin in patients with solid tumors has shown 
possible exposure-dependent neutropenia and thrombocytopenia.  Most of them were 
reversible and clinically manageable. 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 the AML study NP28679, but normal marrow recovery was 
observed in responding patients. In patients with leukemia, drug-induced 
myelosuppression is expected during idasanutlin treatment.  In this study, blood counts 
will be monitored closely throughout study treatment (see Appendix 1).
5.1.1.3
Tumor Lysis Syndrome
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 but had been very rare with idasanutlin.
Please refer to the Idasanutlin Investigator’s Brochure. 
5.1.1.4
Infections
Infections of various etiologies have been reported in patients with AML in 
Study NP28679, and patients with AML generally have a higher susceptibility to infection.  
Infectious diarrhea, and in particular C. difficile infection, was reported in approximately 
10% of patients with AML administered idasanutlin in Study NP28679, including 1 fatal 


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case of C. difficile infection. In addition to institutional guidelines, specific instructions for 
the management of C. difficile infection are provided in Appendix 5.
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
Other Adverse Events
Other adverse events commonly reported with idasanutlin include fatigue, asthenia, 
pyrexia, peripheral edema, headache, dyspnea, dizziness, and chills.  These adverse 
events have been of mild severity and controllable with symptomatic treatment and/or 
nutritional support.
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 
as clinically indicated, vital signs, and laboratory measurements (hematology, chemistry, 
and urinalysis). 
5.1.2
Risk of Overlapping Toxicities
Overlapping toxicities from the combined administration of cytarabine, daunorubicin and 
idasanutlin are anticipated during study treatment phase. These toxicities include 
myelosuppression (thrombocytopenia, neutropenia, and febrile neutropenia), infectious 
complications, and GI disorders (diarrhea, nausea and vomiting; see Table 7).


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Table 7
Overlapping Toxicities Grade 3: Idasanutlin, Cytarabine, and 
Daunorubicin
Adverse Events
73 a
Idasanutlin b
Hematologic
toxicities
Thrombocytopenia
98%
24.5%
Neutropenia/febrile 
neutropenia
91%/35%
12.4%/26%
Anemia
76%
18.2%
Infections
Infections (SOC)
49%73.7% (60 yr)
86% (60 yr)
30.2%
GI toxicities
Diarrhea
10.8%
13%
Nausea/vomiting
4%/1.3%
737 days of cytarabine plus 3 days of daunorubicin; AMLacute myeloid leukemia; 
GIgastrointestinal; R/Rrelapsed or refractory; SOCsystem organ class.
a Fernandez et al. 2009; Löwenberg et al. 2009; Lee 2011.
b Idasanutlin Investigator’s Brochure, Version 10. Cumulative incidences across all solid tumor
and R/R AML studies (except GH29914).
5.1.3
Management of Patients Who Experience Specific 
Adverse Events
Patients should be assessed clinically before each study treatment administration.
Guidelines for management of toxicities (see Appendix 5) are based on laboratory 
values obtained within 3 days prior to Day 1 of each scheduled drug administration.
Dosing will occur only if a patient’s clinical assessment and laboratory test values are 
acceptable.
Treatment delays apply to all toxicities described below; dose modifications apply only to 
toxicities that are considered to be related to idasanutlin.  The dose of idasanutlin may 
be reduced as outlined in Table 8. 


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Table 8
Idasanutlin Dose-Reduction Steps
Initial Dose
Dose Reduction in Milligrams
Step 1
Step 2
Step 3
150 mg
Minus 50 mg
No further 
reduction a 
No further reduction a 
200 mg
Minus 50 mg
Minus 50 mg
No further reduction a 
250 mg
Minus 100 mg
Minus 50 mg
No further reduction a 
300 mg
Minus 100 mg
Minus 50 mg
Minus 50 mg
350 mg
Minus 100 mg
Minus 100 mg
Minus 50 mg
400 mg
Minus 100 mg
Minus 100 mg
Minus 50 mg
a When no further idasanutlin dose reduction is possible, the patient will be 
discontinued from the study drug.
Toxicities that occur during the cycle and subside prior to the next cycle should not 
trigger the suggested dose modifications. Guidelines for management of toxicities 
during treatment are provided in Sections 5.1.3.1 and 5.1.3.2. Exceptions to those 
guidelines may be allowed by the Sponsor after careful review of the case and 
discussion with the Medical Monitor.
5.1.3.1
Toxicities during Induction and Consolidation Treatment
Hematologic Toxicities 
Table 9 provides guidelines for management of hematologic toxicities that occur during 
induction and consolidation treatments. Hematologic toxicity is defined as neutropenia, 
febrile neutropenia, anemia, or thrombocytopenia. If toxicity is thought to be caused 
mainly by AML, the investigator may decide not to reduce idasanutlin dose.


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Table 9
Guidelines for Management of Idasanutlin-Related Hematologic Toxicities in Induction and 
Consolidation Treatment
Event
Action to Be Taken
Grade 3 or 4 
hematologic toxicity
For patients who have had one or no prior dose reductions:

Withhold study treatment.

Administer RBCs or platelets as required.

If patient has not already initiated G-CSF, initiate prophylactic G-CSF for current and subsequent 
cycles (consolidation only) as required.

If improvement to Grade 2 or baseline within 21 days after the scheduled date for the next 
cycle, resume idasanutlin at current dose (consolidation only).

If improvement to Grade 2 or baseline 2128 days after the scheduled date for the next cycle, 
resume idasanutlin at a reduced dose according to guidelines for current and subsequent cycles 
(consolidation only).

No more than two dose reductions of idasanutlin are allowed per study phases (induction, 
consolidation)

If study treatment is withheld for 28 days, permanently discontinue study treatment.

Permanently discontinue study treatment if any of the following events occur:

Grade 3 or 4 thrombocytopenia of any duration if associated with Grade 3 bleeding

Recurrent Grade 3 or 4 neutropenia if associated with fever of 38°C for 5 days or a 
documented infection despite use of G-CSF and after one idasanutlin dose reduction 

Recurrent Grade 4 neutropenia or thrombocytopenia lasting more than 7 days despite use of 
G-CSF (for neutropenia) and after one idasanutlin dose reduction
For patients who present with recurrent Grade 3 thrombocytopenia/neutropenia in consecutive 
cycles:

If despite the use of G-CSF, for subsequent cycles, reduce idasanutlin to the next dose level.
For patients who have had two dose reductions in the same study phase (induction, consolidation) or 
for patients who reach the lowest dose level and no further dose reduction is applicable.

Permanently discontinue study treatment
G-CSF granulocyte colony-stimulating factor.


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5.1.3.1.1
Non-Hematologic Toxicities 
Guidelines for management of non-hematologic toxicities that occur during induction and consolidation treatment are 
presented in Table 10 and Table 11.
Table 10 Guidelines for Management of Idasanutlin-Related Gastrointestinal Toxicities in Induction and 
Consolidation
Event
Action to Be Taken
Diarrhea 
Permanently discontinue study treatment for Grade 4 events.
Grade 3 diarrhea:

If Grade 3 diarrhea occurs between Days 1 and 5 of the treatment cycle, withhold idasanutlin 
only if diarrhea does not improve to Grade 2 within 72 hours with appropriate treatment. After 
the study treatment is withheld, if diarrhea improves to Grade 2, resume idasanutlin at a 
reduced dose according to guidelines in Sections 5.1.3 for current and subsequent cycles.
Vomiting
Grade 4 vomiting:

Permanently discontinue study treatment.
Grade 1, 2, or 3 vomiting:

If vomiting occurs within 15 minutes of taking idasanutlin, and all expelled tablets are still intact, 
another dose may be given and the second dose noted in the drug log.  Otherwise, no 
replacement dose is to be given (see Section 4.3.2).


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Table 11 Guidelines for Management of Idasanutlin-Related Non-Hematologic Toxicities in Induction and 
Consolidation
Event
Action to Be Taken 

General guidance for 
treatment delays, 
discontinuation, and 
resumption

If study treatment is withheld for 21 days because of a toxicity that is attributable to study treatment, 
permanently discontinue study treatment.

Permanently discontinue study treatment for Grade 4 events.

Dosing may be resumed after resolution to Grade 2 or baseline status.  Resumption of dosing without 
complete resolution of toxicity may be considered in special circumstances after having obtained Medical 
Monitor agreement.
IRRs and anaphylaxis

Guidelines for the management of IRRs are provided in Appendix 5.  In case of Grade 4 IRRs or anaphylaxis, 
study treatment should be permanently discontinued.
Clinical and laboratory 
TLS
Grade 4 events:

Permanently discontinue study treatment in the case of Grade 4 events.
Grade 3 events:

Withhold study treatment

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, 
including dialysis as indicated.

If symptoms (laboratory and clinical) have resolved completely, resume idasanutlin at current dose
AST, ALT, or bilirubin 
increase
Grade 4 events: 

Permanently discontinue study treatment.
Grade 2 or 3 events (or 10 ULN for patients with liver involvement):

Withhold study treatment.

If improvement to Grade 1 (or 5ULN [Grade 2]) for patients with liver involvement), resume idasanutlin at 
full dose for current and subsequent cycles per guidelines.  No more than two dose reductions are allowed 
per study phase (induction, consolidation, maintenance).  Patients who have had two prior dose reductions of 
idasanutlin should be permanently discontinued.

Permanently discontinue study treatment for life-threatening liver toxicity (including Hy’s Law cases).
IRRinfusion-related reaction; TLStumor lysis syndrome; ULNupper limit normal.


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Table 11
Guidelines for Management of Idasanutlin-Related Non-Hematologic Toxicities in Induction and 
Consolidation (cont.)
Event
Action to Be Taken 
Other non-hematologic 
toxicities (i.e., not 
described above), 
excluding alopecia 
Grade 4 events

Permanently discontinue study treatment.
Grade 3 events

Withhold study treatment.

If improvement to Grade 2 or baseline, resume idasanutlin at reduced dose for subsequent cycles.  No more 
than three dose reductions of idasanutlin per study phase (induction, consolidation) are allowed.
For patients who have had two dose reductions in the same study phase (induction, consolidation) or for patients 
who reach the lowest dose level and no further dose reduction is applicable.

Permanently discontinue study treatment.
IRRinfusion-related reaction; TLStumor lysis syndrome; ULNupper limit normal.


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5.1.3.2
Toxicities during Maintenance Treatment
Guidelines for management of toxicities that occur during maintenance treatment are 
presented in Table 12.
Table 12 Guidelines for Management of Toxicities That Occur during 
Maintenance 
Event
Action to Be Taken
Hematologic 
toxicity:
Grade 3 or 4

Withhold study treatment.

If improvement to Grade 2 within 14 days, resume treatment at 
full dose.

If improvement to Grade 2 after 14 days, resume study drug
at next lower dose for subsequent cycles per guideline in 
Section 5.1.3.  Patients who are not eligible for further dose 
reductions should be permanently discontinued.

Patients missing two consecutive cycles should be permanently 
discontinued.
Non-hematologic 
toxicity:
Grade 3

Withhold study treatment. 

If improvement to Grade 2 within 14 days, resume treatment at 
full dose.

If improvement to Grade 2 after 14 days, resume study drug 
at next lower dose for subsequent cycles per guideline in 
Section 5.1.3.  Patients who are not eligible for further dose 
reductions should be permanently discontinued.

Patients missing two consecutive cycles should be permanently 
discontinued.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
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


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8 and
5.3.5.9 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 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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).


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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 5.3.5.6)

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.

TLS (clinical TLS per Howard criteria, see Appendix 4)

Bleeding if associated with Grade 3 thrombocytopenia 

Grade 3 febrile neutropenia

Grade 2 diarrhea

Grade 2 C. difficile infection 
Note that patients with hematologic adverse events of special interest should be 
monitored with weekly blood counts until resolution.  The final outcome must be reported 
in the eCRF. Hematologic adverse events of special interest (bleeding and febrile 
neutropenia) are not reportable for patients in whom myelosuppression arises as a result 
of confirmed relapsed disease.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 28 days 
after the final dose of study treatment.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.1.1
Adverse Events Associated with Allo-HSCT
Because of the multiple safety issues associated with the procedure, adverse events 
clearly related to allo-HSCT and associated procedures (e.g., conditioning, DILs, etc.) 
should not be reported.  Reporting in the maintenance following consolidation will 
resume following the first dose of study drug as per standard reporting rules. 
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 time points.  Examples of 
non-directive questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 13 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 13 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:

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

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.


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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.
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 GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
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 (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 


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more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF. If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious"
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
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)

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., ALP 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."


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
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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5.3.5.7
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 acute myeloid leukemia should be recorded on the 
dedicated eCRF page.  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 5.2.2)
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.
5.3.5.8
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").
5.3.5.9
Lack of Efficacy or Worsening of Acute Myeloid Leukemia
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 criteria using 2017 ELN recommendations (see 
Section 4.5.6).  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Hospitalization data will be collected. Any adverse event that results in hospitalization 
(i.e., in-patient admission to a hospital) or prolonged hospitalization should be 


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documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2 except as outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study 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
5.3.5.11
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and sites are 
not expected to review the PRO data for adverse events. The PRO-CTCAE will be used 
to document patient-reported treatment-related symptoms. No attempt will be made to 
reconcile the findings from reports of treatment-related symptoms by clinicians (NCI 
CTCAE) and patients (PRO-CTCAE).
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 any of the study treatments:

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 see Section 5.2.3; see Section 5.4.2
for details on reporting requirements)

DLTs (defined in Section 3.1.2.1; see Section 5.4.2 for details on reporting 
requirements)

Pregnancies (see Section 5.4.3; see Section 5.4.2 for details on reporting 
requirements)

Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for 
details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, Ph.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Roche Medical Responsible:
, M.D. (Secondary) 
Telephone No.:
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study 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 until 28 days after the final dose of study drug.  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 28 days after the last dose of 
study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the final
dose of any study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 


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24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF. The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy. Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
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 
6 months after the final dose of any study treatment. 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.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
After the authorization has been signed, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).


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5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
idasanutlin, 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.


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
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, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose: Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box. If drug abuse is suspected, check the 
"Drug abuse" box. If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose: Enter the drug name and "drug 
abuse" as the event term. Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose: Enter the drug name and "drug 
misuse" as the event term. Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose: Enter the drug name and "intentional 
overdose" as the event term. Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient: Enter the drug name and 
"patient supplied drug to third party" as the event term. Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.


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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. Patients with ongoing hematologic adverse events 
should be monitored with weekly blood counts until resolution. The final outcome must be 
reported in the eCRF. Hematologic adverse events are not reportable for patients for 
whom myelosuppression arises as a result of confirmed relapsed disease.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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 28 days after the final
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term 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 


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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

Local prescribing information for cytarabine

Local prescribing information for daunorubicin
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
6.1
DETERMINATION OF SAMPLE SIZE
Dose finding will be conducted during the dose-escalation phase of this study. The 
estimated sample size follows from the dose-escalation rules for a mCRM algorithm, as 
outlined in Section 3.1. It is anticipated that enrollment of up to five cohorts of 
36 patients each, for a total of 915 evaluable patients, will be required to establish the 
RP2D during the dose-escalation phase (see Appendix 18 for modeling details and 
simulation results). Assuming 5 not-evaluable patients (see Section 3.1.2 for the 
definition of evaluable patients), the expected maximum sample size will be 
approximately 20 patients.
Approximately 40 patients (20 favorable/intermediaterisk patients and 20 high-risk 
patients in two separate cohorts) will be enrolled during the expansion phase. A sample 
size of 20 patients in the high-risk cohort is deemed sufficient to provide adequate 
precision for the point estimate and for the lower end of the 90% CI to rule out a clinically 
uninteresting probability of response of 50% with an observed CR proportion of 70%. 
Depending on the proportions of patients with adverse risk or secondary AML enrolled, a 
CR proportion up to 50%55% is expected for high-risk patients under current 73 
standard of care (see Table 14). This assumption is based on the literature related to 
adverse-risk patients (per ELN 2017 recommendations; Fernandez et al. 2009; 
Löwenberg et al. 2009; Burnett et al. 2015; Luskin et al. 2016) and secondary AML 
efficacy data as well as real world data obtained from the clinic (Østgårdt et al. 2014).




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number of doses, treatment cycles, and the average dose received for each cohort will 
be summarized using descriptive statistics (mean, standard deviation, median, and 
range). Number of patients who enroll, discontinue, or complete the study will be 
summarized.  
6.3
EFFICACY ANALYSES
Efficacy analyses will be performed including all patients who received at least one dose 
of any study drug given in combination or as a single agent. 
Data from patients enrolled during the dose-escalation phase will be analyzed separately, 
by dose.  Data from patients who were treated at the RP2D during the dose-escalation 
phase will be pooled with the corresponding cohort of the expansion phase 
(favorable/intermediate cohort).  Data from the favorable/intermediate cohort, high-risk 
cohort (expansion phase), and post-consolidation cohort will be analyzed separately, 
without direct comparison among cohorts.  Response definitions used in the section 
below are provided in Appendix 19.
6.3.1
Primary Efficacy Endpoint
The primary efficacy analysis will be the estimation of the proportion of patients with a 
CR at the end of induction treatment.
Point estimates will be presented, along with the corresponding two-sided 90% 
Clopper-Pearson exact CIs. Patients without a post-baseline tumor assessment will be 
considered non-responders.
6.3.2
Secondary Efficacy Endpoints
The following secondary efficacy endpoints will be analyzed in patients enrolled during 
specified phases through use of the same methods described for the primary efficacy 
endpoint:
Dose-escalation or expansion phase

Proportion of patients with a CR, CRi, or CRp at the end of induction treatment

Proportion of patients with a CR or CRh at the end of induction treatment

Proportion of patients with a negative MRD status at the end of induction treatment
Post-consolidation phase

Proportion of patients converting from MRD-positive to MRD-negative status at any 
time during treatment
The following secondary efficacy endpoints will be analyzed in patients enrolled during 
the dose-escalation and expansion phases:

EFS, defined as the time from initiation of study treatment (for post-consolidation 
patients, date of initiation of induction treatment prior to this study) to treatment 


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failure (failure to achieve CR, CRi, CRp, or CRh), hematologic relapse, or death 
from any cause, whichever occurs first
Patients with no EFS event at the time of analysis will be censored at the date 
of last response assessment. Patients with no EFS event and no postbaseline 
response assessment will be censored at Day 1. 

OS, defined as the time from initiation of study treatment to death from any cause
Patients who have not died at the time of analysis will be censored at the date 
the patient was last known to be alive.

RFS in patients who achieve remission (CR, CRi, CRp, or CRh), defined as the time 
from remission to the date of hematologic relapse or death from any cause,
whichever occurs first
Patients with no RFS event at the time of analysis will be censored at the date 
of last response assessment. 
The following secondary efficacy endpoints will be analyzed in patients enrolled during 
the post-consolidation phase:

EFS, defined as the time from initiation of induction treatment (prior to study entry) 
to hematologic relapse or death from any cause, whichever occurs first
Patients with no EFS event at the time of analysis will be censored at the date 
of last response assessment. Patients with no EFS event and no postbaseline 
response assessment will be censored at Day 1. 

OS, defined as the time from remission (prior to study entry) to death from any 
cause
Patients who have not died at the time of analysis will be censored at the date 
the patient was last known to be alive.

RFS in patients who achieved remission (CR, CRi, CRp, or CRh), defined as the 
time from remission (prior to study entry) to the date of hematologic relapse or death 
from any cause, whichever occurs first
Patients with no RFS event at the time of analysis will be censored at the date 
of last response assessment. 
The following secondary efficacy endpoint will be analyzed in patients enrolled during all 
phases:

Change from baseline in patient-reported disease-related symptoms and 
health-related quality of life at specified timepoints, as assessed through use of the 
FACIT-Fatigue, EORTC QLQ-C30 (selected scales), and EORTC Item Library 
(selected symptoms)
EFS, OS, and RFS will be analyzed descriptively using the KaplanMeier method 
(Kaplan and Meier 1958).  


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Where medians are reached, the corresponding estimated median will be provided, 
along with the 95% CI by means of the Brookmeyer and Crowley method (Brookmeyer 
and Crowley 1982).  In addition, when available at the time of the analysis, landmark 
estimates of the proportion of patients who are event free at 6 months, 9 months, 1 year, 
and 2 years will be provided, along with 95% asymptotic CIs using Greenwood’s formula 
for standard errors.
Descriptive summary statistics and change from baseline will be calculated at each 
assessment timepoint for the FACIT-Fatigue, EORTC QLQ-C30 scales, and EORTC 
Item Library symptoms.  Further details of the PRO analyses will be provided in the 
Statistical Analysis Plan.
6.3.3
Exploratory Efficacy Endpoints
All endpoints listed as primary and secondary will also be analyzed separately within the 
subset of patients with wild-type p53.
The following exploratory efficacy endpoints will also be assessed:

MRD response over time (i.e., during induction, consolidation, and maintenance)

Time to MRD-negative status, defined as time from initiation of treatment to 
confirmation of negative MRD status
Patients with continuing MRD positive status at the time of analysis will be 
censored at the date of last MRD assessment. Patients with no post baseline 
MRD assessment will be censored at Day 1. 
6.4
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of any study drug, given in combination or as a single agent. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0.
Safety will be determined using incidence rates for adverse events including mortality, 
adverse event severity, seriousness, adverse events leading to discontinuation, 
abnormalities of clinical laboratory tests, and vital signs.  Incidence of clinically 
significant ECG abnormalities will be reported in patient listings and change from 
baseline summarized. ECG QT and QTcF intervals will be summarized using
descriptive statistics.
Exposure to study medication will be summarized by total duration of study medication, 
number of cycles started and cumulative dose using descriptive statistics.  
The number and proportion of patients reporting each symptom (nausea, vomiting, and 
diarrhea) on the PRO-CTCAE and the change from baseline by category ("frequency,"
"severity," "interference") will be reported at each assessment timepoint. A summary of 


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the maximum post-baseline score and change from baseline will also be provided. 
Graphical representation of PRO-CTCAE items over time may be provided.
PRO-CTCAE analyses will be presented separately from the safety analyses.
6.5
PK ANALYSES
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters (e.g., area under the concentrationtime curve [AUC], time 
to maximum concentration, maximum concentration [Cmax], and terminal half-life). 
Individual and mean plasma of each study drugs concentration versus time data will be 
tabulated and plotted by dose level.  The plasma pharmacokinetics of each study drugs 
will be summarized by estimating total exposure (AUC), Cmax, total clearance, volume of 
distribution at steady-state, and terminal half-life (as appropriate for data collected).  
Estimates for these parameters will be tabulated and summarized (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum).  Inter-patient 
variability and drug accumulation will be evaluated.   
Additional PK analyses will be conducted as appropriate.
6.6
BIOMARKER ANALYSES
Biomarker results will be analyzed for association with patient clinical characteristics, 
prognostic and predictive value, as well as outcome, prevalence, and correlation with 
other biomarkers.
Data may be analyzed in the context of this study and in aggregate with data from other 
studies.  
6.7
HEALTH STATUS UTILITY ANALYSES
Change from baseline in EQ-5D-5L health utility index-based and VAS scores will be 
calculated at specified timepoints.
6.8
INTERIM ANALYSES
Optional interim safety and/or efficacy data review may be carried out by an internal 
monitoring committee (IMC) that includes Sponsor members at the discretion of the 
Medical Monitor. The decision to conduct such an analysis and the corresponding 
timing will be documented in the Sponsor's trial master file prior to the conduct of the 
interim analysis.  In particular, given the hypothesis-generating nature of this study, the 
Sponsor may choose to conduct interim efficacy analyses for early stopping (futility) by 
using observed proportion of patients achieving complete response (e.g., predictive 
probability that this trial will have a positive outcome if carried out to completion based 
on historical control data available at the time of analysis).
Further details regarding the rules and guidelines of the data review will be provided in 
an IMC charter if applicable.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format 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.


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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.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test results, 
and medication inventory records, must be retained by the Principal Investigator for at 
least 15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U.
Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or 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.  
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 


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each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
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.


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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.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data 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.
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, 


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prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
An EDC system will be used for this study.  An IxRS will be used to assign patient 
numbers.  A central laboratory will be used for a subset of laboratory assessments as 
specified in Section 4.5.7; otherwise, local laboratories will be used. Data from this 
study will be shared with an expert scientific committee that will provide scientific input 
for the benefitrisk assessment.
9.5
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 of the U.S. National Institutes of Health and the 
European Medicines Agency, 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, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following web site:
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 


Idasanutlin—F. Hoffmann-La Roche Ltd
104/Protocol GO40800, Version 1
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Idasanutlin—F. Hoffmann-La Roche Ltd
105/Protocol GO40800, Version 1
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Appendix 1: Schedule of Activities
Idasanutlin—F. Hoffmann-La Roche Ltd
109/Protocol GO40800, Version 1
Appendix 1
Schedule of Activities
Table 1: Induction
Assessment/Procedure
Screening a
Induction (28-Day Cycle) up to 2 Cycles
Days 14
to 1
D1
D2
D3
D4
D5
D7
D8
D15
D22
D28
Informed consent(s) b
x
Serum pregnancy test c
x
Demographics, medical history, determination of 
cytogenetic and molecular risk, physical 
examination, height, chest X-ray (or chest CT) d
x
Vital signs e, weight, ECOG performance status
x
x
x
x
x
x f
Triplicate 12-Lead ECG g
x
x
x
x
x
MUGA or ECHO
x
Coagulation (INR, aPTT [or PTT], and PT)
x
Targeted physical examination h
x
x
x
x
x f
Urinalysis
x
x
Hepatitis B and C testing i
x
C. difficile toxin and toxin-producing C. difficile in
stool
x
Chemistry j
x
x
x
x
x
x
x
x f
Hematology j
x
x
x
x
x
x
x
x f
FACIT-Fatigue, EORTC Item Library, 
PRO-CTCAE k
x


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
110/Protocol GO40800, Version 1
Table 1: Induction (cont.)
Assessment/Procedure
Screening a
Induction (28-Day Cycle) up to 2 Cycles
Days 14
to 1
D1
D2
D3
D4
D5
D7
D8
D15
D22
D28
EORTC QLQ-C30, EQ-5D-5L k
x l
HMRA
x f
Bone marrow sampling for HMRA m
x
x f
Bone marrow sampling n (MRD/Flow, EDTA, 
PAXgene)
x
x f
Whole blood sampling (flow, EDTA, clinical)
x 
x
x f, o
Whole blood sampling PAXgene
x
RBR sampling/blood serum and plasma (optional)
x
PK sampling and MIC-1
Refer to Appendix 2
Concomitant medications
x
To be recorded continually; see Section 4.4
Adverse events
To be assessed continually; see Section 5.3.1
Daunorubicin treatment 
(60 mg/m2 IV) p
x
x
x
Idasanutlin treatment 
(PO QD) p
x
x
x
x
x
Cytarabine treatment (200 mg/m2 IV) p
x
x
x
x
x
x
AMLacute myeloid leukemia; CTcomputed tomography; CTCAECommon Terminology Criteria for Adverse Events; 
ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; eCRFelectronic Case Report Form; 
EDTAethylenediaminetetraacetic acid; EOIend of induction; EORTCEuropean Organisation for Research and Treatment of Cancer; 
EORTC QLQ-C30EORTC Quality-of-Life QuestionnaireCore 30; EQ-5D-5LEuroQol 5-Dimension, 5-Level; FACITFunctional
Assessment of Chronic Illness Therapy; HMRAhematologic malignancy response assessment; MRDminimal residual disease;


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
111/Protocol GO40800, Version 1
Table 1: Induction (cont.)
MUGAmultiple-gated acquisition (scan); PKpharmacokinetic; POorally; PROpatient-reported outcome; PRO-CTCAEPatient-
Reported Outcomes Common Terminology Criteria for Adverse Events; QDonce a day; RBRResearch Biosample Repository; 
TBtuberculosis.
a The screening period starts with the signing of the Informed Consent Form, including the optional Informed Consent Form if appropriate.  
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be 
used as screening and baseline assessments; such tests do not need to be repeated for screening purposes.
b Informed consent must be documented before any study-specific screening procedure is performed.
c Must be performed within 7 days of the planned D1
d If a chest CT is performed up to 28 days prior to study drug administration, a chest X-ray is not required.  Patients with a medical history 
of fungal and TB infections should have a chest CT performed within 28 days prior to study drug administration.
e Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate.  Body surface area will also 
be measured at screening. 
f
Should Day 28 not be the last day of the cycle the following will be assessed every 7 days following D28 until end of cycle:  
biochemistry, hematology, vital signs, ECOG performance status.  Bone marrow, HMRA and whole blood sampling should be repeated 
on the last day of the cycle with D56 as the limit and if not performed within the previous 2 weeks.
g All ECGs should be performed within 2 hours prior to idasanutlin administration and 6 hours after idasanutlin administration.
h Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly
emergent or monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas 
identified at baseline).  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.
j
All hematology and biochemistry assessments may be performed up to 3 days prior to the scheduled timepoint.  Results must be 
reviewed by the investigator (or designee) prior to study drug administration.
k PRO questionnaires need to be self-administered before the patient receives any information on disease status and prior to the 
administration of study treatment.  Completion of PROs should occur prior to the performance of non-PRO assessments whenever 
possible.  PRO assessments include the FACIT-Fatigue, EORTC QLQ-C30, EORTC Item Library symptoms, PRO-CTCAE, and 
EQ-5D-5L.
l
Only first cycle of induction.
m At screening, bone marrow examination will require biopsy if an aspirate is not evaluable to confirm the AML diagnosis.  For HMRAs 
during study, bone marrow aspirates are required, but bone marrow biopsies may be performed at the discretion of the investigator.


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
112/Protocol GO40800, Version 1
Table 1: Induction (cont.)
n Bone marrow MRD/Flow, EDTA, and PAXgene to be collected at same time as bone marrow for response assessment.  If unscheduled 
bone marrow aspirate is being collected for hematologic response assessment, then bone marrow MRD/flow, EDTA, and PAXgene 
samples should also be collected. If any MRD assessments are done locally, please record this information in the eCRF.  At screening,
the priorities for bone marrow samples are EDTAMRDFlowPAXgene. At subsequent timepoints the priorities are 
MRD/FlowEDTAPAXgene.
o EDTA only.
p Refer to Section 4.3.2 for instructions on study treatment administration.


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
113/Protocol GO40800, Version 1
Table 2:  Chemotherapy Consolidation
Assessment/Procedure
Consolidation (28-Day Cycle) up to 4 Cycles
D1
D2
D3
D4
D5
D8
D15
D22
D28
Vital Signs a, weight, ECOG performance status
x
x
x
x
x b
Single 12-Lead ECG c
x
x
x
x
Targeted physical examination d
x
x
x
x
x b
Urinalysis
x
Biochemistry e
x
x
x
x
x
x
x b
Hematology e
x
x
x
x
x
x
x b
FACIT-Fatigue, EORTC Item Library, PRO-CTCAE, 
EORTC QLQ-C30, EQ-5D-5L f
x
HMRA
x b
Bone marrow sampling for HMRA g
x b
Bone marrow sampling for MRD/Flow, EDTA, PAXgeneh
x b
Whole blood sampling for EDTA and clinical
x 
x b, i
RBR sampling, blood serum and plasma (optional)
x
PK sampling
Refer to Appendix 2
Concomitant medications
To be recorded continually; see Section 4.4
Adverse events
To be assessed continually; see Section 5.3.1
Cytarabine (1.5 g/m2 IV) j
x
x
x
x
x
Idasanutlin (PO QD) j
x
x
x
x
x


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
114/Protocol GO40800, Version 1
Table 2:  Chemotherapy Consolidation (cont.)
CTCAECommon Terminology Criteria for Adverse Events; ECOGEastern Cooperative Oncology Group; eCRFelectronic Case Report Form; 
EDTAethylenediaminetetraacetic acid; EORTCEuropean Organisation for Research and Treatment of Cancer; EORTC QLQ-C30EORTC 
Quality-of-Life QuestionnaireCore 30; EQ-5D-5LEuroQol 5-Dimension, 5-Level; FACITFunctional Assessment of Chronic Illness Therapy; 
HMRAhematologic malignancy response assessment; MRDminimal residual disease; PKpharmacokinetic; POorally; PROpatient-reported 
outcome; PRO-CTCAEPatient-Reported Outcomes Common Terminology Criteria for Adverse Events; QDonce a day; QLQ-30Quality-of-Life 
Questionnaire Core 30; RBRResearch Biosample Repository.
a Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate.  Body surface area will also be 
measured at screening.
b Should D28 not be the last day of the cycle the following will be assessed every 7 days following D28 until end of treatment: biochemistry, 
hematology, vital signs, ECOG performance status.  HMRA and whole blood sampling should be repeated last day of the cycle with D49 as limit 
if not done within the previous 2 weeks.  Bone marrow sampling should not be repeated if already done within the last 56 days
c All ECGs should be performed within 2 hours prior to idasanutlin administration and 6 hours after idasanutlin administration.
d Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF
e All hematology and biochemistry assessments may be performed up to 3 days prior to the scheduled timepoint.  Results must be reviewed by 
the investigator (or designee) PRIOR to study drug administration.
f
PRO questionnaires need to be self-administered before the patient receives any information on disease status and prior to the administration of 
study treatment.  Completion of PROs should occur prior to the performance of non-PRO assessments whenever possible.  PRO assessments 
include the FACIT-Fatigue, EORTC QLQ-C30, EORTC Item Library symptoms, PRO-CTCAE, and EQ-5D-5L.
g For HMRAs during study, bone marrow aspirates are required, but bone marrow biopsies may be performed at the discretion of the investigator
h Bone Marrow MRD/Flow, EDTA, and PAXgene to be collected at same time as bone marrow for response assessment.  If unscheduled bone 
marrow aspirate is being collected for hematologic response assessment, then bone marrow MRD/Flow, EDTA, and PAXgene samples should 
also be collected. If any MRD assessments are done locally, please record this information in the eCRF. The priorities are 
MRD/FlowEDTAPAXgene.
i
EDTA only.
j
Refer to Section 4.3.2 for instructions on study treatment administration.




Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
116/Protocol GO40800, Version 1
Table 3: Maintenance in the Escalation Cohort and Expansion (cont.)
CTCAECommon Terminology Criteria for Adverse Events; ECOGEastern Cooperative Oncology Group;  eCRFelectronic Case Report Form; 
EDTAethylenediaminetetraacetic acid; EORTCEuropean Organisation for Research and Treatment of Cancer; EORTC QLQ-C30EORTC 
Quality-of-Life QuestionnaireCore 30; EQ-5D-5LEuroQol 5-Dimension, 5-Level; FACITFunctional Assessment of Chronic Illness Therapy; 
HMRAhematologic malignancy response assessment; MRDminimal residual disease; PKpharmacokinetic; POorally; PROpatient-reported 
outcome; PRO-CTCAEPatient-Reported Outcomes Common Terminology Criteria for Adverse Events; Q3Monce every 3 months; QDonce a 
day; RBRResearch Biosample Repository.
a Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.  Body surface area will also be 
measured at screening.
b All ECGs should be performed within 2 hours prior to idasanutlin administration and 6 hours after idasanutlin administration.
c Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
d PRO questionnaires need to be self-administered before the patient receives any information on disease status and prior to the administration of 
study treatment. Completion of PROs should occur prior to the performance of non-PRO assessments whenever possible. PRO assessments 
include the FACIT-Fatigue, EORTC QLQ-C30, EORTC Item Library symptoms, PRO-CTCAE, and EQ-5D-5L.
e Every 3 months starting at Cycle 1.
f
All hematology and biochemistry assessments may be performed up to 3 days prior to the scheduled timepoint.  Results must be reviewed by 
the investigator (or designee) PRIOR to study drug administration.
g Only the first 3 cycles of maintenance.
h For HMRAs during study, bone marrow aspirates are required, but bone marrow biopsies may be performed at the discretion of the investigator
i
Only required at maintenance Month 1 to confirm response in patients having received a transplant, bone marrow examination will require biopsy 
if an aspirate is not evaluable.
j
Bone marrow MRD/Flow, EDTA, and PAXgene to be collected at same time as bone marrow for response assessment.  If unscheduled bone 
marrow aspirate is being collected for hematologic response assessment, then bone marrow MRD/Flow, EDTA, and Paxgene samples should 
also be collected. If any MRD assessments are done locally, please record this information in the eCRF. The priorities are 
MRD/FlowEDTAPAXgene.
k EDTA only.
l
Refer to Section 4.3.2 for instructions on study treatment administration.


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
117/Protocol GO40800, Version 1
Table 4:  Maintenance in Post-Consolidation Cohort
Assessment/Procedure
Screening a
Maintenance (28-Day Cycle; 2 days) All Cycles
Days 14
to 1
D1
D2
D3
D4
D5
D15
D28 (Q3M)
Informed consent(s) b
x
Demographics, medical history, determination of 
cytogenetic and molecular risk, physical 
examination, height, chest X-ray (or chest CT) c
x
MUGA or ECHO
x
Urinalysis
x
Hepatitis B and C testing d
x
C. difficile toxin and toxin-producing C. difficile in
stool
x
Serum pregnancy test e
x
Coagulation (INR, aPTT [or PTT], and PT)
x
Vital signs f, weight, ECOG performance status
x
x
Single 12-Lead ECG g
x
x
Targeted physical examination  h
x
Urinalysis
x
x
FACIT-Fatigue, EORTC Item Library, EQ-5D-5L i
x j
PRO-CTCAE, EORTC QLQ-C30 i
x
Biochemistry k
x
x
x l


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
118/Protocol GO40800, Version 1
Table 4:  Maintenance in Post-Consolidation Cohort (cont.)
Assessment/Procedure
Screening a
Maintenance (28-Day Cycle; 2 day) All Cycles
Days 14
to 1
D1
D2
D3
D4
D5
D15
D28 (Q3M)
Hematology k
x
x
x l
HMRA
x
Bone marrow sampling for HMRA m
x
x
Bone marrow sampling for MRD/Flow, EDTA, 
PAXgenen
x 
x
Whole blood sampling for flow, for EDTA and 
clinical
x 
x
x o
RBR sampling, blood serum and plasma
(optional)
x
PK sampling
Refer to Appendix 2
Concomitant medications
x
To be recorded continually; see Section 4.4
Adverse events
To be assessed continually; see Section 5.3.1
Idasanutlin treatment (PO QD) p
x
x
x
x
x
AMLacute myeloid leukemia; CTcomputed tomography; CTCAECommon Terminology Criteria for Adverse Events; Dday; 
ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; eCRFelectronic Case Report Form; EDTAethylenediaminetetraacetic 
acid; EORTCEuropean Organisation for Research and Treatment of Cancer; EORTC QLQ-C30EORTC Quality-of-Life QuestionnaireCore 30; 
EQ-5D-5LEuroQol 5-Dimension, 5-Level; FACITFunctional Assessment of Chronic Illness Therapy; HMRAhematologic malignancy response 
assessment; MRDminimal residual disease; MUGAmultiple-gated acquisition (scan); PKpharmacokinetic; POorally; PROpatient-reported 
outcome; PRO-CTCAEPatient-Reported Outcomes Common Terminology Criteria for Adverse Events; Q3Mevery 3 months; QDonce a day; 
RBRResearch Biosample Repository; TBtuberculosis.
a The screening period starts with the signing of the Informed Consent Form, including the optional Informed Consent Form if appropriate.  Results 
of standard-of-care tests or examinations performed prior to obtaining informed consent and within the defined window may be used as 
screening and baseline assessments; such tests do not need to be repeated for screening purposes.


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
119/Protocol GO40800, Version 1
Table 4:  Maintenance in Post-Consolidation Cohort (cont.)
b Informed consent must be documented before any study-specific screening procedure is performed.
c If a chest CT is performed up to 28 days prior to study drug administration, a chest X-ray is not required.  Patients with a medical history of 
fungal and TB infections should have a chest CT performed within 28 days prior to study drug administration.  All data related to previous AML 
treatment such as but not limited to study drugs, regimens, doses, and dates will be collected.
d Includes hepatitis B surface antigen, total hepatitis B core antibody, and hepatitis C virus antibody.
e Must be performed within 7 days of the planned D1.
f
Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.  Body surface area will also be 
measured at screening.
g All ECGs should be performed within 2 hours prior to idasanutlin administration and 6 hours after idasanutlin administration.
h Includes systems of primary relevance (e.g., cardiovascular and respiratory systems), systems associated with symptoms (newly emergent or 
monitored from baseline), and areas associated with tumor assessment (lymph nodes, liver, spleen, and any other areas identified at baseline).  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
PRO questionnaires need to be self-administered before the patient receives any information on disease status and prior to the administration of 
study treatment. Completion of PROs should occur prior to the performance of non-PRO assessments whenever possible.  PRO assessments 
include the FACIT-Fatigue, EORTC QLQ-C30, EORTC Item Library symptoms, PRO-CTCAE, and EQ-5D-5L.
j
Every 3 months starting at Cycle 1.
k All hematology and biochemistry assessments may be performed up to 3 days prior to the scheduled timepoint.  Results must be reviewed by 
the investigator (or designee) PRIOR to study drug administration.
l
Only the first 3 cycles of maintenance.
m
At screening, bone marrow examination will require biopsy if an aspirate is not evaluable.  For HMRAs during the study, bone marrow aspirates 
are required, but bone marrow biopsies may be performed at the discretion of the investigator.
n Bone marrow MRD/Flow, EDTA, and PAXgene to be collected at same time as bone marrow for response assessment.  If unscheduled bone 
marrow aspirate is being collected for hematologic response assessment, then bone marrow MRD/Flow, EDTA, and PAXgene samples should 
also be collected. If any MRD assessments are done locally, please record this information in the eCRF. At screening, the priorities for bone 
marrow samples are EDTAMRD FlowPAXgene. At subsequent timepoints the priorities are MRD/FLOW EDTAPAXgene.
o EDTA only.
p Refer to Section 4.3.2 for instructions on study treatment administration.


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
120/Protocol GO40800, Version 1
Table 5: Post-Treatment Phase
Assessment/Procedure
Study Drug 
Discontinuation/Early 
Termination Visit
28 Days after Last Dose 
of Study Drug
Post-Tx
Follow-Up Period
Survival 
Follow-Up
Period
(Q3M) b
Q1M up to 2 Years a
Q6M up to 2 Years a
Serum pregnancy test
x
Triplicate 12-lead ECG 
x
Biochemistry 
x
x
Hematology
x
x
Urinalysis
x
HMRA
x
x
Bone marrow sampling for HMRA c
x
x
Bone marrow sampling (MRD/Flow, EDTA, 
PAXgene) d
x
x
Whole blood sampling (EDTA, clinical)
x
x
FACIT-Fatigue, EORTC Item Library, 
PRO-CTCAE, EORTC QLQ-C30, EQ-5D-5L e
x
Concomitant medications
x
Adverse events
x
x
New leukemia treatment
x
x
Survival follow-up
x


Appendix 1: Schedule of Activities (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
121/Protocol GO40800, Version 1
Table 5: Post-Treatment Phase (cont.)
CTCAECommon Terminology Criteria for Adverse Events; eCRFelectronic Case Report Form; EDTAethylenediaminetetraacetic acid; 
EORTCEuropean Organisation for Research and Treatment of Cancer; EORTC QLQ-C30EORTC Quality-of-Life QuestionnaireCore 30; 
EQ-5D-5LEuroQol 5-Dimension, 5-Level; FACITFunctional Assessment of Chronic Illness Therapy; HMRAhematologic malignancy response 
assessment; MRDminimal residual disease; PROpatient-reported outcome; PRO-CTCAEPatient-Reported Outcomes Common Terminology 
Criteria for Adverse Events; Q1Monce a month; Q3Monce every 3 months; Q6Monce every 6 months; Txtreatment.
a Patients who discontinue treatment for any reasons other than morphological relapse (see Section 4.5.6) will undergo assessments during the 
post-treatment follow-up period, which will continue until morphological relapse (see Section 4.5.6) or 2 years, whichever occurs first.  The first 
post-treatment follow-up visit is 1 month after the end of drug discontinuation visit.
b Patients who experience morphological relapse (see Section 4.5.6) or ended their 2 years post-treatment follow-up will be evaluated for survival 
status and new anti-leukemia treatment every 3 months during the survival follow-up period, which will continue until the end of the study.
c For HMRAs during the study, bone marrow aspirates are required, but bone marrow biopsies may be performed at the discretion of the 
investigator.
d Bone marrow MRD/Flow, EDTA, and PAXgene to be collected at same time as bone marrow for response assessment.  If unscheduled bone 
marrow aspirate is being collected for hematologic response assessment, then bone marrow MRD/Flow, EDTA, and PAXgene samples should 
also be collected. If any MRD assessments are done locally, please record this information in the eCRF. The priorities are
MRD/FLOW EDTAPAXgene.
e PRO questionnaires need to be self-administered before the patient receives any information on disease status. Completion of PROs should 
occur prior to the performance of non-PRO assessments whenever possible.  PRO assessments include the FACIT-Fatigue, EORTC QLQ-C30, 
EORTC Item Library symptoms, PRO-CTCAE, and EQ-5D-5L.


Idasanutlin—F. Hoffmann-La Roche Ltd
122/Protocol GO40800, Version 1
Appendix 2
Schedule of Pharmacokinetic and PD Biomarker Samples
Table 1
All Cohorts
Study Visit
Plasma 
Idasanutlin PK 
Sample
Serum MIC-1 
Sample
Plasma 
Cytarabine PK
Sample
Plasma 
Daunorubicin PK 
Sample
Induc-
tion 
Cycle 
1
Day 1
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day) 
Pre-idasanutlin 
administration 
(any time prior to 
dose on that 
day)
Pre-idasanutlin 
administration 
(any time prior 
to dose on that 
day) 
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day) 
30 (10) min after 
end of 
daunorubicin 
infusion
30 (10) min 
after end of 
daunorubicin 
infusion
30 (10) min 
after end of 
daunorubicin 
infusion
30 (10) min 
after end of 
daunorubicin 
infusion
3 hr (20 min) 
post-idasanutlin 
administration
3 hr (20 min) 
post-idasanutlin 
administration
3 hr (20 min) 
post-
idasanutlin 
administration
3 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-
idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
9 (1) hr
post-
idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
Day 3
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day)
Pre-idasanutlin 
administration 
(any time prior to 
dose on that 
day)
Pre-idasanutlin 
administration 
(any time prior 
to dose on that 
day)
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day)
1.5 hr (10 min) 
post-idasanutlin 
administration
1.5 hr (10 min) 
post-idasanutlin 
administration
3 hr (10 min) 
post-idasanutlin 
administration
3 hr (10 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
9 hr (1 h) 
post-idasanutlin 
administration
9 hr (1 h) 
post-idasanutlin 
administration
PKpharmacokinetic.


Appendix 2: Schedule of Pharmacokinetic and PD Biomarker Samples (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
123/Protocol GO40800, Version 1
Table 1
All Cohorts (cont.)
Study Visit
Plasma 
Idasanutlin PK 
Sample
Serum MIC-1 
Sample
Plasma 
Cytarabine PK
Sample
Plasma 
Daunorubicin 
PK Sample
Induc-
tion 
Cycle 1 
(cont.)
Day 
5
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day) 
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day)
Pre-idasanutlin 
administration 
(any time prior to 
dose on that 
day)
Pre-idasanutlin 
administration 
(any time prior 
to dose on that 
day)
30 (10) min after 
end of 
daunorubicin 
infusion
30 (10) min after 
end of 
daunorubicin 
infusion
3 hr (20 min) 
post-idasanutlin 
administration
3 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
Consol-
idation 
Cycle 1
Day 
1
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day) 
Pre-idasanutlin 
administration 
(any time prior to 
dose on that 
day) 
3 hr (end of 
cytarabine 
infusion)
3 hr (end of 
cytarabine 
infusion)
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
PKpharmacokinetic.


Appendix 2: Schedule of Pharmacokinetic and PD Biomarker Samples (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
124/Protocol GO40800, Version 1
Table 1
All Cohorts (cont.)
Study Visit
Plasma 
Idasanutlin PK 
Sample
Serum
MIC-1 
Sample
Plasma 
Cytarabine PK
Sample
Plasma 
Daunorubicin 
PK Sample
Consolidation 
Cycle 1 (cont.)
Day 5
Pre-idasanutlin 
administration 
(any time prior 
to dose on that 
day)
Pre-
idasanutlin 
administration 
(any time prior 
to dose on 
that day)
1.5 hr (10 min) 
post-idasanutlin 
administration
1.5 hr (10 
min) post-
idasanutlin 
administration
3 hr (10 min) 
post-idasanutlin 
administration
3 hr (10 min) 
post-
idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-
idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
9 (1) hr
post-
idasanutlin 
administration
Maintenance 
Cycle 1
(expansion and 
post-consolidation)
Day 1
Pre-idasanutlin 
administration 
(any time prior 
to dose on that 
day) 
6 hr (20 min) 
post-idasanutlin 
administration
PKpharmacokinetic.


Appendix 2: Schedule of Pharmacokinetic and PD Biomarker Samples (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
125/Protocol GO40800, Version 1
Table 1
All Cohorts (cont.)
Study Visit
Plasma 
Idasanutlin PK
Sample
Serum
MIC-1 
Sample
Plasma 
Cytarabine 
PK Sample
Plasma 
Daunorubicin 
PK Sample
Maintenance 
Cycle 1
(expansion 
and post-
consolidation)
(cont.)
Day 5
Pre-idasanutlin 
administration 
(any time prior to 
dose on that day)
1.5 hr (10 min) 
post-idasanutlin 
administration
3 hr (10 min) 
post-idasanutlin 
administration
6 hr (20 min) 
post-idasanutlin 
administration
9 (1) hr
post-idasanutlin 
administration
PKpharmacokinetic.


Idasanutlin—F. Hoffmann-La Roche Ltd
126/Protocol GO40800, Version 1
Appendix 3
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, for example, light housework or office 
work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking 
hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
5
Dead


Idasanutlin—F. Hoffmann-La Roche Ltd
127/Protocol GO40800, Version 1
Appendix 4
Howard Definition and Classification of Tumor Lysis Syndrome 
(Howard et al. 2011)
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 
(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/hr 
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).


Appendix 4: Howard Definition and Classification of Tumor Lysis Syndrome (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
128/Protocol GO40800, Version 1
REFERENCES
Howard SC, Jones P, Pui CH. The Tumor Lysis Syndrome. N Engl J Med. 
2011 May 12;364(19):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—F. Hoffmann-La Roche Ltd
129/Protocol GO40800, Version 1
Appendix 5
Toxicity Management Guidelines 
DIARRHEA MANAGEMENT GUIDELINES AND RECOMMENDATIONS
Diarrhea has been the most frequently reported adverse event in patients with acute 
myeloid leukemia (AML) administered with idasanutlin (Study NP28679).  
Prior to first study medication administration
Patients should be carefully screened for active GI conditions (e.g., graft-versus-
host disease, G2) and uncontrolled irritable bowel disease (i.e., Crohn’s disease, 
ulcerative colitis, diverticulosis-associated colitis, and Behçet disease) prior to 
enrollment.  Patients with active GI conditions as noted in the exclusion criteria are 
not permitted to start treatment.
Establish the individual patient’s normal bowel function.  Discuss how function could 
change in the future with treatment.  Discuss dietary management/rehydration.
Prophylactic antidiarrheal therapy is to be instituted for all patients administered
study medications in induction and consolidation as follows (unless medically 
contra-indicated):
Loading dose of loperamide 4 mg orally 30 minutes before first administration of 
idasanutlin
Instruct patients on warning signs (e.g., bloody stools, associated fever, and 
dizziness). 

Event management
Should diarrhea occur:  administer loperamide 2 mg orally every 4 hours or after 
every unformed stool to a maximum dose of 16 mg/24 hr.
Rule out other or concomitant causes, including medications (e.g., stool softeners, 
laxatives, and antacids), C. difficile infection (CDI), malabsorption/lactose 
intolerance, fecal impaction, and dietary supplements high in fiber
Dietary measures: Discontinue all lactose-containing products, alcohol and 
high-osmolar supplements; instruct patients to eat frequent small meals 
(e.g., bananas, rice, apples, and toast).
Loperamide treatment should be continued until patient is diarrhea-free for 
24 hours or until Day 10 of the specific cycle, whichever occurs first.
Record the number of stools and report complications (e.g., fever or dizziness upon 
standing).
Encourage adequate hydration.
Monitor electrolytes daily (i.e., potassium, magnesium, calcium, and sodium).
Administer IV fluids as clinically indicated and aim at all times for electrolyte 
correction.


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
130/Protocol GO40800, Version 1
Table 1Diarrhea Management According to CTCAE Grade
Diarrhea Grade
Recommended Actions
Grade 1/2
a)
See all supportive recommendations indicated above (i.e., loperamide, 
symptomatic management, dietary counselling, rehydration, and 
electrolyte correction).
b)
No change in study medication dose will be implemented for Grade2 
diarrhea; patients should receive maximal supportive care as described 
above.
c)
If diarrhea persists after 48 72 hours despite administration of the 
maximum recommended daily loperamide dose (16 mg/24 hr), 
second-line agents may be considered.
Grade 3
d)
Consider second-line agents (i.e., diphenoxylate, atropine, octreotide, 
budesonide, or tincture of opium) if the patient is receiving loperamide 
at the maximum recommended daily dose (16 mg/24 hr).
e)
If no improvement is observed within 24 hours, test for CDI.
f)
If, despite adequate supportive care, Grade 3 diarrhea persists 
48 hours without responding to loperamide at the maximum 
recommended daily dose (16 mg/24 hr), the idasanutlin dose should be 
reduced as per Table 11.
g)
If clinical characteristics have NOT improved to Grade 1 or baseline by 
28 days despite the patient receiving maximal supportive care, 
idasanutlin must be permanently discontinued.
h)
If the diarrhea recurs at Grade 3 despite supportive care and idasanutlin 
dose reduction, idasanutlin must be permanently discontinued.
Grade 4 
i)
If, despite prophylaxis and adequate supportive care, Grade 4 diarrhea 
is diagnosed, idasanutlin must be permanently discontinued.
j)
Consider second-line agents (i.e., diphenoxylate, atropine, octreotide, 
budesonide, or tincture of opium) if the patient is currently receiving 
loperamide at the maximum recommended daily dose (16 mg/24 hr).
k)
If no improvement is observed within 24 hours, test for CDI.
CDIClostridium difficile infection; CTCAECommon Terminology Criteria for Adverse Events.
CLOSTRIDIUM DIFFICILE INFECTION
Due to the high incidence of diarrhea, CDI may occur undetected.  Once diagnosed, 
monitoring CDI is also challenging, as treatment-induced diarrhea may be persistent.  
The risk factors for CDI are common in this patient population (treatment with systemic 


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
131/Protocol GO40800, Version 1
antibiotics, decreased leukocyte count, decreased albumin, and increased temperature, 
and increased ATLAS score).  

Prior to first administration of study medication
Patients should be carefully screened for active/uncontrolled infections prior to 
enrollment.  Patients receiving antimicrobial agents with therapeutic intent to 
eradicate C. difficile are not permitted to begin study medication, as noted in the 
exclusion criteria
Testing the stool from asymptomatic patients, at screening, or during an ongoing 
episode of diarrhea to verify cure is not clinically useful.

Diarrhea management
If loperamide at the maximum recommended daily dose (16 mg/24 hours) does not 
improve the severity of diarrhea within 24 hours, test for C. difficile toxin and 
toxin-producing C. difficile in stool. 
Consider clinically appropriate empirical therapy before microbiological evidence is 
found such as the following: 
Metronidazole:  if the initial episode is mild CDI, administer 500 mg orally, three 
times daily for 10–14 days.
Vancomycin: if recurrent disease is suspected or moderate to severe CDI is 
present, administer 125 mg orally four times daily for 10–14 days.
Once CDI is confirmed (colonoscopic or histopathological findings demonstrating 
pseudomembranous colitis may NOT suffice to confirm CDI), perform the following:
Discontinue unnecessary antimicrobial therapy.
Maintain adequate replacement of fluid and electrolytes.
Avoid any anti-motility medications/dietary supplements.
Use of proton pump inhibitors should be reviewed, as it has been shown to 
increase CDI susceptibility (Garey et al. 2008; Janarthanan et al. 2012).
Loperamide should not be used as a primary therapy.
Vancomycin is preferred antibiotic of choice (125 mg orally four times daily for 
10–14 days or 500 mg four times daily for 10 days).
Fidaxomicin (200 mg twice daily for 10 days) can be administered as an 
alternative if CDI is severe or in case of recurrence.
Simple measures such as thorough hand washing with soap and water 
(alcohol-based hand cleanser is not effective against spores) and avoidance of 
rectal thermometers is recommended for patients and healthcare providers.
EMESIS GUIDELINES
Nausea and vomiting have been reported in 30% of AML patients who are 
administered idasanutlin in combination with cytarabine.  


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
132/Protocol GO40800, Version 1
All enrolled patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study.  Treatment to mitigate 
emesis must be given prophylactically in induction and consolidation.  Emesis should be 
managed symptomatically throughout the study conduct.

Second-generation anti-emetics such as palonosetron, ondansetron or granisetron 
should be given prior each Idasanutlin dosing as per individual drug prescribing 
information in induction and consolidation

Re-dosing of study medication after emesis:
If vomiting occurs within 15 minutes of administering study medication and all expelled 
tablets are still intact, another dose may be administered, and the second dose must be 
recorded in the drug log.  Otherwise, no replacement dose is to be administered.
ANTIMICROBIAL GUIDELINES
Patients with leukemia are at increased risk for infections; therefore, the following 
guidelines must be followed and instituted for prophylactic anti-microbial therapy.  Any 
additional prophylactic antimicrobial therapy per institutional/local guidelines is allowed 
for patients unless prohibited otherwise.  

Prior to first administration of study medication in induction and 
consolidation
Patients should be carefully screened for evidence of active/uncontrolled infections prior 
to enrollment.  Patients with acute/active infection or receiving antimicrobial agents with 
therapeutic intent (as noted in the exclusion criteria) are not permitted to begin 
treatment. 
Prophylaxis is strongly recommended in this study.

Recommended antifungal prophylaxis:
Oral posaconazole administered at 200 mg PO three times daily 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
Substitution of PO formulation with IV formulation (e.g., in patients who do not 
tolerate the PO formulation) is not recommended.

Recommended antibacterial prophylaxis
Levofloxacin administered at 500 mg once daily from Day 1 until neutrophil recovery 
or until IV antibiotic treatment is administered (whichever occurs first) or according 
to local/institutional guidelines
Prophylaxis for Pneumocystis carinii will be administered according to 
local/institutional guidelines (trimethoprim [and combinations] is allowed if used with 
prophylactic purposes.


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
133/Protocol GO40800, Version 1
Patients in this study will be closely monitored for infection, and prompt therapy will be
instituted as necessary.
CYTOPENIA MANAGEMENT GUIDELINES
Idasanutlin was associated with myelosuppression in patients with AML in 
Study NP28679, but normal bone marrow recovery was observed in patients showing a 
clinical response.  In the current study, blood counts will be monitored closely throughout 
study treatment.

Recommended transfusion thresholds
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 human leukocyte antigen (HLA) sensitization, HLA-compatible 
platelet transfusions should be administered.
Filtrated packed red blood cells will be administered to maintain the hematocrit 
30% or the hemoglobin 8 g/dL, or for any hemoglobin level if related 
symptomatology is present (e.g., profuse asthenia).  
In patients who have previously received allogenic or autologous bone marrow 
transplantation, filtered and irradiated hemoderivatives are recommended.
Plasma transfusion is recommended in patients with disseminated intravascular 
coagulation or severe hemorrhage with abnormal coagulation parameters. 
Please refer to existing guidelines for optimal management of febrile neutropenia 
(Montesinos et al. 2008; de Naurois et al. 2010; Flowers et al. 2013).
TUMOR LYSIS SYNDROME MANAGEMENT GUIDELINES
Five cases with laboratory evidence of tumor lysis syndrome (TLS) have been reported 
in AML patients who were treated in Study NP28679 as a treatment-related adverse 
event.  Of these, a single case with clinical features was reported.  The patient was 
treated for TLS and recovered. 
Per the exclusion criterion, WBC counts should be 50,000/mm3.  Hydroxyurea (HU) or 
leukapheresis is allowed to meet this criterion.  HU must be discontinued at least 
24 hours prior to initiating study medication.

Prior to first administration of study medication
Assess the risk for TLS based on a clinical assessment and comorbidities 
(e.g., presence of renal dysfunction or cardiac failure) prior to initiating study 
medication.
Risk factors for TLS risk are not unique to idasanutlin and are multifactorial 
(i.e., WBC count 25,000/mm3, serum uric acid 7.5 mg/dL, and LDH4ULN).  


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
134/Protocol GO40800, Version 1
Use of scores or algorithms can help in the assessment (Montensinos et al. 
2008).
Prior to initiating study medication, correct preexisting 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 (further guidance can be found in [Jones et al. 2015]).

TLS management during study treatment
Monitor clinical chemistries (sodium, potassium, chloride, calcium, carbonate, BUN, 
uric acid, serum creatinine, LDH, and phosphorus) and hydration status.
Withhold study medication 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 μmol/L) or SUA 8.0 mg/dL 
(476 μmol/L) with a 25% increase and a creatinine increase 0.3 mg/dL from 
baseline 
Nephrology assessment warrants initiating dialysis
Appropriate hydration is strongly recommended for all patients C1D1C1D5, 
especially patients considered at risk.
Correct relevant clinical chemistry abnormalities promptly.
Maintain a low threshold for recourse with IV fluids and consideration of uric acid 
reducing agents.
REFERENCES
de Naurois J, Novitzky-Basso I, Gill MJ, et al. Management of febrile neutropenia: ESMO 
Clinical Practice Guidelines. Ann of Oncol 2010;21(Suppl 5):v252–6.
Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient 
management of fever and neutropenia in adults treated for malignancy: American 
Society of Clinical Oncology clinical practice guideline. J Clin Oncol 
2013;31:794810.
Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent 
Clostridium difficile infection. J Hosp Infect 2008;70:298–304.
Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American Society Clinical 
Oncology focused guideline update. J Clin Oncol 2016;34(4): 3816. 
Janarthanan S, Ditah I, Adler DG, et al. Clostridium difficile-associated diarrhea and 
proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 
2012;107:1001–10.


Appendix 5: Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
135/Protocol GO40800, Version 1
Jones GJ, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis 
syndrome in adults and children with haematological malignancies on behalf of the 
British Committee for Standards in Haematology. British Journal of Haematology 
2015;169:661–71.
Montesinos P, Lorenzo I, Martin G, et al. Tumor lysis syndrome in patients with acute 
myeloid leukemia: identification of risk factors and development of a predictive
model. Haematologica 2008;93:67–74. 
NCCN Clinical Practice Guidelines in Oncology V.1 2012. Antiemesis. National 
Comprehensive Cancer Network (NCCN) (online) 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: 
results of the Perugia consensus conference. Ann Oncol 2010;21:232–43. 


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Appendix 6
Calculation of Creatinine Clearance Using the Modified 
Cockcroft-Gault Formula
eCCR(140Age)IBM a (kg)[0.85 if female])/(72serum creatinine [mg/dL])
Or, if serum creatinine is in micromoles per liter (mol/L):
eCCR(140Age)IBM a (kg)[1.23 if male, 1.04 if female])/(serum creatinine 
[mol/L])
eCCRestimated creatinine clearance; IBMideal body weight.
a IBM (kg) ([height in cm 154] 0.9)] (50 if male, 45.5 if female).




Appendix 7: Classification of Acute Myeloid Leukemia (World Health Organization, 2016 
revision) (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
138/Protocol GO40800, Version 1
Myeloid leukemia associated with Down syndrome
Acute leukemias of ambiguous lineage
Acute undifferentiated leukemia
Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
MPAL with t(v;11q23.3); KMT2A rearranged
MPAL, B/myeloid, NOS
MPAL, T/myeloid, NOS
a This includes Myeloid neoplasms with germ line predisposition without a preexisting disorder 
or organ dysfunction (AML with germ line CEBPA mutation, Myeloid neoplasms with germ line 
DDX41 mutation*), Myeloid neoplasms with germ line predisposition and preexisting platelet 
disorders (Myeloid neoplasms with germ line RUNX1 mutation*, Myeloid neoplasms with germ 
line ANKRD26 mutation*, Myeloid neoplasms with germ line ETV6 mutation*), and Myeloid 
neoplasms with germ line predisposition and other organ dysfunction (Myeloid neoplasms with 
germ line GATA2 mutation, Myeloid neoplasms associated with BM failure syndromes, Myeloid 
neoplasms associated with telomere biology disorders, JMML associated with 
neurofibromatosis, Noonan syndrome or Noonan syndrome-like disorders, Myeloid neoplasms 
associated with Down syndrome*) * Lymphoid neoplasms also reported.
b Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes 
when ≥20% PB or BM blasts are present and prior therapy has been excluded
Complex karyotype (3 or more abnormalities)
Unbalanced abnormalities: −7/del(7q), del(5q)/t(5q), i(17q)/t(17p), −13/del(13q), del(11q), 
del(12p)/t(12p), idic(X)(q13)
Balanced abnormalities: t(11;16)(q23.3;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.2), 
t(2;11)(p21;q23.3), t(5;12)(q32;p13.2), t(5;7)(q32;q11.2), t(5;17)(q32;p13.2), t(5;10)(q32;q21.2), 
t(3;5)(q25.3;q35.1)
REFERENCE
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood 
2016;127:2391405.


Appendix8:
European LeukemiaNet Standardization Reporting System (CONT.)
Idasanutlin—F. Hoffmann-La Roche Ltd
139/Protocol GO40800, Version 1
Appendix 8
European LeukemiaNet Standardization Reporting System 
2017 ELN Risk Stratification by Genetics
Risk category*
Genetic abnormality
Favorable
t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†
Biallelic mutated CEBPA
Intermediate
Mutated NPM1 and FLT3-ITDhigh†
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow† (without adverse-risk 
genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡
Cytogenetic abnormalities not classified as favorable or adverse
Adverse
t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
−5 or del(5q); −7; −17/abn(17p)
Complex karyotype,§ monosomal karyotype||
Wild-type NPM1 and FLT3-ITDhigh†
Mutated RUNX1¶
Mutated ASXL1¶
Mutated TP53#
Notes:  Frequencies, response rates, and outcome measures should be reported by risk 
category, and, if sufficient numbers are available, by specific genetic lesions indicated.
* Prognostic impact of a marker is treatment-dependent and may change with new therapies.
† Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment 
of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under 
the curve “FLT3-ITD” divided by area under the curve “FLT3-wild type”; recent studies indicate 


Appendix8:
European LeukemiaNet Standardization Reporting System (CONT.)
Idasanutlin—F. Hoffmann-La Roche Ltd
140/Protocol GO40800, Version 1
that AML with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable 
prognosis and patients should not routinely be assigned to allogeneic HCT.
‡ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk 
gene mutations.
§ Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-
designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), 
t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.
|| Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with 
at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding 
factor AML).
¶ These markers should not be used as an adverse prognostic marker if they co-occur with 
favorable-risk AML subtypes.
# TP53 mutations are significantly associated with AML with complex and monosomal 
karyotype.
REFERENCE
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood
2017;129:42447.


Idasanutlin—F. Hoffmann-La Roche Ltd
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Appendix 9
Mosteller and Dubois Calculation for Body Surface Area (BSA)
Mosteller Formula 
Or 
BSA (m²)([Height(cm)Weight(kg)]/3600)
½
DUBOIS FORMULA 
BSA (m2)(W0.425 x H0.725)0.007184 
Weight in kilograms
Height in centimeters


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Appendix 10
New York Heart Association Functional Classification
NYHA
Class 
Symptoms
I 
No symptoms and no limitation in ordinary physical activity, for example, shortness of 
breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than ordinary activity, for 
example, walking short distances (20–100 m).  Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound 
patients. 
NYHA New York Heart Association.


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Appendix 11
Fridericia’s Formula for Corrected QT interval
QTcFQT/RR
0.33


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Appendix 12
FACIT-Fatigue


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Appendix 13
EORTC QLQ-C30 (Selected Scales)


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Appendix 14
EORTC Item Library Symptoms


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Appendix 15
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events (PRO-CTCAE)


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Appendix 16
EQ-5D-5L


Appendix 16:5Q-5D-5L (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
149/Protocol GO40800, Version 1


Appendix 16:5Q-5D-5L (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
150/Protocol GO40800, Version 1


Idasanutlin—F. Hoffmann-La Roche Ltd
151/Protocol GO40800, Version 1
Appendix 17
PROHIBITED MEDICATIONS
Table 1Prohibited CYP2C8 Substrates, Inhibitors, and Inducers
Substrates
Inhibitors
Inducer
Amodiaquine
Gemfibrozil a
Rifampicin
Cerivastatin
Monteleukast
Ibuprofen
Pioglitazone
Paclitaxel
Quercetin
Repaglinide
Rosiglitazone
Rosiglitazone
Trimethoprim b
Torasemide
a Gemfibrozil is also a strong inhibitor of UGT1A3.
b Trimethoprim may be allowed if Pneumocystis pneumonia prophylaxis is required per 
local/institutional guidelines and no therapeutic alternative (pentamidine) is considered 
clinically suitable.  Trimethoprim use and rationale should be documented in the patient 
notes.
Table 2Prohibited CYP3A4 Inducers
Inducers (Strong)
Carbamazepine
Cyproterone
Efavirenz
Etravirine
Modafinil
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Rifampicin
St. John’s wort


Appendix 17:Prohibited Medications (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
152/Protocol GO40800, Version 1
Table 3Prohibited OATP1B1/3 Substrates
OATP1B1/3 Substrates a
Atorvastatin
Atrasentan
Bosentan
Ezetimibe
Fluvastatin
Glyburide
Irinotecan
Olmesartan
Pitavastatin
Pravastatin
Repaglinide
Rifampin
Rosuvastatin
Simvastatin Acid
Telmisartan
Valsartan
OATP1B1/3organic anion-transporting polypeptide 
1B1/3.
a OATP1B1/3 substrates with a half-life shorter than 
1 day are allowed except during idasanutlin 
treatment and for 72 hours after the last dose of 
idasanutlin.


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Appendix 18
Modified Continual Reassessment Method Simulations 
Dose Escalation
This appendix provides details of the design that will guide the dose-escalation stage of 
this study and of its operating characteristics through simulations. All analyses were 
performed using the R statistical software R version 3.4.4 (2018-03-15) (Team 2017) 
(see Section 3.1.2.3 for additional information).
Rationale for Model-Based Design
The modified continuous reassessment method (mCRM) design uses a statistical model 
that actively seeks a dose level close to the maximum tolerated dose (MTD) by using 
toxicity data from all enrolled evaluable patients to compute a precise dose-toxicity curve.
It locates the MTD efficiently and minimizes the number of patients treated at possibly 
pharmacological inactive dose levels. Such model-based designs have been 
successfully applied in many Phase I dose-escalation studies (S. P et al. 2004; C, JJ, 
and LL 2009; B, M, and T 2008). The simulations in this appendix investigate the 
operating characteristics of the design as implemented for this study.
In this design the MTD is defined as the dose maximizing the posterior probability that 
the DLT rate, *(+,-) ∈[0.2,  0.35] while keeping the probability of overdose 
3{
(+,-) > 0.35} < 0.35. 
Statistical Model
A two-parameter logistic model will be used to fit the dose-toxicity relationship. The 
probability of DLT at dose 8, 
(8) is defined as (1) 

	8 =
9:
	 + :8
1 + 9:
	 + :8
  (1)
where
:8 = < =8
∗>
and ∗is the reference dose (in this case ∗= 300 mg). 


Appendix 18:mCRM Simulations (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
154/Protocol GO40800, Version 1
The model (1) thus can be rewritten as (2):
< =

(8)
1 −
(8)> =  + :8
  (2)
where  and  are the parameters to be estimated and assumed to follow a bivariate 
normal distribution.
Model Prior
A minimally informative bivariate normal prior for the parameters of the DLT-dose 
response curve (,  ) is constructed in order to have a weak impact to the final MTD 
determination (B, M, and T 2008).
The parameters of the minimally informative prior are listed below (3):  
? = (,  )
= (−0.797,  0.995)
@ = =
AB
C
ABD
ABD
AD
C >
= 1.699
0.280
0.280
1.076$
  (3)
where ? and @ are the parameters of the bivariate normal distribution.
The prior distribution used to determine the dose-escalation decision for this study is 
shown in Figure 1.
Figure 1 Minimally Informative Prior
Maximum Dose Increments
The maximum dose Increments relative to the previous dose level is 150 mg. Only 
increments that are multiples of 50 mg (e.g. 50 mg, 100 mg or 150 mg) are allowed.


Appendix 18:mCRM Simulations (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
155/Protocol GO40800, Version 1
Stopping Rules
The algorithm will recommend ending the dose escalation if any of the following criteria 
applies:

Maximum number of patients: the maximum sample size of 15 DLT-evaluable 
patients has reached OR

Enough information on MTD: at least a minimum of 6 patients evaluated and at least 
6 patients have been accrued near the MTD dose (where near means differing from 
the MTD by at most 5%) and the posterior probability that the MTD dose lies within 
the target toxicity interval is above 50% OR

Maximum dose is safe: at least 6 subjects have been observed at the maximum 
dose or near (differing from the maximum dose by at most 0.05%) and it is at least 
50% likely that the probability of a DLT for the maximum dose is below 0.2.
Dose Grid
The dose grid that has been used in this design starts from 200 mg and ends at 
800 mg, with an increment of 50 mg.  
Model Performance Evaluation
To illustrate how the design will perform, different escalation scenarios are explored and 
results are tabulated in Table 1. Each row represents four different situations: which 
dose would the model recommend, after seeing no DLTs in previous cohorts and when 0, 
1, 2, or 3 DLTs are observed in the current cohort. The evaluation is based on cohort 
size=3, “200” indicates that the model would stop escalating and the trial would be 
halted. 


Appendix 18:mCRM Simulations (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
156/Protocol GO40800, Version 1
Table 1Hypothetical Trial Realizations (Cohort Size=3)
Dose (mg) at which the First DLTs 
Were Observed (mg)
Number of
DLTs
Recommended 
Next Dose (mg)
200
0
350
200
1
200
200
2
200
200
3
200
350
0
450
350
1
300
350
2
200
350
3
200
450
0
600
450
1
450
450
2
300
450
3
200
As can be seen from the Table above, in general in presence of no DLTs the model will 
suggest to escalate close to what the max increment allow, while in presence of one 
DLT the increment is in general zero. Then, with 2 or 3 DLTs the model always 
recommends to de-escalate or STOP. Therefore, the results show that the design will 
adequately adapt the dose in the presence of observed DLTs.
Simulation Study
A simulation study is conducted to evaluate the operating characteristics for the chosen 
design parameters (priors, reference dose, stopping rule) under various dose-toxicity 
scenarios. The different scenarios have been selected in order to cover a wide range of 
dose-toxicity possibilities and to be able to quantify the risk and benefit, should these 
scenarios actually occur.
DoseToxicity Scenarios
The different scenarios have been selected in order to cover a wide range of dose-
toxicity possibilities and to be able to quantify the risk and benefit, should these 
scenarios actually occur.
As shown in Figure 2, we explore 6 scenarios. The first 5 represent decreasing levels of 
toxicity, while the last one considers the toxicity depicted in the prior as true toxicity. 
Scenario 3 has a steeper dose-toxicity curve meaning that the acceptable dose interval 
is very narrow. Some scenarios are relatively extreme, but still they will be informative on 




Appendix 18:mCRM Simulations (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
158/Protocol GO40800, Version 1
Table 2
Summary of Simulations Results
Scenario
Target 
Dose 
Interval
Total Number 
of Patients
Number of 
Patients Treated 
Above Target 
Toxicity
Proportion of 
DLTs in the 
Trials
Dose 
Selected as 
MTD
1
50 - 100
3 (3, 9)
3 (3, 9)
66.7% 
(33.3%, 100%)
0 (0, 0)
2
100 - 200
6 (3, 15)
6 (3, 15)
41.7% 
(26.7%, 66.7%)
0 (0, 250)
3
200 - 280
15 (3, 15)
3 (0, 12)
33.3%
(20%, 66.7%)
200 (0, 
300)
4
350 - 700
15 (3, 15)
0 (0, 0)
20%
(6.7%, 33.3%)
350 (0, 
650)
5
500 - 1000
15 (6, 15)
0 (0, 0)
13.3%
(6.7%, 33.3%)
450 (0, 
750)
6
166 - 359
15 (3, 15)
0 (0, 6)
33.3%
(20%, 66.7%)
200 (0, 
400)
From these simulations, it can be seen that the design is able to provide a reliable 
estimate of the MTD: usually, the median of the doses selected as MTD is within or 
slightly below the target toxicity dose range (at the lower end of the range), which means 
that the design is relatively conservative.
For dose-toxicity curves corresponding too most toxic scenarios (e.g. scenarios 1, 2) the 
median selected dose is 0, indicating that no MTD within the tested dose range can be 
found most of the time. In these cases, the required number of treated patients is far less 
than 15 evaluable patients, meaning that the design tends to recommend stopping dose 
escalation, avoiding therefore unnecessary exposure to toxic doses
In addition, we see that the number of patients treated over the dose toxicity interval is 
quite limited, with the exception of the first two scenarios where all doses were too toxic 
(all patients being treated at or above the target toxicity).
The good performances of the algorithm are also confirmed by the median proportion of 
DLTs observed in the simulations, which is always 1/3 (except for toxic scenarios 1 and 
2).
Finally, in terms of sample sizes, the median number of patients required to give a MTD 
recommendation is usually 15 patients across all scenarios. In case of too high toxicity, 
the required number is, as outlined above, lower.


Appendix 18:mCRM Simulations (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
159/Protocol GO40800, Version 1
References
Neuenschwander B, Branson M, and Gsponer T. Critical aspects of the Bayesian 
approach to Phase I cancer trials. Stat Med 2008;2713:242039.
Le Tourneau C, Lee JJ, and Siu LL. Dose escalation methods in Phase I cancer clinical 
trials. J Natl Cancer Inst 2009;101:70820.
Schöffski P, Riggert S, Fumoleau P, et al. Phase I trial of intravenous aviscumine 
(rViscumin) in patients with solid tumors: a study of the European Organization for 
Research and Treatment of Cancer New Drug Development Group. Ann Oncol 
2004;15:1816–24.
Team, R Core. 2017. R: A language and environment for statistical computing. Vienna, 
Austria: R Foundation for Statistical Computing. https://www.R-project.org/.


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Appendix 19
Response Criteria for Acute Myeloid Leukemia
Patients will be assessed according to European LeukemiaNet (ELN) response 
categories (adapted from Döhner et al. 2017) and two additional response categories:  
complete remission with incomplete platelet count recovery (CRp) and complete 
remission with partial hematologic recovery (CRh) (see Table 1).
At least 500 nucleated cells on spiculated marrow smears should be counted to qualify 
for complete remission (CR), complete remission with incomplete blood count recovery 
(CRi), CRp, or CRh.  For other response categories, no minimal cell count is required.


Appendix 19:Response Criteria for Acute Myeloid Leukemia (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
161/Protocol GO40800, Version 1
Table 1
Response Criteria for Acute Myeloid Leukemia
Response
Definition
CR
Bone marrow blasts 5%; absence of circulating blasts and blasts with Auer 
rods; absence of extramedullary disease; ANC 1.0109/L (1000/L); and 
platelet count 100109/L (100,000/L)
CRi
All CR criteria except for residual neutropenia (ANC 1.0109/L [1000/L]) or 
residual thrombocytopenia (platelet count 100109/L [100,000/L])
CRp
All CR criteria except for residual thrombocytopenia (platelet count
100109/L [100,000/L])
CRh
All CR criteria except ANC 0.5109/L (500/L) but 1.0109/L (1000/L)
and platelet count 50109/L (50,000/L) but 100109/L (100,000/L)
MLFS
Bone marrow blasts 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; and residual neutropenia (ANC 0.5109/L [500/L]) 
and residual thrombocytopenia (platelet count 50109/L [50,000/L])
PR
All hematologic criteria for CR; bone marrow blast percentage of 5%-25%; 
and 50% decrease from baseline in percentage of bone marrow blasts
SD
Absence of CR, CRi, CRp, CRh, MLFS, and PR; and no clinical or cytologic 
progressive disease by investigator assessment
PD
Evidence of an increase in bone marrow blast percentage and/or increase in
absolute blast counts in the blood, defined as at least one of the following:

50% increase from baseline in bone marrow blasts (a minimum increase 
of 15 percentage points is required in cases with 30% bone marrow 
blasts at baseline)

50% increase in peripheral blasts (WBC count% blasts) to 25109/L 
(25,000/L) (in the absence of differentiation syndrome)

New extramedullary disease
Hematologic 
relapse
Following CR, CRi, CRp, or CRh, development of extramedullary disease or 
reappearance of either of the following that is not attributable to another 
cause (e.g., bone marrow regeneration after consolidation therapy):  
peripheral blasts or 5% bone marrow blasts
Death in aplasia
Death occurring 7 days following completion of induction treatment while 
cytopenic, with an aplastic or hypoplastic bone marrow obtained within 7 days
of death and no evidence of persistent leukemia
Death from 
indeterminate 
cause
Death occurring before completion of induction treatment or 7 days following 
its completion; or death occurring 7 days following completion of induction 
treatment therapy with no peripheral blasts, but no bone marrow examination 
available
BMbone marrow; CRcomplete remission; CRhcomplete remission with partial hematologic 
recovery; CRicomplete remission with incomplete blood count recovery; CRpcomplete 
remission with incomplete platelet count recovery; MLFSmorphologic leukemia-free state; 
PDprogressive disease; PRpartial remission; SDstable disease.