Clinical trial NCT02545283
Conditions: Leukemia, Myeloid, Acute
Sponsor: Hoffmann-La Roche
Start date: 2015-12-30; Completion date: 2020-04-24
Enrollment: 447 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare overall survival in participants with relapsed or refractory AML treated with idasanutlin in combination with cytarabine versus participants treated with placebo and cytarabine. Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle 1). Responding participants may continue to receive a maximum of further two cycles of consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet count recovery (CRp), overall remission rate (ORR), event-free survival (EFS) and percentage of participants with an allogeneic hematopoietic stem cell transplant (HSCT) will also be compared between treatment arms. This study will include participants with and without TP53 wild type (TP53 WT) mutations.

Detailed description:

Arms: arm 1: Participants will receive induction therapy idasanutlin and cytarabine for 5 Days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or complete remission with incomplete blood count recovery (CRi), up to 28 additional days are allowed for blood count recovery, if needed. arm 2: Participants will receive induction therapy idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or CRi, up to 28 additional days are allowed for blood count recovery, if needed.
Interventions: intervention 1: Cytarabine intervention 2: Idasanutlin intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive cytarabine 1 gram per square meter (g/m\^2) intravenous (IV) infusion for 5 days of every treatment cycle. intervention 2: Participants will receive idasanutlin 300 mg per oral (PO) twice daily (BID) (in Cycle 1) or once daily (QD) (in Cycles 2 and 3) for 5 days of every treatment cycle. intervention 3: Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 
III Study of Idasanutlin, an MDM2 Antagonist, With Cytarabine Versus 
Cytarabine Plus Placebo in Patients With Relapsed or Refractory 
Acute Myeloid Leukemia (AML) 
NCT Number: NCT02545283 
Document Date: Protocol Version 6: 12-July-2019 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
PROTOCOL
TITLE:
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, PHASE III STUDY OF 
IDASANUTLIN, AN MDM2 ANTAGONIST, WITH 
CYTARABINE VERSUS CYTARABINE PLUS 
PLACEBO IN PATIENTS WITH RELAPSED OR 
REFRACTORY ACUTE MYELOID LEUKEMIA (AML)
PROTOCOL NUMBER:
WO29519
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003065-15  
TEST PRODUCT:
Idasanutlin (RO5503781) 
MEDICAL MONITOR:
, Ph.D. 
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  10 August 2015
DATES AMENDED:
Version 2:  27 August 2015
Version 3 (VHP):  19 November 2015
Version 4:  2 June 2016 
Version 5:  20 December 2018
Version 6:  See electronic date stamp below.
 
12-Jul-2019 09:42:53
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Idasanutlin—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol WO29519 has been amended to include the addition of an interim overall 
survival (OS) analysis.  Changes to the protocol, along with a rationale for each change, 
are summarized below:

Table 1 has been removed and the reader has been referred instead to the 
Idasanutlin Investigator’s Brochure, which contains the most recent information on 
completed and ongoing studies with idasanutlin (Section 1.2.1).

The secondary and exploratory endpoints have been updated to also assess the 
efficacy of treatment in FLT3, IDH1, and IDH2-mutated AML subpopulations, since 
these have become clinically actionable with targeted treatment (Sections 2.2, 2.3, 
3.3.5, 3.4.3, 6.4.2, and 6.4.3).  

An interim efficacy analysis has been added to allow early testing of OS in the event 
of relevant efficacy, which could influence faster access to study drug for patients 
(Sections 3.1 and 6.11).  

The total length of study has been revised to 5.5 years (Sections 3.2 and 6.4.1.1).

The majority of the patients (~85%) are expected to be TP53 wild type (WT); 
therefore, the overall results for this trial are expected to be driven by the outcome in 
the TP53 WT population.  To assess the efficacy of idasanutlin treatment, the 
assessment of secondary efficacy endpoints has been modified to limit testing within 
the TP53 WT population only (Sections 2.2 and 3.3.2), with analysis of intent-to-treat 
population (all-patient population) as exploratory.  In addition, the efficacy analysis 
section has been revised to reflect the updated study design (Section 6.4). The list 
of secondary and exploratory efficacy endpoints, as well as the list of outcome 
measures, have been modified (Sections 3.4, 6.4.2, and 6.4.3).  

To align with Section 4.4.2.2 of the protocol, a clarification has been added to the 
exclusion criterion that medications known to prolong the QT interval must be 
discontinued 7 days (or 5 half-lives, whichever is shorter) prior to initiating study 
medication until 5 days after the final administration of study medication 
(Section 4.1.2). 

A correction was made in the exclusion criteria from “irritable bowel disease” to 
“inflammatory bowel disease” (Section 4.1.2).

Clarification has been made that written informed consent is necessary again for 
re-screening and must be obtained before any re-screening related tests and 
evaluations (Section 4.5.1 and Appendix 1).

The hematologic malignancy response assessment criteria have been updated to 
align with 2017 European LeukemiaNet recommendations for diagnosis and 
management of AML in adults (Section 4.5.8).

The pharmacodynamic and biomarker section has been updated to include TP53 
mutation status determination and to provide reference to the technical information of 
the assay used, 
 (Section 4.5.10.2).


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
Clarification has been added that reporting of the adverse event of special interest 
thrombocytopenia (Grade3 if associated with hemorrhage or bleeding) requires two 
separate adverse event of special interest forms to be completed (one for each of 
hemorrhage and thrombocytopenia) to facilitate complete safety analysis of patients 
experiencing thrombocytopenia Grade 3 concurrently with hemorrhage or bleeding 
(Section 5.2.3). 

Additional sensitivity analyses have been added in order to develop comprehensive 
interpretation of the data (Section 6.5).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable) (Section 7.6).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

Clarification has been added that the adherence to protocol-mandated prophylaxis 
for diarrhea, emesis, and fungal and bacterial infections is applicable to all treatment 
cycles (Appendix 14).

Emesis guidelines have been modified to clarify that 5-HT3-receptor antagonists with 
long half–life, such as palonosetron, may be taken on Day 1 only of the respective 
cycle (Appendix 14).  

The Medical Monitor names and associated contact information have been updated 
throughout the document.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Acute Myeloid Leukemia............................... 27
1.2
Background on Idasanutlin .................................................... 28
1.2.1
Clinical Experience with Idasanutlin ...................................... 28
1.2.1.1
NP28679 in AML ................................................................... 28
1.2.1.2
NP27872 in Solid Tumors...................................................... 30
1.2.2
Clinical Pharmacology Summary........................................... 31
1.2.2.1
Clinical Pharmacokinetics...................................................... 31
1.2.2.2
Clinical Pharmacodynamics................................................... 31
1.2.2.3
Metabolic Drug-Drug Interactions.......................................... 32
1.3
Background on Cytarabine .................................................... 32
1.4
Study Rationale and Benefit-Risk Assessment...................... 33
2.
OBJECTIVES.............................................................................................. 35
2.1
Primary Objective .................................................................. 35
2.2
Secondary Objectives............................................................ 35
2.3
Exploratory Objectives........................................................... 35
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of Study .............................................................. 36
3.2
End of Study.......................................................................... 38
3.3
Rationale for Study Design.................................................... 38
3.3.1
Rationale for Idasanutlin Dose and Schedule........................ 38
3.3.2
Rationale for Patient Population ............................................ 39
3.3.3
Rationale for Control Group................................................... 41
3.3.4
Rationale for Population 
Pharmacokinetic/Pharmacodynamic Analysis ....................... 42
3.3.5
Rationale for Biomarker Assessments................................... 42
3.3.5.1
Mutation State of TP53.......................................................... 43
3.3.5.2
MDM2 Expression Status/Predictive Gene 
Signatures ............................................................................. 43


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3.3.5.3
MIC-1 Expression .................................................................. 43
3.3.5.4
Exploratory Markers .............................................................. 44
3.3.5.5
AML-Relevant Markers.......................................................... 44
3.3.5.6
Minimal/Measurable Residual Disease 
Assessment in Patients with Complete 
Remission.............................................................................. 44
3.4
Outcome Measures ............................................................... 45
3.4.1
Efficacy Outcome Measures.................................................. 45
3.4.2
Safety Outcome Measures .................................................... 45
3.4.3
Pharmacodynamic/Biomarker Outcome 
Measures............................................................................... 45
3.4.4
Pharmacokinetic Outcome Measures.................................... 46
3.4.5
Patient-Reported Outcome Measures ................................... 46
3.4.6
Exploratory Outcome Measures ............................................ 46
4.
MATERIALS AND METHODS .................................................................... 46
4.1
Patients.................................................................................. 46
4.1.1
Inclusion Criteria.................................................................... 47
4.1.2
Exclusion Criteria................................................................... 48
4.2
Method of Treatment Assignment and Blinding..................... 51
4.3
Study Treatment.................................................................... 51
4.3.1
Formulation, Packaging, and Handling.................................. 51
4.3.1.1
Idasanutlin and Placebo ........................................................ 51
4.3.1.2
Cytarabine ............................................................................. 52
4.3.2
Dosage, Administration, and Compliance.............................. 52
4.3.2.1
Idasanutlin and Placebo ........................................................ 52
4.3.2.2
Cytarabine ............................................................................. 52
4.3.2.3
Guidelines for Induction Therapy (Cycle 1)............................ 52
4.3.2.4
Guidelines for Consolidation Therapy (Cycles 2 
and 3) .................................................................................... 53
4.3.3
Prophylactic Medication......................................................... 54
4.3.4
Investigational Medicinal Product Accountability ................... 54
4.3.5
Continued Access to Idasanutlin....................................... 55
4.4
Concomitant Therapy and Food ............................................ 55
4.4.1
Permitted Therapy................................................................. 55


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4.4.2
Prohibited Therapy ................................................................ 56
4.4.2.1
Drugs Prohibited Due to Potential Drug-Drug 
Interaction.............................................................................. 56
4.4.2.2
Drugs Known to Prolong the QT Interval ............................... 58
4.4.2.3
Oral or Parenteral Anticoagulant/Anti-Platelet 
Agents ................................................................................... 59
4.4.3
Prohibited Food ..................................................................... 60
4.5
Study Assessments ............................................................... 60
4.5.1
Informed Consent Forms and Screening Log........................ 60
4.5.2
Assessments during Treatment and Follow-Up..................... 61
4.5.3
Hematopoietic Stem Cell Transplant ..................................... 63
4.5.4
Medical History and Demographic Data ................................ 63
4.5.5
Physical Examinations........................................................... 63
4.5.6
Performance Status............................................................... 63
4.5.7
Vital Signs.............................................................................. 63
4.5.8
Hematologic Malignancy Response Assessment.................. 64
4.5.9
Laboratory Assessments ....................................................... 66
4.5.10
Mandatory Samples for Pharmacokinetic, 
Pharmacodynamics, and Exploratory Biomarkers................. 67
4.5.10.1
Pharmacokinetic.................................................................... 67
4.5.10.2
Pharmacodynamic and Exploratory Biomarkers.................... 68
4.5.10.3
Whole Blood .......................................................................... 69
4.5.10.4
Clinical Genotyping................................................................ 70
4.5.10.5
Serum Biomarker (Prior to Futility Interim 
Analysis Only)........................................................................ 70
4.5.10.6
Bone Marrow ......................................................................... 70
4.5.11
Electrocardiograms................................................................ 71
4.5.12
Patient-Reported Outcomes .................................................. 72
4.5.13
Samples for Roche Clinical Repository.................................. 73
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 76
4.6.1
Patient Discontinuation.......................................................... 76
4.6.2
Study Drug Discontinuation ................................................... 77
4.6.3
Study and Site Discontinuation.............................................. 77


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5.
ASSESSMENT OF SAFETY....................................................................... 78
5.1
Safety Plan ............................................................................ 78
5.1.1
Safety Risks of Idasanutlin and Cytarabine in 
Leukemia............................................................................... 78
5.1.1.1
Gastrointestinal Toxicity......................................................... 78
5.1.1.2
Cytopenias............................................................................. 78
5.1.1.3
Tumor Lysis Syndrome.......................................................... 79
5.1.1.4
Infections ............................................................................... 79
5.1.1.5
Electrolyte Disorders ............................................................. 79
5.1.1.6
Other Adverse Events............................................................ 79
5.1.2
Management of Patients Who Experience 
Specific Adverse Events........................................................ 80
5.1.2.1
Gastrointestinal Events.......................................................... 80
5.1.2.2
Myelosuppression.................................................................. 80
5.1.2.3
Infections ............................................................................... 81
5.1.2.4
Tumor Lysis Syndrome.......................................................... 81
5.1.2.5
Dose Modification due to Toxicity ..........................................82
5.2
Safety Parameters and Definitions ........................................ 83
5.2.1
Adverse Events ..................................................................... 84
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 84
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 85
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86
5.3.1
Adverse Event Reporting Period ........................................... 86
5.3.2
Eliciting Adverse Event Information....................................... 86
5.3.3
Assessment of Severity of Adverse Events ........................... 87
5.3.4
Assessment of Causality of Adverse Events ......................... 87
5.3.5
Procedures for Recording Adverse Events............................ 88
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 88
5.3.5.2
Adverse Events That are Secondary to Other 
Events.................................................................................... 88
5.3.5.3
Persistent or Recurrent Adverse Events................................ 89
5.3.5.4
Abnormal Laboratory Values ................................................. 89


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5.3.5.5
Abnormal Vital Sign Values ................................................... 90
5.3.5.6
Abnormal Liver Function Tests.............................................. 90
5.3.5.7
Deaths ................................................................................... 91
5.3.5.8
Preexisting Medical Conditions.............................................. 91
5.3.5.9
Lack of Efficacy or Worsening of Leukemia........................... 91
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 92
5.3.5.11
Adverse Events Associated with an Overdose ...................... 92
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92
5.4.1
Emergency Medical Contacts................................................ 93
5.4.2
Reporting Requirements for Serious Adverse 
Events.................................................................................... 94
5.4.2.1
Events That Occur prior to Study Drug Initiation ................... 94
5.4.2.2
Events That Occur after Study Drug Initiation ....................... 94
5.4.3
Reporting Requirements for Pregnancies.............................. 94
5.4.3.1
Pregnancies in Female Patients............................................ 94
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 95
5.4.3.3
Abortions ............................................................................... 95
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 95
5.5
Follow-Up of Patients After Adverse Events.......................... 96
5.5.1
Investigator Follow-Up........................................................... 96
5.5.2
Sponsor Follow-Up ................................................................ 96
5.6
Post-Study Adverse Events................................................... 96
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and
Ethics Committees................................................................. 97
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 97
6.1
Determination of Sample Size ............................................... 97
6.2
Summaries of Conduct of Study............................................ 98
6.3
Summaries of Treatment Group Comparability ..................... 98
6.4
Efficacy Analyses .................................................................. 98
6.4.1
Primary Efficacy Endpoint...................................................... 99
6.4.2
Secondary Efficacy Endpoints............................................... 99
6.4.3
Exploratory Efficacy Endpoints........................................... 100


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6.5
Sensitivity Analyses............................................................. 100
6.6
Safety Analyses................................................................... 101
6.7
Electrocardiograms.............................................................. 101
6.8
Pharmacodynamic and Biomarker Analyses ....................... 101
6.9
Pharmacokinetic Analyses................................................... 102
6.10
Patient-Reported Outcome Analyses .................................. 102
6.11
Interim Analyses.................................................................. 102
6.11.1
Futility ................................................................................ 102
6.11.2
Efficacy................................................................................ 103
6.11.3
Biomarker Recommendation ............................................... 104
7.
DATA COLLECTION AND MANAGEMENT ............................................. 104
7.1
Data Quality Assurance....................................................... 104
7.2
Electronic Case Report Forms............................................. 105
7.3
Electronic Patient-Reported Outcome ................................. 105
7.4
Source Data Documentation................................................ 105
7.5
Use of Computerized Systems ............................................ 106
7.6
Retention of Records........................................................... 106
8.
ETHICAL CONSIDERATIONS.................................................................. 106
8.1
Compliance with Laws and Regulations .............................. 106
8.2
Informed Consent................................................................ 107
8.3
Institutional Review Board or Ethics Committee.................. 108
8.4
Confidentiality...................................................................... 108
8.5
Financial Disclosure ............................................................ 108
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 109
9.1
Study Documentation .......................................................... 109
9.2
Protocol Deviations.............................................................. 109
9.3
Site Inspections ................................................................... 109
9.4
Administrative Structure....................................................... 109
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 110
9.6
Protocol Amendments ......................................................... 111


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10. REFERENCES ......................................................................................... 112
LIST OF TABLES
Table 1
Non-Investigational Medicinal Products...................................... 54
Table 2
List of Prohibited CYP2C8 Substrates, Inhibitors, and 
Inducer........................................................................................ 57
Table 3
List of Prohibited CYP3A4 Inducers............................................ 57
Table 4
List of Prohibited OATP1B1/3 Substrates ................................... 58
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87
LIST OF FIGURES
Figure 1
Regulation of p53 Stability and Activity by MDM2....................... 26
Figure 2
Study Scheme............................................................................. 36
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 117
Appendix 2
Schedule of PK/PD Sampling ................................................... 131
Appendix 3
Schedule of Optional RCR Sampling........................................ 132
Appendix 4
Algorithm Guiding Bone Marrow Collection and Study 
Medication Continuation ........................................................... 133
Appendix 5
Cockcroft Gault Formula for Calculation of Creatinine 
Clearance.................................................................................. 137
Appendix 6
Fridericia’s Formula for Corrected QT interval .......................... 138
Appendix 7
New York Heart Association Functional Classification.............. 139
Appendix 8
Mosteller and Dubois Calculation for Body Surface Area 
(BSA) ........................................................................................ 140
Appendix 9
European Leukemia Net Standardization Reporting System .... 141
Appendix 10
Classification of Acute Myeloid Leukemia (World Health 
Organisation, 2016 Revision).................................................... 142
Appendix 11
List of Drugs That Can Prolong QT Interval and Torsades De 
Pointes...................................................................................... 144
Appendix 12
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 147
Appendix 13
Howard Definition and Classification of Tumor Lysis 
Syndrome (Howard et al. 2011) ................................................ 148
Appendix 14
Toxicity Management Guidelines.............................................. 150


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Appendix 15
Hematopoietic Cell Transplantation-Specific Comorbidity 
Index......................................................................................... 157
Appendix 16
Eligibility Flow Chart for Prior Lines of Therapy ........................ 159


Idasanutlin—F. Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED,
PLACEBO-CONTROLLED, PHASE III STUDY OF 
IDASANUTLIN, AN MDM2 ANTAGONIST, WITH 
CYTARABINE VERSUS CYTARABINE PLUS PLACEBO 
IN PATIENTS WITH RELAPSED OR REFRACTORY 
ACUTE MYELOID LEUKEMIA (AML)
PROTOCOL NUMBER:
WO29519
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003065-15
TEST PRODUCT:
Idasanutlin (RO5503781)
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 return the signed original of this form as instructed by your local study monitor.  
Please retain a copy for your study files.


Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
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PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, PHASE III STUDY OF IDASANUTLIN, AN MDM2 
ANTAGONIST, WITH CYTARABINE VERSUS CYTARABINE PLUS 
PLACEBO IN PATIENTS WITH RELAPSED OR REFRACTORY 
ACUTE MYELOID LEUKEMIA (AML)
PROTOCOL NUMBER:
WO29519
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003065-15
TEST PRODUCT:
Idasanutlin (RO5503781)
PHASE:
Phase III
INDICATION:
Relapsed/Refractory Acute Myeloid Leukemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary Objective
The primary objective for this study is as follows:
Within the TP53 wild type (WT) population

To compare overall survival (OS) in patients with relapsed or refractory acute myeloid 
leukemia (AML) who have been randomized to idasanutlin in combination with cytarabine 
versus those who have been randomized to cytarabine and placebo
Secondary Objective
The secondary objectives for this study are as follows:
Within the TP53 WT population

To compare the proportions of complete remission (CR) between treatment arms 

To compare event-free survival (EFS) between treatment arms

To compare ORR (defined as CR), complete remission with incomplete platelet count 
recovery [CRp], and complete remission with incomplete blood count recovery [CRi]) 
between treatment arms

To compare duration of remission following CR (DOR) between treatment arms

To compare the proportions of allogeneic hematopoietic stem cell transplant (HSCT) 
following CR between treatment arms

To assess OS and CR in clinically actionable mutation-defined AML subpopulations, 
including FLT3, IDH1, and IDH2

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 

To compare the differences in disease and treatment-related symptoms and health-related 
quality of life between treatment arms


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Within the all-patient population

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 

To characterize the pharmacokinetics of both idasanutlin and cytarabine 

To compare the differences in disease and treatment related symptoms and health-related 
quality of life between treatment arms
Exploratory Objective
The exploratory objectives for this study are as follows:
Within the all-patient population 

To evaluate primary and secondary efficacy endpoints, including OS, CR, proportion of 
HSCT, EFS, and DOR in the all-patient population and OS and CR in the clinically 
actionable mutation-defined AML subpopulations (including FLT3, IDH1, and IDH2)
Within the all-patient and TP53 WT populations

To evaluate efficacy endpoints, including proportion of HSCT, CR, ORR, and DOR on 
the basis of response assessed over complete treatment period

To evaluate LFS (leukemia-free survival, or duration of OR)

To explore minimal/measurable residual disease (MRD) in the bone marrow after treatment 
with idasanutlin plus cytarabine compared with cytarabine and placebo

To evaluate candidate response biomarkers (gene expression signatures) and murine 
double minute 2 (MDM2) protein expression in blast cells

To assess prognostic and predictive effect of disease-associated mutations
Study Design
Description of Study
This is a Phase III multicenter, double-blind, randomized, placebo-controlled study of idasanutlin 
in combination with cytarabine compared with cytarabine and placebo.  
A total of 440 patients with AML who have relapsed following, or are refractory to 
cytarabinecontaining standard induction chemotherapy after at least one and no more 
than two prior cytarabinecontaining induction chemotherapy regimen(s) are planned to be 
enrolled.  Relapsed patients are defined as patients with first or second relapse; first relapsed 
patients who are young and had a good response to initial therapy (i.e. age 60 years with first 
CR achieved [CR1] duration 1 year) are excluded.  Refractory patients are defined as patients 
with persistent leukemia after one or two induction cycles, or patients with CR1 duration of 90 
days.  Patients may have received prior HSCT in remission.  Note that patients with prior 
allogenic HSCT within 90 days prior to randomization will not be eligible for this study.  The 
TP53 WT population will consist of patients with WT TP53, established centrally.  
Re-screening is allowed under the conditions listed in the protocol.
Patients will be randomly assigned to each treatment arm.  The arms will be stratified according 
to the following factors:

Age (60 years versus 60 years)

Cytogenetic and molecular risk according to the 2010 European LeukemiaNet (ELN) 
standardized reporting system at initial diagnosis (favorable/intermediate versus adverse). 
Cytogenetic information allowing stratification in those two groups must be available.  

Response to initial anti-leukemic therapy (refractory versus CR 90 days but 1 year; 
versus CR 1 year)

Prior HSCT versus no prior HSCT
Patients will receive induction treatment with idasanutlin/placebo 300 mg twice daily (BID) and 
cytarabine 1 g/m2 for 5 days followed by 23 days of rest (Cycle 1).  For patients who achieve 
clinical response after induction and for whom HSCT for consolidation is not an option, it is 


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strongly recommended to continue study medication with a maximum of two additional cycles of 
consolidation (Cycles 2 and 3) unless clinically contraindicated  
Responding patients, including those who proceed to HSCT, will be followed for EFS and DOR. 
All patients irrespective of response to treatment will be followed for OS until the end of the 
study. 
An interim analysis for futility based on CR, EFS, and safety is planned after 120 TP53 WT 
patients are enrolled, have received at least one cycle, and confirmatory response assessment 
is available, to allow early stopping of the study in the event of inadequate CR, EFS, or safety 
concerns.  The futility interim analysis will be performed by an independent Data Monitoring 
Committee (iDMC).  Enrollment of patients will continue while this interim analysis takes place.  
If the Sponsor decides to stop the study based on iDMC recommendation following the futility 
interim analysis, enrollment will be discontinued. 
An efficacy interim analysis on OS is planned to be conducted by iDMC to allow early testing 
of OS in the event of relevant efficacy. The efficacy interim analysis will be conducted when 
80% of the OS events have occurred (i.e., approximately 220 events). At this time, it is 
anticipated that all patients will have been enrolled.
Accompanying this interim efficacy analysis, a non-binding additional futility assessment 
will be performed based on a hazard ratio on overall survival 1.
In the case of not reaching significance for OS at interim analysis, a primary analysis of OS 
will be performed (i.e., when 275 events have occurred).   
Number of Patients
Overall, 440 patients with relapsed or refractory AML are expected to be enrolled in this study, 
over approximately 41 months.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 18 years 

Documented/confirmed first or second refractory or relapsed AML using World Health 
Organization classification, except acute promyelocytic leukemia.  Please note that first 
relapsed AML patients with CR1 duration of 1 year AND age 60 years are excluded.

No more than 2 prior induction regimens (excl. prior HSCT) in their first line treatment, and 
one must have included cytarabine with an anthracycline (or anthracenedione).

Eastern Cooperative Oncology Group performance status of 02  

Adequate hepatic function assessed by the following:  
Serum total bilirubin 1.5 institutional upper limit of normal (ULN), unless resulting 
from hemolysis, Gilbert’s syndrome, or liver infiltration with leukemia
AST/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

WBC count at randomization of 50,000/mm3
Note:  When treatment is not started immediately upon randomization, the WBC count 
at the start of induction therapy (Cycle 1) must remain at 50,000/mm3.  The use of 
hydroxyurea (HU) or leukapheresis to meet eligibility is allowed.  HU or leukapheresis 
must be discontinued at least 24 hours prior to the initiation of study medication.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at least 
one method with a failure rate of 1% per year, during the treatment period and for up to 
6 months after the last dose of study drug
A woman is considered to be of childbearing potential if she has not reached a 
postmenopausal state (12 months of amenorrhea with no identified cause other than 


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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, and established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  Barrier methods must always be 
supplemented with the use of a spermicide.

For men unless permanently sterile by bilateral orchidectomy:  agreement to remain 
abstinent (refrain from heterosexual intercourse) or use contraceptive measures and 
agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for up to 6 months 
after the last dose of study drug.  Men must refrain from donating sperm during this 
same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. 

Ability to understand and willingness to sign a written informed consent form and comply 
with all study requirements including completion of patient-reported outcome measures.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

First relapsed patients aged 60 years with a CR1 duration of 1 year 

Patients with prior documented antecedent hematological disorder including the following:  
myelodysplastic syndrome, myeloproliferative disease (i.e., chronic myelomonocytic 
leukemia, polycythemia vera, primary myelofibrosis, and essential thrombocythemia), and 
aplastic anemia

AML secondary to any prior chemotherapy unrelated to leukemia 

Patients who are either refractory to or have relapsed within 90 days of receiving a regimen 
containing a cumulative dose of 18 g/m2 cytarabine

Patients who have received allogeneic HSCT within 90 days prior to randomization. HSCT 
should have been performed in remission and not used for salvage (patients who have 
received autologous HSCT as consolidation in CR1 are eligible). 

Patients who have received immunosuppressive therapy for graft-versus-host disease or for 
engraftment syndrome after autologous stem cell transplantation within 2 weeks prior to 
randomization

Prior treatment with an MDM2 antagonist

Patients with clinically relevant QTc prolongation (QT interval corrected using Fridericia’s 
formula [QTcF]480 ms), a family history of long QT syndrome, or who are currently 
receiving treatment with medications that are known to prolong the QT interval
Medications that are known to prolong the QT interval must be discontinued 7 days 
(or 5 half-lives, whichever is shorter) prior to initiating study medication until 
5 days after the final administration of study medication.


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
Patients receiving any other investigational or commercial agents or therapies administered 
with the intention to treat their malignancy within 30 days (or 5 half-lives) from first receipt of 
study drug
Note:  The exception is HU or leukapheresis in patients who need to continue this 
therapy to maintain a WBC count 50,000/mm3.  HU or leukapheresis must be 
discontinued at least 24 hours prior to the initiation of study medication. 

Patients with acute toxicities from any prior anti-leukemia therapy which have not resolved 
to Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.03

Patients with a history of other malignancy within 5 years prior to screening, except for 
malignancy that has been in remission without treatment for at least 2 years prior to 
randomization 

Patients unable to temporarily 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 medication.  

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) during the treatment phase.  These agents 
must be discontinued 7 days (or 5 half-lives) prior to the start of study medication. 
Note: Treatment with or switch to low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) is allowed, according to local practice.  However, platelet 
levels need to be closely monitored in these patients (see protocol).

Patients with a history of systemic hypersensitivity reactions Grade 2 attributed to 
cytarabine or components of the formulated product 

Patients who have 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 III, IV), myocardial infarction 6 months prior to 
first study medication, and cerebrovascular accidents 6 months before study 
medication start
Unstable seizure disorders
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by this study medication, such as hereditary coagulation disorders or 
insulin-dependent diabetes mellitus not optimally controlled with medical management 
(e.g., presence of ketoacidosis) or active gastrointestinal (GI) conditions (e.g., Grade 
2 graft-versus-host disease) and uncontrolled inflammatory bowel disease (i.e., 
Crohn’s disease, ulcerative colitis, diverticulosis-associated colitis, and Behçet's 
disease).

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 
2 weeks of appropriate systemic antifungal therapy  
Active bacterial infection and/or bacterial infection with positive cultures in the 7 days 
prior to dosing
Patients who have received 5 days of appropriate therapeutic antibiotic therapy for 
an identified infection


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History of symptomatic Clostridium difficile infection that required treatment within 
1 month prior to dosing.  Upon clinical response to C. difficile treatment, the stool 
consistency and frequency must have returned to normal. 
In all cases, the patient should be afebrile (exception of AML-related fever) and 
hemodynamically stable for at least 72 hours at the time of study medication initiation.

Patients with a history of active or chronic infectious hepatitis unless serology demonstrates 
clearance of infection
Patients with occult or prior hepatitis B virus (HBV) infection (defined as negative 
hepatitis B surface antigen and positive total hepatitis B core antibody) may be 
included if HBV DNA is undetectable, provided that they are willing to undergo monthly 
DNA testing. Patients who have protective titers of hepatitis B surface antibody after 
vaccination or prior but cured hepatitis B are eligible.  Patients positive for hepatitis C 
virus antibody are eligible provided polymerase chain reaction (PCR) is negative for 
HCV RNA.

Patients who have a history of clinically significant liver cirrhosis (e.g. Child-Pugh class B 
and C). 

Patients with electrolyte abnormalities such as hypokalemia, hyperkalemia, hypocalcemia, 
hypercalcemia, hypomagnesemia, and hypermagnesemia of Grade 1 per NCI CTCAE 
v4.03.  Treatment for correction of above electrolyte imbalances is permitted during 
screening to meet eligibility.

Patients with extramedullary AML with no evidence of systemic involvement

Patients with active CNS leukemia

Pregnant or breastfeeding patients

HIV-positive patients 

Patients who might refuse to receive blood products and/or have a hypersensitivity to blood 
products
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur 2 years after the last patient is enrolled or after 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 5.5 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Idasanutlin/placebo will be administered at 300 mg BID orally, without regard to meals.  Water 
can be given ad libitum.  
In case the patient proceeds to consolidation therapy, only 50% of idasanutlin should be given 
(300 mg once daily [QD] in the morning).
Cytarabine will be administered at a dose of 1 g/m2 QD as a 13 hour intravenous infusion.  In 
case the patient proceeds to consolidation therapy the dose may need to be reduced to 50% 
(0.5 g/m2 QD).  
Statistical Methods
Efficacy Analysis
Patients will be analyzed according to the treatment arm to which they were randomized. The 
TP53 WT population is the efficacy population and refers to all randomized TP53 WT 
patients as identified by a central laboratory test.
Description of efficacy analysis in this section is valid for both interim and primary analysis.


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Primary Efficacy Endpoint
The primary efficacy endpoint, OS, is defined as the time from randomization to death due to 
any cause.  OS for patients who have not died at the time of the analysis will be censored at the 
date last known alive. 
The primary OS analysis of the study will assess the null hypothesis of equality of OS functions 
in the idasanutlin in combination with cytarabine (MDM2-chemo) arm versus the cytarabine 
given with a placebo (chemo) arm in the TP53 WT population as follows:
H0:  OSMDM2-chemoOSchemo versus H1: OSMDM2-chemo ≠OSchemo
A formal treatment comparison will be made using a two-sided stratified log-rank test at a 
significance level defined using the O´Brien-Fleming alpha-spending function with overall 
Type I error rate at 0.05 corresponding to available information.  Stratification factors that will 
be used are the same as for randomization, i.e. age (60 versus 60 years), cytogenic and 
molecular risk (favorable/intermediate versus adverse), prior response to initial anti-leukemic 
therapy (refractory versus CR 3 months but 1 year versus CR 1 year) and prior HSCT 
versus no prior HSCT.  
Survival curves in each treatment arm will be estimated using Kaplan−Meier estimates.  The 
Kaplan–Meier estimates will provide a visual description of the survival curves and the 
difference across treatment arms.  The treatment effect will be quantified via a hazard ratio, 
computed from a stratified Cox proportional-hazards regression, including a 95% CI.  To further 
describe and quantify OS, estimated median OS per arm and 1-year and 2-year survival 
probabilities, all including 95% CI, will be given.  The effect of prognostic factors on OS will be 
assessed in an exploratory analysis using Cox multivariate regression.
Secondary Efficacy Endpoint
The following secondary endpoints will be tested for the TP53 WT population, as described in 
the Statistical Analysis Plan:

CR proportion 

EFS 

ORR (CR, CRp, and CRi) 

DOR (duration of remission following CR)

Proportion of HSCT following CR 

CR proportion and OS in clinically actionable mutation-defined subpopulation (FLT3, 
IDH1, and IDH2)
Patients with no response assessments (for any reason) will be considered non-CR. 
Difference in proportions of CR will be assessed between the two treatment arms using 
Cochran–Mantel–Haenszel test stratified by randomization stratification factors.  In addition, 
proportions and 95% CI will be reported for each treatment arm.  The effect of prognostic 
factors on CR will be assessed in an exploratory analysis using logistic regression.
EFS is defined for all patients and measured from the date of randomization.  It is measured 
until treatment failure, relapse from CR, or death from any cause, whichever occurs first.  For 
patients with none of these events before time of analysis, EFS is censored at the date of the 
patient’s last response assessment.
DOR is defined for patients achieving complete remission and is the time from clinical 
remission until relapse or death from any cause, whichever occurs first.  For patients with 
none of these events before time of analysis, DOR is censored at the date of the patient’s last 
response assessment.
EFS and DOR will in general be analyzed using the same statistical methods as those 
described for OS.  If only very few patients qualify for DOR analysis, only descriptive statistics 
will be given.
ORR (CR, CRp, and CRi) and proportion of HSCT will be compared between the two 
treatment arms using the same statistical methods as those described for CR.


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Sensitivity Analyses
The following sensitivity analyses for OS will be performed in the TP53 WT population:

An unstratified log-rank test.

To assess the relevance of HSCT against other long-term effects, OS will be alternatively 
defined with censoring at date of HSCT and analyzed using the same methods as for the 
primary endpoint.

Discontinuation of assessments or patient lost to follow up considered as an event
Safety Analyses
All safety analyses will be based on both the TP53 WT population (defined here as TP53 WT 
patients who have received any study medication at least once) and the complete safety 
analysis population (defined as all patients who have received any study medication at least 
once), and patients will be analyzed according to the treatment received (patients receiving 
idasanutlin at least once will be analyzed in the idasanutlin arm).  Safety analyses will include, 
but not be limited to, incidence rates for adverse events including mortality, adverse event 
severity, seriousness, and adverse events leading to discontinuation.  In addition, abnormalities 
of clinical laboratory tests and vital signs assessed during the study treatment period and post-
treatment follow-up will be assessed.  Exposure to study medication will be summarized by total 
duration of study medication, number of cycles started and cumulative dose using descriptive 
statistics.  
This trial is designed to allow for early termination or a modification of the protocol for safety 
concerns or lack of efficacy, based on the advice of an iDMC.  The iDMC will be incorporated 
into the study to review safety data on a regular basis, including adverse events of special 
interest.  Both the Sponsor and the iDMC can request ad hoc iDMC meetings if potential safety 
concerns arise.  Following each meeting, the iDMC will recommend to the Sponsor whether the 
study should continue according to the protocol or may suggest changes to the protocol based 
on the outcome of the data review.  In exceptional cases, the iDMC may recommend stopping 
the study or closing a treatment arm as a result of safety reasons.  The iDMC will also perform a 
safety review at the preplanned interim analyses for futility and efficacy.
Pharmacodynamic and Biomarker Analyses
The following pharmacodynamic parameters will be presented by listings and descriptive 
summary statistics.  

Blood samples analyzed for macrophage inhibitory cytokine-1 

Analysis of TP53, FLT3, IDH1, and IDH2 mutation status

MDM2 protein expression level in AML blasts

A 4-gene signature (including MDM2 gene expression) 

MRD
Pharmacokinetic Analyses
Key pharmacokinetic (PK) parameter values (apparent clearance and apparent volume of 
distribution) of idasanutlin and cytarabine (total clearance and volume of distribution) will be 
estimated using a population pharmacokinetics (popPK) approach.  The influence of covariates 
such as gender, race/ethnicity, weight, hematological parameters at baseline, renal/hepatic 
impairment, and degree of underlying disease will be investigated.  Other PK parameters such 
as maximum concentration observed (Cmax), steady-state concentration at the end of a dosing 
interval (i.e., just prior to next drug administration) (Ctrough), area under the concentration–time 
curve during one dosing interval, area under the concentration-time curve during a 24-hour 
dosing interval (AUC0-24h), and half-life will be derived from the individual post hoc predictions.  
Details of the population analysis will be described in the Modeling and Simulation Analysis 
Plan.  Results of this analysis will be reported separately.
If appropriate, an exploratory PK/pharmacodynamic analysis may be performed post hoc.  The 
primary focus will be exploration of the relationship between measures of exposure to 
idasanutlin in combination with cytarabine (Cmax, Ctrough, and AUC0-24h) and ECG, drug-related 
adverse effects as well as clinical efficacy parameters.


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Determination of Sample Size  
A mechanistic simulation model was used to determine the sample size in this event-driven 
study, based on the following global assumptions:

Final analysis for OS in patients with TP53 WT disease based on two-sided log-rank test at 
0.05 level of significance

85% power to detect an OS hazard ratio for idasanutlin cytarabine versus 
cytarabine placebo of 0.67 in patients with TP53 WT disease, corresponding to an 
improvement in median OS from 6 to 9 months (50%) 

Proportion of long term survivors of 8.0% in the cytarabine placebo arm and 16.1% in the 
idasanutlin cytarabine arm
To compute the necessary number of events, we simulated OS times based on the following 
assumptions:

All simulated OS times for patients not considered long-term survivors are exponentially 
distributed.

Probability of being a complete responder in the cytarabine placebo arm is 0.16

Probability of being a complete responder in the idasanutlin cytarabine arm is 0.323, 
implying an odds ratio for CR comparing the idasanutlin cytarabine versus the 
cytarabine placebo arm of 2.5

Probability for a complete responder to be a long-term survivor is 0.5 in either arm

An annual dropout rate of 5% (every effort will be made to contact patients for survival 
information in case of study withdrawal or loss to follow-up) 
To have the targeted 85% power, 275 events in patients with TP53 WT disease are required.  
The minimum detectable hazard ratio in a 2:1 randomized trial corresponding to 275 events and 
a significance level of 0.05 amounts to 0.78, corresponding to a minimal detectable median 
improvement from 6 to 7.7 months assuming exponentiality. 
All patients, regardless of TP53 mutation status, will be randomized to this study.  Assuming 
85% of patients will have TP53 WT disease and 15% will have TP53 mutant disease, 
approximately 440 patients will be enrolled over approximately 29 months, corresponding to an 
estimated number of 374 patients with TP53 WT disease.
In Version 6 of the protocol, an interim analysis for efficacy on OS of TP53 WT patients was 
added.  The sample size assumptions above remain unchanged other than the recruitment time 
(now estimated at 41 months).  The interim analysis will occur at an information fraction of 
80%, providing a maximum power of 83% for the final OS analysis.
Interim Analyses
Futility
A non-binding interim analysis for safety and futility will be performed by an iDMC after 
120 patients with TP53 WT have been enrolled and assessed for response.  For the purposes 
of the futility interim analysis, CR is defined as confirmed CR.  Sponsor personnel will not 
have access to by-arm efficacy and safety summaries prior to the formal reporting of study 
results.  The iDMC may recommend stopping the study for futility if:

the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the cytarabine 
and placebo arm in the population of patients WT for TP53, is 2.0,

or the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the 
cytarabine and placebo arm in the population of patients WT for TP53, is 2.5 and the 
hazard ratio for EFS 1.
To compute stopping probabilities for the futility interim analysis, the following additional 
assumptions are made within TP53 WT patients and the simulation model is extended 
accordingly:

Median OS for non-responders in cytarabine arm is 5.1 months

Median OS for responders, but short-term survivors in cytarabine arm is 7.5 months

EFS follows an exponential distribution


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
Median EFS times for non-responders and CR short-term responders is assumed to be 
shorter by a factor 2.5 compared to OS in these same subpopulations

The correlation between uncensored EFS and OS times is 0.5

Hazard ratio for a comparison of idasanutlin cytarabine versus cytarabineplacebo in both 
non-responders and short-term responders is 0.8
Using these assumptions, we expect 63 EFS events at the futility interim analysis under the 
alternative hypothesis.  The probability of early stopping due to futility is 89.9% if the null 
hypothesis of equal OS survival functions is true and 31.9% if the alternative assumption of an 
increase in median OS from 6 to 9 months is true.  
The analysis in both the TP53 WT population and in the overall population will be provided to 
the iDMC.
The iDMC may recommend stopping the study for safety at the futility interim analysis if any of 
the following criteria are met (note:  early death is defined as any death within the first 30 days 
after randomization):

The proportion of GI toxicity (nausea, vomiting, diarrhea) events in the experimental arm 
(idasanutlin cytarabine): Grade 3 >40% or Grade 4 >15%

The proportion of early deaths in the experimental arm (idasanutlin cytarabine) is 
≥10 percentage points greater than in the control arm (cytarabine placebo) 

>20% of early deaths overall in the treatment arm
More details on the interim analysis are provided in the iDMC charter.
Efficacy
An interim analysis for efficacy on OS is planned to be conducted by iDMC. The efficacy 
interim analysis will be conducted when 80% of the OS events have occurred (i.e., 
approximately 220 events). At this time, it is anticipated that all patients will have been 
enrolled.
For the interim efficacy analysis of OS, the significance level will be determined using the 
O’Brien-Fleming alpha-spending function with overall type I error rate at 0.05 level.  At the 
time of the interim efficacy analysis, it is expected that 80% of the OS events will have 
occurred, corresponding to an alpha spending of 0.025 for the interim and 0.043 for the final 
OS analysis leading to a power of 83% for the final analysis.
The iDMC will test OS for efficacy and check if there is a significant difference (alpha level 
0.025 or as assessed based on actual number of OS events) in OS in favor of the experimental 
arm.
Accompanying this interim efficacy analysis, a non-binding additional futility assessment 
will be performed and the iDMC may recommend stopping the study for futility if the hazard 
ratio on overall survival is greater than or equal to one.
Further details of the interim analyses will be described in the iDMC Charter and Statistical 
Analysis Plan.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AHD
antecedent hematological disorder
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 daily
BSA
body surface area
bWBC
baseline white blood cell count
CI
confidence interval
CL
total clearance of drug
CL/F
apparent clearance
Cmax
maximum concentration observed
CR
complete remission
CR1
first CR achieved
CRi
complete remission with incomplete blood count recovery
CRp
complete remission with incomplete platelet count recovery
CSR
clinical study report
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
DOR
duration of remission following CR
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EFS
event-free survival
ELN
European LeukemiaNet
EORTC QLQ-C30
European Organisation for the Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQol 5 Dimension 5-Level


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FDA
U.S. Food and Drug Administration
GI
gastrointestinal
HBV
hepatitis B virus
HCT-CI
hematopoietic cell transplantation-specific comorbidity index
HI
hematologic improvement
HiDAC
high-dose cytarabine
HMRA
hematologic malignancy response assessment
HSCT
hematopoietic stem cell transplant
HU
hydroxyurea
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDAC
intermediate-dose cytarabine
IDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
LAIP
leukemia-associated immunophenotype
LFS
leukemia-free survival or duration of OR (CR, CRp, CRi)
LMWH
low molecular weight heparin
LPLV
last patient, last visit
LTLS
laboratory TLS
MBP
microprecipitated bulk powder
MDM2
murine double minute 2
MIC-1
macrophage inhibitory cytokine-1
MRD
minimal/measurable residual disease
MTD
maximum tolerated dose
NCI
National Cancer Institute
NIMP
non-investigational medicinal product
OATP
organic anion-transporting polypeptide
ORR
overall remission rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PK
pharmacokinetic
PO
orally


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popPK
population pharmacokinetics
PR
partial remission
PRO
patient-reported outcome
QD
once daily
qRT-PCR
quantitative real-time polymerase chain reaction
QTcF
QT interval corrected using Fridericia’s formula
RBC
red blood cell
RCR
Roche Clinical Repository
RT-PCR
reverse transcription polymerase chain reaction
SC
subcutaneous
SD
stable disease
SDP
spray-dried bulk powder
t1/2
half-life:  time for drug in the body to be reduced by one-half
TLS
tumor lysis syndrome
UFH
unfractionated heparin
ULN
upper limit of normal
Vd
volume of distribution
Vd/F
apparent volume of distribution
WT
wild type


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1.
BACKGROUND
The tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein 
that plays a central role in protection from tumor development and is frequently 
inactivated in human cancer.  It is a transcription factor that is activated following cellular
stress and regulates multiple downstream genes implicated in cell cycle control, 
apoptosis, DNA repair, and senescence (Kussie et al. 1996).  Some cancer cells have 
mutant p53, which lacks these activities and as a result permits the proliferation of cells 
that carry damaged DNA.  Tumor cells with wild type (WT) p53 can inactivate p53 in 
alternative ways (in order to proliferate) including overexpression of murine double 
minute 2 (MDM2).  
In non-stressed normal cells, the level of p53 is controlled tightly by MDM2.  As 
illustrated in Figure 1, MDM2 regulates p53 through a negative feedback loop.  When 
nuclear p53 level is elevated, it activates the transcription of the MDM2 gene.  In turn, 
MDM2 binds to p53, which blocks its transactivation domain and targets p53 for 
ubiquitin-dependent degradation in the proteasome.  Both p53 and MDM2 have short 
half-lives and their nuclear concentrations are kept very low as a result of the functioning 
of the regulatory circuit.  However, this feedback loop is deregulated in cancer cells that 
overexpress MDM2.  Stress-induced p53 activation mechanisms in these tumors are 
believed to be inadequate to overcome the negative control of MDM2, leading to 
inefficient growth arrest and/or apoptosis.  Therefore, blocking the p53-MDM2 interaction 
is expected to overcome the oncogenic consequences of MDM2 overproduction and to 
restore p53 function.  Blocking the p53-MDM2 interaction is also expected to increase 
p53 function in tumors that do not overexpress MDM2, leading to anticancer activity.
Figure 1
Regulation of p53 Stability and Activity by MDM2
MDM2murine double minute 2.
a An autoregulatory feedback loop between p53 and its negative regulator MDM2.
b MDM2 antagonist blocks the p53-MDM2 binding, thereby releasing p53 from negative control 
and activating the p53 pathway.


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Genetic and biochemical studies mapped p53MDM2 binding sites to the N-terminal 
domain of MDM2 and the Nterminal part of the transactivation domain of p53.  The 
crystal structure of a p53derived peptide bound to the p53 binding domain of MDM2 
reveals the existence of a relatively deep cavity on the surface of the MDM2 molecule 
(Vassilev et al. 2004).  More importantly, only three amino acid residues from the p53 
peptide (i.e., Phe19, Trp23, and Leu26) appear to play a critical role in the binding 
between the two proteins, by projecting residues deep into the hydrophobic cavity of the 
p53 pocket (Kussie et al.1996).  These structural features of the p53MDM2 complex 
suggest an increased likelihood of the identification of small molecules that might 
interfere successfully with the protein–protein binding by mimicking the key amino acid 
contacts between the two proteins.
A class of small-molecule compounds has been identified as potent and selective 
inhibitors of the p53-MDM2 interaction (Tovar et al. 2006).  These molecules, termed 
nutlins, interact specifically with the p53-binding pocket of MDM2, and therefore, free 
p53 from negative control.  Treatment of cancer cells expressing WT p53 with nutlins
stabilizes p53 and activates the p53 pathway leading to activation of p53 target genes, 
cell cycle arrest, and apoptosis (Tovar et al. 2006; Vassilev 2007).
1.1
BACKGROUND ON ACUTE MYELOID LEUKEMIA
The yearly incidence of acute myeloid leukemia (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 15–25/100,000 per annum (Fey 2013).  Approximately 
20,000 patients will be diagnosed with AML with greater than 10,000 AML patient deaths 
in the United States during 2015 (American Cancer Society 2015).  By intensive initial 
treatment of AML, using cytarabine and anthracyclinebased chemotherapy induction 
regimens, complete remission (CR) proportions ranging from 50% to 80% can be 
achieved.  Nonetheless, the majority of responding patients under the age of 60 relapse 
(60%70%), and results are poorer in older patients, with fewer than 20% of elderly 
patients being long-term survivors (Burnett et al. 2011).
Prognostic factors for AML include age, WBC count, percentage of CD34-positive
blasts, cytogenetic and molecular risk factors, and secondary or therapy-related AML.  
Improvements have been made in prognostic subclassification of patientsincluding
those with normal cytogeneticsby testing for molecular abnormalities (i.e., FLT3,
NPM1, CEBPalpha, MLL, WT-1, and EVI1) to allow early identification of patients at 
high risk of relapse who should be treated with more intensive therapies (i.e., 
hematopoietic stem cell transplant (HSCT), or for whom experimental therapies are
warranted. Patients who do not respond to standard therapy or who relapse within a
year of initial treatment have median survival measured in months (Breems et al. 2005; 
Wattad et al. 2017). No standard regimen exists for the treatment of patients with
relapsed or refractory AML, particularly in patients with a remission duration of less 
than 1 year in response to their initial induction regimen.  These patients are candidates


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for novel therapeutic interventions with the goal of disease remission, making potentially
curative transplant options available for appropriate patients (Forman 2005).  This will be 
the population studied in this clinical trial.  
1.2
BACKGROUND ON IDASANUTLIN
Roche has clinical experience with MDM2 antagonists.  An initial compound brought to 
the clinic (RO5045337) was tested in Phase I and Ib trials in both hematologic and solid 
tumor indications.  This compound demonstrated proof of mechanism in 
MDM2amplified liposarcomas (Ray-Coquard et al. 2012), as well as clinical responses 
in hematologic malignancies, including CRs in patients with AML treated with 
monotherapy, as well as CRs in combination with cytarabine (Andreeff et al. 2012; 
Yee et al. 2013).  Development of this compound was halted because of less than 
optimal potency and pharmacologic properties in favor of the current compound 
(idasanutlin).  
Idasanutlin is a second generation MDM2 antagonist containing a different chemical 
backbone.  As with RO5045337, idasanutlin is a small molecule with high affinity that 
binds selectively to the p53 site on the surface of the MDM2 molecule in vitro and can 
effectively displace p53 from MDM2, which leads to stabilization and accumulation of the 
p53 protein, and activation of the p53 pathway.  However, idasanutlin has substantially 
improved pharmacologic properties, for example, it has lower variability of exposure than 
RO5045337 because it does not have significant pH-dependent solubility; fasted- and 
fed-state simulated intestinal fluid solubility is similar.  Idasanutlin exhibits improved in 
vitro and in vivo potency against tumor cell lines and xenografts, an improved 
cytochrome P450 (CYP) inhibition profile, and shows a several fold lower efficacious 
dose in AML clinical studies. 
For clinical development, idasanutlin was initially formulated as microprecipitated bulk 
powder (MBP) tablets.  While Phase I/Ib studies were ongoing, an alternative idasanutlin 
formulation termed the spray-dried bulk powder (SDP) formulation was developed which 
improved the stability of the drug with regard to decreased formation of a genotoxic 
impurity over the shelf life.  This formulation was extensively tested in the AML patient 
population.  Details on the use of both formulations in idasanutlin clinical trials are 
provided in Section 3.3.1. 
1.2.1
Clinical Experience with Idasanutlin
To date, idasanutlin has been studied in several Phase I/Ib and Phase Ib/II programs;
safety and efficacy results from relevant studies are outlined below.  For more 
information, please refer to the idasanutlin Investigator’s Brochure (IB). 
1.2.1.1
NP28679 in AML
Study NP28679 in patients with AML is completed.  The study enrolled 122 patients; 
however, 1 patient initially diagnosed with AML was subsequently diagnosed with 
chronic myelomonocytic leukemia.  This was a dose escalation study for idasanutlin 


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monotherapy (Part 1) and idasanutlin in combination with cytarabine 1 g/m2 (Part 2) with 
two extensions for Part 1 and Part 2, both parts using the MBP formulation of idasanutlin.  
Part 4 of this study investigated the pharmacokinetics and safety of 300 mg twice daily 
(BID) and 400 mg BID of the optimized idasanutlin SDP formulation in combination with 
1 g/m2 cytarabine.  In comparison with the MBP formulation, the SDP formulation was 
shown to be approximately two-fold more bioavailable in patients treated with idasanutlin 
(Study NP28902).  Therefore, doses of 300 mg BID and 400 mg BID of the SDP 
formulation were chosen to be investigated for a target exposure range of idasanutlin 
similar to that reported in the dose escalation and extensions for the MBP formulation.  
The 300 mg BID dose was chosen for the current Phase III study as available data 
demonstrated a trend towards higher efficacy and a better safety profile compared with 
the 400 mg BID dose. 
Safety
In Study NP28679, consistent with other ongoing studies of idasanutlin, gastrointestinal 
(GI) adverse eventsincluding nausea, vomiting, and diarrheawere the most common 
adverse events across all study groups (90%).  Other frequently reported adverse 
events were infection-related.  The most common serious adverse events were febrile 
neutropenia, sepsis, neutropenic sepsis, and pneumonia.  The most common Grade 3 
adverse events were febrile neutropenia, hypokalemia, thrombocytopenia, diarrhea, and 
anemia.
The maximum tolerated dose (MTD), as defined in Study NP28679, was not reached.  
Dose escalation was halted after the 800 mg MBP BID monotherapy cohort consistently 
experienced GI adverse events, and, thus, this dose was considered a tolerability 
threshold.  The dose of idasanutlin recommended for further development was 
determined to be 600 mg MBP BID for both monotherapy and combination therapy with 
cytarabine for subsequent extensions of the study.
The overall adverse event profile in patients treated with idasanutlin alone was similar to 
that of patients treated with idasanutlin in combination with cytarabine; however, the 
number of adverse events was higher for the combination treatment.  The adverse event 
profile of the SDP formulation of idasanutlin is similar to that of the MBP formulation.  
The incidence and severity of gastrointestinal toxicity and associated electrolyte 
abnormalities was higher in the 400 mg SDP cohorts than in the 300 mg SDP cohorts.
Additional information on clinical safety is found in the idasanutlin IB.
Efficacy
In Study NP28679, all 121 patients with AML in the per-protocol population were 
evaluated for hematological response.  One patient was found to have chronic 
myelomonocytic leukemia and not AML, and was therefore not included in the efficacy 
analysis. 


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In total, 46 patients received monotherapy with the MBP formulation during the 
dose escalation and extension parts of the study, and 43 patients received the MBP 
formulation in combination with cytarabine.
An additional 32 patients were enrolled in the bridging arm and received 300 or 400 mg 
BID per day of the SDP formulation of idasanutlin in combination with cytarabine.
The proportion of evaluable patients with CR/CRp who were treated with either MBP or 
SDP in combination with cytarabine was 28% (21 of 75 patients), and the proportion of 
evaluable patients with clinical response (defined as CR+ complete remission with 
incomplete platelet count recovery [CRp]+ complete remission with incomplete blood 
count recovery [CRi]) was 29% (22 of 75 patients). Patients with clinical response were 
followed until relapse or until 1 year from the start of therapy; the median duration of 
clinical response was 8.35 months (range: 1.111.7 months).
For patients receiving the SDP formulation in combination with cytarabine, the proportion 
of patients with CR/CRp was 31% (10 of 32 patients), and the proportion of patients with 
clinical response was 34% (11 of 32 patients). The median duration of clinical response 
in patients receiving 300 mg BID or 400 mg BID was 10.4 months (range: 
1.1−11.4 months) and 10.2 months (range: 2.310.4 months), respectively.
1.2.1.2
NP27872 in Solid Tumors
A Phase I study of idasanutlin monotherapy (Study NP27872) in solid tumors has also 
been conducted.  In Study NP27872, patients with solid tumors received escalating 
doses of idasanutlin.  The dose limiting toxicities on a 5-day dosing schedule were 
primarily thrombocytopenia and neutropenia.  At the MTD (500 mg MBP once daily 
[QD]5 days), patients demonstrated evidence of MDM2 antagonist mechanism of 
action in tumor biopsies including, p53 activation, increased p21 and MDM2 expression 
by immunohistochemistry, and increased MDM2 gene expression by reverse 
transcription polymerase chain reaction (RT-PCR).  There was also 
evidence of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling.  
Dose escalation was limited by myelosuppression.  No responses by Response 
Evaluation Criteria in Solid Tumors were seen; however, prolonged stable disease (SD; 
median 72.5 days, minimum 8 days, and maximum 696 days) and long treatment 
duration (21%, 2 cycles) were seen in some patients.  
Two additional dosing schedules had been evaluated in solid tumor patients:  
daily3 days and weekly3.  While there was evidence of p53 activation, the 
daily3 days dose regimen did not achieve steady-state exposure, displayed shorter 
duration for SD (median 57 and 103 days for daily 3-day and daily 5-day schedules, 
respectively), and did not alleviate thrombocytopenia.  


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1.2.2
Clinical Pharmacology Summary
1.2.2.1
Clinical Pharmacokinetics
Evaluable pharmacokinetic (PK) data for patients treated with the idasanutlin MBP or 
SDP formulation are available from Studies NP27872, NP28902, NP28679, and 
NP29910.  Overall, clinical PK data are summarized as follows:

Half-life (t1/2) was approximately 1 day.

There was apparent dose-proportionality for the daily schedule in patients with solid 
tumors (Study NP27872).

There was no apparent difference in idasanutlin PK exposure between patients with 
solid tumors (Study NP27872) and patients with AML (Study NP28679) in the dose 
range of 400 to 1600 mg daily dosing for 5 days.

Inter-patient variability was approximately 50% and intra-patient variability was 
approximately 26%.

In comparison with the MBP formulation, the SDP formulation is approximately 
two-fold more bioavailable in patients with AML treated with idasanutlin in 
combination with cytarabine.

There was no major effect of high-fat or low-fat food on PK exposure.

Metabolite M4 (RO6802287) was the only major metabolite in human plasma 
samples (at steady-state on Day 5).

At steady-state, the drug level in the bone marrow was approximately 70% of plasma.

Idasanutlin is not excreted through urine.

There was no major impact of a strong CYP3A4 inhibitor, posaconazole, or 
concomitant cytarabine on idasanutlin pharmacokinetics.
1.2.2.2
Clinical Pharmacodynamics 
Macrophage inhibitory cytokine-1 (MIC-1) is a secreted protein that is induced by 
activated p53 in response to MDM2 antagonists and can be detected in the serum.  
MIC-1 levels were used to assess pharmacodynamic effects of idasanutlin in the Phase I 
studies.  An analysis of patients given 1003200 mg/day of idasanutlin showed that MIC-
1 induction was demonstrated at the lowest tested dose of 100 mg/day, with a 
corresponding exposure level of 500 ng/mL of idasanutlin.  No upper limit has been 
observed for MIC-1 induction (plateau not reached).
There is an apparent PK/pharmacodynamic relationship for the daily dosing regimen in 
regards to Cycle 1 platelet nadir and maximum grade of ANC and platelet. 
No correlation was observed between drug concentration and QT interval corrected 
using Fridericia’s formula (QTcF) or its change from baseline.


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1.2.2.3
Metabolic Drug-Drug Interactions
Idasanutlin is a CYP2C8 inhibitor that may affect concomitant CYP2C8 substrates, and 
its M4 metabolite is an organic anion-transporting polypeptide (OATP)-1B1/3 transporter 
inhibitor that may affect concomitant OATP1B1/3 substrates.  These are the basis for the 
prohibited therapy list for the present study.  However, idasanutlin is not expected to 
interact with substrates of deaminases such as cytarabine (no interaction observed with 
cytarabine from Study NP28679).  
Only one inactive metabolite RO6802287 (Hydroxy pyrrolidine metabolite M4)
(approximately 25% of parent exposure) was identified in plasma samples.  This 
metabolite is generated by CYP3A4 and CYP2C8 metabolic pathways.  A strong 
CYP3A4 inhibitor, posaconazole, had no impact on idasanutlin maximum concentration 
observed (Cmax) values but increased area under the concentration-time curve (AUC) 
values by 32%, which suggests a minimal (no clinically significant) drug-drug interaction 
(DDI) potential with a single use of a strong/moderate CYP3A4 or CYP2C8 inhibitor.  
However, a concomitant second strong/moderate inhibitor of the other CYP pathway 
(e.g., from CYP2C8 to CYP3A4) may increase idasanutlin exposure to a clinically 
significant level. 
UGT1A3 is also a major clearing enzyme; its strong inhibitor gemfibrozil is also a 
CYP2C8 inhibitor that will be excluded from the current study.
As idasanutlin is a substrate for both CYP3A4 and CYP2C8, the known inducers of 
CYP3A4 and CYP2C8 will also be prohibited from the current study to prevent loss of 
exposure for idasanutlin.
Guidance on the use of these drugs within the study is provided in Section 4.4.2.1.
See the idasanutlin IB for additional details on nonclinical and clinical studies.
1.3
BACKGROUND ON CYTARABINE
The anti-metabolite cytarabine enters the cell and is phosphorylated to the active 
triphosphorylated state known as Ara-CTP.  Cytarabine exerts its cytotoxic effect in two 
ways:  by DNA polymerase inhibition and by incorporation into the DNA strand causing 
chain termination, which blocks DNA synthesis.  After intravenous (IV) administration, 
the pharmacokinetics are most commonly described with a two-compartment model.  
The initial distribution phase is rapid (t½ of about 10 minutes) followed by a slower 
elimination t½ (about 2.5 hours).  Baseline white blood cell count (bWBC) influenced the 
pharmacokinetic for cytarabine; its clearance was significantly decreased by increased 
bWBC.  However, 10-fold changes in bWBC were needed for these relationships to have 
potential clinical relevance (cytarabine package insert; Section 4.3.1.2).  


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The main toxic effect of cytarabine injection is bone marrow suppression with leukopenia, 
thrombocytopenia, and anemia.  Less serious toxicity includes nausea, vomiting, 
diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction.  For further details 
of efficacy and toxicity of cytarabine in relapsed/refractory AML patients, refer to 
Section 3.3.3.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Patients who relapse after standard induction chemotherapy for AML have a poor 
prognosis, particularly if they do not achieve a CR, relapse within 1 year of initial therapy 
or after stem cell transplantation, experience AML that developed from an antecedent 
hematologic disorder, or experience multiple relapses (Löwenberg et al. 1989; 
Breems et al. 2005; Ofran and Rowe 2012).  No standard regimen exists for the 
treatment of patients with relapsed or refractory AML, particularly for patients with initial 
remission duration of 1 year, whose median survival is measured in months (Breems et 
al. 2005).  These patients urgently need more effective new therapies.  
Idasanutlin is a potent and selective inhibitor of the p53-MDM2 interaction that activates 
the p53 pathway and induces cell cycle arrest and/or apoptosis in a variety of tumor 
types expressing functional p53 in vitro and in vivo.  Idasanutlin given orally (PO) caused 
tumor growth inhibition in a variety of different dosing schedules in a human 
osteosarcoma cancer xenograft model.  When tested in combination with cytarabine in a 
preclinical disseminated AML model, both the once weekly and daily for 5 days (5 days
on/23 days off) schedules in combination with cytarabine demonstrated an increase in 
survival when compared with correlative monotherapy arms.  The daily for 5 days
(5 days on/23 days off) schedule of idasanutlin in combination with cytarabine was 
selected as the dosing regimen for clinical development (idasanutlin IB).
Meanwhile, efficacy and safety data from 122 patients from the Phase I/Ib
Study NP28679 are available.  Overall, 121 patients receiving idasanutlin monotherapy 
or combination therapy with cytarabine 1 g/m2 were evaluable for response.  Patients 
listed as achieving CR underwent a subsequent bone marrow assessment that 
confirmed continued bone marrow response approximately 28 days following the initial 
CR assessment (confirmed CR).  For patients achieving CR, the duration of clinical 
response was measured until relapse or until 1 year from the start of therapy.
Across cohorts the combination with cytarabine led to a CR/CRp rate in evaluable 
patients of 28% (21 of 75 patients) (Section 1.2.1.1).  The CR/CRp rate in evaluable 
patients receiving 300 mg BID of the idasanutlin SDP formulation, which is the dose 
selected for the present Phase III study, was 36.8% (7 of 19 patients) (Section 1.2.1.1). 


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Analysis of the number and type of prior regimens, exposure, and best response on 
study for patients treated with idasanutlin in combination with cytarabine demonstrated 
activity in patients who have received prior cytarabine-containing regimens and were 
refractory or relapsed.  Ongoing analysis of characteristics of patients responding to 
therapy demonstrates activity in patients who have antecedent hematologic disorders 
and prior malignancies, as well as being refractory to initial induction therapies.  One 
patient with AML treated with idasanutlin plus cytarabine achieved a CR despite 
harboring a TP53 mutation.  The median duration of response for combination therapy in 
patients who did not have disease progression was approximately 8.35 months (range:  
1.111.7 months).
Cytarabine is a potent bone marrow suppressant and as such has an overlapping 
toxicity profile with idasanutlin.  In the AML population this combination appears 
nevertheless desirable because the additive effect might lead to increased blast 
clearance and higher efficacy for the combination treatment.  Preliminary efficacy data 
from Phase I appear to confirm this hypothesis.
Safety data from the 122 patients exposed to idasanutlin monotherapy or combination 
therapy in the Phase I/Ib AML Study NP28679 showed that the most common adverse 
events across all study groups were GI disorders, in particular diarrhea, nausea, and 
vomiting, all of which were clinically manageable by appropriate treatment and 
prophylaxis.  The most frequent serious adverse events were infectious events and 
blood and lymphatic system disorders.
Comorbidities and characteristics such as older age, frailty, and presence of prolonged 
cytopenias prior to study initiation are common among relapsed/refractory AML patients.  
The treatment proposed in this study is anticipated and expected to lead to cytopenias 
rendering patients susceptible to infections.  Cytopenia or aplasia may be a 
consequence of clearance of the bone marrow blasts, which leads to the possibility of 
normal hematopoietic recovery.  To reduce the risk to patients enrolled, this study will 
rely on stringent enrollment criteria for performance status, diligent clinical observation 
and management (i.e., initiation of mandatory diarrhea and infectious events 
prophylaxis/management and guidelines for tumor lysis syndrome [TLS] management; 
for detailed information on toxicity management guidelines, please refer to Appendix 14), 
and pharmacovigilance.  The safety data for patients in the study will be reviewed 
regularly during study conduct by an independent Data Monitoring Committee (iDMC; 
see Section 6.6).  
Relapsed/refractory AML is a condition with high, unmet medical need.  Idasanutlin in 
combination with cytarabine showed promising activity in Phase I AML with a 
manageable safety profile, therefore its benefit-risk is considered positive. 


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2.
OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary objective for this study is as follows:
Within the TP53 WT population

To compare OS in patients with relapsed or refractory AML who have been 
randomized to idasanutlin in combination with cytarabine versus those who have 
been randomized to cytarabine and placebo
2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:
Within the TP53 WT population 

To compare the proportions of complete remission (CR) between treatment arms 

To compare event-free survival (EFS) between treatment arms

To compare ORR (defined as CR), complete remission with incomplete platelet 
count recovery [CRp], and complete remission with incomplete blood count recovery 
[CRi]) between treatment arms

To compare duration of remission following CR (DOR) between treatment arms

To compare the proportions of allogeneic HSCT following CR between treatment 
arms

To assess OS and CR in clinically actionable mutation-defined AML subpopulations, 
including FLT3, IDH1, and IDH2

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 

To compare the differences in disease and treatment-related symptoms and 
health-related quality of life between treatment arms
Within the all-patient population

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 

To characterize the pharmacokinetics of both idasanutlin and cytarabine 

To compare the differences in disease and treatment related symptoms and 
health-related quality of life between treatment arms
2.3
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:
Within the all-patient population 

To evaluate primary and secondary efficacy endpoints, including OS, CR, 
proportion of HSCT, EFS, and DOR in the all-patient population and OS and CR 
in the clinically actionable mutation-defined AML subpopulations (including FLT3, 
IDH1, and IDH2)


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Within the all-patient and TP53 WT populations

To evaluate efficacy endpoints, including proportion of HSCT, CR, ORR, and DOR 
on the basis of response assessed over entire treatment period

To evaluate LFS (leukemia-free survival, or duration of OR)

To explore minimal/measurable residual disease (MRD) in bone marrow after 
treatment with idasanutlin plus cytarabine compared with cytarabine and placebo

To evaluate candidate response biomarkers (gene expression signatures) and 
MDM2 protein expression in blast cells 

To assess prognostic and predictive effect of disease-associated mutations
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a Phase III multicenter, double-blind, randomized, placebo-controlled study 
of idasanutlin in combination with cytarabine compared with cytarabine and placebo.  
See Study Scheme in Figure 2.
Figure 2
Study Scheme
AMLacute myeloid leukemia; BIDtwice daily; CRcomplete remission; HSCT hematopoietic 
stem cell transplant; IVintravenous; OSoverall survival; PO orally; WTwild type.




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The futility interim analysis will be performed by an iDMC.  Enrollment of patients will 
continue while this interim analysis takes place.  If the Sponsor decides to stop the study 
based on iDMC recommendation following the futility interim analysis, enrollment will 
be discontinued. 
An efficacy interim analysis on OS is planned to be conducted by iDMC to allow early 
testing of OS in the event of relevant efficacy. The efficacy interim analysis will be 
conducted when 80% of the OS events have occurred (i.e., approximately 220 events). 
At this time, it is anticipated that all patients will have been enrolled.
Accompanying this interim efficacy analysis, a non-binding additional futility
assessment will be performed based on a hazard ratio on overall survival 1.
In the case of not reaching significance for OS at interim analysis, a primary analysis 
of OS will be performed (i.e., when 275 events have occurred).   
3.2
END OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur 2 years after the last patient is enrolled or after 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 5.5 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Idasanutlin Dose and Schedule
Idasanutlin dosing for this study was based on experience with an initial MBP 
formulation in both single agent testing (Studies NP27872 and NP28902) and from the 
combination with 1g/m2 cytarabine in Study NP28679 in patients with both 
relapsed/refractory and elderly frontline AML.  An alternative idasanutlin SDP formulation 
was developed, which improved the stability of the drug with regard to decreased 
formation of a genotoxic impurity over the shelf life, and will be used for all future studies, 
including this one.  An integrated dose and PK exposure response analysis and a 
comparative safety assessment have been conducted in Study NP28679 between the 
two formulations.  Based on this, the recommended dose of the SDP formulation is 300 
mg BID (or 600 mg/day)5 days, which can be administered without regard to food.  
The dose selected, optimizes the proportion of patients (90%) to achieve an efficacious 
exposure threshold (Day-5 area under the concentration-time curve during a 24 hour 
dosing interval (AUC0-24h) 100 gh/mL), at which approximately 50% of patients 
achieved a CR, and with acceptable safety/tolerability profiles (refer to the idasanutlin IB 
for further details).


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Idasanutlin PK exposure, pharmacodynamic effects (e.g., increased expression of serum 
MIC-1 as a p53 activation marker), and target-mediated hematological changes (platelet 
reduction in particular) were evaluated to define the optimal dosing schedule (idasanutlin
IB).  A comparison of MIC-1 elevation between the idasanutlin dosing schedules 
demonstrated limited ability to activate p53 with the weekly schedule.  The daily3 days 
dose regimen did not achieve steady-state exposure, displayed shorter duration for SD 
(median 57 and 103 days for daily3-day and daily5-day schedules, respectively), and 
did not alleviate thrombocytopenia.  Therefore, the daily5-day schedule was chosen as 
optimal for future clinical trials.  Because thrombocytopenia in solid tumor patients and 
bone marrow clearance in leukemia patients share the target-mediated hematological 
effects, this optimal schedule found in solid tumor patients is deemed to be applicable to 
AML patients.
Because idasanutlin is a highly lipid-soluble small molecule, a food-effect evaluation of a 
high-energy/high-fat meal (1000 kcal with 50% from fat) and low-fat meal (500 kcal with 
30% from fat) was explored in patients with solid tumors using the optimized SDP 
formulation in Study NP28902.  The PK results from 19 evaluable patients (all whom 
received three crossover treatments) showed that the highfat meal demonstrated 
equivalence in all PK exposure parameters analyzed with 90% CI values.  The low-fat
meal demonstrated less than 20% increase in all PK exposure parameters analyzed and 
was just outside the upper limit of 90% CI for equivalence, but is unlikely to be clinically 
significant as the inter-patient variability is approximately 50%.  Thus, idasanutlin may be 
administered PO with or without food.  Water can be given ad libitum.  
3.3.2
Rationale for Patient Population
The target patient population for this Phase III study includes first or second 
relapsed/refractory AML patients, excluding APL (i.e., AML patients who are refractory or 
have relapsed following at least one and no more than two prior cytarabinecontaining 
induction chemotherapy regimen[s]).  As reflected in the current practice guidelines for 
AML (National Comprehensive Cancer Network Version 1. 2015, European Society for 
Medical Oncology, and ELN) patients who have relapsed after completion of, or are 
refractory to primary therapy are encouraged to participate in clinical trials. 
The efficacy of study treatment is assessed based on bone marrow status.  Patients with 
extramedullary disease with no evidence of systemic involvement are excluded from the 
study as their disease cannot be properly followed for response under this protocol.
Patients who have received allogeneic HSCT 90 days prior to randomization will be 
eligible for this study.  No time frame applies to patients who have received autologous 
HSCT as consolidation therapy.  HSCT should have been performed in remission and 
not used for salvage.
In order to control for variability in AML prognosis, and thus outcome, patients in this 
trial will be stratified on the basis of known prognostic factors including age, molecular 


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and cytogenetic risk factors, and response to initial therapy (Cheson et al. 2003; 
Döhner 2010).  Eligible patients must have received at least one induction regimen that 
included cytarabine with an anthracycline (or anthracenedione).  In order to determine 
potential benefit and protect patients unlikely to respond to therapy, patients with an 
extremely poor prognosis will be excluded from this trial. This includes patients who 
have received more than 2 prior induction regimens in their first line treatment, patients 
with AML secondary to a documented antecedent hematologic disorder, patients with 
AML secondary to prior chemotherapy, and patients who have poor performance status.  
Additionally, patients either refractory to or who have relapsed within 90 days of having 
received a course of high-dose cytarabine (HiDAC) of cumulative dose ≥18 g/m2 will be 
ineligible for the proposed trial (see details in Appendix 16).
Allogeneic HSCT was shown to offer the best chance for cure of relapsed/refractory 
AML for patients in CR2 or greater and is therefore allowed under this protocol (Breems 
et al. 2005).  However, the benefit of HSCT is impaired by non-relapse-related mortality, 
depending on the performance status, age, disease status, and transplant toxicity.  
HSCT-associated mortality may potentially confound the primary endpoint OS and may 
even risk failure to meet the primary endpoint, as observed in previous studies (Faderl et 
al. 2012; Ravandi et al. 2015).  For this reason, the present study will rely on enrollment 
criteria regarding the physical status of potentially eligible patients, thereby selecting for 
patients with a chance to successfully undergo a later HSCT procedure.
Patients with mutations that render the p53 protein inactive are not expected to respond 
to an MDM2 antagonist.  However, hundreds of mutations in the TP53 gene have been 
described, and the relationship to the gene’s functionality is not well characterized 
(Petitjean et al. 2007).  In Study NO21279 (Phase I in AML with RO5045337), most 
patients treated with RO5045337 with mutant TP53 failed to show evidence of response.  
Two AML patients with TP53 mutations demonstrated clinical activity by decreased 
peripheral blast counts, but none had sustained clinical improvement (prolonged CRs).  
In NP28679 study, 1 patient with TP53 mutation who received idasanutlin in combination 
with cytarabine achieved a confirmed CR (confirmatory assessment approximately 28 
days following initial CR determination). 
Given the uncertain role of TP53 mutational status on p53 tumor suppressor activity, 
patients harboring TP53 mutation will be allowed into this study.  
The expected proportion of TP53 mutations in the relapsed/refractory AML patient 
population is approximately 10% (Hu et al. 1992; Trecca et al. 1994; Wattel et al. 1994).  
Review of large public databases (Forbes et al. 2008; TCGA) confirms these rates.  
Phase I experience with both idasanutlin and RO5045337 has been consistent with 
TP53 mutation rates of approximately 20%.  A slightly higher rate is expected in a 
heavily pretreated AML population, in keeping with the larger percentage of TP53
mutations seen in complex karyotype AML (Rucker et al. 2012).  


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Taking all evidence together, the mutation proportion in this study populationwith
fewer lines of prior therapy and excluding patients with a prior documented antecedent 
hematological disorder (AHD)is expected to be approximately 15%.  
Since the majority of the patients are expected to be TP53 WT (85%) and efficacy is 
primarily expected in the TP53 WT patients, the primary and secondary efficacy 
endpoints will be tested in patients who are WT for TP53 who have been randomized to 
idasanutlin in combination with cytarabine versus those who have been randomized to 
cytarabine and placebo.  Efficacy in the all-patient population will be tested as 
exploratory endpoints. 
3.3.3
Rationale for Control Group
No standard of care exists for the treatment of relapsed/refractory AML, but the most 
effective agent in the relapsed setting is cytarabine.  Studies conducted more than three
decades ago demonstrated that remission can be induced in the relapsed setting by 
increasing the exposure to cytarabine used in induction regimens or by prolonging the 
infusion duration to achieve higher intracellular concentrations (Momparler 1974).  These 
findings have been confirmed in numerous Phase II and III studies utilizing cytarabine 
given in a variety of dosing regimens, including “intermediate-dose” (e.g., 1 g/m2
Q12hour612 doses) and “high-dose” (e.g., 3 g/m2 Q12hour812 doses), either as 
monotherapy or in combination with other agents (Leopold and Willemze 2002; 
Rudnick et al. 1979).  In general, higher exposures to cytarabine produced modestly 
higher remission rates, but did not prolong OS, and were associated with significant and 
life-threatening clinical toxicities and higher rates of early death in the immediate 
post-treatment period.  Treatment outcome was mostly influenced by patient age and the 
duration of CR1 and not by cytarabine dose.  Similarly, patients with second or greater 
relapse have a worse prognosis, but can achieve remission based on cytogenetics, age 
and achievement of previous CR being the most important factors (Stoiser et al. 2000).
The MTD of cytarabine was found to be 3 g/m2 per day for several days based on severe 
cerebellar toxicity which can be irreversible (Gottlieb et al. 1987; Herzig et al. 1987; 
Nand et al. 1986).  The major toxicities are age-related and worsen with hepatic or renal 
insufficiency, such that usual clinical practice for treatment of AML at any point in 
therapy generally prohibits the use of repeated doses of cytarabine greater than 
12 g/m2 per day in patients over the age of 60 years.  
Cytarabine at a dose of 1 g/m2 rather than 2 g/m2 was chosen as the comparator and 
combination partner for idasanutlin in the Phase I setting on the basis of data from the 
induction setting of AML therapy, where the benefit/risk of high-dose cytarabine (greater 
than/equal to 2 g/m2) versus 1 g/m2 has been questioned (Löwenberg et al. 1989; 
Reese and Schiler 2013; Momparler et al. 2013).  Among specific cytogenetic/molecular 
subsets of AML in patients 60 years, there may be a benefit associated with 
post-remission consolidation therapy with high-dose cytarabine, but the benefit is not 
clear for the population overall (Byrd et al. 2002).  Doses greater than 1 g/m2 are above 


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the metabolic limit for cytarabine conversion to cytarabine triphosphate for the majority of 
patients, and thus such treatment may add only toxicity (Löwenberg 2013).  This is 
particularly important for patients over the age of 50 years who have the greatest risk of 
CNS toxicity with cytarabine, and will most likely comprise the majority of the patients 
enrolled in this trial for relapsed/refractory disease (median age for AML onset 
approximately 66 years) (Herzig et al. 1987).  
It is important to note that with the exclusion of first relapsed patients who are younger 
than 60 years of age and had a durable CR to initial therapy, a patient set is excluded 
where standard practice would be to use multi-agent chemotherapy (e.g., FLAG-IDA).  
Patients who have received more than two prior induction regimens as part of their first 
line treatment and those who are either refractory to or who have relapsed within 90 
days after receiving HiDAC of cumulative dose 18g/m2 are excluded from enrollment to 
limit the study population to patients with the potential to respond to cytarabine as a 
single agent.  Furthermore, patients are randomized 2:1 from the start to the 
combination regimen of idasanutlin and cytarabine to limit the exposure to the control 
arm (Figure 2).  
3.3.4
Rationale for Population Pharmacokinetic/Pharmacodynamic 
Analysis
Minimal blood sampling is required for conducting population pharmacokinetics (popPK) 
analyses to characterize the pharmacokinetics of idasanutlin and cytarabine in plasma in 
the patient population.  The population and individual PK parameters will be estimated 
and the influence of covariates (such as age, sex, body weight, ethnicity, and disease 
status including organ impairments) on these parameters will be investigated in order to 
determine any subpopulations with higher/lower than expected exposure.  
With these PK exposure data, the exposure-response relationship of idasanutlin in 
combination with cytarabine on efficacy measures, such as best overall response and 
OS, as well as the relationship between the exposure of idasanutlin in combination with 
cytarabine, 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 which indicate whether sub-populations may be at increased risk will be 
investigated.  
3.3.5
Rationale for Biomarker Assessments
This study will look at TP53 mutation status and other disease-associated genetic 
alterations, including FLT3, IDH1, and IDH2; gene expression signatures that may be 
associated with clinical response to idasanutlin; flow cytometry assessment of MDM2 
expression in blast cells; and MIC-1 expression levels. 


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Activity of idasanutlin is derived from the stabilization and accumulation of p53. The 
level of MDM2 is important because MDM2 is overexpressed in approximately 50% of 
AML, leading to destabilization of TP53 (Fenaux et al.1992; Hu et al. 1992; Wattel et al. 
1994).  This is believed to result in decreased p53 levels and activity, and thus p53 
function could be restored by MDM2 antagonists.  Activated p53 induces or inhibits the 
expression of multiple genes, some of which are secreted and may be useful as 
pharmacodynamic indicators of clinical activity of idasanutlin (e.g., MIC-1).
Additional biomarkers related to p53 and MDM2 activity may be evaluated as 
appropriate.  
3.3.5.1
Mutation State of TP53
In AML, the TP53 mutation rate is less than that of solid tumors, estimated to be 
approximately 7%13% (Forbes et al. 2008).  16% of patients in the Phase I AML 
population in Study NO21279 treated with RO5045337 demonstrated a mutation in TP53.  
Leukemia cells from patients will be tested for TP53 mutation during this study by NGS.  
Mutation testing will be done retrospectively because of the low anticipated rate of 
TP53 mutation in the AML population.
3.3.5.2
MDM2 Expression Status/Predictive Gene Signatures
MDM2 protein expression in blast cells analyzed by flow cytometry is associated with 
response in Study NP28679 (Reis et al. 2016).  MDM2 transcript (mRNA) expression 
from pretreatment AML patient blood specimens also trends with clinical response both 
in Phase I Study NO21279 with RO5045337 and in Phase I/Ib Study NP28679 with 
idasanutlin. However, the association is not sufficiently robust to use MDM2 alone for 
selection of responsive patients.  Gene expression signature(s) may provide a means of 
predicting patient response to MDM2 inhibitors and a number of other gene signatures 
that predict response to MDM2 inhibition have been reported in the literature 
(Ishizawa et al. 2018).  Nonclinical and clinical data (Studies NO21279 and NP28679) 
suggest that an mRNA signature of four genes (MDM2, BBC3/PUMA, XPC, and 
CDKN2A) is associated with response to MDM2 antagonist RO5045337 (Zhong et al. 
2015).  An evaluation of this signature is also planned in this Phase III study.  At the 
futility interim analysis, the iDMC will use guidelines as specified in the iDMC charter to 
issue a recommendation indicating the status of the gene signature. 
3.3.5.3
MIC-1 Expression 
MIC-1, a secreted protein that is strongly induced by activated p53, can be detected in 
the blood of mice bearing human tumor xenografts after treatment with doxorubicin, a 
genotoxic p53 activator (Yang et al. 2003).  Therefore, MIC-1 may have utility as a 
pharmacodynamic biomarker for idasanutlin.  In Study NO21279 for RO5045337which 
included patients with AMLas well as in the AML Phase I Study NP28679 for 
idasanutlin, MIC-1 expression has been shown to be a useful pharmacodynamic 
biomarker providing evidence that the mechanism of action was engaged at a systemic 
level.


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3.3.5.4
Exploratory Markers
Ongoing evaluation of pharmacodynamic biomarker activity in a subset of patients in 
Study NO21279 has demonstrated treatment-related increases in p53 activity, 
particularly through the activation of p53 gene targets and induction of apoptosis 
(Kojima et al. 2005).  On the basis of the results from this study, additional analyses on 
blood and/or bone marrow specimens may be performed in this trial to explore 
biomarkers related to p53 and MDM2 activity and the activity of idasanutlin.  
3.3.5.5
AML-Relevant Markers
Additional biomarkers may also contribute to the selection of AML patients most likely to 
respond to idasanutlin treatment.  For example, the status of one of the most commonly
mutated genes in AML, FLT3, has been shown to be linked to the ex vivo response of 
AML blasts to an MDM2 inhibitor (MI2190) (Long et al. 2010).  In addition, FLT3, IDH1, 
and IDH2 are clinically actionable mutations for approved treatments (Rowe et al. 2018; 
Bewersdorf et al. 2019).  Other mutations and genetic abnormalities have prognostic 
value in AML.  Additional genetic analyses include sequencing of genes associated 
with AML and/or those related to the mechanism of action for idasanutlin.
3.3.5.6
Minimal/Measurable Residual Disease Assessment in Patients 
with Complete Remission
The updated ELN guidelines qualify the complete remissions in AML additionally by 
MRD response (Döhner et al. 2017).  Patients who achieve clinical remission, defined 
as cytomorphologic clearance of the bone marrow of leukemia (CR, CRi, or CRp, see 
Section 3.4.1), will undergo serial MRD assessments in bone marrow at the time of 
hematologic malignancy response assessment (HMRA).  These will be done primarily 
with flow cytometry assessments for detection of the leukemia-associated 
immunophenotype (LAIP) at a central laboratory.  Alternative technologies (detection 
of disease characteristic clonal markers by NGS or polymerase chain reaction [PCR] or 
expression of WT-1) may be used for confirmation of the MRD response at the time of 
CR.  Stabilization or reduction of MRD measures (MRD response) could serve as a 
potential surrogate marker of efficacy of idasanutlin.
In patients achieving clinical remission, MRD monitoring from bone marrow aspirates will 
be prioritized over analysis of other exploratory markers.  Other markers that may be 
evaluated at the time of MRD monitoring include gene sequencing to detect disease 
related markers.  


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3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
The efficacy outcome measures for this study are:

OS

EFS

DOR

CR

CRp

CRi

Overall remission rate (ORR) (CR, CRp, and CRi)

Allogeneic HSCT 
For definition of response criteria (CR, CRp, CRi), see Section 4.5.8; for all other 
definitions, see Section 6.4.
In this study, CR or CRp achieved by induction Cycle 1 must be confirmed for the 
purpose of the futility interim analysis.
For all patients in CR or CRp who do not proceed to Cycle 2, an additional HMRA will be 
scheduled 30 (3) days after the previous HMRA performed at the end of Cycle 1 (Note 
that this assessment will not be required after the futility interim analysis).  For all 
patients proceeding to Cycle 2, the HMRA at the end of Cycle 2 will be used as the 
confirmatory response in the analysis.  If a patient proceeds directly to HSCT in aplasia 
after Cycle 1 or prior to undergoing an HMRA, this will be considered confirmed CR for 
the purpose of futility analysis unless the HSCT was clearly performed in disease 
progression or relapse.
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are:

Incidence and severity of adverse events and serious adverse events

Incidence of clinically significant laboratory abnormalities

ECGs

Vital signs

30- and 60-day mortality rates
3.4.3
Pharmacodynamic/Biomarker Outcome Measures
The pharmacodynamic/biomarker outcome measures for this study are:

Mutation analysis in TP53, FLT3, IDH1, IDH2, and other tumor-associated genes

Serum MIC-1 profile (raw and/or adjusted from baseline as percentage of change)


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
MDM2 expression by qRT-PCR and flow cytometry as well as gene signatures by 
qRT-PCR and/or RNA sequencing
3.4.4
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:

Apparent clearance (CL/F) and apparent volume of distribution (Vd/F) as well as 
Cmax, steady-state concentration at the end of a dosing interval (i.e., just prior to next 
drug administration) [Ctrough], area under the concentration–time curve during one 
dosing interval (AUC0-, AUC0-24h, and t1/2 of idasanutlin (and M4 metabolite 
RO6802287)

Total clearance (CL) and volume of distribution (Vd) of cytarabine

Effect of idasanutlin on cytarabine pharmacokinetics

Effect of cytarabine on idasanutlin pharmacokinetics 
3.4.5
Patient-Reported Outcome Measures
The patient-reported outcome (PRO) measures for this study are:

European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30)

EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire
3.4.6
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

Pharmacodynamic biomarkers and other biomarkers (e.g., protein, nucleic acid, and 
other tumor cellderived markers related to the mechanism of action of the study 
drug, which include, but are not limited to, markers of MDM2 or p53 pathway 
alterations) that may help predict patient subpopulations that are more likely to 
respond to the therapies in this study and support a better understanding of disease 
biology or improvement of diagnostic assays.   

Evaluation of MRD (LAIP, AML-specific mutations and translocations, expression of 
AML-related genes such as WT-1)
4.
MATERIALS AND METHODS
4.1
PATIENTS
The population will include patients with first or second relapsed/refractory AML as 
defined in Section 4.1.1 and Section 4.1.2. At enrollment, patients should have a 
physical status that is considered compatible to allow for a later HSCT procedure.


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4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 18 years 

Documented/confirmed first or second refractory or relapsed AML using World 
Health Organization classification (Appendix 10), except acute promyelocytic 
leukemia.  Please note that first relapsed AML patients with a CR1 duration of 
1 year AND age 60 years are excluded (see Section 4.1.2).

No more than 2 prior induction regimens (excluding prior HSCT) in their first line 
treatment, and one must have included cytarabine with an anthracycline (or 
anthracenedione).

Eastern Cooperative Oncology Group (ECOG) performance status of 02  

Adequate hepatic function assessed by the following:  
Serum total bilirubin 1.5institutional upper limit of normal (ULN), unless 
resulting from hemolysis, Gilbert’s syndrome, or liver infiltration with leukemia
AST/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 

WBC count at randomization of 50,000/mm3
Note:  When treatment is not started immediately upon randomization, the WBC 
count at the start of induction therapy (Cycle 1) must remain at 50,000/mm3.  
The use of hydroxyurea (HU) or leukapheresis to meet eligibility is allowed.  HU 
or leukapheresis must be discontinued at least 24 hours prior to the initiation of 
study medication.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of 1% per year, during the treatment period 
and for up to 6 months after the last dose of study drug.
A woman is considered to be of childbearing potential if she has not reached a 
postmenopausal state (12 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, and established, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  Barrier 
methods must always be supplemented with the use of a spermicide.


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
For men unless permanently sterile by bilateral orchidectomy:  agreement to remain 
abstinent (refrain from heterosexual intercourse) or use contraceptive measures and 
agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for up 
to 6 months after the last dose of study drug.  Men must refrain from donating 
sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 

Ability to understand and willingness to sign a written informed consent form and 
comply with all study requirements including completion of PRO measures.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

First relapsed patients aged 60 years with a CR1 duration of 1 year 

Patients with prior documented AHD including the following:  myelodysplastic 
syndrome, myeloproliferative disease (i.e., chronic myelomonocytic leukemia, 
polycythemia vera, primary myelofibrosis, and essential thrombocythemia), and 
aplastic anemia

AML secondary to any prior chemotherapy unrelated to leukemia 

Patients who are either refractory to or have relapsed within 90 days of receiving a 
regimen containing a cumulative dose of 18 g/m2 cytarabine

Patients who have received allogeneic HSCT within 90 days prior to randomization.  
HSCT should have been performed in remission and not used for salvage (patients 
who have received autologous HSCT as consolidation in CR1 are eligible). 

Patients who have received immunosuppressive therapy for graft-versus-host 
disease or for engraftment syndrome after autologous stem cell transplantation
within 2 weeks prior to randomization

Prior treatment with an MDM2 antagonist

Patients with clinically relevant QTc prolongation (QTcF480 ms), a family history of 
long QT syndrome, or who are currently receiving treatment with medications that 
are known to prolong the QT interval (see Appendix 11; Yap and Camm 2003)
Medications that are known to prolong the QT interval must be discontinued 
7 days (or 5 half-lives, whichever is shorter) prior to initiating study 
medication until 5 days after the final administration of study medication 
(Section 4.4.2.2).

Patients receiving any other investigational or commercial agents or therapies 
administered with the intention to treat their malignancy within 30 days (or 5 half-lives) 
from first receipt of study drug


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Note:  The exception is HU or leukapheresis in patients who need to continue 
this therapy to maintain a WBC count 50,000/mm3.  HU or leukapheresis must 
be discontinued at least 24 hours prior to the initiation of study medication. 

Patients with acute toxicities from any prior anti-leukemia therapy that have not 
resolved to Grade 2 per National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.03

Patients with a history of other malignancy within 5 years prior to screening, except 
for malignancy that has been in remission without treatment for at least 2 years prior 
to randomization 

Patients unable to temporarily 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 
Table 2, Table 3, and Table 4 during the treatment phase.  These agents must be 
discontinued 714 days prior to the start of study medication. 

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) during the treatment 
phase.  These agents must be discontinued 7 days (or 5 half-lives) prior to the start 
of study medication. 
Note: Treatment with or switch to low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) is allowed, according to local practice.  However, 
platelet levels need to be closely monitored in these patients (see 
Section 4.4.2). 

Patients with a history of systemic hypersensitivity reactions Grade 2 attributed to 
cytarabine or components of the formulated product 

Patients who have 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 III, IV), myocardial 
infarction 6 months prior to first study medication, and cerebrovascular 
accidents 6 months before study medication start
Unstable seizure disorders
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by this study medication, such as hereditary coagulation disorders 
or insulin-dependent diabetes mellitus not optimally controlled with medical 
management (e.g., presence of ketoacidosis) or active GI conditions (e.g., 
Grade 2 graft-versus-host disease) and uncontrolled inflammatory bowel
disease (i.e., Crohn’s disease, ulcerative colitis, diverticulosis-associated colitis, 
and Behçet's disease).


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
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 
2 weeks of appropriate systemic antifungal therapy 
Active bacterial infection and/or bacterial infection with positive cultures in the 7 
days prior to dosing
Patients who have received 5 days of appropriate therapeutic antibiotic 
therapy for an identified infection
History of symptomatic Clostridium difficile infection that required treatment 
within 1 month prior to dosing.  Upon clinical response to C. difficile treatment, 
the stool consistency and frequency must have returned to normal. 
In all cases, the patient should be afebrile (exception of AML-related fever) and 
hemodynamically stable for at least 72 hours at the time of study medication
initiation. 

Patients with a history of active or chronic infectious hepatitis unless serology 
demonstrates clearance of infection
Patients with occult or prior hepatitis B virus (HBV) infection (defined as 
negative hepatitis B surface antigen and positive total hepatitis B core antibody) 
may be included if HBV DNA is undetectable, provided that they are willing to 
undergo monthly DNA testing.  Patients who have protective titers of hepatitis B 
surface antibody after vaccination or prior but cured hepatitis B are eligible.  
Patients positive for hepatitis C virus antibody are eligible provided PCR is 
negative for HCV RNA.

Patients who have a history of clinically significant liver cirrhosis (e.g., Child-Pugh 
class B and C). 

Patients with electrolyte abnormalities such as hypokalemia, hyperkalemia, 
hypocalcemia, hypercalcemia, hypomagnesemia, and hypermagnesemia of 
Grade 1 per NCI CTCAE v4.03.  Treatment for correction of above electrolyte 
imbalances is permitted during screening to meet eligibility.

Patients with extramedullary AML with no evidence of systemic involvement

Patients with active CNS leukemia

Pregnant or breastfeeding patients

HIV-positive patients

Patients who might refuse to receive blood products and/or have a hypersensitivity to 
blood products.


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After signed informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s unique identification number and treatment 
assignment from the interactive web response system (IWRS).  Randomization will be 
performed through the IWRS using stratified permuted block randomization.  
Randomization stratification factors are age (60 versus 60 years), cytogenetic and 
molecular risk (favorable/intermediate versus adverse, see Appendix 9 for definitions) 
at initial diagnosis, prior response to initial anti-leukemic therapy (refractory versus CR 
90 days but 1 year versus CR 1 year) and prior HSCT versus no prior HSCT.  
Randomization will be 2:1 (higher probability to be in the idasanutlin plus cytarabine arm).
This is a double-blind trial, that is, neither the patient nor the treating physician will know 
the assigned treatment arm.  The randomization code may however be made available 
to the Bioanalytical manager to facilitate the analysis of PK samples.
An iDMC will be established to monitor patient safety and efficacy and will assess the 
outcome of the interim analyses.  All analyses for the iDMC’s reviews will be prepared by
an independent Data Coordinating Center (IDCC).  Sponsor personnel will not have 
access to by-arm efficacy and safety summaries prior to the formal reporting of study 
results.  iDMC membership and procedures to be followed for the study will be detailed 
in an iDMC charter.
In general, treatment codes should not be broken, except in emergency situations.  If 
unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IWRS.  If the investigator wishes to know the identity of the study drug for any other 
reason, he or she should contact the Medical Monitor directly.  The investigator should 
document and provide an explanation for any premature unblinding (e.g., accidental 
unblinding, unblinding due to a serious adverse event).  Unblinding should not result in 
the withdrawal of a patient from the study.  Every effort should be made to retain 
unblinded patients in the study.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Idasanutlin and Placebo
Idasanutlin and matching placebo will be supplied by the Sponsor.  Idasanutlin will be 
supplied as 300 mg tablets.  For information on the formulation, packaging, and handling 
of idasanutlin see the idasanutlin IB.


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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.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Idasanutlin and Placebo
Idasanutlin/placebo will be administered at 300 mg BID PO for 5 days, without regard to 
meals.  Water can be given ad libitum.  During induction the first (morning) dose of 
idasanutlin/placebo should be administered immediately before cytarabine infusion starts 
and the second (evening) dose should be administered 1014 hours after the first dose.  
In case the patient proceeds to consolidation therapy, only 50% of idasanutlin should be 
given (300 mg QD in the morning) for 5 days.
Guidelines for dosage modification for efficacy are provided in Section 4.3.2.4.  
Guidelines for dosage modification and treatment interruption or discontinuation for 
safety reasons are provided in Section 5.1.2.5.
4.3.2.2
Cytarabine
Cytarabine will be administered at a dose of 1 g/m2 QD for 5 days as a 13 hour IV 
infusion (local practice applicable within this guideline). 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 8.  Guidelines for dosage modification for efficacy are provided in 
Section 4.3.2.4.  Guidelines for dosage modification and treatment interruption or 
discontinuation for safety reasons are provided in Section 5.1.2.5.
4.3.2.3
Guidelines for Induction Therapy (Cycle 1)
Induction therapy must begin 3 days after randomization.  For patients who need to 
continue HU or leukapheresis during the screening period to maintain a WBC count 
50,000/mm3, HU or leukapheresis must be discontinued at least 24 hours prior to the 
initiation of study medication. 
Patients will be treated for an initial 28-day induction cycle (5 days PO idasanutlin or 
placebo [Days 15] plus IV cytarabine for 5 days [Days 15] followed by 23 days off 
treatment [Days 628]).  In patients achieving CRp or CRi up to 28 additional days (up to 
Day 56) following treatment are allowed for blood count recovery, if needed.  Patients 
must receive antibiotic, anti-diarrheal, and anti-emetic prophylaxis during the treatment 
and recovery periods (see Appendix 14).  Patients should receive appropriate anti-TLS 
prophylaxis during the treatment and recovery periods according to patient’s TLS risk 
factors and investigator’s clinical judgement (see Appendix 14).
Induction therapy in this study is limited to a single cycle, as there are very limited data 
indicating any benefit of an additional induction cycle based on Phase I studies.  For 


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patients achieving a good partial remission (PR) however, a second cycle of induction 
therapy at the same dose level as Cycle 1 may be allowed on a case-by-case basis after 
discussion and agreement with the Sponsor. 
4.3.2.4
Guidelines for Consolidation Therapy (Cycles 2 and 3)
Responding patients (CR/CRp or CRi with neutrophil recovery [0.5109/L]) who do not 
proceed to transplant, directly or at all, are recommended to continue with consolidation 
therapy with cytarabine and idasanutlin or placebo for a maximum of two additional 
cycles if not medically contraindicated.  Mandatory prophylaxis must be adhered to in the 
same manner as in Cycle 1.
Continuation of study medication into consolidation therapy is determined based on the 
presence of clinical response at the end of Cycle 1 (see Appendix 4).  Once 
CR/CRp/CRi with neutrophil recovery (0.5109/L) is observed, consolidation therapy 
should begin within 7 days from the day that clinical response is observed.  If Cycle 2 is 
started 7 days after clinical response is observed (e.g., due to prolonged toxicity), 
weekly blood counts must be performed to confirm that the patient remains in clinical 
remission.  If relapse is suspected, a bone marrow aspirate must be taken and an HMRA 
performed as an unscheduled assessment.  These same rules apply when patients 
move from Cycles 2 to 3. 
It was observed in Study NP28679 that patients who continued on full doses of 
treatment following achievement of CR frequently required additional time for blood 
count recovery. Therefore, the daily dose of idasanutlin/placebo (300 mg BID in Cycle 1) 
will be reduced to 50% (300 mg QD for subsequent cycles) for consolidation because a 
50% dose reduction was tolerated for multiple cycles in leukemia patients with a 
minimum of dosing delays. 

Patients with CR at the Day 28 HMRA may proceed immediately to consolidation
therapy with 50% idasanutlin (300 mg QD in the morning) and 100% cytarabine
(1 g/m2).

For patients with CRp/CRi at the Day 28 weekly blood counts should be obtained 
between the Day 29 and Day 42.  As soon as blood counts recovered and CR/CRp 
is observed (but latest at Day 42), patients may start Cycle 2 with 50% idasanutlin 
(300 mg QD in the morning) and 100% cytarabine (1 g/m2). 

For patients remaining in CRi until Day 42 weekly blood counts should be obtained 
up to Day 56.  As soon as blood counts recovered and CR, CRp or CRi with ANC 
≥0.5109/L is observed (but latest at Day 56), patients may start Cycle 2 with 50% 
idasanutlin (300 mg QD in the morning) and 50% cytarabine (0.5 g/m2).  Once the 
cytarabine dose is reduced, the dose reduction should be maintained for the 
remainder of the cycles. 
For more detailed instructions on continuation of study medication based on response 
criteria see Appendix 4.  For guidelines on mandatory and recommended prophylaxis 
regimens, consult Appendix 14.


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4.3.3
Prophylactic Medication
The use of oral or IV prophylactic anti-emetics, anti-diarrheals, and antimicrobials is 
mandatory in all patients (see Appendix 14).  As outlined in regulatory guidelines, 
mandatory prophylaxis is considered a non-investigational medicinal product (NIMP).  
Administration of an NIMP must be recorded on the Concomitant Medication electronic 
Case Report Form (eCRF).  Side effects associated with an overdose or incorrect 
administration of an NIMP must be recorded as an adverse event in the eCRF.  The 
potential causality to NIMPs must be assessed by the investigator for any adverse event.  
Please refer to Table 1 for a complete list of NIMPs.
Table 1
Non-Investigational Medicinal Products
NIMP
5-HT3-receptor antagonists (e.g., palonosetrona and granisetron)
Dexamethasone
Levofloxacin
Loperamide
Posaconazole
NIMPnon-investigational medicinal product.
a Palonosetron is the recommended option due to its efficacy against delayed nausea and lack 
of QT interval prolonging effects.  
4.3.4
Investigational Medicinal Product Accountability
Idasanutlin and matching placebo as well as cytarabine are considered investigational 
medicinal products (IMPs) in this trial.  Idasanutlin and matching placebo required for 
completion of this study will be provided by the Sponsor.  Cytarabine and NIMPs will be 
provided from local sources.
The study site will acknowledge receipt of idasanutlin and placebo, using the IWRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator is responsible for the control of drugs under investigation. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  Local or institutional regulations may require immediate destruction of 
used IMP for safety reasons.  In these cases, it may be acceptable for investigational 
study site staff to destroy dispensed investigational product before a monitoring 
inspection, provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned, and destroyed, and provided that adequate storage and integrity of drug has 
been confirmed.  The site’s method of IMP destruction must be agreed to by the 


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Sponsor in advance.  The site must obtain written authorization from the Sponsor before 
any IMP is destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
Accountability and patient compliance with IMPs will be assessed by adequately tracking 
“drug dispensing” and returned bottles at each site.
These records must contain the following information:

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposing of all unused study drug not dispensed to patients
A Drug Dispensing Log must be kept current and should contain the following 
information:

The identification number of the patient to whom the study medication was 
dispensed

The date and quantity of the study drug dispensed to the patient

The date and quantity of the study drug returned by the patient
All records and drug supplies must be available for inspection by the Roche Clinical Trial 
Monitor at every visit.
4.3.5
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 website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted 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., red blood cells [RBCs] and platelets) used by a patient from 28 days prior to 
screening up to the study drug completion/discontinuation visit.  All such therapy 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 


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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). 
The use of antimicrobials, anti-emetics, and anti-diarrhea prophylaxis for patients taking 
idasanutlin/placebo in combination with cytarabine is mandatory (see Section 4.3.3 and 
Appendix 14 for guidance).  Their use must be documented in the eCRF.
The use of TLS prophylaxis and/or treatment is recommended according to the 
guidelines in Appendix 14.  Growth factors may be used according to local guidelines 
and/or usual practice at the study site.  Their use must be documented in the eCRF.
Treatment with or switch to LMWH or UFH is allowed, according to local practice.  
Importantly, platelet levels need to be closely monitored in these patients (see 
Section 4.4.2.3).
4.4.2
Prohibited Therapy
4.4.2.1
Drugs Prohibited Due to Potential Drug-Drug Interaction
Oral or parenteral use of the following drugs will be prohibited during the treatment 
phase in order to prevent undesirable DDIs (see Section 1.2.2.3).

Strong/moderate inducers or inhibitors of CYP2C8, including gemfibrozil, which is 
also an inhibitor of UGT1A3 (Table 2)

CYP2C8 (Table 2) or OATP1B1/3 (Table 4)  substrates

Strong inducers of CYP3A4 (Table 3)  
Substrates and inhibitors listed in Table 2 and Table 4 must be discontinued 7 days prior 
to start of study treatment.  
Inducers listed in Table 2 and Table 3 must be discontinued 14 days prior to start of 
study treatment. 
Drugs listed in Table 2, Table 3, and Table 4 may be re-initiated per protocol after the 
study drug completion/discontinuation visit.  


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Table 2
List of Prohibited CYP2C8 Substrates, Inhibitors, and Inducer
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 3
List of Prohibited CYP3A4 Inducers
Inducers (Strong)
Carbamazepine
Cyproterone
Efavirenz
Etravirine
Modafinil
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Rifampicin
St. John’s wort


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Table 4
List of Prohibited OATP1B1/3 Substrates
OATP1B1/3 Substrates
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.
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the internet references provided below when determining whether a certain 
medication 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/Gu
idances/UCM292362.pdf

http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.4.2.2
Drugs Known to Prolong the QT Interval
Medications that are known to prolong the QT interval (see Appendix 11) must be 
discontinued 7 days (or 5 half-lives, whichever is shorter) prior to initiating study 
medication until 5 days after the final administration of study medication.
Patients will require azole drugs for prophylactic or treatment purposes (see 
Appendix 14).  Oral fluconazole and ketoconazole are known to prolong the QT interval 
(see  Appendix 11); therefore, other members of the azole class (i.e., posaconazole, 
itraconazole, and voriconazole) should be used in lieu of oral fluconazole and 


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ketoconazole as indicated for the specific disease and/or fungal pathogen (see 
Appendix 14 for antifungal prophylaxis guidance).
4.4.2.3
Oral or Parenteral Anticoagulant/Anti-Platelet Agents
MDM2 antagonists were shown in vitro to affect all types of hematopoietic progenitors, 
including megakaryocytic differentiation.  They inhibit both early and late stages of 
megakaryopoiesis, including ploidization and proplatelet formation (Mahfoudhi et al. 
2016).  As a consequence, the effect on early progenitors might induce long-lasting 
thrombocytopenia in vivo.  Clinical data on thrombocytopenia severity and duration in 
AML are limited.  In Study NP28679, the time to platelet recovery was highly variable, 
with a mean time to recovery for platelet counts (Kaplan-Meier estimates) of 34 days in 
patients who responded to idasanutlin and cytarabine combination therapy.
Therefore, due to the potential severity and duration of thrombocytopenia induced by 
study treatment, patients in clinical need for chronic treatment with oral or parenteral 
anticoagulant/anti-platelet agents (e.g., warfarin, chronic daily treatment with aspirin 
[325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban) are excluded from this 
study.  In patients considered eligible for the study because they are able to tolerate 
anticoagulant/anti-platelet treatment interruption, these agents must be discontinued 
7 days (or 5 half-lives, whichever is shorter) prior to initiating study medication.  After the 
study drug completion/discontinuation visit, treatment with anticoagulant/anti-platelet 
agents may be re-initiated for patients with transfusion-independent adequate platelet 
levels as clinically indicated.
Thrombocytopenic patients are not devoid of risk for thrombosis.  Although patients with 
low platelet counts are at decreased risk for venous thrombosis compared to patients 
with normal platelet counts, thrombosis may still occur.  Hence, in patients remaining 
transfusion-dependent or patients with an adverse event requiring anti-thrombotic 
therapy during the study treatment period, the clinical benefit of using anticoagulation 
therapy (acute risk of thromboembolism/stroke) should be carefully weighed against its 
risks (acute risk of hemorrhage/uncontrolled bleeding) and only initiated if 
anticoagulant/anti-platelet use is acutely required and use cannot be postponed until 
after the study drug completion/discontinuation visit. Close monitoring of platelet levels 
is recommended. Frequent measurement of peak anti-Xa levels and tight maintenance 
between 0.5 and 1.0 IU/ml are advised and may improve the risk/benefit ratio (Rickels et 
al. 2007).  The maintenance of anti-thrombotic treatment should be continuously 
reassessed.  Sustained use over time must be clinically warranted.  Treatment of central 
venous catheterrelated venous thromboembolisms may not always require 
anticoagulants, since many of these thrombi resolve spontaneously in patients with 
acute leukemia following removal of the catheter. Anti-thrombotic treatment should be 
reserved for those patients with established conditions, such as venous 
thromboembolism.  LMWH preparations or UFH with doses adjusted to platelet levels 
are allowed and would be the preferred therapeutic intervention.  LMWH and UFH are 


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recommended for patients who do not have contraindications to anticoagulant use (see 
Khorana et al. 2007).  
4.4.3
Prohibited Food 
None.
4.5
STUDY ASSESSMENTS 
The schedule of assessments performed during the study is detailed in Appendix 1, 
Appendix 2, and Appendix 3.
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 randomization.  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.
Screening and pretreatment assessments will be performed within 14 days prior to 
Cycle 1/Day 1 unless otherwise specified.  Test results or examinations (except for the
bone marrow aspirate) performed as standard of care prior to obtaining informed 
consent and within the protocol-defined screening 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 biomarker analysis.  Cytogenetic and molecular risk according to 
ELN standardized reporting system (see Appendix 9) must be available from initial 
diagnosis prior to randomization of the patient to allow stratification by risk category.  At 
a minimum cytogenetic information allowing stratification into the risk categories 
favorable/intermediate versus adverse needs to be available.  Additional information on 
molecular markers is desirable and should be entered into the eCRF. 
Those patients who fail the screening due to organizational reasons moving them out of 
the screening window (e.g., long waiting times for results, wash-out period, technical 
reasons) will be allowed to be re-screened once. Additionally, those patients who fail the 
screening for previously identified infection, for ECOG greater than 2, for acute toxicities 
from any prior anti-leukemia therapy, for previous electrolyte abnormalities, or patients 
pregnant or breastfeeding will also be allowed to be re-screened once upon resolution of 
the excluding criterion.  Results of screening tests within the protocol-defined screening 
window (prior to randomization/Cycle 1, Day 1) may be used rather than repeating 
required tests.


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Written informed consent must be obtained again before performing any rescreening 
tests or evaluations.  
4.5.2
Assessments during Treatment and Follow-Up
All assessments must be performed as outlined in Appendix 1, Appendix 2, Appendix 3  
Assessments scheduled on the day of study medication administration should be 
performed prior to administration of study medication, unless otherwise noted in the 
schedule of assessments.  All other assessments, including hematology and 
biochemistry assessments scheduled on non-study medication dosing days, should be 
performed on the day of the specified visit within a window of 2 days.  Please see
Appendix 4 for a detailed description of bone marrow sampling for HMRAs and 
biomarker assessments, and the underlying algorithm governing continuation of study 
medication into consolidation therapy. 
Treatment Phase (Cycle 1 [Induction] and Cycles 2 and 3 [Consolidation])
Assessments should be collected on the day and time period required as per the 
schedule of assessments (Appendix 1).  
If the specified screening assessments found in Appendix 1 are performed up to 
72 hours prior to Cycle 1, Day 1, these assessments do not have to be repeated on 
Cycle 1, Day 1 except for hematology and biochemistry, which must be performed 1 day 
prior to Cycle 1, Day 1.  Note:  Hematology assessments should be obtained and 
checked PRIOR to randomization.  
At the end of each cycle, the response to treatment will be determined.  Patients in 
CRp/CRi by Day 28 will be allowed a maximum of an additional 28 days (until Day 56) 
for blood counts to recover before proceeding with consolidation therapy.  The end of 
cycle is hence defined as either Day 28 or the day of the best peripheral blood count 
recovery, up until Day 56.  
Please see Appendix 1 and Appendix 4  for detailed instructions on bone marrow 
collection and HMRA assessment during the treatment phase. 
Note that the futility interim analysis will include a comparison of the proportion of 
confirmed CR/CRp between study arms (see Section 3.4.1).  For patients proceeding to 
Cycle 2, the best response at the end of Cycle 2 will be used as the confirmed response.  
For patients not proceeding to Cycle 2, the response observed at the end of Cycle 1 
must be confirmed 30 days (3 days) later. 
Sampling timepoints for bone marrow aspirate and/or blood for HMRA are outlined in 
Appendix 1.


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Study Drug Completion/Discontinuation Visit
Once a patient completes study treatment or discontinues study drug for any reason, the 
Study Drug Completion/Discontinuation eCRF page must be completed.  To allow for 
this, patients will be asked to return to the clinic 28 days (+28 day window) after the last 
dose of study medication is administered. 
In the event that the decision to withdraw from further therapy on the study occurs after 
28 days from the last dose of idasanutlin/placebo (e.g., due to an interruption of an 
intended cycle continuation due to an adverse event), then the study drug 
discontinuation visit should occur on the date of withdrawal.  
For a patient in remission after induction who is not continuing on to consolidation after 
the allowed recovery period for blood counts (up until Day 56), the study drug 
completion/discontinuation visit and the confirmatory response assessment visit may 
occur during the same time window.  Please consult Appendix 1 for guidance on data 
entry into the eCRF in this scenario.
Follow-Up
Patients in CR/CRp/CRi after terminating study treatment will be followed for EFS, DOR,
and LFS.  HMRAs will be performed monthly (5 days) until disease progression/relapse 
is noted or until the patient moves to HSCT.  Every 3 months HMRAs will include 
assessment of bone marrow aspirate; in all other instances, HMRA will be based on 
peripheral blood counts only. 
In the event of relapse, a HMRA based on a bone marrow aspirate is required.  In 
addition, whole blood in EDTA for biomarker analysis should be obtained.
For patients who move to HSCT, an HMRA based on a bone marrow aspirate should be 
performed to document the bone marrow status prior to the start of conditioning therapy.  
The quantity of the bone marrow aspirate should also allow for exploratory biomarker 
analyses (MRD/Flow, EDTA, and Paxgene), and the hematopoietic cell transplantation-
specific comorbidity index (HCT-CI) score (Sorror et al. 2005; Sorror 2013) should be 
obtained to document the patient’s health status prior to the start of conditioning therapy. 
All patients will be followed every 3 months for study treatment-related serious adverse 
events, fatal adverse events, subsequent anti-cancer therapies, and survival status.  
Survival follow-up ends with death or end of study.  Adverse events should be followed 
as outlined in Section 5.3.1 and Section 5.6.  Please see Appendix 1 for the schedule of 
follow-up assessments.


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4.5.3
Hematopoietic Stem Cell Transplant 
For patients who proceed to undergo HSCT after completion/discontinuation of study 
medication, data regarding the health status (HCT-CI score [Appendix 15]), leukemia 
status (HMRA) within 28 days prior to start of conditioning, date of transplant, type of 
transplant (allogeneic versus autologous, peripheral blood versus bone marrow versus 
cord blood, matched sibling versus matched unrelated donor, or mismatched donor or 
haploidentical donor), and conditioning (myeloablative versus reduced) will be collected.  
Information on engraftment status and survival will be requested every 3 months. Note:  
Donor lymphocyte infusion is allowed under this protocol and should be recorded in the 
eCRF as an anti-cancer therapy. 
4.5.4
Medical History and Demographic Data
Medical history includes clinically significant diseases within the last 5 years, surgeries, 
AML cancer history (including prior cancer therapies and procedures, cytogenetics, and 
leukemia markers) and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
28 days prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.5
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
GI, genitourinary, and neurological systems.  Any abnormality identified at baseline
should be recorded on the General Medical History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  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.
4.5.6
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 12.
4.5.7
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. 


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4.5.8
Hematologic Malignancy Response Assessment
The following criteria should be used to determine hematologic malignancy response 
(Cheson et al. 2003; Döhner et al 2017; NCCN guidelines): 

CR:  Bone marrow blasts < 5%, absence of blasts with Auer rods; absence of 
extramedullary disease; ANC ≥1.0109/L; platelets ≥100.0109/L

CRi:  All CR criteria except for residual neutropenia (ANC <1.0109/L) or 
thrombocytopenia (platelets <100.0109/L) 

CRp:  All CR criteria except for thrombocytopenia (platelets <100.0109/L)

Treatment failure: 
Resistant disease: 
Failure to achieve CR, CRi, or CRp; only includes patients surviving 7 days 
following completion of initial treatment, with evidence of persistent leukemia by 
blood and/or bone marrow examination. 
PR and SD/hematologic improvement (HI) will be considered treatment failure. 
PR 50% decrease in bone marrow blasts
SD/HIdecreased peripheral blast percentage, decreased frequency of 
transfusions, improvement in peripheral cell counts
Death in aplasia:  
Deaths occurring 7 days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days 
of death, without evidence of persistent leukemia
Deaths from indeterminate cause:  
Deaths occurring before completion of therapy, or 7 days following its 
completion; or deaths occurring 7 days following completion of initial therapy 
with no blasts in the blood, but no bone marrow examination available

Relapse of Disease: 5% bone marrow blasts; or reappearance of blasts in the 
blood, or development of extramedullary disease.  
HMRAs require sampling of blood and bone marrow as indicated.  Bone marrow 
aspirates are required, but if bone marrow biopsies are performed, the biopsy results 
should be provided.  Depending on timepoint in the schedule of assessments the HMRA 
is established based on 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 


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time to complete HMRA.  If a patient progresses/relapses outside of the scheduled visit, 
an unscheduled HMRA must be provided.
If a bone marrow aspirate is performed at any unscheduled timepoint while on 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 exploratory analyses (MRD by flow 
cytometry, EDTA, Paxgene) and amount taken should be taken into consideration 
(Section 4.5.10.6).  
Throughout the Study
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, weekly 
blood counts must be performed for HMRA to document evidence of non-progression.  
Treatment failure and relapse will lead to discontinuation of the study medication (See 
Appendix 1, Appendix 3, and Appendix 4 for further details).  
Bone marrow and blood will be required for HMRA after Cycle 1 for all patients. 
Depending on blood count recovery, this will be between Day 28 and Day 56 latest.  
Patients with CR or CRp by Day 42 may proceed with Cycle 2 (50% idasanutlin [300 mg 
QD in the morning], 100% cytarabine [1 g/m2]).  Patients remaining in CRi up to Day 42
will need to undergo another HMRA to determine response status.  Based on this, 
patients with CR, CRp, or CRi with ANC 0.5109/L may continue with Cycle 2 
(50% idasanutlin [300 mg QD in the morning], 50% cytarabine [0.5 g/m2]).  Once the 
cytarabine dose is reduced, the dose reduction should be maintained for the remaining 
cycles.  With respect to continuation with Cycle 3 different criteria apply before and after 
the futility interim analysis (please see below).  Refer to the schedule of assessments 
(Appendix 1) and the treatment algorithm (Appendix 4) for further details.  
During the follow-up of patients who remain in CR, CRp, or CRi after treatment, blood 
will be required every month and a bone marrow aspirate will be required every 
3 months to allow for HMRA until relapse or HSCT.  Refer to Appendix 1 and Appendix 3
for further details.
Before Futility Interim Analysis
The futility interim analysis will include a comparison of the proportion of confirmed CR 
or CRp between study arms.  If a patient proceeds to Cycle 2, then the HMRA at the end 
of Cycle 2 (on Days 2856 of Cycle 2) will be used as confirmation of response.  If a 
patient does not receive a second cycle of therapy then the response from Cycle 1 
should be confirmed 30 days (3 days) later.  In both cases confirmation of response 
requires bone marrow aspirate. 


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The decision criteria to continue with Cycle 3 are the same as applied in Cycle 1 for 
Cycle 2.  Refer to the schedule of assessments (Appendix 1) and the treatment 
algorithm (Appendix 4) for further details.
After Futility Interim Analysis
After the futility interim analysis bone marrow aspirate for confirmation of response is 
no longer required.  However, HMRA including bone marrow assessment needs to be 
available for the last cycle received, that is, if a patient stops study medication after 
Cycle 2, then a HMRA including bone marrow aspirate is required; if a patient continues 
with Cycle 3 HMRA based on blood counts only is sufficient and HMRA based on bone 
marrow will be performed at the end of Cycle 3. 
The decision to continue with Cycle 3 will no longer be based on bone marrow data, but 
on blood counts only.  Refer to the schedule of assessments (Appendix 1) and the 
treatment algorithm (Appendix 4) for further details.
4.5.9
Laboratory Assessments
Normal ranges for the study laboratory parameters must be submitted to Roche 
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 (glucose, urea or BUN, serum creatinine, creatinine clearance [at 
screening only determined by Cockcroft-Gault Formula], AST, ALT, LDH, alkaline 
phosphatase, 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.

Serum pregnancy test in females of child bearing potential and postmenopausal 
females with less than 1 year of amenorrhea.

Bone marrow aspirate (total cells counted, absolute mature neutrophils, mature 
eosinophils, mature basophils, monocytes, lymphocytes, blasts, promyelocytes, 
myelocytes, metamyelocytes, plasma cells, pronormoblasts, normoblasts, nucleated 
erythrocytes)

Bone marrow biopsy (leukemia histology, cellularity, percent cellularity, percent 
blasts)


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4.5.10
Mandatory Samples for Pharmacokinetic, Pharmacodynamics, 
and Exploratory Biomarkers
All samples listed below will be collected according to the Schedule of Assessments 
outlined in Appendix 1, Appendix 2, and Appendix 3.  Unscheduled PK samples 
matched to ECG recordings may be required in case any prolongation of the QTc 
interval or other adverse cardiac findings are identified (see Section 4.5.11 for details). 
For PK analysis, it is of utmost importance to record dosing and blood sampling times 
accurately. 
Allowed sampling time windows are as follows:

Predose (before idasanutlin/placebo morning dose):  Within 2 hours prior to dosing of 
cytarabine

End of cytarabine infusion:  within 5 minutes after the ECG at end of cytarabine 
infusion

6 hours post idasanutlin/placebo morning dose:  0.5 hours
For sampling procedures, storage conditions, and shipment instructions see the 
Laboratory Manual(s).
4.5.10.1
Pharmacokinetic
PK blood samples will be collected in all patients in Cycle 1 on Days 1, 2, 5, and 8 for
idasanutlin/placebo and in Cycle 1 on Days 1, 2, and 5 for cytarabine to measure the 
amount of study drug and relevant metabolites in the blood.  An additional PK blood 
sample for idasanutlin/placebo will be collected on Cycle 1 on Day 10 until approximately 
80 samples are received for this timepoint (Appendix 2).  
Patients that receive more than Cycle 1 of treatment will have additional blood sampling 
for PK analyses (Cycles 2 and 3 on Days 2 and 5 for idasanutlin/placebo, Cycles 2 and 3 
on Day 2 for cytarabine).  Note:  The PK blood sample for idasanutlin/placebo on Day 5 
will only be collected until the futility interim analysis.  
The placebo-treated samples will also be collected (due to blinding) but will not be 
analyzed.  A safe-guard procedure will be in place to maintain integrity of blinding.
All PK samples will be collected from the arm (limb) which is not being used during the 
administration of cytarabine (i.e., from the alternate arm).  If cytarabine is 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. 


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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.
4.5.10.2
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.  Analyses include, but are not limited to:

Quantification of MIC-1 by ELISA-based assay

Determination of the TP53 mutation status and transcriptome and/or genome 
sequencing of cancer-related genes including TP53  

Measurement of transcript gene expression signatures that may predict response to 
MDM2 antagonists

MRD will be monitored on the basis of aberrant immunophenotypes (flow),
AML-specific mutations/translocations (NGS/PCR), or aberrant gene expression of 
WT-1 (qRT-PCR).

WT-1 mRNA expression will be analyzed by qRT-PCR, and 
mutations/translocations will be analyzed as AML-specific clonal markers by 
PCR/sequencing.

MDM2 protein expression level in AML blasts will be analyzed by flow cytometry.

A 4-gene signature (including MDM2 gene expression) will be analyzed by 
qRT-PCR.  The predictive or prognostic value of these markers will be analyzed at 
futility interim analysis (gene signature) and at the time of OS primary analysis.  
For protein expression and 4gene signature evaluations at futility interim analysis, 
see Section 6.11.3. 
Mutations in TP53 have been reported in approximately 15% of patients with AML, 
including single nucleotide variants, truncations, and frameshifts, with mutations 
found throughout the gene (Haferlach et al. 2008).  Therefore, mutation analysis for 
TP53 requires sequencing the entire coding sequence of TP53 by a next generation 
sequencing (NGS) method.
The TP53 mutation status determination in Study WO29519 was initially performed 
using a laboratory-developed test (LDT).  In September 2018, the Sponsor decided to 
switch to the investigational use only F1CDx assay from Foundation Medicine, Inc. 
(FMI) in a central Clinical Laboratory Improvement Amendment (CLIA) certified 
laboratory to include the assessment of other mutations with clinical relevance in AML, 
including FLT3, IDH1, and IDH2.  Technical information on the assay is available on 
the FMI website:
https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx


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F1CDx is a comprehensive NGS assay that can detect genomic alterations in 324 genes.  
These include IDH1, IDH2, and FLT3 that have been shown to be prognostically 
relevant and clinically actionable for patients with AML.  The assay has comparable 
sensitivity to the LDT for TP53 status determination (5% mutant allele frequency).
F1CDx has gone through analytical and clinical validation to become FDA approved as 
a CDx assay for multiple therapies for solid tumors using formalin-fixed 
paraffin-embedded tissues as input.  Bone marrow specimen and blood have been shown 
in pilot studies to be equally usable as input material for DNA extraction and 
sequencing analysis.  Additional analytical validation is being performed to fully 
qualify bone marrow aspirate and peripheral blood samples for use with this assay.  
Retrospective testing of all available specimens previously analyzed with the LDT is 
also conducted.
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.  Samples could be used for validation of assays.  
Additional markers may be measured in case a strong scientific rationale for these 
analyses develops.  Based on continuous analysis of biomarker data (blinded to the 
treatment arm) any analysis, timepoint, or sample type not considered to be critical for 
safety may be stopped at any time if the data does not support a strong scientific 
justification to continue.  Some samples that are collected may not be analyzed.  Some 
analysis may not occur in placebo patients (e.g., clinical genotyping).  Furthermore, 
some analysis may depend on patient’s molecular status or response to treatment. 
Unless specified, samples will be destroyed within 7 years after the clinical study report 
(CSR) is finalized.
4.5.10.3
Whole Blood
Whole blood will be collected to evaluate candidate biomarkers related to MDM2 and/or 
p53 pathways as well as other biomarkers related to treatment response, dose response 
or re-treatment. 

EDTA whole blood:  analysis to include, but not be limited to, sequencing of TP53
and genes in MDM2 and p53 pathways and disease-related markers such as gene 
mutations and rearrangements

Paxgene whole blood RNA:  analysis to include, but not limited to, sequencing of 
gene fusions that are frequent in AML, gene expression analysis for predictive gene 
signature and MRD monitoring by measuring WT-1 transcript levels.

Whole blood for Flow Cytometry:  analysis to include protein expression of MDM2 
in peripheral blood in AML blast cells 


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4.5.10.4
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
4.5.10.5
Serum Biomarker (Prior to Futility Interim Analysis Only)
Blood samples for analysis of Serum MIC-1 will be collected up until only the futility 
interim analysis.  These samples may also be evaluated for the presence of candidate 
biomarkers of the proposed mechanism of action of idasanutlin.  Exploratory 
assessments may include, but are not limited to, markers of cell death and apoptosis,
circulating microRNA, as well as exploratory studies of circulating tumor specific DNA.  
4.5.10.6
Bone Marrow 
Bone marrow samples will be collected to evaluate candidate biomarkers related to 
MDM2 and/or p53 pathways as well as other biomarkers related to treatment response, 
dose response or re-treatment.  Evaluations may include proteomic tests, gene 
expression analyses, and nucleic acid sequencing of mechanism or disease-related 
markers. 
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, Appendix 2, Appendix 4,
and Section 4.5.8).  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:  analysis will include determination of 
abnormal cell phenotypes by flow cytometry. 
After screening, the bone marrow for MRD flow cytometry is the priority sample.

EDTA bone marrow:  analysis to include, but not be limited to, sequencing of TP53
and genes in MDM2 and p53 pathways, and analysis of gene mutations, 
rearrangements, and fusions commonly seen in AML patients (potentially to be used 
for MRD monitoring).  
Sample for DNA is the priority bone marrow sample at screening. 

Paxgene bone marrow: analysis to include, but not be limited to, gene expression 
analysis for predictive gene signature. MRD monitoring by measuring WT-1
transcript levels will be assessed prior to futility interim analysis. 
Bone marrow RNA is the last bone marrow sample at all timepoints.


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For patients who proceed to transplant, pretransplant bone marrow samples for MRD 
and biomarkers should be obtained, when possible.  
If sites do their own MRD assessments locally or collect mutational data, please provide 
this information in the eCRF. 
In case a patient consents to optional exploratory research the remainder of the 
bone marrow sample(s) will be stored in the Roche Clinical Repository (RCR), 
(see Section 4.5.13.1) for up to 15 years after the date of final closure of the clinical 
database.
4.5.11
Electrocardiograms
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the 
Schedule of Assessments (Appendix 1 and Appendix 2).  Additional ECG recordings 
may be performed at unscheduled timepoints as clinically indicated.  Please note that 
the time points of ECG recordings are matched to PK sampling time points and should 
be performed sequentially as indicated in Section 4.5.10.
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).  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 the patient’s 
permanent study file at the site.  The following should be recorded in the appropriate 
eCRF:  ECG abnormality (including waveform), heart rate; PQ, PR, RR, QRS intervals; 
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 postdose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, co-medications known to prolong 
the QT interval, severe bradycardia) and provide this information to the eCRF.  In case a 
patient presents with an episode of grade 2 supraventricular arrhythmia (atrial 
fibrillation, atrial flutter, sinus tachycardia, etc.), an unscheduled ECG should be 
recorded.  Standard-of-care treatment may be instituted per the discretion of the 


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investigator.  If a PK sample is not scheduled for that timepoint, an unscheduled PK 
sample should be obtained.  
If at a particular postdose timepoint in Cycle 1 the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, then ECG assessments at time points as in Cycle 1 are 
to be repeated in all following cycles.
Allowed ECG sampling assessment windows are as follows:

Predose assessment:  within 2 hours prior to idasanutlin morning dosing

Assessments end of cytarabine infusion:  up to 10 minutes after infusion

Assessments 6 hours after idasanutlin morning dosing:18 minutes

Assessments 24 hours (equivalent to Day 2 predose idasanutlin):  2 hours 
4.5.12
Patient-Reported Outcomes
PRO data will be collected via electronic questionnaires to more fully characterize the 
clinical profile of idasanutlin.  The questionnaires will be translated as required in the 
local language.  To ensure instrument validity and that data standards meet health 
authority requirements, questionnaires scheduled for administration during a clinic visit 
should be completed prior to the performance of non-PRO assessments and the 
administration of study medication.
The EORTC QLQ-C30 is a validated and reliable self-reporting measure 
(Fayers et al. 2001) consisting of 30 questions incorporated into five functional scales 
(physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, 
nausea, and vomiting), and a global health status/global quality-of-life scale.  The 
remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and 
diarrhea) assess the additional symptoms experienced by patients with cancer and the 
perceived financial burden of treatment.  The EORTC QLQ-C30 questionnaire takes 
5 minutes to complete.  The EORTC QLQ-C30 will be conducted using electronic
patient-reported outcome (ePRO) prior to treatment across all cycles on Days 1, 8, 15,
and 28, and between Days 2956, if applicable.  Additionally, the EORTC QLQ-C30 will 
be collected during study drug completion/discontinuation visit and every 3 months until 
relapse during long-term follow-up of patients in clinical remission.  An additional 
EORTC QLQ-C30 questionnaire must also be completed after progressive disease (PD).
The EQ-5D-5L is a self-report health status questionnaire that consists of six questions 
used to calculate a health utility score for use in health economic analysis (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 visual 
analogue scale that measures overall health state.  Published weighting systems allow 
for creation of a single summary score.  Overall scores range from 0 to 1, with low 
scores representing a higher level of dysfunction.  The EQ-5D-5L questionnaire takes 


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5 minutes or less to complete, and assessments are made at the same time as the 
EORTC QLQ-C30.  An additional EQ-5D-5L questionnaire is also required to be 
completed after PD.
Patients will use an ePRO device to capture PRO data for the above two 5-minute 
surveys.  The ePRO device and/or instructions for completing the PRO questionnaires 
electronically will be provided by the investigator staff.  The data will be transmitted via 
transmission method (wireless daily) automatically to a centralized database at the 
ePRO vendor.  The data can be accessed by appropriate study personnel securely via 
the Internet.
4.5.13
Samples for Roche Clinical Repository
4.5.13.1
Overview of the Roche Clinical Repository
The RCR 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 and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.13.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.13) will not be 
applicable at that site.


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4.5.13.3
Sample Collection
If RCR consent is provided, any mandatory bone marrow material (cells, RNA, and DNA) 
remaining after protocol defined analysis will be stored for up to 15 years in the RCR.
The following samples will be collected for identification of dynamic (non-inherited) 
biomarkers:

Blood for serum isolation on Day 1, Day 5, and at disease relapse (in those patients 
who have hematological response).

Blood for plasma isolation on Day 1, Day 5, and at disease relapse (in those patients 
who have hematological response).
The following samples will be collected for identification of genetic (inherited) biomarkers:

Blood for DNA isolation will be collected on Day 1.  If the sample is missed on Day 1, 
it can be collected at any time in the study. 
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the Laboratory Manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.  
4.5.13.4
Confidentiality
Confidentiality for All RCR Specimens
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 


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aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Additional Confidentiality for Specimens Used for Genetic Research
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" by 
replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail. Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  
Access to the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche's Legal Department, as applicable.
4.5.13.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research.
4.5.13.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient’s wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RCR samples after closure of the site, the investigator must 


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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 
specimens from the RCR.  Likewise, a patient’s withdrawal from the RCR does not 
constitute withdrawal from this study.
4.5.13.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  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 RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as unable or unwilling to complete the required 
study dosing or assessments    
In the case that the patient decides to prematurely discontinue study medication
(“refuses treatment”), all efforts should be undertaken to keep the patient in the study for 
further follow-up.  In case the patient does not wish to return for study assessments or 
follow up, he/she should be asked if he/she can still be contacted every 3 months to 
collect survival information.  The outcome of that discussion should be documented in 
both the medical records and in the eCRF.  If necessary, the investigator should contact 
the subject or a responsible relative by telephone followed by registered mail or through 
a personal visit to establish as completely as possible the reason for the withdrawal.  A 
complete final evaluation at the time of the subject’s withdrawal should be made with an 
explanation of why the subject is withdrawing from the study.


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Patients who withdraw from the study will not be replaced.
4.6.2
Study Drug Discontinuation
Patients must discontinue study medication if they experience any of the following:

Pregnancy

Treatment failure

Unacceptable toxicity
The primary reason for study medication discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study medication prematurely will not be 
replaced.  Patients discontinuing study medication will be followed as per Schedule of 
Assessment (Appendix 1 and Appendix 3).
After the study drug completion/discontinuation visit, adverse events should be followed 
as outlined in Section 5.3.1 and Section 5.6.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
5.1.1
Safety Risks of Idasanutlin and Cytarabine in Leukemia  
Patient well-being and safety will be protected by applying stringent exclusion criteria 
specified in Section 4.1.2, applying the toxicity management guidelines detailed in 
Appendix 14, and through pharmacovigilance/safety monitoring of all adverse events 
and laboratory assessments and will be graded according to the CTCAE v4.03 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.  In addition to 
the oversight provided by the Medical Monitor and drug safety personnel for this trial, an 
iDMC will review safety data on a regular and unblinded basis.  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.  More details on the frequency and content of 
the iDMC meetings can be found in the iDMC charter. 
Information related to the risks associated with idasanutlin treatment is described in the 
idasanutlin IB.  Potential risks associated with idasanutlin include GI toxicity, cytopenias, 
TLS, electrolyte abnormalities, and infectious complications. Given the clinical need for 
effective treatment for patients with AML, the benefit-risk relationship for idasanutlin is 
acceptable.  Many of the toxicities experienced by patients were manageable with 
appropriate prophylaxis and supportive therapy and/or were reversible with 
discontinuation of idasanutlin.  As a result, stringent toxicity management 
recommendations were introduced and are detailed in Appendix 14.  Refer to the current 
idasanutlin IB for details on the safety data from previous idasanutlin studies and for 
additional information on idasanutlin warnings and precautions.  
5.1.1.1
Gastrointestinal Toxicity
GI adverse events reported in Phase I idasanutlin studies were primarily diarrhea, 
nausea, vomiting, abdominal pain, constipation, and anorexia.  Diarrhea was the most 
common adverse event and was observed in 90% of patients in the AML Study 
NP28679 (mostly Grade 1 and Grade 2 in severity).  Nausea and vomiting were also 
frequently reported but to a lesser extent, and the majority of adverse events were 
Grade 1 and Grade 2.  In addition to institutional guidelines, specific instructions for the 
management of GI side effects are provided in Section 5.1.2.1 and in Appendix 14.
5.1.1.2
Cytopenias
Cytopenias, including myelosuppression, are expected under the anti-leukemia 
treatment proposed, and the therapeutic effect is expected to be associated with toxicity 
on normal bone marrow progenitors.  Bone marrow toxicity may manifest as cytopenias 
(i.e., pancytopenia, neutropenia, febrile neutropenia, thrombocytopenia, and anemia).  In 
Study NP27872, which evaluated idasanutlin in patients with solid tumors, possible 


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exposure-dependent neutropenia and thrombocytopenia were observed; these events 
were reversible and able to be monitored.  In leukemia patients, drug-induced 
myelosuppression is expected during idasanutlin treatment, and idasanutlin 
administered in combination with cytarabine may prolong the aplasia window.  In Study 
NP28679, the time to platelet and neutrophil recovery were highly variable, and the 
mean time to recovery for platelet and leukocyte counts (Kaplan-Meier estimates) were 
34 days in patients who responded to idasanutlin and cytarabine administered in 
combination.
5.1.1.3
Tumor Lysis Syndrome
TLS is a potentially life-threatening metabolic disorder that occurs when tumor cells 
release their contents into the bloodstream, either spontaneously or in response to 
therapy, leading to characteristic findings of hyperuricemia, hyperkalemia, 
hyperphosphatemia, and hypocalcemia.  This complication is common in patients with 
acute leukemia.  Five cases with laboratory evidence of TLS were reported in Study 
NP28679 as an idasanutlin-related event.  Of these 5 cases, a single case with clinical 
abnormalities was reported.  The patient was subsequently treated for TLS and 
recovered.  To date, there have been no other cases of TLS among the 282 patients 
exposed to idasanutlin.
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 
case of C. difficile infection.  In addition to institutional guidelines, specific instructions for 
the management of C. difficile infection are provided in Appendix 14.
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 included fatigue/asthenia, 
pyrexia, peripheral edema, headache, dyspnea, dizziness, and chills.  These adverse 
events have been of mild severity and controllable with symptomatic treatment and/or 
nutritional support.
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 


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as clinically indicated, vital signs, and laboratory measurements (hematology, chemistry, 
and urinalysis). 
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
5.1.2.1
Gastrointestinal Events
GI adverse events are the most common toxicity observed during idasanutlin therapy.  
All enrolled patients will be evaluated at regular intervals clinically and with standard 
laboratory tests before and during their participation in this study.  Frequent monitoring 
and supportive treatment (including hydration and electrolyte monitoring and correction) 
are strongly encouraged.  Prophylactic treatment to mitigate GI toxicity is mandatory 
during the treatment phase after the initial toxicity assessment is made (ASCO, ESMO, 
and NCCN; Roila et al. 2010; Ettinger et al. 2012; Hesketh et al. 2016). 
Prophylaxis guidelines for moderately emetogenic chemotherapy must be 
followed.  
Diarrhea was the most common adverse event observed, occurring in 90% of patients 
in Study NP28679.  Mandatory prophylaxis with antidiarrheal agents must therefore be 
implemented in all patients.  Close clinical monitoring for signs of diarrhea is required.  
Patients who develop diarrhea should have other or concomitant causes ruled out 
(including infection due to C. difficile).  Once other or concomitant causes of diarrhea are 
evaluated, prompt treatment with anti-diarrheal agents must be administered to prevent 
severe diarrhea during study treatment.  See Appendix 14 for specific recommendations 
and guidelines on anti-emesis and anti-diarrheal prophylaxis, adverse event 
management, and C. difficile infection.
Please note that diarrhea adverse events (Grade 2) and C. difficile infection (Grade 2) 
are considered adverse events of special interest for idasanutlin (see Section 5.2.3). 
5.1.2.2
Myelosuppression
For patients who are neutropenic and thrombocytopenic at baseline due to their 
underlying leukemia, elimination of leukemic blasts is essential for normal bone marrow 
recovery.  Idasanutlin was associated with myelosuppression in Study NP28679, but 
normal bone marrow recovery was observed in patients showing a clinical response.  
Additive effects from idasanutlin administered in combination with cytarabine on normal 
bone marrow progenitors (including early progenitors) are possible. 
In anticipation of a potential extended period of myelosuppression, the standard 
precautions for neutropenia, thrombocytopenia, and anemia will be used for patients in 
the trial.  In this study, blood counts will be monitored closely throughout treatment (see 
Appendix 1).  Administration of growth factors will be permitted for neutropenic sepsis 
according to local practice, and patients will be monitored and treated promptly should 
infection occur.  Patients will be excluded from study participation if they are unwilling to 


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undergo supportive blood transfusion therapy.  Please refer to Appendix 14 for 
guidelines for hematological toxicity management.
Please note that events of febrile neutropenia Grade 3 and thrombocytopenia 
Grade 3 (if associated with hemorrhage or bleeding) are considered adverse events of 
special interest for idasanutlin (see Section 5.2.3).
5.1.2.3
Infections
Infections of various etiologies have been reported in patients with AML in 
Study NP28679.  Drug-induced myelosuppression and AML-linked cytopenia increases 
the risk for infectious complications.  In addition, AML is associated with impaired 
immune function and an increased susceptibility to infection.  Assessment of causality in 
these cases can be difficult, and it is unclear whether or how much the incidence of 
infection may be increased due to idasanutlin treatment.
Prophylactic antimicrobial and antifungal therapy are mandatory for all patients in 
the study.  Prophylaxis for Pneumocystis carinii infection will be administered according 
to local and institutional guidelines.  Patients receiving antimicrobial agents with a 
therapeutic intent, as described in the exclusion criteria (Section 4.1.2), are not permitted 
to start study medication.  Patients should be carefully screened for evidence of active or 
uncontrolled infection or other uncontrolled disorder prior to enrollment.  Patients in this 
study will be closely monitored for infection, and prompt therapy will be instituted as 
necessary.  In any patient with uncontrolled and/or severe diarrhea, the presence of 
C. difficile infection should be investigated.  See Appendix 14 for specific 
recommendations and guidelines for antimicrobials, antifungals, and C. difficile
infection.
Please note that C. difficile infection (Grade 2) is considered an adverse events of 
special interest for idasanutlin (see Section 5.2.3).
5.1.2.4
Tumor Lysis Syndrome
There is a potential for TLS in patients treated with idasanutlin.  Patients with an initial 
WBC count at randomization of 50,000/mm3, as described in the inclusion criteria 
(Sections 4.1.1), are not permitted to start study medication.  Treatment to decrease the 
WBC count (e.g., HU or leukapheresis) is permitted prior to randomization and up to 
24 hours prior to the start of study medication to meet eligibility criteria.  The risk of TLS 
should be assessed prior to initiating study medication, and standard institutional 
guidelines for TLS prophylaxis for leukemia patients should be followed.  The following 
clinical laboratory parameters will be monitored in all patients receiving study medication:  
sodium, potassium, chloride, calcium, carbonate, BUN, uric acid, serum creatinine, LDH, 
and phosphorus.  In the event that clinical laboratory abnormalities arise that are 
suggestive of TLS, in addition to following institutional guidelines, study-specific 
guidelines are provided in Appendix 14.  Please refer to Appendix 14 for further 
guidance on TLS management.


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Per the Howard  criteria, clinical tumor lysis syndrome (CTLS) is defined as laboratory 
evidence of metabolic changes concomitant with significant clinical toxicity requiring 
clinical intervention, that is, the presence of laboratory TLS (LTLS) and one or more 
clinical manifestations of TLS such as seizures, cardiac arrhythmia, and renal 
abnormality (see Appendix 13).  Due to the life-threatening nature of CTLS, this 
condition is considered an adverse event of special interest for idasanutlin (see 
Section 5.2.3).
5.1.2.5
Dose Modification due to Toxicity
Reasons for dose modifications or delays to the start of the next cycle, the supportive 
measures taken, and the outcome, will be documented in the patient’s chart and 
recorded in the eCRF.
As a general rule, all study medication should be held and resumed together to remain 
synchronized when toxicity resulting from any component of the regimen occurs.  Missed 
doses of study medication cannot be administered at a later timepoint in the case of 
treatment interruption.
All treatment-related toxicities should be resolved to Grade 1 or the baseline grade 
prior to beginning the next cycle.  Patients will be allowed a maximum of an additional 
28 days (up until Day 56) for recovery of toxicities to Grade1 or the baseline grade.  In 
the event that a non-hematologic toxicity occurs prior to the start of a subsequent cycle 
until Day 56, the case may be discussed with the medical monitor or designee, who may 
allow an additional recovery period. 
Continuation on study medication is gated by the clinical response observed at the end 
of a cycle (see Appendix 4).  Once clinical response is observed and continuation is 
allowed per Appendix 4, the next cycle should be initiated.  A delay 7 days from clinical 
response is considered a delay of therapy.  In such cases, weekly blood counts must be 
performed to confirm that the patient remains in clinical remission.  Upon suspicion of 
relapse, a bone marrow aspirate must be taken and an HMRA performed as an 
unscheduled assessment. Reduction/interruption of dosing of cytarabine due to adverse 
events (other than hematologic toxicities) should be according to available National 
Prescribing Information, Summary of the Product Characteristics, or other relevant 
documents and institutional practice.
Reduction of exposure to idasanutlin/placebo may be managed by reducing the dose to 
50% (i.e., 300 mg dose administered in the morning only).  As a further step, the 
treatment length may be shortened (i.e., 3 days instead of 5 days of study drug 
administration); however, all efforts should be undertaken by using optimal 
premedication to allow all patients completion of Cycle 1, Day 15.  


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Hematological toxicity Grade 3, 4: 

Hematologic toxicity is defined as neutropenia, anemia, or thrombocytopenia that 
worsens after initiation of study medication.  

Administer RBCs or platelets as required (see Appendix 14).

For patients targeted to receive consolidation Cycles 2 and/or 3, follow dosing 
guidelines based on blood counts depicted in Appendix 4.
AST, ALT, or bilirubin increase Grade 3, 4:

For Grade 3 AST/ALT elevation, study medication may be continued without 
interruption and/or dose reduction at the discretion of the investigator per institutional 
practice.

For Grade 4 AST/ALT elevation, study medication must be withheld until the severity 
of the AST/ALT elevation is Grade 1.

If improvement to Grade 1, resume idasanutlin/placebo and cytarabine with original 
dose and schedule. 

Permanently discontinue study medication if Hy’s Law criteria (defined in 
Section 5.3.5.6) are met, AST/ALT elevation does not resolve to Grade 1 within 
28 days, or if Grade 4 AST/ALT elevation recurs.
Diarrhea, nausea, or vomiting:

Please refer to Appendix 14  for specific recommendations.
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.
Patients will be evaluated for adverse events (all grades according to the 
NCI CTCAE v4.03), serious adverse events, and any adverse events requiring treatment 
interruption or discontinuation.  Patients who have an ongoing adverse event leading to 
treatment discontinuation will be followed until the event resolves, the investigator 
assesses the event as stable, the patient is lost to follow-up, the patient undergoes 
HSCT, or the patient starts a different anti-tumor therapy.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

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:

Fatal (i.e., the adverse event actually causes or leads to death)

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 (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)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).


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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6)

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 13) 

Febrile neutropenia (Grade 3)

Thrombocytopenia (Grade3 if associated with hemorrhage or bleeding)
Reporting of this adverse event of special interest requires two separate forms:  
one form to report thrombocytopenia and one form to report hemorrhage/or 
bleeding. 

Diarrhea (Grade2)

Clostridium difficile infection (Grade 2)
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.  Hematological adverse events of special interest are not reportable for 
patients in whom myelosuppression arises as a result of confirmed relapsed disease.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, 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 drug until 56 days after the last dose of study drug, all 
adverse events should be reported.  Patients who, at 56 days after the last dose of study 
medication is administered, have an ongoing adverse event will be followed until the 
event resolves or the patient is lost to follow-up. 
After informed consent has been obtained until 6 months after the last dose of 
study medication is administered, adverse events of special interest are reportable 
with the exception of hematological adverse events of special interest arising as a result 
of confirmed relapsed disease (see Section 5.2.3  for adverse event of special interest 
definition). 
After 56 days from the last dose of study drug until the end of the study, the 
investigator should only report any serious adverse events that are believed to be 
related to the prior administration of study drug treatment or any fatal adverse events.  
Those should be reported on the eCRF Adverse Event page over the course of the study 
(see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
“How have you felt since your last visit to the clinic?”
“Have you had any new or changed health problems since you were last here?” 


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.03 will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 5
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
CTCAECommon Terminology Criteria for Adverse Events; NCINational Cancer Institute.
Note:  Based on the most recent version of NCI CTCAE v4.03, 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 or 
not 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, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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


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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 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent/intermittent 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 
should be considered clinically significant and only reported as an adverse event if it 
meets at least one of the following criteria:

Is accompanied by clinical symptoms (e.g., Grade 3 thrombocytopenia accompanied 
by bleeding)

Results in a change in investigational study medication (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

Meets serious adverse event criteria as defined in Section 5.2.2
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.  If the 
laboratory abnormality is related to the underlying disease (for example neutropenia, 
thrombocytopenia or pancytopenia is a clinical manifestation of leukemia), the laboratory 
abnormality would not be required to be reported as an adverse event.  In the event that 
a patient achieves a CR with recovery of peripheral blood counts, then subsequent 
hematologic toxicities should be reported as adverse events. 


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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 if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
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:

Accompanied by clinical symptoms

Results in a change in investigational study medication (e.g., dosage modification, 
treatment interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
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.  
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)


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
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).
5.3.5.7
Deaths
For this protocol, mortality is the primary 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 AML should be recorded only on the Study 
Discontinuation eCRF.  All other on study deaths, regardless of relationship to study 
drug, must be recorded on the Adverse Event eCRF and immediately reported to the 
Sponsor (see Section 5.4.2). 
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").
All deaths, including those attributed to disease progression, will be monitored by the 
iDMC in an unblinded manner and analyzed by the iDMC with recommendations of 
those analyses reported to the Sponsor as described in the iDMC charter. 
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 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 rare cases, the determination of clinical 


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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
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study 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
5.3.5.11
Adverse Events Associated with an Overdose
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study medication is not 
itself an adverse event, but it may result in an adverse event.  
All adverse events associated with an overdose or incorrect administration of study 
medication should be recorded on the Adverse Event eCRF.  
If the associated adverse event fulfills serious 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).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 


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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2)

Adverse events of special interest (defined in Section 5.2.3)

Pregnancies (see Section 5.4.3 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 
Primary Contact
Medical Monitor:
, Ph.D.
Telephone No.:
Secondary Contact
Medical Monitor/Roche Medical Responsible:
, M.D., DMSc
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk and Medical Monitor contact 
information will be distributed to all investigators (see “Protocol Administrative and 
Contact Information & List of Investigators”). 


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5.4.2
Reporting Requirements for Serious Adverse Events
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.  
A paper Serious Adverse Event Reporting Form and fax cover sheet should be 
completed and faxed to Roche Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), using the fax numbers provided 
to investigators (see “Protocol Administrative and Contact Information & List of 
Investigators”).
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, all serious adverse events irrespective of drug-event 
relationship will be reported until 56 days after the last dose of study drug.  Thereafter 
only adverse events of special interest and serious adverse events related to study drug
should be reported as per guidance in Section 5.6.  Please note that this is not 
applicable to fatal adverse events who should be reported as serious adverse events 
irrespective of study drug relationship and be recorded on the Adverse Event eCRF until 
the end of the study.  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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Roche Safety 
Risk Management or its designee immediately (i.e., no more than 24 hours after learning 
of the event), using the fax numbers provided to investigators (see “Protocol 
Administrative and Contact Information & List of Investigators”).  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events 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 last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 


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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 last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  If 
the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form 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
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).


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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 of the event 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.  Hematological 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, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the study, if the event is believed to be related 
to the prior study medication. 
Adverse events of special interest are reportable until 6 months after the last dose of 
study medication is administered, with the exception of hematological adverse events of 
special interest arising as a result of confirmed relapsed disease (refer to Section 5.2.3  
for adverse events of special interest definitions).
The investigator should report these events directly to Roche Safety Risk Management 
either by faxing or by scanning and emailing the Serious Adverse Event/ Adverse Event 
of Special Interest Reporting Form using the fax number or email address provided by 
the Sponsor. 


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Idasanutlin IB

Cytarabine Summary of Product Characteristics
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
A mechanistic simulation model was used to determine the sample size in this event-
driven study, based on the following global assumptions:

Final analysis for OS in patients with TP53 WT disease based on two-sided log-rank 
test at 0.05 level of significance

85% power to detect an OS hazard ratio for idasanutlincytarabine versus
cytarabineplacebo of 0.67 in patients with TP53 WT disease, corresponding to an 
improvement in median OS from 6 to 9 months (50%)

Proportion of long term survivors of 8.0% in the cytarabineplacebo arm and 16.1% 
in the idasanutlincytarabine arm
To compute the necessary number of events, we simulated OS times based on the
following assumptions:

All simulated OS times for patients not considered long-term survivors are 
exponentially distributed

Probability of being a complete responder in the cytarabineplacebo arm is 0.16

Probability of being a complete responder in the idasanutlincytarabine arm is 0.323, 
implying an odds ratio for CR comparing the idasanutlincytarabine versus the 
cytarabineplacebo arm of 2.5

Probability for a complete responder to be a long-term survivor is 0.5 in either arm


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
An annual dropout rate of 5% (every effort will be made to contact patients for 
survival information in case of study withdrawal or loss to follow-up) 
To have the targeted 85% power, 275 events in patients with TP53 WT disease are
required.  The minimum detectable hazard ratio in a 2:1 randomized trial corresponding 
to 275 events and a significance level of 0.05 amounts to 0.78, corresponding to a 
minimal detectable median improvement from 6 to 7.7 months assuming exponentiality. 
All patients, regardless of TP53 mutation status, will be randomized to this study.  
Assuming 85% of patients will have TP53 WT disease and 15% will have TP53 mutant 
disease, approximately 440 patients will be enrolled over approximately 29 months,
corresponding to an estimated number of 374 patients with TP53 WT disease.
In Version 6 of the protocol, an interim analysis for efficacy on OS of TP53 WT 
patients was added.  The sample size assumptions above remain unchanged other than 
the recruitment time (now estimated at 41 months). The interim analysis will occur at 
an information fraction of 80%, providing a maximum power of 83% for the final OS 
analysis (see Section 6.11.2). 
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, eligibility violations, and study drug administration will be summarized by 
treatment arm.  Patient disposition will be summarized by treatment arm and will include 
whether treatment was completed or discontinued early, and the reason for early 
treatment discontinuation.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and disease 
status, will be summarized by treatment arm.  Descriptive summaries of continuous data 
will present the group mean, standard deviation, median, minimum and maximum, and 
number of observations.  Descriptive summaries of discrete data will include frequencies 
and percentages.
6.4
EFFICACY ANALYSES
Patients will be analyzed according to the treatment arm to which they were randomized.  
The TP53 WT population is the efficacy population and refers to all randomized 
TP53 WT patients as identified by a central laboratory test (see Section 4.5.10.2).
Description of efficacy analysis in this section is valid for both interim and primary 
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6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint, OS, is defined as the time from randomization to death 
due to any cause.  OS for patients who have not died at the time of the analysis will be 
censored at the date last known alive. 
The primary OS analysis of the study will assess the null hypothesis of equality of OS 
functions in the idasanutlin in combination with cytarabine (MDM2-chemo) arm versus 
the cytarabine given with a placebo (chemo) arm in the TP53 WT population as follows:
H0:  OSMDM2-chemoOSchemo versus H1:  OSMDM2-chemo ≠OSchemo
A formal treatment comparison will be made using a two-sided stratified log-rank test at 
a significance level defined using the O´Brien-Fleming alpha-spending function with 
overall Type I error rate at 0.05 corresponding to available information (see 
Section 6.11.2).   Stratification factors that will be used are the same as for 
randomization, that is, age (60 versus 60 years), cytogenic and molecular risk 
(favorable/intermediate versus adverse), prior response to initial anti-leukemic therapy 
(refractory versus CR 3 months but 1 year versus CR 1 year) and prior HSCT 
versus no prior HSCT.  
Survival curves in each treatment arm will be estimated using Kaplan−Meier estimates.  
The Kaplan–Meier estimates will provide a visual description of the survival curves and 
the difference across treatment arms.  The treatment effect will be quantified via a 
hazard ratio, computed from a stratified Cox proportional-hazards regression, including a 
95% CI.  To further describe and quantify OS, estimated median OS per arm and 1-year 
and 2-year survival probabilities, all including 95% CI, will be given.  The effect of 
prognostic factors on OS will be assessed in an exploratory analysis using Cox 
multivariate regression. 
6.4.2
Secondary Efficacy Endpoints
The following secondary endpoints will be tested for the TP53 WT population, as 
described in the Statistical Analysis Plan:

CR proportion

EFS

ORR (CR, CRp, and CRi) 

DOR (duration of remission following CR)

Proportion of HSCT following CR 

CR proportion and OS in clinically actionable mutation-defined subpopulation 
(FLT3, IDH1, and IDH2)
Patients with no response assessments (for any reason) will be considered non-CR. 


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Difference in proportions of CR will be assessed between the two treatment arms using 
Cochran–Mantel–Haenszel test stratified by randomization stratification factors.  In 
addition, proportions and 95% CI will be reported for each treatment arm.  The effect of 
prognostic factors on CR will be assessed in an exploratory analysis using logistic 
regression.
EFS is defined for all patients and measured from the date of randomization.  It is 
measured until treatment failure, relapse from CR, or death from any cause, whichever 
occurs first.  For patients with none of these events before time of analysis, EFS is 
censored at the date of the patient’s last response assessment.
DOR is defined for patients achieving CR and is the time from achieving CR until 
relapse or death from any cause, whichever occurs first.  For patients with none of these 
events before time of analysis, DOR is censored at the date of the patient’s last response 
assessment.
EFS and DOR will in general be analyzed using the same statistical methods as those 
described for OS.  If only very few patients qualify for DOR analysis, only descriptive 
statistics will be given.
ORR (CR, CRp, and CRi) and proportion of HSCT will be compared between the two 
treatment arms using the same statistical methods as those described for CR. 
6.4.3
Exploratory Efficacy Endpoints
Primary and secondary efficacy endpoints (OS, CR, ORR, HSCT, EFS, and DOR) in 
the all-patient population, as well as OS and CR in the subpopulation of FLT3, IDH1,
and IDH2, will be analyzed.
The following endpoints will be assessed in the all-patient and TP53 WT populations: 
CR and ORR over entire treatment period; LFS; and HSCT in patients with OR 
(CR/CRp/Cri) and all patients. CR over entire treatment period will also be assessed in 
the subpopulation of FLT3, IDH1, and IDH2.
Biomarker analyses are described in Section 6.8.
6.5
SENSITIVITY ANALYSES
The following sensitivity analyses for OS will be performed in the TP53 WT population:

An unstratified log-rank test.

To assess the relevance of HSCT against other long-term effects, OS will be 
alternatively defined with censoring at date of HSCT and analyzed using the same 
methods as for the primary endpoint.

Discontinuation of assessments or patient lost to follow up considered as an event


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6.6
SAFETY ANALYSES
All safety analyses will be based on both the TP53 WT population (defined here as 
TP53 WT patients who have received any study medication at least once) and the 
complete safety analysis population (defined as all patients who have received any study 
medication at least once), and patients will be analyzed according to the treatment
received (patients receiving idasanutlin at least once will be analyzed in the idasanutlin 
arm).  Safety analyses will include, but not be limited to, incidence rates for adverse 
events including mortality, adverse event severity, seriousness, and adverse events 
leading to discontinuation.  In addition, abnormalities of clinical laboratory tests and vital 
signs assessed during the study treatment period and post-treatment follow-up will be 
assessed.  Exposure to study medication will be summarized by total duration of study 
medication, number of cycles started and cumulative dose using descriptive statistics.  
This trial is designed to allow for early termination or a modification of the protocol for 
safety concerns or lack of efficacy, based on the advice of an iDMC.  The iDMC will be 
incorporated into the study to review safety data on a regular basis, including adverse 
events of special interest.  Both the Sponsor and the iDMC can request ad hoc iDMC 
meetings if potential safety concerns arise.  Following each meeting, the iDMC will 
recommend to the Sponsor whether the study should continue according to the protocol 
or may suggest changes to the protocol based on the outcome of the data review.  In 
exceptional cases, the iDMC may recommend stopping the study or closing a treatment 
arm as a result of safety reasons.  The iDMC will also perform a safety review at the 
preplanned interim analyses for futility and efficacy. 
6.7
ELECTROCARDIOGRAMS
Incidence of clinically significant ECG abnormalities will be reported in patient listings 
and change from baseline summarized in tables by treatment arm.  ECG QT and QTcF 
intervals will be summarized by descriptive statistics. 
6.8
PHARMACODYNAMIC AND BIOMARKER ANALYSES
The following pharmacodynamic parameters will be presented by listings and descriptive 
summary statistics.  

Blood samples analyzed for MIC-1 

Analysis of TP53, FLT3, IDH1, and IDH2 mutation status 

MDM2 protein expression level in AML blasts

A 4-gene signature (including MDM2 gene expression) 

MRD


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6.9
PHARMACOKINETIC ANALYSES
Key PK parameter values (CL/F and Vd/F) of idasanutlin and cytarabine (CL and Vd) will 
be estimated using a popPK approach.  The influence of covariates such as gender, 
race/ethnicity, weight, hematological parameters at baseline, renal/hepatic impairment, 
and degree of underlying disease will be investigated.  Other PK parameters such as 
Cmax, Ctrough, AUC0-, AUC0-24h, and t1/2 will be derived from the individual post hoc 
predictions.  Details of the population analysis will be described in the Modeling and 
Simulation Analysis Plan.  Results of this analysis will be reported separately.
If appropriate, an exploratory PK/pharmacodynamic analysis may be performed post hoc.  
The primary focus will be exploration of the relationship between measures of exposure 
to idasanutlin in combination with cytarabine (Cmax, Ctrough, and AUC0-24h) and ECG, 
drug-related adverse effects as well as clinical efficacy parameters.
6.10
PATIENT-REPORTED OUTCOME ANALYSES
Scoring for the EORTC QLQ-C30 questionnaire will be based on the scoring manual.  
Consistent with the user manual, prorated scores will be computed for a subscale if 
more than 50% of the constituent items have been completed for that subscale.  For 
subscales with less than 50% of the items completed, the subscale will be considered as 
missing. 
Summary statistics of the EORTC QLQ-C30 scales and their changes from baseline will 
be calculated at each assessment timepoint for both study arms.  Analysis details of 
these PROs will be provided in the Statistical Analysis Plan.  
Health utility scores, as assessed by the EQ-5D-5L, will be evaluated for patients with a 
baseline assessment and at least one post-baseline EQ-5D-5L assessment that 
generate a score.  Scores at baseline and change from baseline scores for each 
timepoint will be quantified using descriptive statistics.  The results will be used for more 
complete health economic data analysis.
6.11
INTERIM ANALYSES
6.11.1
Futility
A non-binding interim analysis for safety and futility will be performed by an iDMC after 
120 patients with TP53 WT have been enrolled and assessed for response.  For the 
purposes of the futility interim analysis, CR is defined as confirmed CR (see definition 
in Section 3.4.1).  Sponsor personnel will not have access to by-arm efficacy and safety 
summaries prior to the formal reporting of study results.  The iDMC may recommend 
stopping the study for futility if:

the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the 
cytarabine and placebo arm in the population of patients WT for TP53, is 2.0,


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
or the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the 
cytarabine and placebo arm in the population of patients WT for TP53, is 2.5 and 
the hazard ratio for EFS 1.
To compute stopping probabilities for the futility interim analysis, the following 
additional assumptions are made within TP53 WT patients and the simulation model is 
extended accordingly:

Median OS for non-responders in cytarabine arm is 5.1 months

Median OS for responders, but short-term survivors in cytarabine arm is 7.5 months

EFS follows an exponential distribution

Median EFS times for non-responders and CR short-term responders is assumed to 
be shorter by a factor 2.5 compared to OS in these same subpopulations

The correlation between uncensored EFS and OS times is 0.5

Hazard ratio for a comparison of idasanutlincytarabine versus cytarabine +placebo 
in both non-responders and short-term responders is 0.8
Using these assumptions, we expect 63 EFS events at the futility interim analysis 
under the alternative hypothesis.  The probability of early stopping due to futility is 89.9% 
if the null hypothesis of equal OS survival functions is true and 31.9% if the alternative 
assumption of an increase in median OS from 6 to 9 months is true.  
The analysis in both the TP53 WT population and in the overall population will be 
provided to the iDMC.
The iDMC may recommend stopping the study for safety at the futility interim analysis if 
any of the following criteria are met (note:  early death is defined as any death within the 
first 30 days after randomization):

The proportion of GI toxicity (nausea, vomiting, diarrhea) events in the experimental 
arm (idasanutlin cytarabine):  Grade 3 >40% or Grade 4 >15%

The proportion of early deaths in the experimental arm (idasanutlincytarabine) is 
≥10 percentage points greater than in the control arm (cytarabineplacebo) 

> 20% of early deaths overall in the treatment arm
More details on the interim analysis are provided in the iDMC charter.
6.11.2
Efficacy
An interim analysis for efficacy on OS is planned to be conducted by iDMC. The
efficacy interim analysis will be conducted when 80% of the OS events have occurred 
(i.e., approximately 220 events). At this time, it is anticipated that all patients will 
have been enrolled (see Section 6.1).


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For the interim efficacy analysis of OS, the significance level will be determined using 
the O’Brien-Fleming alpha-spending function with overall type I error rate at 0.05 level.  
At the time of the interim efficacy analysis, it is expected that 80% of the OS events 
will have occurred, corresponding to an alpha spending of 0.025 for the interim and 
0.043 for the final OS analysis leading to a power of 83% for the final analysis.
The iDMC will test OS for efficacy and check if there is a significant difference (alpha 
level 0.025 or as assessed based on actual number of OS events) in OS in favor of the 
experimental arm.
Accompanying this interim efficacy analysis, a non-binding additional futility 
assessment will be performed and the iDMC may recommend stopping the study for 
futility if the hazard ratio on OS is greater than or equal to one.
Further details of the interim analyses will be described in the iDMC Charter and 
Statistical Analysis Plan.
6.11.3
Biomarker Recommendation
The iDMC will use guidelines as specified in the iDMC charter for making a 
recommendation for the gene signature and MDM2 expression on the basis of the 
interim futility analysis.
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.  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.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME 
ePRO data will be collected through use of an electronic device provided by an ePRO 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations 
for electronic records (21 CFR Part 11).  The ePRO device data are available for view 
access only via secure access to a web server.  Only identified and trained users may 
view the data, and their actions become part of the audit trail.  The Sponsor will have 
view access only.  System backups for data stored by the Sponsor and records retention 
for the study data will be consistent with the Sponsor’s standard procedures.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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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 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
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.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for 15 years after completion or discontinuation of the study, or for the length 
of time required by relevant national or local health authorities, whichever is longer.  
After that period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the European Union or European Economic 


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Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, 
regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver’s 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.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  
A separate, specific signature will be required to document a patient’s agreement to 
allow any remaining specimens to be used for exploratory research.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.


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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 investigational new 
drug 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.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
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 study is sponsored by F. Hoffmann-La Roche Ltd.  Study centers will participate in 
this study globally, enrolling a total of approximately 440 patients.  An IWRS will be used 
to manage site drug supply and to randomize patients to study drug.  
Plasma samples for PK assessment will be sent to a central laboratory for sample 
storage and to an external vendor for analysis.  Plasma and serum will be sent to a 
central laboratory for analysis and sample storage.  Sample analysis will be performed 
by an external vendor or the Sponsor.  
An iDMC will review unblinded data on a regular basis at predefined timepoints during 
the study.  The iDMC will review results from the analyses of unblinded accumulating 
safety data and make recommendations to the Sponsor regarding continuation and/or 
modification of the study.  The final decision on the iDMC recommendation will be made 
by the Sponsor.  The details of the composition, roles, and responsibilities of the iDMC 
will be documented in detail in the iDMC charter, and submitted to Health Authorities as 
applicable.  An IDCC will perform statistical analyses of accumulated safety data every 


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6 months (deaths and serious adverse events every 3 months) during the study for 
review by the iDMC. 
A Steering Committee including trial investigators will provide scientific and medical 
advice during the study will regularly review blinded reports on study conduct, efficacy 
and safety and will help to ensure accurate and complete data collection.  Details on 
member selection, roles and responsibilities are outlined in the Steering Committee 
Charter.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  For more information, refer 
to the Roche Global Policy on Sharing of Clinical Trials Data at the following website:
http://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 CSR.  In addition, for all clinical trials in patients involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer 
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Appendix 1
Schedule of Assessments
Table 1
Cycle 1
APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
Informed Consent a
x
Demographics, 
Medical History, 
Determination of 
cytogenetic and 
molecular risk b, 
Physical 
Examination, 
Height, Chest X 
Ray (or Chest CT) c
x
Idasanutlin/placebo 
Dosing 
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
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APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
Cytarabine Dosing
x
x
x
x
x
Symptom Directed 
Physical 
Examination
x d
x
x
x
x
x
x
Vital Signs e, 
Weight, ECOG
x
x d
x
x
x
x
x
x
ECG (repeated) f
x
x
x
x
Urinalysis 
x
x d
ePRO Assess-
ments g
x
x
x
x
x n
x n


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
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APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
Serum Pregnancy 
Test
x
x d
Concomitant 
Medication
x
x
Adverse Events 
and Serious 
Adverse Events
x
x
Biochemistry i
x
x
x
x
x
x
x
x
(weekly blood 
counts latest up to 
D42)
x
(weekly blood 
counts latest up to 
D56)


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
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APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
Hematology i
x
x
x
x
x
x
x
x
(weekly blood 
counts latest up to 
D42)
x
(weekly blood 
counts latest up to 
D56)
x
HMRA
x
perform if 
peripheral 
blasts present 
OR if blood 
counts 
recovered
x
perform if peripheral 
blasts present OR 
as soon as blood 
counts recovered.  If 
no recovery, perform 
at D42
x
perform if 
peripheral blasts 
present OR if blood 
counts recovered 
by Day 56
x


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
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APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
BM sampling for 
HMRA j
x
x
if peripheral 
blasts present 
OR if blood 
counts 
recovered
x
if peripheral blasts 
present OR as soon 
as blood counts 
recovered.  If no 
recovery, sample at 
D42
x
if peripheral blasts 
present OR if blood 
counts recovered 
by Day 56
x


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
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APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
BM sampling l

MRD/Flow

EDTA

Pax-gene
x
x k
x k
x k
x k
Whole blood 
sampling

Flow

EDTA

Clinical 
Genotyping
x m


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
123
APPLICABLE TO ALL PATIENTS
APPLICABLE TO 
PATIENTS NOT 
CONTINUING TO 
CYCLE 2 (UNTIL fIA)
Screening
Cycle 1 (Induction)
Confirmation of 
Response
Treatment Period Cycle28 days
Only Applicable in 
Case of Incomplete 
Blood Count 
Recovery by D28
Only Applicable in 
Case of 
Incomplete Blood 
Count Recovery 
by D42 h
Only Applicable to 
Patients with CR, CRp
Cycle Day 
-14 to -1
1
2
3
4
5
8
15
22
28
2942
4356 h
30 Days after 
CR or CRp in Cycle 1 
HMRA 
(3 days)
Whole blood 
sampling Paxgene
x
x
x
x o
x o
x o
AMLacute myeloid leukemia; BMbone marrow; CRcomplete remission; CRpcomplete remission with incomplete platelet count recovery; 
CTcomputed tomography; ECOG Eastern Cooperative Oncology Group; eCRF electronic case report form; EDTAethylenediaminetetraacetic 
acid; ePRO electronic patient-reported outcome; fIA futility interim analysis; HMRAHematologic Malignancy Response Assessment.
Note: Results of screening tests or examinations (except for the bone marrow aspirate) performed as standard of care prior to obtaining informed 
consent and within the protocol-defined screening window (prior to randomization/Cycle 1, Day 1) may be used rather than repeating required tests.
Note:  All assessments scheduled on study drug administration days must be performed PRIOR to first dose of study drug.  
See Table 2 and Table 3 for additional visits during Cycles 2 and 3 and post-treatment, respectively.
a For re-screening, written informed consent must be obtained again before performing any re- screening tests or evaluations.  
b
From initial AML diagnosis.


Appendix 1
Schedule of Assessments (cont.)
Table 1
Cycle 1 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
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c
If a Chest CT is performed up to 28 days prior to study drug administration, a chest x-ray is not required.
d If performed within 72 hours before the first study drug administration, the assessment does not have to be repeated on the first day of Cycle 1. 
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
Time points: 
Cycle 1, Days 1: predose idasanutlin, end of cytarabine infusion, 6, and 24 (equivalent to Day 2, predose) hours post dose idasanutlin (a.m.)
Cycle 1, Day 5: predose idasanutlin, end of cytarabine infusion and 6 hours post dose idasanutlin (a.m.)
g ePRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-ePRO assessments 
and the administration of study medication. ePRO questionnaires need to be completed only once during each of the recovery periods D29-42 
and D43-56, if applicable.
h If patient is eligible to continue with consolidation therapy, be aware that a maximum of 56 days is allowed for recovery between cycles.
i
All hematology and biochemistry assessments may be performed up to 1 day prior to the scheduled timepoint.  Results must be reviewed by the 
investigator (or designee) PRIOR to study drug administration.
j 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 should be performed at the discretion of the investigator.
k
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.
l
At screening, the priorities for bone marrow samples are EDTAMRDFlowPaxgene. At subsequent timepoints the priorities are 
MRD/FLOW EDTAPaxgene.
m If clinical genotyping sample is missed on Day 1, sample can be collected at any point in the study.
n If assessment is within time window of confirmation of response or Study Drug Completion/Discontinuation visit, then assessment does not need 
to be repeated.
o
Whenever bone marrow is sampled for HMRA assessment.


Appendix 1
Schedule of Assessments (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
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Table 2
Cycles 2 and 3
Cycles 2 and 3 (Consolidation)
Treatment Period Cycle28 days
Only Applicable in Case of Incomplete 
Blood Count Recovery by D28a
Cycle Day 
1
2
3
4
5
8
15
22
28
2956
Idasanutlin/ placebo Dosing 
x
x
x
x
x
Cytarabine Dosing
x
x
x
x
x
Symptom Directed Physical 
Examination 
x 
x
x
x
x
x
Vital Signs b, Weight, ECOG
x 
x
x
x
x
x
ECG c (repeated, in triplicate)
x
x
Urinalysis 
x
ePRO Assessments d
x
x
x
x
x
Serum Pregnancy Test
x
Concomitant Medication
x
Adverse Events and Serious 
Adverse Events
x
Biochemistry e
x
x
x
x
x
x
x
(weekly blood counts, latest up to D56)
Hematology e
x
x
x
x
x
x
x
(weekly blood counts, latest up to D56)


Appendix 1
Schedule of Assessments (cont.)
Table 2
Cycles 2 and 3 (cont.)
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Cycles 2 and 3 (Consolidation)
Treatment Period Cycle28 days
Only Applicable in Case of Incomplete 
Blood Count Recovery by D28a
Cycle Day 
1
2
3
4
5
8
15
22
28
2956
HMRA
x
x
if blood counts do not recover, perform 
latest by D56
BM sampling for HMRA f
x j
x j
if blood counts do not recover, sample 
latest by D56
BM sampling g

MRD/Flow

EDTA

Paxgene
x h
x h
Whole blood sampling Paxgene
x i, k
x j
BMbone marrow; ECGelectrocardiogram; ECOG Eastern Cooperative Oncology Group; EDTAethylenediaminetetraacetic acid; 
ePROelectronic patient-reported outcome; fIA futility interim analysis; HMRAHematologic Malignancy Response Assessment.
Note:  All assessments scheduled on study drug administration days must be performed PRIOR to first dose of study drug.  
See Table 3 for additional visits during post-treatment.
a if patient is eligible to continue with consolidation therapy, be aware that maximally 56 days are allowed between cycles.  For rules to continue 
with Cycle 3, please consult Appendix 4.
b Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate. 


Appendix 1
Schedule of Assessments (cont.)
Table 2
Cycles 2 and 3 (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
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127
c Time points: 
Day 1: predose idasanutlin, end of cytarabine infusion, 6, and 24 (equivalent to Day 2, predose) hours post-dose idasanutlin (only if there is 
QT prolongation found in Cycle 1 measurements)
d ePRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-ePRO assessments 
and the administration of study medication.  ePRO questionnaires need to be completed only once during the recovery period D29-56 if 
applicable.
e All hematology and biochemistry assessments may be performed up to 1 day prior to the scheduled timepoint.  Results must be reviewed by the 
investigator (or designee) PRIOR to study drug administration.
f
For HMRAs during the study, bone marrow aspirates are required, but bone marrow biopsies should be performed at the discretion of the 
investigator.
g The priorities for bone marrow sampling are MRD/FlowEDTAPaxgene.
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.
i
Collect whenever bone marrow is sampled for HMRA assessment.
j
In Cycle 2, required up to futility interim analysis OR after futility interim analysis; if patient does not proceed to Cycle 3, please see 
Appendix 4 for additional details.
k After futility interim analysis, sample should be collected for all patients regardless if bone marrow is being collected.


Appendix 1
Schedule of Assessments (cont.)
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Table 3
Post-Treatment Phase
Applicable to All Patients
Applicable to Patients in Remission 
(CR, CRp, CRi) 
Applicable to 
Patients with 
Treatment 
Failure/
After Relapse/
After HSCT
Study Drug Completion/
Discontinuation Visit
Follow-Up after Last Dose 
of Study Drug
Relapse
Pre-HSCT
Survival 
Follow-Up
Cycle Day 
28 Days after Last Dose of 
Idasanutlin/
Placebo (28 Days)
Q1m
Q3m
Symptom directed physical exam 
x
Vital signs a, weight, ECOG
x
ECG (repeated, in triplicate) 
x
Urinalysis 
x
ePRO assessments b
x c
x b, d
x b
Serum pregnancy test
x
Concomitant medication
x
Adverse events and serious adverse 
events
x
x e
x
x e
Survival, HSCT, subsequent anti-cancer 
therapies
x
x


Appendix 1
Schedule of Assessments (cont.)
Table 3
Post-Treatment Phase (cont.)
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Biochemistry f
x c
x g
Hematology f
x c
x g
x
HMRA
x g
x
x
BM sampling for HMRA h
x g
x
BM sampling i

MRD/Flow

EDTA

Paxgene
x g, j
x j
x
Whole blood sampling EDTA
x
Whole blood sampling Paxgene
x  g, k
x
AEadverse event; BMbone marrow; CRcomplete remission; CRicomplete remission with incomplete blood count recovery; CRpcomplete
remission with incomplete platelet count recovery; ECOG Eastern Cooperative Oncology Group; eCRF electronic Case Report Form; 
EDTAethylenediaminetetraacetic acid; ePRO electronic patient-reported outcome; HMRAHematologic Malignancy Response Assessment; 
HSCT hematopoietic stem cell transplant; MRDminimal residual disease; PDprogressive disease; Q1m every month; Q3m every 3 months; 
SAEserious adverse event.
Note:  All assessments scheduled on study medication administration days must be performed PRIOR to the first dose of study medication. 
a Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate, and respiration rate. 
b ePRO questionnaires scheduled for administration during a clinic visit should be completed prior to the performance of non-ePRO assessments 
and the administration of study medication.  An additional ePRO assessment is also required to be completed after PD.
c If assessment is within time window of confirmation of response or extended recovery period D29-56, then assessment does not need to be 
repeated.
d Until relapse.
e Only SAEs related to study treatment or fatal AEs.


Appendix 1
Schedule of Assessments (cont.)
Table 3
Post-Treatment Phase (cont.)
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f
All hematology and biochemistry assessments may be performed up to 1 day prior to the scheduled timepoint.
g While patient remains in remission or until HSCT.
h For HMRAs during the study, bone marrow aspirates are required, but bone marrow biopsies should be performed at the discretion of the 
investigator.
i
The priorities are MRD/FlowEDTAPaxgene. 
j
Bone marrow MRD/Flow, EDTA, and Paxgene to be collected at the 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.
k Whenever bone marrow is sampled for HMRA assessment.


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Appendix 2
Schedule of PK/PD Sampling
Cycle
1 (Induction)
2 (Consolidation)
3 (Consolidation)
Cycle Day
1
2
5
8
10 a
1
2
5b
2
5b
Time
Pre-
dose c 
End of 
cytarabine 
infusion 
(within 5 
minutes 
from ECGs 
at end of 
cytarabine 
infusion)
Post-
idasanutlin/
placebo 
morning 
dose 
6 hours 
(30 min)
Pre-
dose c 
Pre-
dose c
Post ECG 
at end of 
cytarabine 
infusion
(5 min)
Post-
idasanutlin/
placebo 
morning 
dose 
6 hours 
(30 min)
any 
time
any 
time
Pre-
dose c
Pre-
dose c
Pre-
dose c Pre-dose 
c
Pre-dose 
c
PK-idasanutlin/placebo 
x
x
x
x
x
x
x
x
x
x
x
x
x
PK-cytarabine 
x
x
x
x
x
x
x
x
x
Serum Biomarker b
x
x
x
x
x
x
PDpharmacodynamics; PKpharmacokinetics.
a
Sample collection will stop once we have approximately 80 samples.
b
Until futility interim analysis.
c
Predose (before idasanutlin morning dose) and within 2 hours prior to dosing of cytarabine.


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Appendix 3
Schedule of Optional RCR Sampling
Cycle
1 (Induction)
Relapse
Study Day a
1
5
DNA
x b
Plasma
x
x
x
Serum
x
x
x
RCRRoche Clinical Repository
a Predose (before idasanutlin morning dose) and within 2 hours prior to dosing of cytarabine 
b If missed on Day 1, can be collected at any point in the study.


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Appendix 4
Algorithm Guiding Bone Marrow Collection and Study 
Medication Continuation
Figure 1
Response Treatment Decision Tree Cycle 1
CRcomplete remission; CRicomplete remission with incomplete blood count recovery; CRpcomplete 
remission with incomplete platelet recovery; HMRAHematologic Malignancy Response Assessment; 
Idasanutlinidasanutlin or placebo; TFtreatment failure. 


Appendix 4
Algorithm Guiding Bone Marrow Collection and Study 
Medication Continuation (cont.)
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Figure 2
Response Treatment Decision Tree Cycle 2 (Before Futility 
Interim Analysis)
CRcomplete remission; CRicomplete remission with incomplete blood count recovery; CRpcomplete 
remission with incomplete platelet recovery; HMRAHematologic Malignancy Response Assessment; 
Idasanutlinidasanutlin or placebo. 


Appendix 4
Algorithm Guiding Bone Marrow Collection and Study 
Medication Continuation (cont.)
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Figure 3
Response Treatment Decision Tree Cycle 2 (After Futility Interim 
Analysis)
CRcomplete remission; CRicomplete remission with incomplete blood count recovery; CRpcomplete 
remission with incomplete platelet recovery; HMRAHematologic Malignancy Response Assessment; 
Idasanutlinidasanutlin or placebo. 


Appendix 4
Algorithm Guiding Bone Marrow Collection and Study 
Medication Continuation (cont.)
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Figure 4
Recovery Follow-up Decision Tree Cycle 3
CRcomplete remission; CRicomplete remission with incomplete blood count recovery; CRpcomplete 
remission with incomplete platelet recovery; HSCThematopoietic stem cell transplant; 
Idasanutlinidasanutlin or placebo. 


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Appendix 5
Cockcroft Gault Formula for Calculation of Creatinine Clearance
Calculation of Creatinine Clearance 
Creatinine Clearance (ml/min) for Males:  
Creatinine Clearance (ml/min) for Females:  


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Appendix 6
Fridericia’s Formula for Corrected QT interval
QTcFQT/RR
0.33


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Appendix 7
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 8
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 kg
Height in cm


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Appendix 9
European Leukemia Net Standardization Reporting System 
Source:  Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid 
leukemia in adults: recommendations from an international expert panel, on behalf of the 
European LeukemiaNet. Blood 2010;115:45374.




Appendix 10
Classification of acute myeloid leukemia (World Health 
Organisation, 2016 revision) (cont.)
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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 May 
2016;127(20):2391-2405.


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Appendix 11
List of Drugs That Can Prolong QT Interval and Torsades De 
Pointes
This table has been adapted from Yap and Camm (2003).  Please note that this list is 
not comprehensive.
Antiarrhythmic drugs Type 1A (TdP reported in all)
Quinidine (TdP reported)
Procainamide (TdP reported)
Disopyramide (TdP reported)
Ajmaline (TdP reported)
Type 1C (increase QT by prolonging QRS interval)
Encainide
Flecainide
Type 3 (TdP reported in all)
Amiodarone
Sotalol
d-Sotalol
Bretylium
Ibutilide
Dofetilide
Amakalant
Semantilide
Calcium channel blockers Prenylamine (TdP reported, withdrawn)
Bepridil (TdP reported, withdrawn)
Terodiline (TdP reported, withdrawn)
Psychiatric drugs Thioridazine (TdP reported)
Chlorpromazine (TdP reported)
Haloperidol (TdP reported)
Droperidol (TdP reported)
Amitriptyline
Nortriptyline
Imipramine (TdP reported)
Desipramine (TdP reported)
Clomipramine
Maprotiline (TdP reported)
Doxepin (TdP reported)


Appendix 11
List of Drugs That Can Prolong QT Interval and Torsades De 
Pointes (cont.)
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Psychiatric drugs (cont.) Lithium (TdP reported)
Chloral hydrate
Sertindole (TdP reported, withdrawn in the U.K.)
Pimozide (TdP reported)
Ziprasidone
Antihistamines Terfenadine (TdP reported, withdrawn in the U.S.A.)
Astemizole (TdP reported)
Diphenhydramine (TdP reported)
Hydroxyzine
Ebastine
Loratadine
Mizolastine
Antimicrobial and antimalarial drugs Erythromycin (TdP reported)
Clarithromycin (TdP reported)
Ketoconazole
Fluconazole
Pentamidine (TdP reported)
Quinine
Chloroquine (TdP reported)
Halofantrine (TdP reported)
Amantadine (TdP reported)
Sparfloxacin
Grepafloxacin (TdP reported, withdrawn in the U.K. 
and U.S.A.)
Pentavalent antimonial meglumine
Serotonin agonists/antagonists Ketanserin (TdP reported)
Cisapride (TdP reported, withdrawn in the U.K. and 
U.S.A.)
Immunosuppressant Tacrolimus (TdP reported)
Antidiuretic hormone Vasopressin (TdP reported)
Other agents Adenosine
Organophosphates
Probucol (TdP reported)
Papaverine (TdP reported)
Cocaine
TdPTorsades de pointes; U.K.United Kingdom; U.S.A.United States of America.


Appendix 11
List of Drugs That Can Prolong QT Interval and Torsades De 
Pointes (cont.)
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REFERENCE
Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 
2003;89:136372.


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Appendix 12
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


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Appendix 13
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/hours for 6 hours
a In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present 
during the same 24-hour period within 3 days before the start of therapy or up to 7 days 
afterward.  Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis 
syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
b The corrected calcium level in milligrams per deciliter measured calcium level in milligrams 
per deciliter0.8(4albumin in grams per deciliter).
c Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dL 
(26.5 mol/L) or a period of oliguria lasting 6 hours or more.  By definition, if acute kidney 
injury is present, the patient has clinical tumor lysis syndrome.  Data about acute kidney injury 
are from Levin et al. (2007).


Appendix 13
Howard Definition and Classification of Tumor Lysis Syndrome 
(Howard et al. 2011) (cont.)
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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.


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Appendix 14
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 idasanutlin (Study NP28679).  The following 
provisions should be strictly followed:

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's disease) prior to 
enrollment.  Patients with active GI conditions as noted in the exclusion criteria are 
not permitted to start treatment (see Section 4.1.1 and Section 4.1.2)
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 medication as follows:
Loading dose of loperamide 4 mg orally 30 minutes before first administration of 
study medication (applicable to all treatment cycles)
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 hours.
Rule out other or concomitant causes, including medications (e.g., stool softeners, 
laxatives, and antacids), Clostridium 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 intravenous (IV) fluids as clinically indicated and aim at all times for 
electrolyte correction.


Appendix 14
Toxicity Management Guidelines (cont.)
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Table 1
Diarrhea Management According to CTCAE Grade
Diarrhea Grade
Recommended Actions
Grade 1/2

See all supportive recommendations indicated above (i.e., 
loperamide, symptomatic management, dietary counselling, 
rehydration, and electrolyte correction).

No change in study medication dose will be implemented for 
Grade2 diarrhea; patients should receive maximal supportive care 
as described above.

If diarrhea persists after 48 72 hours despite administration of the 
maximum recommended daily loperamide dose (16 mg/24 hours), 
second-line agents may be considered.
Grade 3

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 hours).

If no improvement is observed within 24 hours, test for CDI.

If, despite adequate supportive care, Grade 3 diarrhea persists 
48 hours without responding to loperamide at the maximum 
recommended daily dose (16 mg/24 hours), reduction of the 
idasanutlin/placebo dose to 50% may be considered.

If clinical characteristics have NOT improved to Grade 1 or 
baseline by 28 days despite the patient receiving maximal supportive 
care, idasanutlin/placebo must be permanently discontinued.

If the diarrhea recurs at Grade 3 despite supportive care and 
idasanutlin dose reduction, idasanutlin/placebo must be permanently 
discontinued.
Grade 4 

If, despite prophylaxis and adequate supportive care, Grade 4 
diarrhea is diagnosed, idasanutlin/placebo must be permanently 
discontinued.

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 hours).

If no improvement is observed within 24 hours, test for CDI.
CDIClostridium difficile infection; CTCAECommon Terminology Criteria for Adverse Events.


Appendix 14
Toxicity Management Guidelines (cont.)
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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
antibiotics, decreased leukocyte count, decreased albumin, and increased temperature, 
and increased ATLAS score).  Regardless, prophylactic anti-microbial therapy MUST be 
administered to all patients (see Section 4.3.3).

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 (see Section 4.1.1 and Section 4.1.2).
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.


Appendix 14
Toxicity Management Guidelines (cont.)
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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 administered 
idasanutlin in combination with cytarabine.  International guidelines on antiemesis 
prophylaxis for moderately emetogenic agents MUST be followed (Roila et al. 2010; 
NCCN Clinical Practice Guidelines in Oncology V.1 2012; Hesketh et al. 2016).
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 (applicable to all treatment cycles).  Emesis
should be managed symptomatically throughout the study conduct.

3060 minutes before administration of study medication
Preferably long acting 5-HT3-receptor antagonist (RA) orally (PO) or IV on Day 1 of 
the treatment cycle (palonosetron IV 0.25 mg or PO 0.5 mg); otherwise, 
short-acting 5-HT3-RA PO or IV on Days 15
Dexamethasone 12 mg PO/IV on Day 1 then 8 mg PO on Days 2–5 (may also 
reduce cytarabine-induced skin toxicity)
Rescue medication:  Consider adding a NK-1 RA (aprepitant 125 mg PO on Day 1, 
then 80 mg PO daily, fosaprepitant 150 mg IV on Day 1 or switch to PO fixed-
combination netupitant/palonosetron [dexamethasone dose should be adjusted if 
netupitant/palonosetron is administered]).
Administer IV fluids and correct electrolytes as clinically required.

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 (see Section 4.4.2 for information on prohibited 
concomitant medication).  

Prior to first administration of study medication


Appendix 14
Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
154
Patients should be carefully screened for evidence of active/uncontrolled infections prior 
to enrollment.  Patients receiving antimicrobial agents with therapeutic intent (as noted in 
the exclusion criteria) are not permitted to begin treatment (see Section 4.1.1 and 
Section 4.1.2)

Mandatory antifungal prophylaxis (applicable to all treatment cycles)
Recommended: 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.

Mandatory antibacterial prophylaxis (applicable to all treatment cycles)
Recommended: 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; refer to Section 4.4.2).
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 (see Schedule of Assessments in Appendix 1).

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).  The hemoglobin level should 
be maintained at 9 g/dL in patients with documented cardiac insufficiency (ejection 
fraction 50%).


Appendix 14
Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
155
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 
(Flowers et al. 2013; de Naurois et al. 2010; Montesinos et al. 2008).
TUMOR LYSIS SYNDROME MANAGEMENT GUIDELINES
Five cases with laboratory evidence of tumor lysis syndrome (TLS) have been reported 
in AML patients 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 (see Section 4.1.2).

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).  
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


Appendix 14
Toxicity Management Guidelines (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
156
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. Annals of Oncology 2010;21(Supplement 5):v252–
v256.
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(6):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.
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(1):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. 


Idasanutlin—F. Hoffmann-La Roche Ltd
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157
Appendix 15
Hematopoietic Cell Transplantation-Specific Comorbidity Index
Comorbidity a
Definitions of Comorbidities Included in the New HCT-CI
HCT-CI 
Weighted 
Scores
Arrhythmia
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias
1
Cardiac b
Coronary artery disease, c congestive heart failure, 
myocardial infarction, or EF 50%
1
Inflammatory bowel 
disease
Crohn disease or ulcerative colitis
1
Diabetes
Requiring treatment with insulin or oral hypoglycemics but 
not diet alone
1
Cerebrovascular 
disease
Transient ischemic attack or cerebrovascular accident
1
Psychiatric disturbance 
d
Depression or anxiety requiring psychiatric consult or 
treatment
1
Hepatic, mild b
Chronic hepatitis, bilirubinULN to 1.5ULN, or 
AST/ALT ULN to 2.5ULN
1
Obesity d
Patients with a body mass index 35 kg/m2
1
Infection d
Requiring continuation of antimicrobial treatment after Day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD, or polymyalgia 
rheumatica
2
Peptic ulcer
Requiring treatment
2
Moderate/severe renal 
b
Serum creatinine2 mg/dL, on dialysis, or prior renal 
transplantation
2
Moderate pulmonary b
DLCO and/or FEV1 66%80% or dyspnea on slight activity
2
Prior solid tumor b
Treated at any timepoint in the patient’s past history, 
excluding nonmelanoma skin cancer
3
Heart valve disease
Except mitral valve prolapse
3
Severe pulmonary b
DLCO and/or FEV165% or dyspnea at rest or requiring 
oxygen
3
Moderate/severe 
hepatic b
Liver cirrhosis, bilirubin1.5ULN, or AST/ALT 2.5ULN
3
CCICharlson Comorbidity Index; CTDconnective tissue disease; DLCOdiffusion capacity of 
carbon monoxide; EFejection fraction; HCT-CIhematopoietic cell transplantation-specific 
comorbidity index; RArheumatoid arthritis; SLEsystemic lupus erythematosus; ULNupper 
limit of normal.
Note:  To convert creatinine from milligrams per deciliter to micromoles per liter, multiply 
milligrams per deciliter by 88.4.
a Definitions of comorbidities included in the original CCI are defined in the appendix of a prior 
publication (Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-


Appendix 15
Hematopoietic Cell Transplantation-Specific Comorbidity Index
(cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
158
383.).
b Comorbidities with modified definitions compared with the original CCI.
c One or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass 
graft.
d Newly investigated comorbidities.
Adapted from Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-
specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 
2005;106(8):29129.


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159
Appendix 16
Eligibility Flow Chart for Prior Lines of Therapy
This flow chart provides guidance on how prior lines of therapy may impact eligibility.
The regimens shown are examples commonly used in clinical practice. Please note that 
to be eligible a patient must comply with all eligibility criteria as listed in Sections 4.1.1
and 4.1.2.


Appendix 16
Eligibility Flow Chart for Prior Lines of Therapy (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
160
Table 1
Conventional and Novel Cytotoxic Salvage Chemotherapy 
Regimens Utilized in Patients with Relapsed/Refractory Acute 
Myeloid Leukemia
Regimen
Agents
HIDAC
Cytarabine 3 g/m2 every 12 h days 1–6
FLAG FLAG-IDA
Fludarabine 30 mg/m2 days 1–5
Cytarabine 2 g/m2 days 1–5
G-CSF 5 mcg/kg day 0 until ANC recovery
Fludarabine 30 mg/m2 days 1–5
Cytarabine 2 g/m2 days 1–5
G-CSF 300 mcg day 0 until ANC recovery
Idarubicin 8 mg/m2 days 1–3
FLA
Fludarabine 30 mg/m2 days 1–5
Cytarabine 2 g/m2 days 1–5
CLAG CLAG-M
Cladribine 5 mg/m2 days 2–6
Cytarabine 2 g/m2 days 2–6
G-CSF 300 mcg days 1–6
Cladribine 5 mg/m2 days 1–5
Cytarabine 2 g/m2 days 1–5
G-CSF 300 mcg days 0–5
Mitoxantrone 10 mg/m2 days 1–3
MEC
Mitoxantrone 6 mg/m2 days 1–6
Etoposide 80 mg/m2 days 1–6
Cytarabine 1 g/m2 days 1–6
Mitoxantrone 8 mg/m2 days 1–5
Etoposide 100 mg/m2 days 1–5
Cytarabine 1 mg/m2 days 1–5


Appendix 16
Eligibility Flow Chart for Prior Lines of Therapy (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
161
Table 1
Conventional and Novel Cytotoxic Salvage Chemotherapy 
Regimens Utilized in Patients with Relapsed/Refractory Acute 
Myeloid Leukemia (cont.)
Regimen
Agents
MEC/Decitabine
Decitabine 20 mg/m2 days 1–10
Mitoxantrone 8 mg/m2 days 16–20
Etoposide 100 mg/m2 days 16–20
Cytarabine 1 mg/m2 days 16–20
EMA-86
Mitoxantrone 12 mg/m2 days 1–3
Cytarabine 500 mg/m2 CI days 1–3 & 8–10
Etoposide 200 mg/m2 CI days 8–10
MAV
Mitoxantrone 10 mg/m2 days 4–8
Cytarabine 100 mg/m2 CI days 1–8
Etoposide 100–120 mg/m2 days 4–8
FLAD
Fludarabine 30 mg/m2 days 1–3
Cytarabine 2 g/m2 days 1–3
Liposomal daunorubicin 100 mg/m2 days 1–3
FLAM
Flavopiridol 50 mg/m2 days 1–3
Cytarabine 2 g/m2/72 h starting day 6
Mitoxantrone 40 mg/m2 day 9
Hybrid FLAM
Flavopiridol 30mg/m2 bolus, 60 mg/m2 over 4 h days 1–3
Cytarabine 2 g/m2/72 h starting day 6
Mitoxantrone 40 mg/m2 day 9
Clofarabine Cytarabine
Clofarabine 40 mg/m2 days 2–6
Cytarabine 1 g/m2 days 1–5
Clofarabine 40 mg/m2 days 1–5; Cytarabine 1 g/m2 days 1–5
Clofarabine 22.5 mg/m2 days 1–5; Cytarabine 1 g/m2 days 1–
5
GCLAC
Clofarabine 25 mg/m2 days 1–5; Cytarabine 2 g/m2 days 1–5; 
G-CSF 5 mcg/kg day 0 until ANC recovery


Appendix 16
Eligibility Flow Chart for Prior Lines of Therapy (cont.)
Idasanutlin—F. Hoffmann-La Roche Ltd
Protocol WO29519, Version 6
162
Table 1
Conventional and Novel Cytotoxic Salvage Chemotherapy 
Regimens Utilized in Patients with Relapsed/Refractory Acute 
Myeloid Leukemia (cont.)
HAA
Homoharringtonine 4 mg/m2 days 1–3
Cytarabine 150 mg/m2 days 1–7
Aclarubicin 12 mg/m2 days 1–7
CPX 351
CPX 351 101 units/m2 days 1, 3, and 5
CPX 351 100 units/m2 days 1, 3, 5 (first induction) and days 
1 and 3 (second induction and consolidation)
CIcontinuous infusion; G-CSFgranulocyte colony stimulating factor; HIDAChigh-dose 
arabinoside cytarabine. 
Adapted from Ramos NR, Mo CC, Karp JE, et al. Current approaches in the treatment of 
relapsed and refractory acute myeloid leukemia. Journal of Clinical Medicine 2015 4(4): 665-695.
REFERENCES
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. 
Acute myeloid leukemia [resource on the Internet]. 2015 Available after registration 
from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Ramos NR, Mo CC, Karp JE, et al. Current approaches in the treatment of relapsed and 
refractory acute myeloid leukemia. Journal of Clinical Medicine 2015;4(4):665-695.

SAP_001.pdf: 
 
Official Title: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 
III Study of Idasanutlin, an MDM2 Antagonist, With Cytarabine Versus 
Cytarabine Plus Placebo in Patients With Relapsed or Refractory 
Acute Myeloid Leukemia (AML) 
NCT Number: NCT02545283 
Document Date: SAP Version 3: 30-September-2019 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO29519 Version 3 
STATISTICAL ANALYSIS PLAN
TITLE:
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PHASE III STUDY OF 
IDASANUTLIN, AN MDM2 ANTAGONIST, WITH 
CYTARABINE VERSUS CYTARABINE PLUS
PLACEBO IN PATIENTS WITH RELAPSED OR 
REFRACTORY ACUTE MYELOID LEUKEMIA (AML)
PROTOCOL NUMBER:
WO29519
STUDY DRUG:
Idasanutlin (RO5503781)
VERSION NUMBER:
3
EUDRACT NUMBER:
2014-003065-15
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
, M.Sc.
, M.Sc.
DATE FINAL:
25 September 2019
Date and Time(UTC)        Reason for Signing                              Name
30-Sep-2019 14:40:49
Company Signatory


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO29519 Version 3 
RATIONALE FOR STATISTICAL ANALYSIS PLAN VERSION 3
The purpose of this draft statistical analysis plan amendment (Version 3) is to 
provide updates accompanying protocol version 6 as follows:  

To add an interim analysis for OS at an information fraction of 80%.

To update the primary/secondary analysis population to only TP53 wild type
(WT) Intent-to-treat (ITT) patients (all ITT patients are only assessed in 
exploratory endpoints), and to add the definition of the TP53 WT ITT primary 
population.  

To redefine list and order of hierarchical testing framework for secondary 
endpoints

To add exploratory endpoints

To add sensitivity analyses 

To make handling of missing data more precise


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO29519 Version 3 
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 7
2.2
Outcome Measures ................................................................. 7
2.2.1
Primary Efficacy Outcome Measures ...................................... 7
2.2.2
Secondary Efficacy Outcome Measures.................................. 7
2.2.3
Safety Outcome Measures ...................................................... 8
2.2.4
Exploratory Outcome Measures .............................................. 8
2.2.5
Pharmacokinetic Outcome Measures...................................... 9
2.2.6
Patient-Reported Outcome Measures ..................................... 9
2.3
Determination of Sample Size ............................................... 10
2.4
Analysis Timing ..................................................................... 11
3.
STUDY CONDUCT..................................................................................... 11
3.1
Randomization Issues ........................................................... 11
3.2
Data Monitoring ..................................................................... 12
4.
STATISTICAL METHODS .......................................................................... 13
4.1
Analysis Populations ............................................................. 13
4.1.1
Randomized Population......................................................... 13
4.1.1.1
TP53 Wild type Intent-to-Treat Primary 
Population.............................................................................. 13
4.1.1.2
All-Patient Intent-to-Treat Population..................................... 13
4.1.2
Per Protocol Population......................................................... 13
4.1.3
Pharmacokinetic-Evaluable Population ................................. 14
4.1.4
Safety Population .................................................................. 14
4.2
Analysis of Study Conduct..................................................... 14
4.3
Analysis of Treatment Group Comparability .......................... 14
4.4
Efficacy Analysis.................................................................... 15
4.4.1
Primary Efficacy Endpoint...................................................... 15
4.4.2
Secondary Efficacy Endpoints............................................... 16
4.4.3
Sensitivity Analyses:.............................................................. 17
4.4.4
Subgroup Analyses ............................................................... 18


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WO29519 Version 3 
4.5
Pharmacodynamic and Biomarker Analyses ......................... 18
4.6
Pharmacokinetic Analyses..................................................... 19
4.7
Safety Analyses..................................................................... 19
4.7.1
Exposure of Study Medication............................................... 19
4.7.2
Adverse Events ..................................................................... 19
4.7.3
Laboratory Data..................................................................... 20
4.7.4
Vital Signs.............................................................................. 21
4.7.5
ECGs..................................................................................... 21
4.8
Patient-Reported Outcomes .................................................. 21
4.8.1
EORTC QLQ-C30.................................................................. 22
4.9
Exploratory Analyses............................................................. 23
4.10
Missing Data.......................................................................... 24
4.11
Interim Analyses .................................................................... 25
4.11.1
Futility Interim Analysis.......................................................... 25
4.11.2
Safety Interim Analysis .......................................................... 26
4.11.3
Efficacy Interim Analysis........................................................ 26
5.
REFERENCES ........................................................................................... 27
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
/,67 2) APPENDICES
Appendix 1     WO29519 Protocol Synopsis………………………….……….........28
Appendix 2     Calling Rules to Define TP53 WT Intent-to-treat Primary  
Population…………………………………………………….……….38


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan WO29519 Version 3 
1.
BACKGROUND
This document is based on the statistical section of the study protocol and will 
provide more details to the planned statistical analyses.  Any analyses that 
deviate from or are added to those outlined in the protocol will be delineated in 
this document. 
Study WO29519 was developed to examine the efficacy and safety of idasanutlin 
(RO5503781) in combination with cytarabine (idasanutlincytarabine) in patients 
with relapsed or refractory acute myeloid leukemia (AML) compared with placebo 
in combination with cytarabine (placebocytarabine).
2.
STUDY DESIGN
This is a Phase III, multicenter, double-blind, randomized, placebo-controlled 
study comparing the efficacy and safety of idasanutlincytarabine versus 
placebocytarabine in patients with relapsed or refractory AML. 
Approximately 440 patients with AML who have relapsed following or are 
refractory to cytarabine-containing standard induction chemotherapy after one or 
two prior cytarabine-containing induction chemotherapy regimen(s) are planned 
to be enrolled (see study schema in Figure 1).   
Patients will be enrolled from approximately 80 centers in 18 countries across 
Europe, the Americas, and the Asia-Pacific region.  Patients will be randomized 
in a 2:1 ratio to receive either idasanutlincytarabine (i.e., the experimental 
treatment arm) or placebocytarabine (i.e., the control treatment arm).  The 
randomization will be stratified by age (60 years old vs. 60 years old), 
cytogenetic and molecular risk (favorable/intermediate vs. adverse) at initial 
diagnosis, prior response to initial anti-leukemic therapy (refractory vs. CR 90 
days but 1 year vs. CR 1 year), and prior autologous or allogeneic 
hematopoietic stem cell transplant (HSCT) versus no prior HSCT. 
Patients will receive induction treatment during Cycle 1 with 300 mg idasanutlin 
or placebo twice a day and 1 g/m2 cytarabine for 5 days followed by 23 days of 
rest.  If needed, an additional 4 weeks up to Day 56 can be used to allow for 
blood count recovery.  For patients who achieve clinical response after induction 
and for whom HSCT for consolidation is not an option, it is strongly 
recommended to continue study medication with a maximum of two additional 
cycles of consolidation (Cycles 2 and 3) unless clinically contraindicated.   
Patients who have a good partial response (PR) at the end of Cycle 1, can 
receive another cycle of induction upon Sponsor’s approval, and their responses 
will not be taken into account for the interim futility analysis under Version 3 of 
the protocol.


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan WO29519 Version 3 
Figure 1
Study Schema
AML acute myeloid leukemia; BID twice daily; CR complete remission; HSCT hematopoietic stem 
cell transplant; IV intravenous; OS overall survival; PO orally; WT wild type
Idasanutlin interferes with the binding of MDM2 to tumor protein -53 (TP53), 
thereby stabilizing p53 and allowing it to exert its anti-tumor activity. Because not 
all TP53 mutations lead to a loss-of-function of the p53 protein, some patients 
with mutant TP53 may still respond to treatment.  The study will therefore allow 
enrolment of all patients irrespective of TP53 mutation status. However, to best 
assess idasanutlin efficacy in AML, the primary analysis will be tested in TP53 
WT patients (see definition in section 4.1.1.1 and Appendix 2), representing 
about 85% of all patients enrolled.  It is expected that about 15% of the enrolled 
patients in this study will carry a TP53 mutation.  
Prior to the final analysis, a non-binding interim analysis for futility is planned as 
well as a binding interim analysis for efficacy.  Both interim analyses will be 
conducted by an iDMC (independent Data Monitoring Committee).


Idasanutlin (RO5503781)—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan WO29519 Version 3 
The futility interim analysis will be based on the endpoints of confirmed CR + CR 
with incomplete platelet recovery (CRp), event-free survival (EFS), and other 
safety data (see details of data monitoring in Section 3.2).  
The interim analysis for efficacy on OS is planned at an information 
fraction of 80% OS events (220 OS events) in TP53 WT patients (see 
Section 4.11.3).
Accompanying this efficacy-interim-analysis, a non-binding futility assessment 
will be performed based on an OS hazard ratio (HR) greater than or equal to one.
With regard to study continuation on the basis of OS data at the interim efficacy 
analysis, a final OS analysis would occur at 275 OS events in TP53 WT patients 
and a follow up OS analysis will occur at end of study. 
2.1
PROTOCOL SYNOPSIS
The protocol synopsis is in   
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Outcome Measures
The primary endpoint for this study is OS in the TP53 WT population. OS is 
defined as the time from randomization to death from any cause. OS for patients 
who have not died at the time of the analysis will be censored at the last date the 
patient was known to be alive.
2.2.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are as follows, for the 
TP53 WT population: 

CR is defined as a complete remission as reported by the investigator over
the induction cycle (Cycle 1).

EFS is defined as the time from the date of randomization to treatment failure 
(failure to achieve CR, set as day of final response assessment), relapse 
from CR, or death from any cause, whichever occurs first.  Patients with no 
EFS event will be censored at the date of last response assessment (pre-
HSCT) or last date known to be alive (post-HSCT).  Patients with no EFS 
event and no post-baseline response assessment will be censored at date of 
randomization.  

Overall remission (ORR; CR, CRp, and complete remission with incomplete 
blood count recovery [CRi]) over the induction cycle (Cycle 1)

DOR (or Duration of CR) is defined only for patients who achieve a CR and is 
measured from the date of achievement of CR until the date of relapse from 
CR, or death from any cause.  Patients who do not have a DOR event will be 


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censored the date of last response assessment (pre-HSCT) or last known 
alive date (post-HSCT). 

The proportion of HSCT following a CR is defined as proportion of patients 
undergoing allogeneic HSCT following the corresponding CR

CR in clinically actionable mutation defined subpopulations (FLT3, 
IDH1 and IDH2)  

OS in clinically actionable mutation defined subpopulations (FLT3, 
IDH2 and IDH2)
2.2.3
Safety Outcome Measures
The safety and tolerability of idasanutlincytarabine in comparison with 
placebocytarabine will be assessed on both the TP53 WT safety population 
and the all-patient safety population using the following safety outcome 
measures: 

Incidence, nature, severity, and seriousness of adverse events 

Incidence of clinically significant laboratory abnormalities

Electrocardiograms (ECGs)

Vital signs

Death, including 30- and 60-day mortality rates
2.2.4
Exploratory Outcome Measures
The pharmacodynamic (PD)/biomarker outcome measures for this study are as 
follows: 

PD biomarkers and other biomarkers (e.g., protein, nucleic acid, and other 
tumor cell-derived markers related to the mechanism of action of the study 
drug, which include, but are not limited to, markers of MDM2 or p53 pathway 
alterations) that may help predict patient subpopulations who are more likely 
to respond to the therapies in this study.

Minimal residual disease (MRD) 

Kinetics of MRD by flow cytometry and association of MRD response 
with outcomes  

MRD by tracking AML-specific mutations and translocations and/ or 
expression of AML-related genes such as Wilms tumor 1 [WT1])

Prognostic value of disease related mutations 

Serum macrophage inhibitory cytokine-1 (MIC-1) profile (raw and/or adjusted 
from baseline as a percentage of change)

4-gene signatures by quantitative real-time polymerase chain reaction (qRT-
PCR) as well as gene expression levels of the individual components of the 
signature (including MDM2)


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
MDM2 protein expression measured by flow analysis 
The efficacy exploratory Outcome Measures are as follows: 

Rate of CRMRD (CR without MRD as per European LeukemiaNet [ELN] 
guidelines [Dohner 2017] at a 0.1% cut-off for negativity as per ELN MRD 
working party consensus [Schuurhuis 2018]) within the ITT-all-patient and 
TP53 WT populations 

OS within the ITT-all-patient population 

Secondary efficacy endpoints within the ITT-all-patient population.

CR during treatment: defined as complete remission as reported by the 
investigator at any time during treatment

The proportion of HSCT as proportion of patients undergoing allogeneic 
HSCT regardless of response

The proportion of HSCT following a CR/CRp/CRi is defined as proportion of 
patients undergoing allogeneic HSCT following the corresponding response 
(i.e. CR or CRp or Cri)  

Leukemia-free Survival (LFS, or duration of OR) is defined only for patients who 
achieve a remission (CR, CRp, or CRi) and is measured from the date of 
achievement of remission until the date of relapse from CR, CRp, CRi, or death 
from any cause. Patients who do not have an LFS event will be censored at the 
date of last response assessment. 
2.2.5
Pharmacokinetic Outcome Measures
The pharmacokinetic (PK) outcome measures for this study are as follows: 

Apparent clearance and apparent volume of distribution as well as the 
maximum concentration observed in plasma (Cmax), steady-state 
concentration at the end of a dosing interval (i.e., just prior to next drug 
administration [Ctrough]), area under the concentration–time curve during one 
dosing interval, area under the concentrationtime curve from 0 to 24 hours, 
and half-life of idasanutlin (and M4 metabolite RO6802287)

Total clearance and volume of distribution of cytarabine

Effect of idasanutlin on cytarabine PK

Effect of cytarabine on idasanutlin PK
The PK outcome measures will be investigated by the Roche Modeling and 
Simulation group.  Results of the PK analyses will be reported in the population 
PK report.
2.2.6
Patient-Reported Outcome Measures
The patient-reported outcome (PRO) measures for this study are as follows: 

European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30)


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
EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire
2.3
DETERMINATION OF SAMPLE SIZE
A mechanistic simulation model was used to determine sample size based on the 
following assumptions:

Final analysis on OS in patients with TP53 wild type (WT) using a 2-sided 
log-rank test at the 5% significance level

85% power to detect an OS HR (HR) of 0.67 for idasanutlin cytarabine 
versus placebo cytarabine in patients with TP53 WT, corresponding to a 33% 
risk reduction of death, corresponding to an improvement in median OS from 
6 months to 9 months (50%)

Proportions of long-term survivors of 8.0% in the placebo cytarabine
treatment arm and 16.1% in the idasanutlin cytarabine treatment arm
To compute the necessary number of events, OS times were simulated based on 
the following assumptions:

All simulated OS times for patients not considered to be long-term survivors 
were exponentially distributed.

Probability of being a CR in the placebo cytarabine treatment arm was 0.16.

Probability of being a CR in the idasanutlin cytarabine treatment arm was 
0.323, implying an odds ratio for CR of 2.5 for idasanutlin cytarabine versus 
placebo cytarabine.

Probability for a CR to be a long-term survivor was 0.5 in either treatment 
arm.

An annual dropout rate was 5%.
Based on these assumptions, approximately 275 OS events in patients with 
TP53 WT are required to provide 85% power for the primary analysis.  The 
minimum detectable OS HR in this study is 0.78, assuming 275 OS events and a 
significance level of 5%, which corresponds to a minimal detectable median 
improvement from 6 to 7.7 months assuming exponentiality.  
All patients will be randomized in this study.  Assuming 85% of patients will have 
TP53 WT and 15% will have TP53 mutant disease, approximately 440 patients 
will be enrolled over approximately 29 months, corresponding to an estimated 
number of 374 patients with TP53 WT. 
In Version 6 of the protocol, an interim analysis for efficacy on OS of TP53 WT 
patients was added. The sample size assumptions above remain unchanged
other than the recruitment time (now estimated as 41 months). The interim 
analysis will occur at an information-fraction of 80% providing a power of 83% for 
the final OS analysis (see section 4.11.3).


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2.4
ANALYSIS TIMING
The final OS analysis will occur when approximately 275 OS events in patients 
with TP53 WT have been observed.  It is expected that this analysis will take 
place approximately 4 years after enrollment start (assuming 9 TP53 WT patients 
enrolled per month).
A follow up (updated) OS analysis will be performed at the end of the study, 
expected approximately 5.5 years after enrollment start (2 years after the last 
patient is enrolled or after all patients have died, whichever occurs first).
A non-binding futility interim analysis will be performed by the independent data 
coordinating center (iDCC) and reviewed by the independent Data Monitoring 
Committee (iDMC).  The futility interim analysis will be based on the confirmed 
CR response, which is defined in Section 4.4.2. 
At the time of the study design, the timing of the futility and final analyses have 
been estimated assuming that on average 12 patients per month are enrolled for 
the first 15 months, followed by 18 patients per month for 14 months and 8 
patients for the last month. 
It was expected that the futility interim analysis will occur approximately 18 
months after study start.  Further details on the interim analyses, such as 
stopping rules and criteria, are provided in the iDMC charter and in section 4.11.
An interim OS analysis will occur at an information-fraction of 80% (see Section 
4.11.3).
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Approximately 440 patients will be enrolled in this 2:1 randomized trial, 
corresponding to a higher probability to be in the idasanutlincytarabine 
treatment arm (i.e., about 293 patients in the idasanutlincytarabine treatment 
arm and 147 patients in the placebocytarabine treatment arm). 
Randomization will be performed through the interactive web response system 
(IWRS) using a stratified permuted block randomization scheme.  The 
randomization stratification factors are as follows:

Age (60 years vs. 60 years)

Cytogenetic and molecular risk (favorable/intermediate vs. adverse) at initial 
diagnosis

Prior response to initial anti-leukemic therapy (refractory vs. CR 90 days 
but 1 year vs. CR 1 year)


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
Prior HSCT versus no prior HSCT
Discordance between the IWRS and the electronic Case Report Form (eCRF) 
data will be summarized.
This is a double-blind study (i.e., neither the sponsor personnel, the patients, nor 
the treating physician will know the assigned treatment arm).  However, the 
randomization code will be made available to the bioanalytical manager to 
facilitate the analysis of PK samples.
3.2
DATA MONITORING
An iDMC will be used to assess patient safety and treatment efficacy at defined 
intervals.  Specific details of the schedule of iDMC activities can be found in the 
iDMC charter.  
The iDMC will first meet to assess the safety of the study after 30 patients have 
been enrolled and completed the first cycle with clinical response assessment 
available.  Thereafter, the iDMC will have regular safety review meetings 
approximately every 3 months until the futility interim analysis.  After this interim 
futility analysis, the iDMC will meet approximately every 6 months to assess the 
safety of the study.  In addition, the iDMC will perform an interim efficacy analysis 
on OS at an information-fraction of 80% (see section 4.11.3). Both the Sponsor 
and the iDMC can request ad hoc iDMC meetings for any reason. 
Following each meeting, the iDMC will recommend to the Sponsor whether the 
study should continue according to the protocol or may suggest changes to the 
protocol based on the outcome of data review.   
At the futility interim analysis, the iDMC will also perform an ordinary safety 
review and a review of biomarker data.  The iDMC will make recommendations 
on the following:

Safety monitoring (including gastrointestinal toxicity and early death criteria)

ECG monitoring 

Biomarker classification (see Section 4.5)
The details about the iDMC recommendation after the futility interim analysis are
described in Section 4.11.1, each safety analysis in section 4.11.2 and the 
interim efficacy analysis in section 4.11.3. 
The Sponsor will make the final decision for continuation or discontinuation of the 
study, or early unblinding, on the basis of the iDMC’s recommendation (see 
Section 6.4 of the iDMC Charter).


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4.
STATISTICAL METHODS
Except where specified otherwise, continuous data will be summarized with 
descriptive statistics (number of non-missing data, mean, standard deviation, 
median, minimum, and maximum).  Categorical parameters data will be 
described using frequencies and percentages.
Descriptive summaries will be provided by treatment group.  The main treatment 
comparison is between idasanutlincytarabine and placebocytarabine in TP53
WT patients and all patients who have been randomized.  All the statistical tests 
will be 2-sided.
4.1
ANALYSIS POPULATIONS
4.1.1
Randomized Population
4.1.1.1
TP53 Wild type Intent-to-Treat Primary Population
All randomized TP53 WT patients will be included in the TP53 intent-to-treat 
(TP53 ITT) population.  The TP53 ITT population is the primary population for the 
analysis of the primary and secondary efficacy endpoints (see 4.4).  Efficacy 
analyses will be done according to the randomized treatment arm regardless of 
which treatments the patients received. 
Patients with wild-type TP53 and TP53 mutants with retained functionality will, 
together, form the TP53 WT ITT primary population based on the variant types 
as described in Appendix 2.
The futility interim analysis population will comprise the first 120 patients with 
TP53 WT who were randomized, have received at least 80% of first treatment 
cycle (of the total planned dose of each study compound) and have data for 
response (including confirmed response for those with CR, CRp at end of Cycle 
1) or who were withdrawn before time of response/confirmation.
4.1.1.2
All-Patient Intent-to-Treat Population
All randomized patients, that is, patients who areTP53 WT or mutant or with a 
mutation status at screening unknown, will be included in the intent-to-treat (ITT) 
population.  Efficacy analyses will be done according to the randomized 
treatment arm regardless of which treatments the patients received. 
4.1.2
Per Protocol Population
A per protocol analysis population is not defined for this study.  Major protocol 
deviations will be summarized by treatment arm.


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4.1.3
Pharmacokinetic-Evaluable Population
The PK-evaluable population includes all patients with PK data.  PK analyses will 
be performed on the PK-evaluable population according to the treatment the 
patients received. 
4.1.4
Safety Population
The all-patient safety population will include all patients who received any 
amount of study drug (i.e., idasanutlin, placebo, or cytarabine) and the safety 
TP53 WT population will include all patients with TP53 WT and TP53 mutants 
with retained functionality based on the variant types as described in Appendix 2
who have received any amount of study drug.  Patients will be analyzed 
according to the received treatment, that is, patients who received at least one 
dose of idasanutlin for whatever reason will be analyzed under the 
idasanutlincytarabine treatment arm.  Patients who only received cytarabine 
and/or placebo will be analyzed under the placebocytarabine treatment arm.  
4.2
ANALYSIS OF STUDY CONDUCT
The following analyses of study conduct will be provided by treatment arm for all 
randomized patients unless specified differently: 

A summary of the randomized patients by treatment arm, center, and country

A summary of the analysis populations 

A summary of the patient disposition, study treatment administration, and 
reasons for study treatment discontinuation

A summary of observation time

A summary of the major protocol deviations 
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Descriptive summaries will be provided by treatment arm.  These will include, but 
are not limited to, the following parameters: 

Stratification factors
Age (60 vs. 60 years)
Cytogenetic and molecular risk (favorable/intermediate vs. adverse)
Prior response to initial anti-leukemic therapy (refractory vs. CR 3 
months but 1 year vs. CR 1 year)
Prior HSCT versus no prior HSCT

Demographic characteristics at baseline:
Gender
Age (years)
Race


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Eastern Cooperative Oncology Group performance status 

AML disease characteristics at baseline
AML disease status at study entry (first relapse, second relapse, first 
refractory to induction, or second refractory to induction)
Number of prior treatment regimens 
European LeukemiaNet Risk category at initial diagnosis
TP53 status
Type of previous HSCT (allogenic vs. autologous)
Should country policy prohibit the collection of race and/or age information, 
patients will appear in the missing category of summary tables.
4.4
EFFICACY ANALYSIS
The primary and secondary efficacy outcomes will be assessed for the TP53 WT
ITT population (primary population), as defined in Section 4.1.1.1. 
4.4.1
Primary Efficacy Endpoint
The OS analysis will assess the null hypothesis of equality of OS distributions in 
the idasanutlincytarabine and placebocytarabine treatment arms in TP53 WT
patients:
H0:  OSidasanutlin cytarabineOSplacebocytarabine versus H1:  OSidasanutlin cytarabine≠OSplacebocytarabine
OS distributions will be compared between the treatment groups using a 2-sided 
stratified log-rank test at an overall significance α level of maximum 4%.  The 
stratification factors will be the randomization stratification factors:  age 
(60 years vs. 60 years), cytogenetic and molecular risk 
(favorable/intermediate vs. adverse), prior response to initial anti-leukemic 
therapy (refractory vs. CR 3 months but 1 year vs. CR 1 year) and prior 
HSCT versus no prior HSCT.  The IWRS data will be compared with the eCRF 
data for each patient.  For cases where there is a difference between the IWRS 
and eCRF data, the stratification factors as entered in the eCRF will be used in 
the primary endpoint analysis.
The OS survival curves in each treatment arm will be estimated using Kaplan-
Meier methodology and summarized using Kaplan-Meier plots.  The treatment 
effect of idasanutlincytarabine versus placebocytarabine will be expressed as 
an HR using a stratified Cox proportional-hazard regression, including a 95% CI.  
In addition to the OS HR, 6-monthly OS probabilities and the estimated median 
OS in each arm (if reached) will be presented, including 95% CI.


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4.4.2
Secondary Efficacy Endpoints
The fixed-sequence testing procedure will be used (Westfall and Krishen 2001) 
to adjust for multiple statistical testing of the primary and key secondary efficacy 
endpoints, thereby controlling the overall type I error rate at a 2-sided 
significance level of 5%.
The following secondary endpoints will be tested in the TP53 WT population in 
the following order provided the null hypothesis of the OS primary endpoint is 
rejected: 
1.
CR rate
2.
EFS 
3.
OR (CR, CRp and CRi) rate
4.
DOR (duration of CR) 
5.
Proportion of patients who received HSCT following CR
6.
CR rate in mutation defined subgroup: FLT3 
7.
OS in mutation defined subgroup: FLT3 
8.
CR rate in mutation defined subgroup: IDH2 
9.
OS in mutation defined subgroup: IDH2 
10. CR rate in mutation defined subgroup: IDH1 
11. OS in mutation defined subgroup: IDH1
A given hypothesis in the list above will only be rejected once all previous 
hypotheses have been rejected at the 2-sided significance level 5%.
Response will be evaluated according to the HMRA criteria (see protocol section 
4.5.8) as the best assessment of response over the induction cycle (cycle 1).  
The frequencies and percentages of patients assigned to each HMRA response 
category, that is, CR, CRp, CRi, non-responder (partial response [PR], stable 
disease [SD], resistant disease, relapsed disease, death in aplasia, and death 
from indeterminate cause), or not available (NA) will be summarized by treatment 
arm along with the 2-sided 95% CI according to the Pearson-Clopper method.  
For the interim futility analysis patients with no response assessments will be 
considered as NA, unless they directly proceeded to HSCT after Cycle 1.  These 
patients will be considered confirmed CR unless transplantation was clearly 
performed in relapse.  
Proportions of CR as well as ORR (CR, CRp, and CRi) and HSCT will be 
compared between the two treatment groups using Cochran–Mantel–Haenszel 
test stratified by the randomization stratification factors.  The effect of prognostic 
factors on these binary endpoints will be assessed in an exploratory analysis 
using logistic regression.


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The time-to-event endpoints, EFS and DOR, will be analyzed using the same 
statistical methods as described for the primary OS analysis.  If very few patients 
qualify for DOR analysis, only descriptive statistics of DOR will be given.
4.4.3
Sensitivity Analyses:
The following sensitivity analysis will be performed in the TP53 WT population 
and all-patient ITT population: 

An unstratified log-rank test for OS 

Discontinuation of assessments or patient lost to follow up considered as an 
OS event

An unstratified chi-squared test for CR  
A check of the proportional hazards assumption for OS will be performed by 
plotting the log negative log of the estimated survivor function against log time.
The following sensitivity analysis for OS will be performed in the ITT population:

A multivariate sensitivity analysis of OS in the ITT population using Cox 
proportional hazards multiple regression to assess the treatment effect after 
adjustment for TP53 mutation status.
To assess the relevance of new treatment for AML against other long-term 
effects, OS in the TP53 WT population will be alternatively defined with censoring 
at date of new treatment and analyzed using the same methods as for the 
primary OS endpoint
A sensitivity analysis of OS on the subset of patients TP53 WT (i.e. not including 
those with retained functionality) will be performed.
To assess the relevance of HSCT against other long-term effects, OS in the 
TP53 WT population will be alternatively defined with censoring at date of HSCT 
and analyzed using the same methods as for the primary OS endpoint. 
The confounding effect of HSCT on OS will be assessed using a Cox multivariate 
regression including major covariates (e.g., prior HSCT, HCT-CI score, leukemia 
status, type of donor and transplant, engraftment status, conditioning therapy 
type, site). Only covariates that are significant at 0.15 level in the univariate 
analysis will then be included in a multivariate analysis, and backward selections 
at the 5% level will be performed to obtain the model.
Different definitions of EFS will be assessed in sensitivity analyses, in which EFS 
is defined as  
a)
time from randomization to the date of treatment failure (failure to achieve CR, 
set as day 1), relapse from CR, or death from any cause, whichever comes 
first


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b)
time from randomization to the date of treatment failure (failure to achieve CR, 
CRp or CRi, set as day of final response assessment), relapse (from CR, CRp or 
CRi) or death from any cause, whichever comes first 
c)
time from randomization to the date of relapse from CR (for subjects who 
achieved CR) or death from any cause, whichever comes first
d)
the above definitions censoring at HSCT.
For time to event analysis the following sensitivity analyses will be performed:

Patients who report a new treatment post-randomization for follow-up cancer 
therapy will be considered as having an event (OS and EFS for respective 
sensitivity analysis) at time of new treatment intake.

Discontinuation of assessments or patient lost to follow up considered as an 
event (for OS, and EFS)
4.4.4
Subgroup Analyses
The effects of prognostic factors at baseline, as well as demographic and 
disease characteristics at baseline, on treatment comparisons for OS (in TP53
WT ITT population) will be examined and assessed using Cox multivariate 
regression.  
The estimated Kaplan-Meier OS event rates, as well as the HR estimated using 
an unstratified Cox regression model and 95% CI will be displayed by treatment 
arm for each level of the subgroup.  The subgroup analysis results will be 
displayed using forest plots (Lewis and Clarke 2001) for stratification factors, the 
demographic and disease characteristics at baseline, including history of AML.  
Descriptive statistics on disease and patient status as well as transplant 
procedure and engraftment use will be produced to support the analysis of
confounding effect of HSCT on OS.
The study is not powered to detect a treatment difference in subgroups.  Results 
from these analyses should be interpreted as exploratory. 
4.5
PHARMACODYNAMIC AND BIOMARKER ANALYSES
Exploratory analyses might be performed on bone marrow and blood specimens 
to identify and/or evaluate the presence of PD biomarker and other biomarkers 
that might help predict patient subpopulations that are more likely to respond to 
idasanutlincytarabine. 
The following PD and biomarker parameters will be presented in patient listings 
and descriptive summary statistics by treatment arm: 

Mic-1 protein levels in blood samples (analyzed by ELISA)


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
TP53 mutation status 

Rate of CRMRD (MRD response as per ELN guidelines) using multiparameter 
flow cytometry

Baseline expression levels of a 4-gene signature will be analyzed by qRT-
PCR from patient blood. The predictive or prognostic value of these markers 
will be analyzed at futility-interim analysis (gene signature) and at the time of 
primary analysis.  These biomarker analyses are exploratory and are not part 
of the futility interim analysis assessment.  However, the iDMC will make a 
recommendation based on the prognostic and potential value of these 
markers to inform the decision on how these markers will be further 
evaluated after the futility-interim analysis; see Section 6.4.4 of the iDMC 
Charter for further details. 

MDM2 protein expression in blasts may also be analyzed relative to patient 
outcomes at the end of study.
Details of the biomarker analyses will be described in a separate biomarker 
analysis plan. 
4.6
PHARMACOKINETIC ANALYSES
Details of the PK analyses will be described in the Modeling and Simulation 
Analysis Plan.  Results of this analysis will be reported separately.
4.7
SAFETY ANALYSES
The safety analysis population will be used for all safety analyses (Section 4.1.4). 
4.7.1
Exposure of Study Medication
Study treatment exposure (idasanutlincytarabine and placebocytarabine) will 
be summarized using descriptive statistics (by treatment arm) for the following 
measures:

Number of patients treated overall and by treatment cycle

Number of days on treatment

Study medication duration  

Number of treatment cycles started

Number of doses received and missed doses 

Cumulative dose received

Dose intensity

Number and reasons for dose modification and discontinuation
4.7.2
Adverse Events
Coding of adverse events will be done using the most recent version of the 
Medical Dictionary for Regulatory Activities (MedDRA).  All adverse events and 


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laboratory parameters will be assessed according to the National Cancer Institute 
Common Terminology Criteria for Adverse Event (NCI CTCAE) version 4.03 
grading system. 
All adverse events will be reported from the day of first study treatment.  All 
adverse events will be displayed by body system (system organ class), NCI 
CTCAE grade, and relation to study treatment.  All serious adverse events, 
Grade 3 adverse events, adverse events leading to death, adverse events 
leading to study treatment modification, adverse events leading to study 
treatment discontinuations, and adverse events leading to early study 
withdrawals will be summarized by treatment arm. 
Deaths and reason for deaths reported during the study will be summarized by 
treatment arm.  Deaths occurring within 30 and 60 days after randomization will 
also be summarized. 
In the summary tables showing the overall incidence of adverse events, patients 
who experienced the same event on more than one occasion will be counted 
only once in the calculation of the event frequency.  The adverse event with the 
most extreme intensity will be used for reporting.  
Additional analyses will be performed by treatment arm based on the selected 
adverse events of special interest, which are defined in the study protocol, as 
well as based on any adverse event, which might require further investigation.  
Analyses of the time to onset of these adverse events will be performed.  Time to 
adverse events will be listed.  Patients without an adverse event will be censored 
at last date known to be alive.
In order to account for potential differences in the duration of adverse event 
reporting between treatment groups, an exploratory analysis of selected adverse 
events by duration of exposure might be performed based on adverse event 
rates adjusted for patient-years at risk when enough events are observed. 
4.7.3
Laboratory Data
Laboratory data with values outside of the normal ranges will be identified.  
Laboratory values will be summarized by treatment arm and grade using the 
NCI-CTCAE version 4.03 grading system.  Shift tables will be used to present the 
number and percentage of patients with values within, above, or below the 
normal range comparing baseline to subsequent assessments by treatment arm.
Nadir is defined as the lowest value observed in the interval between Cycle 1, 
Day 1 up to and including predose on Cycle 2, Day 1.  If there is no Cycle 2, Day 
1 value, and the interval between Cycle 1 Day 1 and Cycle 2 Day 1 is not 
definable then the latest value in Cycle 1 will be used to define the interval. If no 


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value is lower than baseline (i.e., Cycle 1, Day 1 cannot be the nadir), then the 
nadir does not exist, and the patient is excluded from the analysis.
For all patients summary statistics and boxplots for time to nadir (in days) will be 
produced by treatment arm, as well as Kaplan Meier for time to nadir starting on 
study drug first administration.
Time to recovery is defined as the time until the value crossed back up and over 
100 for platelets and over the thresholds 0.5 or 1 for neutrophils after the interval 
between Cycle 1, Day 1 and the predose on Cycle 2, Day 1.  If there is no Cycle 
2, Day 1 value, then the latest value in Cycle 1 will be selected. Patients 
receiving a transfusion within 24 hours prior to the laboratory assessment 
selected will be excluded.
For responders only (CR, CRp, CRi), summary statistics and boxplots for time to 
recovery (in days) for both neutrophils and platelets will be produced by 
treatment arm, as well as Kaplan Meier for time to recovery starting on study 
drug first administration.
4.7.4
Vital Signs
Vital signs (absolute values and change from baseline) will be summarized by 
treatment arm over time without any replacement for missing data. 
4.7.5
ECGs
Incidence of clinically significant ECG abnormalities will be reported in patient 
listings.  ECG absolute values and change from baseline will be summarized by 
treatment arm.  ECG QT interval and QT interval with Fridericia’s correction will 
also be summarized. 
ECGs will also be analysed in combination with the PK data (area under the 
concentration–time curve [AUC] and Cmax) to assess the relationship between 
study drug plasma concentrations (AUC and Cmax) and correct QT interval 
duration.
4.8
PATIENT-REPORTED OUTCOMES
The PRO-evaluable population will include all randomized patients who have a 
baseline and at least one post-baseline PRO assessment.  The PRO-evaluable 
population will be used for descriptive analyses of visit summary and change 
from baseline, and responder analyses. All TP53 WT randomized patients will be 
used for completion analyses and time-to-event (improvement/deterioration) 
analyses. All PRO analyses will be performed based on the treatment arm 
assigned at randomization.


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4.8.1
EORTC QLQ-C30
The EORTC QLQ-C30 is composed of both multi-item and single-item scales 
scored 0 to 100. Scoring for the EORTC QLQ-C30 questionnaire will be based 
on the EORTC guidelines (Fayers et al. 2001).  Consistent with the EORTC 
guidelines, prorated scores will be computed for a multi-item scale if more than 
50% of the constituent items have been completed for that scale.  For multi-item 
scales with less than 50% of the items completed, the scale will be considered as 
missing. Values for missing single-item scales will not be imputed.
Completion analysis will be performed for the overall EORTC QLQ-C30 
questionnaire. The number and proportion of patients who completed the 
EORTC QLQ-C30 questionnaire will be summarized by treatment arm and for 
each time point. The completion rate will be based on the number of patients 
expected to complete the questionnaire at a particular time point, that is, those 
patients who had the opportunity to complete the EORTC QLQ-C30 
questionnaire.
Visit summary and change from baseline analyses will be performed for all 
scales of the EORTC QLQ-C30.  Summary statistics (number of patients, mean, 
standard deviation, median, minimum, maximum) of scores and change from 
baseline to each time point will be presented by treatment arm. Plots of mean 
change from baseline will be generated for EORTC QLQ-C30 physical 
functioning, fatigue, and global health status/QoL scales. In addition, for the 
subset of patients receiving HSCT, physical functioning and fatigue will be 
descriptively summarized at their last visit prior to transplant.
For responders’ analysis, the number and proportion of patients with a clinically 
meaningful improvement (as defined below), deterioration, or who remained 
stable will be summarized by treatment arm, for the EORTC QLQ-C30 physical 
functioning, fatigue, and global health status/QoL scales. The 95% CI around the 
proportion will be calculated using the Clopper-Pearson method for each 
treatment arm. These will be calculated at Cycle 1 Day 28, Cycle 2 Day 28, Cycle 
3 Day 28, and at treatment discontinuation
For physical function and global health status/QoL, higher scores are reflective of 
better HRQoL and a clinically meaningful improvement is defined as at least a 
10-point increase. For fatigue, lower scores are reflective of less fatigue and a 
clinically meaningful improvement is defined as at least a 10-point decrease. 
Conversely, clinically meaningful deterioration is defined as at least a 10-point 
decrease and 10-point increase, respectively. 
Time to deterioration is defined as the time from randomization to the first 
documentation of a 10-point decrease in EORTC QLQ-C30 physical functioning 
and global health status and a 10-point increase in fatigue from baseline. Time to 


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improvement is defined as the time from randomization to the first documentation 
of a 10-point increase in EORTC QLQ-C30 physical functioning and global health 
status and a 10-point decrease in fatigue from baseline. 
Time to deterioration and time to improvement will be displayed using Kaplan 
Meier curves. Patients who do not have an observed deterioration or 
improvement, respectively, at the time of clinical data cut-off will be censored at 
the last non-missing assessment date. Patients without a post-baseline 
assessment will be censored at randomization. 
The EQ-5D-5L questionnaire consists of two components:  the EQ-5D-5L 
descriptive system, which has 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) with five levels (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) and a 
visual analogue scale (EQ VAS) ranging from 0 (worst possible heath state) to 
100 (best possible health state), which measures an overall health state. 
The EQ-5D-5L health states, which are defined based on the EQ-5D-5L 
descriptive system, will be converted into a single index value according to the 
EQ-5D-5L guidelines (van Reene and Janssen 2015).  The EQ-5D-5L single 
index value will be calculated using the United Kingdom preference weights.  
Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) and change from baseline will be presented by treatment arm and at 
each timepoint. 
Data from the EQ-VAS will be used to assess the overall health status.  
Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) and change from baseline at each timepoint will be displayed by 
treatment arm. 
4.9
EXPLORATORY ANALYSES
Primary and secondary efficacy endpoints will be repeated for the all-patient-ITT 
population using the same methods as described for the TP53 WT population. 
Rate of CRMRD will be analysed using same methods as CR.
CR during treatment will be analysed using the same methods as for CR.
Proportion of HSCT following response (OR) and HSCT regardless of response 
will be analysed using the same methods as HSCT following CR.
LFS (Duration of OR) will be analysed using the same methods as DOR.
Depending on the number of patients, exploratory analyses might be performed 
to assess the possible relationship between idasanutlin consolidation therapy in 
Cycle 2 and Cycle 3 and the time-to-event measures (OS, EFS, DOR). 


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Depending on the number of patients who undergo allogeneic HSCT, a landmark 
OS analysis will be performed with the date of HSCT as baseline using the same 
methods as for the primary OS endpoint.  In addition, a comparison of patients 
between treatment groups with a similar level of response (i.e., CR, CRi, and
CRp) proceeding to transplant or not, might be assessed to describe if there is a 
difference on their survival outcome. 
As a supportive analysis, a competing risk analysis of cause-specific death (with 
event types "death due to progression of disease" and "death due to adverse 
event or other reasons") as an exploratory analysis will be performed including
the following:

A visualization of the corresponding cumulative incidence functions 

A cause-specific hazard and Fine-Gray regression models for the competing 
events 
with randomized treatment assignment as the main covariate and potential 
adjustment for additional potential prognostic variables.
Additional biomarker analyses might be performed as appropriate. 
4.10
MISSING DATA
The missing data rules for the primary and secondary efficacy endpoints and for 
PROs are detailed in Sections 4.4 and 4.8, respectively.
For the reporting of safety data, the following missing data imputation rules will 
be applied:

Adverse events with missing grades will be included in the summaries as 
Grade 35 adverse events.

Adverse events with missing relationship to trial medication will be included 
in the summaries of treatment related adverse events.

Adverse events with missing seriousness will be included in all summaries of 
serious adverse events.
In case of missing day in a time-to-event-date, an imputation is done on the first 
day of the month or date of randomization, whichever occurs last; otherwise no 
imputations are performed for the main analysis. 
In case of missing assessment of patient primary population (i.e. wild type status), 
according to FMI an imputation may be done depending on availability of 
alternative data by Almac, as specified in Section 4.4
Specific sensitivity analyses are going to be performed on missing data as 
specified in Section 4.4.3.


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4.11
INTERIM ANALYSES
The iDMC will perform regular safety review, assess the lack of efficacy (futility) 
for this study, and perform the interim efficacy analysis (Section 3.2) on testing 
OS. iDMC recommendations to stop the study due to safety, or because of 
substantial evidence of lack of efficacy of the study drug, and for early unblinding
for OS-efficacy, are based on the pre-specified interim analysis methodology as 
defined in the iDMC charter.  The iDMC will provide their recommendation to the 
Sponsor.  The Sponsor will make the final decision regarding the early 
termination of the study for safety or futility or early unblinding for efficacy. 
All summaries and analyses will be prepared by an Independent Data 
Coordinating Center (IDCC) and presented by treatment arm for the iDMC’s 
review as described in the iDMC charter.  Members of the IDCC and the iDMC 
will be external to the Sponsor and the study management team.  The IDCC and 
iDMC members will comply with the iDMC charter that outlines their roles and 
responsibilities.
4.11.1
Futility Interim Analysis
The non-binding futility interim analysis will be based on confirmed CR, which is 
defined as CR or CRp with a duration of least 28 days post initial response 
assessment; EFS; and safety.  Note that EFS definition at time of futility analysis 
(treatment failure defined as failure to achieve CR, CRp or CRi) was different to 
that now proposed at final analysis, due to comments by regulatory agencies. 
The futility interim analysis will be performed on the interim analysis population
(defined in Section 4.1.1.1).  The iDMC may recommend stopping the study for 
futility if, in the sample of patients who are wild type for TP53 (as assessed by 
the laboratory: Almac Diagnostic Services), either of the following is observed:

The observed odds ratio for confirmed CR, which compares 
idasanutlin cytarabine to placebo cytarabine, is 2.0.
or

The observed odds ratio for confirmed CR, which compares 
idasanutlin cytarabine to placebo cytarabine, is 2.5, and the HR for 
EFS is 1.
The iDMC recommendation for this trial to not be considered futile is based on 
the observed odds ratio CR 2.5, which sets a high-bar target for more than 
doubling the CR, assuming 16% CR in the placebo cytarabine arm versus 32.3% 
CR in the idasanutlin cytarabine arm.  If the observed odds ratio falls between 
2 and 2.5, then EFS is included as an event time-based measure of activity for 
the lower gate of odds ratio, and its HR should be 1 to continue.  Durable CR, 
as described above, was chosen instead of a survival endpoint because OS 
carries the risk of incorrect decision-making being confounded by treatment-


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related mortality at this early time of the study.  EFS (as defined in Section 4.4.2) 
was added to support the association between CR and OS.
To compute stopping probabilities for the futility interim analysis, the following 
additional assumptions are made within TP53 WT patients and the simulation 
model is extended accordingly:

Median OS for non-responders in cytarabine arm is 5.1 months

Median OS for responders, but short-term survivors in cytarabine arm is 
7.5 months

EFS follows an exponential distribution.

Median EFS times for non-responders and CR short-term responders is 
assumed to be shorter by a factor 2.5 compared to OS in these same 
subpopulations.

The correlation between uncensored EFS and OS times is 0.5.

HR for a comparison of idasanutlin cytarabine versus cytarabine placebo 
in both, non-responders and short-term responders, is 0.8
Approximately 63 EFS events are expected to occur at the interim analysis under 
the alternative hypothesis of an increase in median OS from 6 to 9 months.  The 
probability of early stopping due to futility is approximately 89.9% if the null 
hypothesis of equal OS survival functions is true and is approximately 31.9% if 
the alternative assumption is true.
4.11.2
Safety Interim Analysis
The iDMC might also recommend stopping the study for safety at the futility 
interim analysis if any of the following criteria are met in all patients, regardless of 
TP53 mutational status (note:  early death is defined as any death within the first 
30 days after randomization): 

The proportion of gastrointestinal toxicity (nausea, vomiting, diarrhea) events 
in the idasanutlin cytarabine treatment arm is 40% of events that are 
Grade 3 or 15% of events that are Grade 4
or

The proportion of early deaths in the idasanutlin cytarabine treatment arm 
is 10 percentage points greater than in the placebo cytarabine treatment 
arm.
or

20% of early deaths overall in the idasanutlin cytarabine treatment arm
4.11.3
Efficacy Interim Analysis
At the time of the efficacy interim analysis (on OS) that will be conducted when 
80% of the events have occurred (i.e., approximately 220 events), it is 


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anticipated that all patients have been enrolled. OS will be tested at the 
significance level determined using the O´Brien-Fleming alpha-spending function 
so the overall Type I error rate will be maintained at the 0.05 level. With 80% 
information, the alpha spending is 0.024.
The iDMC may recommend unblinding the study for efficacy if there is a 
significant difference in OS in favor of the experimental arm (alpha level 0.024 or 
as assessed based on actual number of OS events).
Accompanying this interim efficacy analysis, a non-binding additional futility 
assessment will be performed and the iDMC may recommend stopping the study 
for futility if the hazard ratio on overall survival is greater than or equal to one.
Further details about the interim analyses will be described in the iDMC Charter.
5.
REFERENCES
Dohner H, Estey E, Grimwade D et al. Diagnosis and management of AML in 
adults: 2017 ELN recommendations from an international expert panel.  Blood 
2017;129:424-447. 
Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of 
Life Group. The EORTC QLQ-C30 scoring manual. 3rd ed. Brussels: European 
Organisation for Research of Cancer, 2001.
Lewis S, Clarke M. Forest Plots: trying to see the wood and the trees. BMJ 
2001;322:147980.
Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual 
disease in AML: a consensus document from the European LeukemiaNet MRD 
Working Party. Blood. 2018;131:1275-1291.
Van Reene M, Janssen B, editors. EQ-5D-5L User Guide: Basic informtaion on 
how to use the EQ-5D-5L instrument. Version 2.1. The Netherlands: EuroQol 
Research Foundation, April 2015.
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper 
multiple testing procedures. J Stat Planning Inference 2001;99:2540


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Appendix 1
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, PHASE III STUDY OF IDASANUTLIN, AN MDM2 
ANTAGONIST, WITH CYTARABINE VERSUS CYTARABINE PLUS 
PLACEBO IN PATIENTS WITH RELAPSED OR REFRACTORY 
ACUTE MYELOID LEUKEMIA (AML)
PROTOCOL NUMBER:
WO29519
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003065-15
TEST PRODUCT:
Idasanutlin (RO5503781)
PHASE:
Phase III
INDICATION:
Relapsed/Refractory Acute Myeloid Leukemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Primary Objective
The primary objective for this study is as follows:
Within the TP53 wild type (WT) population

To compare overall survival (OS) in patients with relapsed or refractory acute myeloid 
leukemia (AML) who have been randomized to idasanutlin in combination with cytarabine 
versus those who have been randomized to cytarabine and placebo
Secondary Objective
The secondary objectives for this study are as follows:
Within the TP53 WT population

To compare the proportions of complete remission (CR) between treatment arms 

To compare event-free survival (EFS) between treatment arms

To compare ORR (defined as CR), complete remission with incomplete platelet count 
recovery [CRp], and complete remission with incomplete blood count recovery [CRi]) 
between treatment arms

To compare duration of remission following CR (DOR) between treatment arms

To compare the proportions of allogeneic hematopoietic stem cell transplant (HSCT) 
following CR between treatment arms

To assess OS and CR in clinically actionable mutation-defined AML subpopulations, 
including FLT3, IDH1, and IDH2

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 


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
To compare the differences in disease and treatment-related symptoms and health-related 
quality of life between treatment arms
Within the all-patient population

To assess the safety of idasanutlin plus cytarabine as compared with cytarabine and 
placebo 

To characterize the pharmacokinetics of both idasanutlin and cytarabine 

To compare the differences in disease and treatment related symptoms and health-related 
quality of life between treatment arms
Exploratory Objective
The exploratory objectives for this study are as follows:
Within the all-patient population 

To evaluate primary and secondary efficacy endpoints, including OS, CR, proportion of 
HSCT, EFS, and DOR in the all-patient population and OS and CR in the clinically 
actionable mutation-defined AML subpopulations (including FLT3, IDH1, and IDH2)
Within the all-patient and TP53 WT populations

To evaluate efficacy endpoints, including proportion of HSCT, CR, ORR, and DOR on 
the basis of response assessed over complete treatment period

To evaluate LFS (leukemia-free survival, or duration of OR)

To explore minimal/measurable residual disease (MRD) in the bone marrow after treatment 
with idasanutlin plus cytarabine compared with cytarabine and placebo

To evaluate candidate response biomarkers (gene expression signatures) and murine 
double minute 2 (MDM2) protein expression in blast cells

To assess prognostic and predictive effect of disease-associated mutations
Study Design
Description of Study
This is a Phase III multicenter, double-blind, randomized, placebo-controlled study of idasanutlin 
in combination with cytarabine compared with cytarabine and placebo.  
A total of 440 patients with AML who have relapsed following, or are refractory to 
cytarabinecontaining standard induction chemotherapy after at least one and no more 
than two prior cytarabinecontaining induction chemotherapy regimen(s) are planned to be 
enrolled.  Relapsed patients are defined as patients with first or second relapse; first relapsed 
patients who are young and had a good response to initial therapy (i.e. age 60 years with first 
CR achieved [CR1] duration 1 year) are excluded.  Refractory patients are defined as patients 
with persistent leukemia after one or two induction cycles, or patients with CR1 duration of 90 
days.  Patients may have received prior HSCT in remission.  Note that patients with prior 
allogenic HSCT within 90 days prior to randomization will not be eligible for this study.  The 
TP53 WT population will consist of patients with WT TP53, established centrally.  
Re-screening is allowed under the conditions listed in the protocol.
Patients will be randomly assigned to each treatment arm.  The arms will be stratified according 
to the following factors:

Age (60 years versus 60 years)

Cytogenetic and molecular risk according to the 2010 European LeukemiaNet (ELN) 
standardized reporting system at initial diagnosis (favorable/intermediate versus adverse). 
Cytogenetic information allowing stratification in those two groups must be available.  

Response to initial anti-leukemic therapy (refractory versus CR 90 days but 1 year; 
versus CR 1 year)

Prior HSCT versus no prior HSCT


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Patients will receive induction treatment with idasanutlin/placebo 300 mg twice daily (BID) and 
cytarabine 1 g/m2 for 5 days followed by 23 days of rest (Cycle 1).  For patients who achieve 
clinical response after induction and for whom HSCT for consolidation is not an option, it is 
strongly recommended to continue study medication with a maximum of two additional cycles of 
consolidation (Cycles 2 and 3) unless clinically contraindicated  
Responding patients, including those who proceed to HSCT, will be followed for EFS and DOR. 
All patients irrespective of response to treatment will be followed for OS until the end of the 
study. 
An interim analysis for futility based on CR, EFS, and safety is planned after 120 TP53 WT 
patients are enrolled, have received at least one cycle, and confirmatory response assessment 
is available, to allow early stopping of the study in the event of inadequate CR, EFS, or safety 
concerns.  The futility interim analysis will be performed by an independent Data Monitoring 
Committee (iDMC).  Enrollment of patients will continue while this interim analysis takes place.  
If the Sponsor decides to stop the study based on iDMC recommendation following the futility 
interim analysis, enrollment will be discontinued. 
An efficacy interim analysis on OS is planned to be conducted by iDMC to allow early testing 
of OS in the event of relevant efficacy. The efficacy interim analysis will be conducted when 
80% of the OS events have occurred (i.e., approximately 220 events). At this time, it is 
anticipated that all patients will have been enrolled.
Accompanying this interim efficacy analysis, a non-binding additional futility assessment 
will be performed based on a hazard ratio on overall survival 1.
In the case of not reaching significance for OS at interim analysis, a primary analysis of OS 
will be performed (i.e., when 275 events have occurred).   
Number of Patients
Overall, 440 patients with relapsed or refractory AML are expected to be enrolled in this study, 
over approximately 41 months.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 18 years 

Documented/confirmed first or second refractory or relapsed AML using World Health 
Organization classification, except acute promyelocytic leukemia.  Please note that first 
relapsed AML patients with CR1 duration of 1 year AND age 60 years are excluded.

No more than 2 prior induction regimens (excl. prior HSCT) in their first line treatment, and 
one must have included cytarabine with an anthracycline (or anthracenedione).

Eastern Cooperative Oncology Group performance status of 02  

Adequate hepatic function assessed by the following:  
Serum total bilirubin 1.5 institutional upper limit of normal (ULN), unless resulting 
from hemolysis, Gilbert’s syndrome, or liver infiltration with leukemia
AST/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

WBC count at randomization of 50,000/mm3
Note:  When treatment is not started immediately upon randomization, the WBC count 
at the start of induction therapy (Cycle 1) must remain at 50,000/mm3.  The use of 
hydroxyurea (HU) or leukapheresis to meet eligibility is allowed.  HU or leukapheresis 
must be discontinued at least 24 hours prior to the initiation of study medication.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at least 
one method with a failure rate of 1% per year, during the treatment period and for up to 
6 months after the last dose of study drug


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A woman is considered to be of childbearing potential if she has not reached a 
postmenopausal state (12 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, and established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  Barrier methods must always be 
supplemented with the use of a spermicide.

For men unless permanently sterile by bilateral orchidectomy:  agreement to remain 
abstinent (refrain from heterosexual intercourse) or use contraceptive measures and 
agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for up to 6 months 
after the last dose of study drug.  Men must refrain from donating sperm during this 
same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. 

Ability to understand and willingness to sign a written informed consent form and comply 
with all study requirements including completion of patient-reported outcome measures.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

First relapsed patients aged 60 years with a CR1 duration of 1 year 

Patients with prior documented antecedent hematological disorder including the following:  
myelodysplastic syndrome, myeloproliferative disease (i.e., chronic myelomonocytic 
leukemia, polycythemia vera, primary myelofibrosis, and essential thrombocythemia), and 
aplastic anemia

AML secondary to any prior chemotherapy unrelated to leukemia 

Patients who are either refractory to or have relapsed within 90 days of receiving a regimen 
containing a cumulative dose of 18 g/m2 cytarabine

Patients who have received allogeneic HSCT within 90 days prior to randomization. HSCT 
should have been performed in remission and not used for salvage (patients who have 
received autologous HSCT as consolidation in CR1 are eligible). 

Patients who have received immunosuppressive therapy for graft-versus-host disease or for 
engraftment syndrome after autologous stem cell transplantation within 2 weeks prior to 
randomization

Prior treatment with an MDM2 antagonist

Patients with clinically relevant QTc prolongation (QT interval corrected using Fridericia’s 
formula [QTcF] 480 ms), a family history of long QT syndrome, or who are currently 
receiving treatment with medications that are known to prolong the QT interval
Medications that are known to prolong the QT interval must be discontinued 7 days 
(or 5 half-lives, whichever is shorter) prior to initiating study medication until 
5 days after the final administration of study medication.


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
Patients receiving any other investigational or commercial agents or therapies administered 
with the intention to treat their malignancy within 30 days (or 5 half-lives) from first receipt of 
study drug
Note:  The exception is HU or leukapheresis in patients who need to continue this 
therapy to maintain a WBC count 50,000/mm3.  HU or leukapheresis must be 
discontinued at least 24 hours prior to the initiation of study medication. 

Patients with acute toxicities from any prior anti-leukemia therapy which have not resolved 
to Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.03

Patients with a history of other malignancy within 5 years prior to screening, except for 
malignancy that has been in remission without treatment for at least 2 years prior to 
randomization 

Patients unable to temporarily 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 medication.  

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) during the treatment phase.  These agents 
must be discontinued 7 days (or 5 half-lives) prior to the start of study medication. 
Note: Treatment with or switch to low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) is allowed, according to local practice.  However, platelet 
levels need to be closely monitored in these patients (see protocol).

Patients with a history of systemic hypersensitivity reactions Grade 2 attributed to 
cytarabine or components of the formulated product 

Patients who have 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 III, IV), myocardial infarction 6 months prior to 
first study medication, and cerebrovascular accidents 6 months before study 
medication start
Unstable seizure disorders
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by this study medication, such as hereditary coagulation disorders or 
insulin-dependent diabetes mellitus not optimally controlled with medical management 
(e.g., presence of ketoacidosis) or active gastrointestinal (GI) conditions (e.g., Grade 
2 graft-versus-host disease) and uncontrolled inflammatory bowel disease (i.e., 
Crohn’s disease, ulcerative colitis, diverticulosis-associated colitis, and Behçet's 
disease).

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 
2 weeks of appropriate systemic antifungal therapy  
Active bacterial infection and/or bacterial infection with positive cultures in the 7 days 
prior to dosing
Patients who have received 5 days of appropriate therapeutic antibiotic therapy for 
an identified infection


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History of symptomatic Clostridium difficile infection that required treatment within 
1 month prior to dosing.  Upon clinical response to C. difficile treatment, the stool 
consistency and frequency must have returned to normal. 
In all cases, the patient should be afebrile (exception of AML-related fever) and 
hemodynamically stable for at least 72 hours at the time of study medication initiation.

Patients with a history of active or chronic infectious hepatitis unless serology demonstrates 
clearance of infection
Patients with occult or prior hepatitis B virus (HBV) infection (defined as negative 
hepatitis B surface antigen and positive total hepatitis B core antibody) may be 
included if HBV DNA is undetectable, provided that they are willing to undergo monthly 
DNA testing. Patients who have protective titers of hepatitis B surface antibody after 
vaccination or prior but cured hepatitis B are eligible.  Patients positive for hepatitis C 
virus antibody are eligible provided polymerase chain reaction (PCR) is negative for 
HCV RNA.

Patients who have a history of clinically significant liver cirrhosis (e.g. Child-Pugh class B 
and C). 

Patients with electrolyte abnormalities such as hypokalemia, hyperkalemia, hypocalcemia, 
hypercalcemia, hypomagnesemia, and hypermagnesemia of Grade 1 per NCI CTCAE 
v4.03.  Treatment for correction of above electrolyte imbalances is permitted during 
screening to meet eligibility.

Patients with extramedullary AML with no evidence of systemic involvement

Patients with active CNS leukemia

Pregnant or breastfeeding patients

HIV-positive patients 

Patients who might refuse to receive blood products and/or have a hypersensitivity to blood 
products
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur 2 years after the last patient is enrolled or after 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 5.5 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Idasanutlin/placebo will be administered at 300 mg BID orally, without regard to meals.  Water 
can be given ad libitum.  
In case the patient proceeds to consolidation therapy, only 50% of idasanutlin should be given 
(300 mg once daily [QD] in the morning).
Cytarabine will be administered at a dose of 1 g/m2 QD as a 13 hour intravenous infusion.  In 
case the patient proceeds to consolidation therapy the dose may need to be reduced to 50% 
(0.5 g/m2 QD).  
Statistical Methods
Efficacy Analysis
Patients will be analyzed according to the treatment arm to which they were randomized.  The 
TP53 WT population is the efficacy population and refers to all randomized TP53 WT 
patients as identified by a central laboratory test.
Description of efficacy analysis in this section is valid for both interim and primary analysis.


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Primary Efficacy Endpoint
The primary efficacy endpoint, OS, is defined as the time from randomization to death due to 
any cause.  OS for patients who have not died at the time of the analysis will be censored at the 
date last known alive. 
The primary OS analysis of the study will assess the null hypothesis of equality of OS functions 
in the idasanutlin in combination with cytarabine (MDM2-chemo) arm versus the cytarabine
given with a placebo (chemo) arm in the TP53 WT population as follows:
H0:  OSMDM2-chemo OSchemo versus H1: OSMDM2-chemo ≠OSchemo
A formal treatment comparison will be made using a two-sided stratified log-rank test at a 
significance level defined using the O´Brien-Fleming alpha-spending function with overall 
Type I error rate at 0.05 corresponding to available information.  Stratification factors that will 
be used are the same as for randomization, i.e. age (60 versus 60 years), cytogenic and 
molecular risk (favorable/intermediate versus adverse), prior response to initial anti-leukemic 
therapy (refractory versus CR 3 months but 1 year versus CR 1 year) and prior HSCT 
versus no prior HSCT.  
Survival curves in each treatment arm will be estimated using Kaplan−Meier estimates.  The 
Kaplan–Meier estimates will provide a visual description of the survival curves and the 
difference across treatment arms.  The treatment effect will be quantified via a hazard ratio, 
computed from a stratified Cox proportional-hazards regression, including a 95% CI.  To further 
describe and quantify OS, estimated median OS per arm and 1-year and 2-year survival 
probabilities, all including 95% CI, will be given.  The effect of prognostic factors on OS will be 
assessed in an exploratory analysis using Cox multivariate regression.
Secondary Efficacy Endpoint
The following secondary endpoints will be tested for the TP53 WT population, as described in 
the Statistical Analysis Plan:

CR proportion 

EFS 

ORR (CR, CRp, and CRi) 

DOR (duration of remission following CR)

Proportion of HSCT following CR 

CR proportion and OS in clinically actionable mutation-defined subpopulation (FLT3, 
IDH1, and IDH2)
Patients with no response assessments (for any reason) will be considered non-CR. 
Difference in proportions of CR will be assessed between the two treatment arms using 
Cochran–Mantel–Haenszel test stratified by randomization stratification factors.  In addition, 
proportions and 95% CI will be reported for each treatment arm.  The effect of prognostic 
factors on CR will be assessed in an exploratory analysis using logistic regression.
EFS is defined for all patients and measured from the date of randomization.  It is measured 
until treatment failure, relapse from CR, or death from any cause, whichever occurs first.  For 
patients with none of these events before time of analysis, EFS is censored at the date of the 
patient’s last response assessment.
DOR is defined for patients achieving complete remission and is the time from clinical 
remission until relapse or death from any cause, whichever occurs first.  For patients with 
none of these events before time of analysis, DOR is censored at the date of the patient’s last 
response assessment.
EFS and DOR will in general be analyzed using the same statistical methods as those 
described for OS.  If only very few patients qualify for DOR analysis, only descriptive statistics 
will be given.
ORR (CR, CRp, and CRi) and proportion of HSCT will be compared between the two 
treatment arms using the same statistical methods as those described for CR.


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Sensitivity Analyses
The following sensitivity analyses for OS will be performed in the TP53 WT population:

An unstratified log-rank test.

To assess the relevance of HSCT against other long-term effects, OS will be alternatively 
defined with censoring at date of HSCT and analyzed using the same methods as for the 
primary endpoint.

Discontinuation of assessments or patient lost to follow up considered as an event
Safety Analyses
All safety analyses will be based on both the TP53 WT population (defined here as TP53 WT 
patients who have received any study medication at least once) and the complete safety 
analysis population (defined as all patients who have received any study medication at least 
once), and patients will be analyzed according to the treatment received (patients receiving 
idasanutlin at least once will be analyzed in the idasanutlin arm).  Safety analyses will include, 
but not be limited to, incidence rates for adverse events including mortality, adverse event 
severity, seriousness, and adverse events leading to discontinuation.  In addition, abnormalities 
of clinical laboratory tests and vital signs assessed during the study treatment period and post-
treatment follow-up will be assessed. Exposure to study medication will be summarized by total 
duration of study medication, number of cycles started and cumulative dose using descriptive 
statistics.  
This trial is designed to allow for early termination or a modification of the protocol for safety 
concerns or lack of efficacy, based on the advice of an iDMC.  The iDMC will be incorporated 
into the study to review safety data on a regular basis, including adverse events of special 
interest.  Both the Sponsor and the iDMC can request ad hoc iDMC meetings if potential safety 
concerns arise.  Following each meeting, the iDMC will recommend to the Sponsor whether the 
study should continue according to the protocol or may suggest changes to the protocol based 
on the outcome of the data review.  In exceptional cases, the iDMC may recommend stopping 
the study or closing a treatment arm as a result of safety reasons.  The iDMC will also perform a 
safety review at the preplanned interim analyses for futility and efficacy.
Pharmacodynamic and Biomarker Analyses
The following pharmacodynamic parameters will be presented by listings and descriptive 
summary statistics.  

Blood samples analyzed for macrophage inhibitory cytokine-1 

Analysis of TP53, FLT3, IDH1, and IDH2 mutation status

MDM2 protein expression level in AML blasts

A 4-gene signature (including MDM2 gene expression) 

MRD
Pharmacokinetic Analyses
Key pharmacokinetic (PK) parameter values (apparent clearance and apparent volume of 
distribution) of idasanutlin and cytarabine (total clearance and volume of distribution) will be 
estimated using a population pharmacokinetics (popPK) approach.  The influence of covariates 
such as gender, race/ethnicity, weight, hematological parameters at baseline, renal/hepatic 
impairment, and degree of underlying disease will be investigated.  Other PK parameters such 
as maximum concentration observed (Cmax), steady-state concentration at the end of a dosing 
interval (i.e., just prior to next drug administration) (Ctrough), area under the concentration–time 
curve during one dosing interval, area under the concentration-time curve during a 24-hour 
dosing interval (AUC0-24h), and half-life will be derived from the individual post hoc predictions.  
Details of the population analysis will be described in the Modeling and Simulation Analysis 
Plan.  Results of this analysis will be reported separately.
If appropriate, an exploratory PK/pharmacodynamic analysis may be performed post hoc.  The 
primary focus will be exploration of the relationship between measures of exposure to 
idasanutlin in combination with cytarabine (Cmax, Ctrough, and AUC0-24h) and ECG, drug-related 
adverse effects as well as clinical efficacy parameters.


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Determination of Sample Size  
A mechanistic simulation model was used to determine the sample size in this event-driven 
study, based on the following global assumptions:

Final analysis for OS in patients with TP53 WT disease based on two-sided log-rank test at 
0.05 level of significance

85% power to detect an OS hazard ratio for idasanutlin cytarabine versus 
cytarabine placebo of 0.67 in patients with TP53 WT disease, corresponding to an 
improvement in median OS from 6 to 9 months (50%) 

Proportion of long term survivors of 8.0% in the cytarabine placebo arm and 16.1% in the 
idasanutlin cytarabine arm
To compute the necessary number of events, we simulated OS times based on the following 
assumptions:

All simulated OS times for patients not considered long-term survivors are exponentially 
distributed.

Probability of being a complete responder in the cytarabine placebo arm is 0.16

Probability of being a complete responder in the idasanutlin cytarabine arm is 0.323, 
implying an odds ratio for CR comparing the idasanutlin cytarabine versus the 
cytarabine placebo arm of 2.5

Probability for a complete responder to be a long-term survivor is 0.5 in either arm

An annual dropout rate of 5% (every effort will be made to contact patients for survival 
information in case of study withdrawal or loss to follow-up) 
To have the targeted 85% power, 275 events in patients with TP53 WT disease are required.  
The minimum detectable hazard ratio in a 2:1 randomized trial corresponding to 275 events and 
a significance level of 0.05 amounts to 0.78, corresponding to a minimal detectable median 
improvement from 6 to 7.7 months assuming exponentiality. 
All patients, regardless of TP53 mutation status, will be randomized to this study.  Assuming 
85% of patients will have TP53 WT disease and 15% will have TP53 mutant disease, 
approximately 440 patients will be enrolled over approximately 29 months, corresponding to an 
estimated number of 374 patients with TP53 WT disease.
In Version 6 of the protocol, an interim analysis for efficacy on OS of TP53 WT patients was 
added.  The sample size assumptions above remain unchanged other than the recruitment time 
(now estimated at 41 months).  The interim analysis will occur at an information fraction of 
80%, providing a maximum power of 83% for the final OS analysis.
Interim Analyses
Futility
A non-binding interim analysis for safety and futility will be performed by an iDMC after 
120 patients with TP53 WT have been enrolled and assessed for response.  For the purposes 
of the futility interim analysis, CR is defined as confirmed CR.  Sponsor personnel will not 
have access to by-arm efficacy and safety summaries prior to the formal reporting of study 
results.  The iDMC may recommend stopping the study for futility if:

the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the cytarabine 
and placebo arm in the population of patients WT for TP53, is 2.0,

or the observed odds ratio for CR in the cytarabine and idasanutlin arm versus the 
cytarabine and placebo arm in the population of patients WT for TP53, is 2.5 and the 
hazard ratio for EFS 1.
To compute stopping probabilities for the futility interim analysis, the following additional 
assumptions are made within TP53 WT patients and the simulation model is extended 
accordingly:

Median OS for non-responders in cytarabine arm is 5.1 months

Median OS for responders, but short-term survivors in cytarabine arm is 7.5 months

EFS follows an exponential distribution


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
Median EFS times for non-responders and CR short-term responders is assumed to be 
shorter by a factor 2.5 compared to OS in these same subpopulations

The correlation between uncensored EFS and OS times is 0.5

Hazard ratio for a comparison of idasanutlin cytarabine versus cytarabineplacebo in 
both non-responders and short-term responders is 0.8
Using these assumptions, we expect 63 EFS events at the futility interim analysis under the 
alternative hypothesis.  The probability of early stopping due to futility is 89.9% if the null 
hypothesis of equal OS survival functions is true and 31.9% if the alternative assumption of an 
increase in median OS from 6 to 9 months is true.  
The analysis in both the TP53 WT population and in the overall population will be provided to 
the iDMC.
The iDMC may recommend stopping the study for safety at the futility interim analysis if any of 
the following criteria are met (note:  early death is defined as any death within the first 30 days 
after randomization):

The proportion of GI toxicity (nausea, vomiting, diarrhea) events in the experimental arm 
(idasanutlin cytarabine): Grade 3 > 40% or Grade 4 > 15%

The proportion of early deaths in the experimental arm (idasanutlin cytarabine) is 
≥10 percentage points greater than in the control arm (cytarabine placebo) 

> 20% of early deaths overall in the treatment arm
More details on the interim analysis are provided in the iDMC charter.
Efficacy
An interim analysis for efficacy on OS is planned to be conducted by iDMC. The efficacy 
interim analysis will be conducted when 80% of the OS events have occurred (i.e., 
approximately 220 events). At this time, it is anticipated that all patients will have been 
enrolled.
For the interim efficacy analysis of OS, the significance level will be determined using the 
O’Brien-Fleming alpha-spending function with overall type I error rate at 0.05 level.  At the 
time of the interim efficacy analysis, it is expected that 80% of the OS events will have 
occurred, corresponding to an alpha spending of 0.025 for the interim and 0.043 for the final 
OS analysis leading to a power of 83% for the final analysis.
The iDMC will test OS for efficacy and check if there is a significant difference (alpha level 
0.025 or as assessed based on actual number of OS events) in OS in favor of the experimental 
arm.
Accompanying this interim efficacy analysis, a non-binding additional futility assessment 
will be performed and the iDMC may recommend stopping the study for futility if the hazard 
ratio on overall survival is greater than or equal to one.
Further details of the interim analyses will be described in the iDMC Charter and Statistical 
Analysis Plan.


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Appendix 2
Calling Rules to Define TP53 WT Intent-to-treat Primary  
Population
Variant Type
Description
Assay* Reporting 
Result
No variant
Absence of any change in sequence from 
reference sequence
TP53WT
Synonymous 
substitution
Silent mutations where the amino acid 
sequence is unchanged
TP53WT
Known germline 
variants
Inclusion in dbSNP version 135 filtered by 
inclusion in 1000 Genomes phase 1 or 
HapMap with some custom filtering
TP53WT
Missense - Fully 
Functional
Missense mutation that are categorized as 
“fully functional” in IARC database under 
transactivation class; 
http://p53.iarc.fr/TP53GeneVariations.aspx
TP53 mutant with 
retained 
functionality
*TP53 mutation status was initially assessed using a single target NGS assay (ILLUMINA 
Truesight platform, customized for TP53) by Almac Diagnostic Services. Following the interim 
futility analysis, the assay was switched to the F1CDx panel by Foundation Medicine Inc. 
(FMI), to afford a regulatory path for companion diagnostic (CDx) development and to test other 
clinically actionable mutations. All available samples previously tested by ILLUMINA assay have 
been retrospectively tested with the F1CDX assay. Going forward, concordance of results with 
ILLUMINA is being established for all available samples to support the CDx assay validation.
The primary population will be defined from FMI data. The Almac data will only be used if FMI 
data are not available; In all cases the above described calling rules will be applied. =