Phase 3 Multicenter Randomized Trial to Evaluate Efficacy and Safety of CPI-613 in Combination With HD Cyt. and Mito. vs HD Cyt. and Mito. Therapy and Control Sub-groups in Older Patients With R/R AML
Phase: PHASE3
Conditions: Relapsed/Refractory Acute Myeloid Leukemia
Sponsor: Cornerstone Pharmaceuticals

Phase III Multicenter Open-Label Randomized Trial to Evaluate 
Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to 
High Dose Cytarabine and Mitoxantrone (HAM) therapy and 
control sub-groups: combination of Mitoxantrone, Etoposide and 
Cytarabine (MEC) and combination of Fludarabine, Cytarabine, 
and Filgrastim (FLAG) in Older Patients (≥ 50 years) with 
Relapsed/Refractory Acute Myeloid Leukemia (AML) 
 
 
 
Protocol Identifying Number: AML003 
Study Name: ARMADA 2000 
 
IND Number: 114-372 
EudraCT Number: 2018-001588-22 
 
IND Sponsor: Rafael Pharmaceuticals Inc. 
1 Duncan Drive 
Cranbury, NJ 08512-3629 
 
Version Number: 8.00  
Amendment 5.0 
 
October 19th, 2020 
 
Superseded Version: 
Version 7.0, August 17th, 2020 
Version 6.0, April 10th, 2020 
Version 5.1 (Belgium), March 10th, 2020 
Version 5.0, October 28th, 2019 
Version 4.0, September 13th, 2018 
Version 3.0, April 11th, 2018 
 
The information contained in this document is the property of Rafael Pharmaceuticals and may not be 
reproduced, published or disclosed to others without written authorization from Rafael Pharmaceuticals. 
RAFA E L 
Pharmaceutica ls, Inc. 
"To Save A Life Is To Save A Universe" 
Cornerstone Pharmaceuticals Inc.
Version 1.0
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination 
with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy 
and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, 
Cytarabine, and Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 27 of 198                                                        Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
Table of Content 
SPONSOR SIGNATORIES ..........................................................................................................................ii 
INVESTIGATOR’S AGREEMENT ........................................................................................................... iii 
Amendment 1 (Version 4.0) ....................................................................................................................... iv 
Amendment 2 (Version 5.0) ....................................................................................................................... xi 
Amendment 2.1 (Version 5.1) ................................................................................................................... 14 
Amendment 3 (version 6.0) ....................................................................................................................... 15 
Amendment 4 (version 7.0) ....................................................................................................................... 19 
Amendment 5 (version 8.0) ....................................................................................................................... 25 
KEY ROLES ............................................................................................................................................... 26 
LIST OF ABBREVIATIONS...................................................................................................................... 31 
1. PROTOCOL SUMMARY AND SCHEMATIC OF STUDY DESIGN .............................................. 34 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............. 44 
2.1. Background Information ................................................................................................................. 44 
2.1.1. 
Clinical, Epidemiological and Public Health Background ..................................................... 44 
2.1.2. 
Description of the Investigational Product ............................................................................. 47 
2.1.3. 
Nonclinical Studies  ............................................................................................................... 48 
2.1.4. 
Summary of Relevant Clinical Research ................................................................................ 57 
2.1.5. 
Importance of the Study ......................................................................................................... 72 
2.2. Rationale ......................................................................................................................................... 72 
2.3. Risk/Benefit Assessment ................................................................................................................ 73 
3. OBJECTIVES AND PURPOSE ........................................................................................................... 76 
3.1. Primary Objective: .......................................................................................................................... 76 
3.2. Secondary Objectives: .................................................................................................................... 76 
3.2.1. 
Other Secondary Objectives: .................................................................................................. 76 
3.3. Exploratory Objectives: .................................................................................................................. 77 
4. STUDY DESIGN AND ENDPOINTS ................................................................................................. 78 
4.1. Description of the Study Design ..................................................................................................... 78 
4.2. Study Endpoints .............................................................................................................................. 78 
4.2.1. 
Primary Endpoint  ............................................................................................................... 78 
4.2.2. 
Secondary Endpoints .............................................................................................................. 79 
4.2.3. 
Exploratory Endpoints ............................................................................................................ 80 
5. STUDY PARTICIPATION AND WITHDRAWAL ............................................................................ 81 
5.1. Inclusion Criteria ............................................................................................................................ 81 
5.2. Exclusion Criteria ........................................................................................................................... 83 
5.3. Contraception .................................................................................................................................. 86 
5.3.1. 
Definition of Females of Childbearing Potential.................................................................... 86 
5.3.2. 
Acceptable Methods of Effective Contraception ................................................................... 87 
5.3.3. 
Contraception Methods for Male Patients .............................................................................. 87 
5.3.4. 
Unacceptable Methods of Birth Control for Male and Female Patients ................................ 87 
5.4. Strategies for Recruitment and Retention ....................................................................................... 88 
5.4.1. 
Participant Status Definitions ................................................................................................. 88 
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination 
with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy 
and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, 
Cytarabine, and Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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5.5. Participant Discontinuation from Treatment or Termination from Study ...................................... 88 
5.5.1. 
Reasons for Discontinuation of Treatment or Termination from Study................................. 88 
5.5.2. 
Criteria for Replacing Patients ............................................................................................... 90 
5.6. Premature Termination or Suspension of Study ............................................................................. 90 
6. STUDY AGENT ................................................................................................................................... 91 
6.1. Study Agent and Control Description, Formulation, Appearance, Packaging, and Labeling ........ 91 
6.1.1. 
High Dose Cytarabine and Mitoxantrone: .............................................................................. 91 
6.1.2. 
Mitoxantrone, Etoposide and Cytarabine: .............................................................................. 91 
6.1.3. 
Fludarabine, Cytarabine and Filgrastim: ................................................................................ 92 
6.2. Product Storage and Stability ......................................................................................................... 92 
6.2.1. 
CPI-613® (devimistat) ............................................................................................................ 92 
6.2.2. 
Cytarabine 
 ............................................................................................................... 92 
6.2.3. 
Mitoxantrone 
 ............................................................................................................... 92 
6.2.4 
Etoposide 
 ............................................................................................................... 92 
6.2.5 
Fludarabine 
 ............................................................................................................... 92 
6.2.6. 
Filgrastim 
 ............................................................................................................... 92 
6.3. Preparation ...................................................................................................................................... 93 
6.3.1. 
CPI-613® (devimistat) ............................................................................................................ 93 
6.3.2. 
Cytarabine, Mitoxantrone, Etoposide, Fludarabine and Filgrastim ....................................... 94 
Should be prepared for administration as outlined in the manufacturers’ instructions in locally approved 
prescribing information. ........................................................................................................................... 94 
6.4. Dosing and Administration ............................................................................................................. 94 
6.4.1. 
CPI-613® (devimistat) ............................................................................................................ 94 
6.4.2. 
Control Group (HAM) and Control Sub-groups (MEC and FLAG) ...................................... 95 
6.4.3. 
Treatment Arms and Cycles ................................................................................................... 96 
6.4.4. 
Dose Adjustments/Modifications/Delays ............................................................................. 111 
6.4.5. 
Duration of Therapy ............................................................................................................. 113 
6.5. Study Agent Accountability Procedures ....................................................................................... 113 
7. STUDY PROCEDURES AND SCHEDULE ..................................................................................... 115 
7.1. Study Procedures/Evaluations ...................................................................................................... 115 
7.1.1. 
Medical History 
 ............................................................................................................. 115 
7.1.2. 
Medications History ............................................................................................................. 115 
7.1.3. 
Physical Examination ........................................................................................................... 115 
7.1.4. 
Vital Signs 
 ............................................................................................................. 115 
7.1.5. 
ECOG Performance Status ................................................................................................... 115 
7.1.6. 
Pharmacokinetic Analysis Blood Sampling (CHAM [Arm 1] Only) .................................. 116 
7.1.7. 
ECG Analysis 
 ............................................................................................................. 119 
7.1.8. 
Cardiac marker (Troponin I) ................................................................................................ 124 
7.1.9. 
Administration of Questionnaires / Other Instruments for Patient-Reported Outcomes (PRO)  
 
 
 ............................................................................................................. 125 
7.2. Standard of Care Study Procedures .............................................................................................. 126 
7.3. Laboratory Procedures/Evaluations .............................................................................................. 126 
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination 
with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy 
and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, 
Cytarabine, and Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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Page 29 of 198                                                        Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
7.3.1. 
Clinical Laboratory Evaluations ........................................................................................... 126 
7.3.2. 
Other Assays 
 ............................................................................................................. 127 
7.4. Study Schedule ............................................................................................................................. 128 
7.4.1. 
Screening 
 ............................................................................................................. 128 
7.4.2. 
Randomization/Baseline Visit .............................................................................................. 130 
7.4.3. 
Study Treatment 
 ............................................................................................................. 131 
7.4.4. 
End of Treatment Visit ......................................................................................................... 131 
7.4.5. 
Safety Follow-Up Visit......................................................................................................... 131 
7.4.6. 
Long-Term Follow-Up Visit ................................................................................................ 131 
7.4.7. 
End of Study Visit  ............................................................................................................. 132 
7.4.8. 
Schedule of Events Tables.................................................................................................... 133 
7.5. Concomitant Medications, Treatments, and Procedures .............................................................. 168 
7.6. Prophylactic Medications, Treatments, and Procedures ............................................................... 168 
7.7. Rescue Medications, Treatments, and Procedures ....................................................................... 169 
7.8. Participant Access to Study Agent at Study Closure .................................................................... 169 
8. ASSESSMENT OF SAFETY ............................................................................................................. 170 
8.1. Specification of Safety Parameters ............................................................................................... 170 
8.1.1. 
Definition of Adverse Events ............................................................................................... 170 
8.1.2. 
Definition of Serious Adverse Events .................................................................................. 170 
8.1.3. 
Pregnancy 
 ............................................................................................................. 171 
8.2. Classification of an Adverse Event............................................................................................... 172 
8.2.1. 
Severity of Event 
 ............................................................................................................. 172 
8.2.2. 
Severity of Adverse Events .................................................................................................. 172 
8.2.3. 
Expectedness 
 ............................................................................................................. 174 
8.3. Time Period and Frequency for Event Assessment and Follow-Up ............................................ 174 
8.4. Reporting Procedures.................................................................................................................... 175 
8.4.1. 
Adverse Event Reporting ..................................................................................................... 175 
8.4.2. 
Serious Adverse Event Reporting ........................................................................................ 176 
8.5. Study Stopping Rules ................................................................................................................... 177 
8.6. Safety Oversight ........................................................................................................................... 177 
9. STATISTICAL CONSIDERATIONS ................................................................................................ 178 
9.1. Statistical and Analytical Plans .................................................................................................... 178 
9.2. Statistical Hypotheses ................................................................................................................... 178 
9.3. Analysis Datasets .......................................................................................................................... 178 
9.4. Description of Statistical Methods................................................................................................ 178 
9.4.1. 
General Approach  ............................................................................................................. 178 
9.4.2. 
Analysis of Primary Efficacy Endpoint ................................................................................ 179 
9.4.3. 
Analysis of Secondary Endpoints ......................................................................................... 180 
9.4.4. 
Handling Missing Data in Efficacy Analyses ...................................................................... 181 
9.4.5. 
Safety Analyses 
 ............................................................................................................. 181 
9.4.6. 
Planned Interim Analyses ..................................................................................................... 181 
9.4.7. 
Additional Sub-Group Analyses........................................................................................... 181 
Cornerstone Pharmaceuticals Inc.
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination 
with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy 
and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, 
Cytarabine, and Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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9.4.8. 
Multiple Comparison/Multiplicity........................................................................................ 182 
9.4.9. 
Other Secondary Objective Analyses ................................................................................... 182 
9.4.10. Exploratory Objective Analyses ........................................................................................... 183 
9.5. Blinding Plan for Statistical Analysis ........................................................................................... 184 
9.6. Sample Size .................................................................................................................................. 184 
9.7. Measures to Minimize Bias .......................................................................................................... 185 
9.7.1. 
Randomization Procedures ................................................................................................... 185 
10. QUALITY ASSURANCE AND QUALITY CONTROL .................................................................. 186 
11. ETHICS/PROTECTION OF HUMAN PATIENTS ........................................................................... 187 
11.1. Ethical Standard ............................................................................................................................ 187 
11.2. Institutional Review Board/Ethics Committee ............................................................................. 187 
11.3. Informed Consent Process ............................................................................................................ 187 
11.3.1. Consent/Assent and Other Informational Documents Provided to Patients ......................... 187 
11.3.2. Consent Procedures and Documentation .............................................................................. 187 
11.4. Participant and Data Confidentiality ............................................................................................ 188 
11.5. Research Use of Stored Human Samples, Specimens or Data ..................................................... 189 
11.6. Future Use of Stored Specimens................................................................................................... 189 
12. DATA HANDLING AND RECORD KEEPING ............................................................................... 190 
12.1. Data Collection and Management Responsibilities ...................................................................... 190 
12.2. Study Records Retention .............................................................................................................. 190 
12.3. Protocol Deviations ...................................................................................................................... 190 
12.4. Publication and Data Sharing Policy ............................................................................................ 191 
13. STUDY ADMINISTRATION ............................................................................................................ 192 
13.1. Study Leadership .......................................................................................................................... 192 
14. CONFLICT OF INTEREST POLICY ................................................................................................ 193 
15. LITERATURE REFERENCES .......................................................................................................... 194 
16. APPENDIX A ..................................................................................................................................... 196 
Cornerstone Pharmaceuticals Inc.
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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Page 31 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
LIST OF ABBREVIATIONS 
AE 
Adverse Events 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
AUC 
Area Under the Plasma Concentration-Time Curve 
AUCinf 
Area Under the Plasma Concentration-Time Curve from Time Zero 
Extrapolated to Infinite Time 
AUC0-t 
Area Under the Plasma Concentration-Time Curve from Time Zero to the Time 
of the Last Quantifiable Concentration 
BM 
Bone Marrow 
BP 
Blood Pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CCAAT 
Cytosine-cytosine-adenosine-adenosine-thymidine 
CEBPα 
CCAAT Enhancer Binding Protein A 
CFR 
Code of Federal Regulations 
CHAM 
 CPI-613® (devimistat) in Combination with High Dose Cytarabine and 
Mitoxantrone 
CI 
Confidence Interval 
CL 
Apparent Total Body Clearance 
CrCl 
Creatinine Clearance 
Cmax 
The Maximum (Peak) Plasma Drug Concentration 
Cmin 
The Minimum (Trough) Plasma Drug Concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central Nervous System 
CR 
Complete Remission 
CRh 
CR (Complete Remission) with Partial Hematologic Recovery 
Cri 
CR (Complete Remission) with Incomplete Recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTnT 
Cardiac Troponin T 
D5W 
Dextrose 5% in Water 
DEHP 
Diethylhexyl Phthalate 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EF 
Ejection Fraction 
EORTC QLQ 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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EOS 
End-of-Study 
EOT 
End-of-Treatment 
FDA 
Food and Drug Administration 
FLAG 
Fludarabine, Cytarabine, and Filgrastim 
Flt3 
FMS-Like Tyrosine Kinase 3 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HAM 
High Dose Cytarabine and Mitoxantrone 
HAMA or HM High Dose Cytarabine + Mitoxantrone + Asparaginase 
hERG 
The Human Ether-À-Go-Go-Related Gene 
HiDAC 
High Dose Cytarabine 
HM 
High Dose Cytarabine + Mitoxantrone + Asparaginase 
HR 
Heart Rate 
HSCT 
Hematopoietic Stem Cell Transplantation 
5-HT 
5-Hydroxytryptamine 
IB 
Investigator’s Brochure 
IC50 
The Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization  
IDH1/2 
Isocitrate Dehydrogenase 1 and 2 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITD 
Internal Tandem Duplication 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormonal-Releasing System 
IV 
Intravenous 
IWRS 
Interactive Web Response Systems 
KGDH 
Alpha-Ketoglutarate Dehydrogenase 
L-T 
Long-Term 
LVEF 
Left Ventricular Ejection Fraction 
MAP 
Mean Arterial Pressure 
MEC 
Mitoxantrone, Etoposide and Cytarabine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Minimal (Clinical) Important Difference 
MLFS 
Morphological Leukemia-Free State 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
NA 
North American 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NOS 
Not Otherwise Specified 
ORR 
Overall Response Rate 
Cornerstone Pharmaceuticals Inc.
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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Page 33 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
OS 
Overall Survival 
PDH 
Pyruvate Dehydrogenase 
PK 
Pharmacokinetic(s) 
pKa 
Dissociation Constant 
PP 
Per Protocol 
PR 
Partial Remission 
PRO 
Patient-Reported Outcome 
PS 
Performance Score 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
Q12h 
Twice a Day with 12 hours Interval 
QC 
Quality Control 
QD 
Once a Day 
QTc 
Corrected QT Interval 
RNA 
Ribonucleic Acid 
ROW 
Rest of the World 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SFU 
Safety Follow-up 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction(s) 
T1/2 
Elimination half-life 
TEA 
Triethanolamine 
TF 
Treatment Failure 
TKD 
Tyrosine kinase domain 
Tmax 
Time to Reach the Maximum (Peak) Plasma Concentration following Drug 
Administration 
TTE 
Transthoracic Echocardiogram 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
Vd 
Apparent Volume of Distribution 
WBC 
White Blood Cells 
Cornerstone Pharmaceuticals Inc.
Version 1.0
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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1. PROTOCOL SUMMARY AND SCHEMATIC OF STUDY DESIGN 
Name of Sponsor: 
Rafael Pharmaceuticals, Inc.  
Protocol Number: 
AML003 
Name and Description of 
Investigational Product: 
CPI-613® (devimistat) 
Mechanism of Action: Targets altered metabolism in cancer cells 
[Pyruvate 
Dehydrogenase 
(PDH) 
and 
α-Ketoglutarate 
Dehydrogenase (KGDH) Inhibitor] 
Dose: 2,000 mg/m2/day in Induction and Consolidation Cycles 
and 2,500 mg/m2/day in Maintenance Cycles 
Route of Administration: Intravenous (IV) infusion, 2 hours 
Title: 
Phase III Multicenter Open-Label Randomized Trial to Evaluate 
Efficacy and Safety of CPI-613® (devimistat) in Combination 
with High Dose Cytarabine and Mitoxantrone (CHAM) 
Compared to High Dose Cytarabine and Mitoxantrone (HAM) 
therapy and control sub-groups: combination of Mitoxantrone, 
Etoposide and Cytarabine (MEC) and combination of 
Fludarabine, Cytarabine, and Filgrastim (FLAG) in Older 
Patients (≥50 years) with Relapsed/Refractory Acute Myeloid 
Leukemia (AML) 
Study Duration: 
Approximately 48 months 
Participation Duration: 
Approximately 12 months 
Objectives: 
 
Primary Objective:  
▪ To determine efficacy of CHAM in terms of complete 
remission (CR) and compare with HAM (control). CR will 
be determined as per standard response criteria for AML 
(Döhner et al. 2017; 129[4]:424-447). 
Secondary Objectives: 
▪ To determine efficacy of CHAM in terms of overall 
survival (OS) and complete remission + complete 
remission with partial hematologic recovery (CR+CRh) 
as the two key secondary objectives to compare with HAM 
(control). The OS and CR+CRh will be determined as per 
standard response criteria for AML (Döhner et al. 2017; 
129[4]:424-447). 
▪ Safety: The assessment of safety will be based mainly on 
the frequency of adverse events (AEs) based on the 
Common Terminology Criteria for AEs (version 5.0 or 
later) grade. Adverse events will be coded according to the 
Medical Dictionary for Regulatory Activities (MeDRA 
(version 22.0 or higher). The safety outcomes will include 
the occurrence of at least one serious AE, of at least one 
Grade 3/4 AE, and of at least one AE requiring the 
discontinuation of study treatment. Electrocardiogram 
QTc intervals and cardiac markers will also be evaluated. 
Other Secondary Objectives: 
▪ Pharmacokinetics (PK): to evaluate Cmax, Cmin, AUC, 
T1/2, Tmax, CL and Vd for both CPI-613® (devimistat) and 
Cornerstone Pharmaceuticals Inc.
Version 1.0
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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its metabolites CPI-2850 and CPI-1810. To evaluate 
Patient-Reported Outcome (PRO) among patients 
receiving CHAM compared to HAM as per European 
Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30 (EORTC QLQ-C30). 
▪ Cancer-associated mutations and/or genetic 
alterations in bone marrow aspirates/biopsies and/or 
peripheral blood. Up to 10 unstained slides from 
baseline and time of disease progression will be 
collected. These slides will be used for immuno 
histochemistry staining for PDKs, PDH, KGDH, SOD2 
and CD79a. and as a source of material for RNA and 
whole exome sequencing should the bone marrow 
aspirate/biopsy material be inadequate. 
Exploratory Objectives: 
▪ Gene expression analysis by RNA sequencing for baseline 
bone marrow aspirate/biopsy samples to validate 
previously described response signature from the Phase I 
study (study CCCWFU 22112). Efficacy and safety 
analyses per gene mutations will also be assessed (may 
include FLT3, IDH1/2, TP53, CEBP, NPM1, etc). 
▪ PK/PD analyses for dose/exposure-response on efficacy 
and safety.  
▪ Patient Survival: 30-day and 60-day mortality after first 
dose of study-related treatment. 
Endpoints: 
Primary Endpoint:  
▪ CR 
Secondary Endpoints:  
▪ OS (key secondary)  
▪ CR+CRh (key secondary) 
▪ Safety  
▪ PK  
▪ PRO by EORTC QLQ-C30 
▪ Cancer-associated mutations and/or genetic alterations 
in bone marrow aspirate/biopsy and/or peripheral 
blood 
Exploratory Endpoints:  
▪ The determination of the positive and negative predictive 
value of the gene expression signature found from 
studying patients on study CCCWFU 22112. Efficacy and 
safety analyses per gene mutations.  
▪ PK/PD analysis for dose/exposure-response will be 
explored for clinical efficacy and safety. 
▪ Patient Survival: 30-day and 60-day mortality after first 
dose of study-related treatment. 
▪ Collection of buccal swabs at Screening/Baseline as a 
source of germline DNA for comparison with DNA 
obtained from bone marrow aspirate/biopsy samples.  
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 36 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
Study Design: 
Phase: III 
Study Design: open label, multicenter, randomized trial 
Sample Size: approximately 500 
Study Groups: 
▪ Arm 1: CPI-613® (devimistat) + High Dose Cytarabine 
and Mitoxantrone (CHAM) 
▪ Arm 2: Control group 1: High Dose Cytarabine and 
Mitoxantrone (HAM) 
o Control sub-group 1: Mitoxantrone, Etoposide 
and Cytarabine (MEC) 
o Control sub-group 2: Fludarabine, Cytarabine, 
and Filgrastim (FLAG) 
Dosing Schedule of Interventions for CHAM arm (Arm 1):  
Induction Therapy (up to 2 cycles, each cycle: 14 days): 
Induction Cycle 1 (14-day cycle):  
▪ CPI-613® (devimistat) (2,000 mg/m2 over 2 hours as a 
central line IV infusion): 5 doses, once a day (QD) Days 1 
to 5.  
Followed by: 
▪ High Dose Cytarabine following completion of CPI-613® 
(devimistat) infusion (1 g/m2 over 3 hours as a central line 
IV infusion): 5 doses, every 12 hours (Q12h) starting on 
Day 3 through Day 5. Time between completion of CPI-
613® (devimistat) infusion and the start of Cytarabine 
infusion should be not more than 2 hours. 
Followed by: 
▪ Mitoxantrone following completion of High dose 
Cytarabine infusion (6 mg/m2 over 15 minutes as a central 
line IV infusion): 3 doses, QD following the 1st, 3rd and 5th 
doses of Cytarabine starting on Day 3 through Day 5 
(3 doses). Mitoxantrone given as soon as possible, but no 
later than 2 hours, after completion of each Cytarabine 
administration. 
Induction Cycle 2 (14-day cycle; based on Day 14 bone marrow 
aspirate/biopsy results): 
▪ Patients are only eligible to receive full Induction Cycle 2 
therapy if they are hemodynamically stable i.e. mean 
arterial pressure (MAP) > 60 mm Hg (not on pressors or 
fluid boluses), have maintained an ejection fraction (EF) 
sufficient to allow treatment with Mitoxantrone and are 
able to tolerate it in the opinion of the treating Investigator. 
▪ If no nadir marrow is obtained or after full Induction Cycle 
2 therapy, a recovery marrow will be obtained when 
peripheral blood counts are consistent with remission 
(absolute neutrophil count [ANC] > 1,000/µL, platelets 
> 100,000/µL and freedom from blood transfusions) or on 
Cornerstone Pharmaceuticals Inc.
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 37 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
Day 42 from the most recent chemotherapy, whichever 
comes first. 
If no Day 14 bone marrow aspirate/biopsy is obtained, no 
Induction Cycle 2 (Full or Abbreviated) will be given.  
Note: Sites that do not perform day 14 bone marrow will not 
perform induction cycle 2 (full or abbreviated) on any patients at 
that site. Induction Cycle 2 details: 
 
Same as Cycle 1 or an Abbreviated cycle (14-day cycle) as shown 
below: 
▪ 
 CPI-613® (devimistat) (2,000 mg/m2): 3 doses, QD Days 
1 to 3 
Followed by: 
▪ High Dose Cytarabine (1 g/m2) following completion of 
CPI-613® (devimistat) infusion: 3 doses, Q12 h starting on 
Day 2 through Day 3 
Followed by: 
▪ Mitoxantrone (6 mg/m2): 2 doses, QD following the 1st and 
3rd doses of Cytarabine 
Cycle 2 is administered as soon as possible, but no later than 
5 calendar days, following Day 14 bone marrow aspirate/biopsy 
results.  
Consolidation Therapy (for responders to induction): 
▪ Abbreviated course as per Induction Cycles described 
above (up to 2 consolidation cycles). 
▪ Patients must meet study eligibility criteria for organ 
function and performance status in order to be eligible for 
consolidation therapy. 
Maintenance Therapy (for responders to induction/ 
consolidation for CHAM arm only): 
▪ 
 CPI-613® (devimistat) (2,500 mg/m2): 5 doses, QD Days 
1 to 5 (28-day cycle); continued until disease recurrence, 
availability of stem cell transplant, the advent of 
intolerable side effects, or patient withdrawal of consent. 
NO administration of High Dose Cytarabine and Mitoxantrone in 
Maintenance Therapy. Patient may move directly into 
maintenance therapy if not eligible for re-induction or 
consolidation therapy. 
Dosing Schedule of Interventions for HAM arm (Control 
group, arm 2): HAM group is treated identically with the 
exception of the omission of CPI-613® (devimistat) and no 
Maintenance Therapy. 
 
 
 
 
Cornerstone Pharmaceuticals Inc.
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 38 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
Induction Cycle 1 (14-day cycle): 
▪ High Dose Cytarabine (1 g/m2 over 3 hours as a central 
line IV infusion): 5 doses, Q12 hours starting on Day 1 
through Day 3.  
Followed by: 
▪ Mitoxantrone (6 mg/m2 over 15 minutes as a central line 
IV infusion): 3 doses, QD following the 1st, 3rd and 5th 
doses of Cytarabine starting on Day 1 through Day 3. 
Mitoxantrone given as soon as possible, but no later than 
2 
hours, 
after 
completion 
of 
each 
Cytarabine 
administration. 
Induction Cycle 2 (14-day cycle; based on Day 14 bone marrow 
aspirate/biopsy results [as described for CHAM Arm 1 above]). 
▪ Patients are only eligible to receive Induction Cycle 2 
therapy if they are hemodynamically stable i.e. MAP 
> 60 mm Hg (not on pressors or fluid boluses), have 
maintained an EF sufficient to allow treatment with 
Mitoxantrone and are able to tolerate it in the opinion of 
the treating Investigator. 
▪ If no nadir marrow is obtained or after Induction Cycle 2 
therapy, a recovery marrow will be obtained when 
peripheral blood counts are consistent with remission 
(ANC > 1,000/µL, platelets > 100,000/µL and freedom 
from blood transfusions) or on Day 42 from the most 
recent chemotherapy, whichever comes first. 
▪ If no Day 14 bone marrow aspirate/biopsy is obtained, no 
Induction Cycle 2 (Full or Abbreviated) will be given. 
Abbreviated Induction Cycle 2: 
▪ High Dose Cytarabine at 1 g/m2 administered over 3 hours 
as a central line IV infusion (as per institutional guidelines 
or package insert instructions) Q12h starting on Day 1 
through Day 2 (total of 3 doses). 
Followed by: 
▪ Mitoxantrone at 6 mg/m2 administered over 15 minutes as 
a central line IV infusion after the 1st and 3rd doses of 
Cytarabine (total of 2 doses). 
Consolidation Therapy (for responders to induction): 
▪ Abbreviated course as per Induction Cycles described 
above (up to 2 consolidation cycles). 
Dosing Schedule of Interventions for MEC (Control sub 
group, arm 2): MEC sub-group will be treated as per below 
defined schedule and there is no Maintenance Therapy. 
Induction Cycle 1 and 2 (2, 14 day-cycles): Induction cycle 2  
based on Day 14 bone marrow aspirate/biopsy results. 
▪ Etoposide 80mg/m2 over 60 minutes as a central line IV 
infusion; 6 doses Day 1 though 6 
Cornerstone Pharmaceuticals Inc.
Version 1.0
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 39 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
▪ Cytarabine 1000mg/m2 over 3 hours as a central line IV 
infusion:  6 doses, Day 1 through 6  
▪ Mitoxantrone 6 mg/m2 over 30 minutes as a central line IV 
infusion: 6 dose, Day 1 through 6 
Consolidation Cycle (1 and 2) (for responders to induction): 
▪ Etoposide 80mg/m2 over 60 minutes as a central line IV 
infusion; 6 doses Day 1 though 6 
▪ Cytarabine 1000mg/m2 over 3 hours as a central line IV 
infusion:  6 doses, Day 1 through 6  
▪ Mitoxantrone 6 mg/m2 over 30 minutes as a central line 
IV infusion: 6 dose, Day 1 through 6 
Dosing Schedule of Interventions for FLAG (Control sub-
group, arm 2): FLAG sub-group will be treated as per below 
defined schedule and there is no Maintenance Therapy. 
Induction Cycle 1 and 2 (2, 14-day cycles):  Induction cycle 2 
based on Day 14 bone marrow aspirate/biopsy results. 
▪ Fludarabine 30mg/m2/day over 30 minutes as a central 
line IV infusion; 5 doses Day 1 though 5 
▪ Cytarabine 2g/m2 over 4 hours as a central line IV 
infusion; after Fludarabine: 5 doses, Day 1 through 5 
▪ Filgrastim 5µg/kg/day by SQ or as per institutional 
guidelines starting from Day 1 through Day 5 and can 
resume 7 days after completion of chemo until ANC ≥ 
0.5mcL 
Note: Sites performing Day 14 bone marrow should not 
administer Filgrastim until the bone marrow is complete. 
Consolidation Cycle 1 and 2 (2 cycles): 
▪ Fludarabine 30mg/m2/day over 30 minutes as a central 
line IV infusion; 5 doses Day 1 though 5 
▪ Cytarabine 2g/m2 over 4 hours as a central line IV 
infusion: 4 hours after Fludarabine: 5 doses, Day 1 
through 5 
▪ Filgrastim 5µg/kg/day by SQ or as per institutional 
guidelines starting from Day 1 through Day 5 and can 
resume 7 days after completion of chemo until ANC ≥ 
0.5mcL 
Note: Sites performing Day 14 bone marrow should not 
administer Filgrastim until the bone marrow is complete. 
Treatment Regimen Window: 
▪ For all treatment regimens (CHAM, HAM, MEC and 
FLAG) up to a 2 hour dosing window is allowed between 
the agents in each regimen.   
Number of Sites Enrolling 
participants: 
Approximately 90 sites 
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 40 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
Population: 
▪ Sample Size: approximately 500  
▪ Gender: Both male and female 
▪ Age: ≥ 50 years 
▪ Demographic Group: All 
▪ Eastern Cooperative Oncology Board Performance 
Score (ECOG PS): 0-2 
▪ Geographic Location: United States, Canada, Austria, 
Belgium, Poland, France, Germany, Spain, Italy, 
Australia, South Korea, India and potentially other 
countries 
Main Inclusion Criteria: 
▪ Males and females age ≥ 50 years must have histologically 
documented AML that is relapsed from, or refractory to, 
prior standard therapies 
▪ Refractory is defined as failure to achieve CR or complete 
remission with incomplete recovery (CRi) following:  
a. At least one cycle of any anthracycline, cytarabine 
or fludarabine containing induction regimen or 
persistence of disease on a nadir marrow following 
at least one cycle of any anthracycline, cytarabine 
or fludarabine containing induction regimen 
b. Persistent disease after at least 2 cycles of a 
hypomethylating agent (azacytidine or decitabine) 
with or without venetoclax 
▪ Relapse is defined as development of recurrent AML 
(Döhner et al. 2017; 129[4]:424-447) after CR or CRi has 
been achieved with a prior chemotherapy or after disease 
progression on a hypomethylating agent with or without 
venetoclax 
▪ ECOG PS (performance score) 0-2 
▪ Expected survival greater than 3 months 
Main Exclusion Criteria: 
▪ Patients 
who 
have 
received 
previous 
cytotoxic 
chemotherapy treatment for their relapsed or refractory 
AML. Treatment with hypomethylating agents (decitabine 
or azacytidine) either alone or in combination with 
Venetoclax are allowed until the day prior to starting of 
CHAM or HAM therapy or control sub-groups (MEC and 
FLAG). Targeted therapies including FLT3 or IDH1/2 
inhibitors and/or Hydrea and/or venetoclax are allowed. 
Targeted therapies and Hydrea may be taken until the day 
prior to starting of CHAM or HAM therapy or control sub-
groups (MEC and FLAG). 
▪ Female patients who are pregnant or breastfeeding or 
planning to become pregnant or breastfeed during 
treatment and for an additional 6 months after the last dose 
Cornerstone Pharmaceuticals Inc.
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00                                                                                                                                                             October 19, 2020 
Page 41 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
of CHAM or HAM therapy or control sub-groups (MEC 
and FLAG) (the teratogenic potential of CPI-613® 
(devimistat) is unknown). Female patients of childbearing 
potential with a positive pregnancy test assessed by a 
serum pregnancy test at Screening. 
▪ Patients receiving any other standard or investigational 
treatment for AML, or any other investigational agent for 
any indication within the past 1 week prior to initiation of 
CPI-613® (devimistat) treatment (the use of Hydrea and/or 
venetoclax, oral tyrosine kinase inhibitors FLT3 or IDH 
1/2 inhibitors are allowed until the day prior to starting 
CHAM or HAM therapy or control sub-groups (MEC and 
FLAG). Previous exposure to a hypomethylating agents 
either alone or in combination with venetoclax is allowed  
until the day prior to starting of  CHAM or HAM therapy 
or control sub-groups (MEC and FLAG). 
▪ Patients who have received immunotherapy of any type 
within the past 1 week prior to initiation of CPI-613® 
(devimistat) treatment. 
▪ Requirement for immediate palliative treatment of any 
kind including minor surgery. 
▪ Patients who have received a chemotherapy regimen with 
autologous 
stem 
cell 
support 
(bone 
marrow 
transplantation) within 6 months of starting CHAM or 
HAM therapy or control sub-groups (MEC and FLAG). 
▪ Patients who have had allogenic bone marrow 
transplantation within the last 6 months. Patients who 
have had an allogenic transplant more than 6 months ago 
are eligible provided they have no graft vs host disease. 
Statistical Methods: 
Primary Endpoint – CR 
The treatment arm will be compared with the control arm in terms 
of CR. The significance level will be determined using an 
O’Brien-Fleming type Lan-DeMets boundary for efficacy equal 
to 0.023, which will be reached if the difference in CR is larger 
than 8.3%. This requires 500 patients evaluable for response and 
will take 36 months after randomization. 
Endpoint for the 1st Interim Analysis – CR 
This will be performed when 125 patients are evaluable for 
response after randomization. The significance level for efficacy 
will be 0.0001 and it will be reached if the difference in CR is 
larger than 26.7%. The significance level for futility is 0.48 and it 
will be reached if the difference in CR is less than 0.5%. 
Cornerstone Pharmaceuticals Inc.
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            AML003
    15 June 2022

Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
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Page 42 of 198                                                                 Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary.  
 
Endpoint for the 2nd Interim Analysis – CR 
This will be performed when 250 patients are evaluable for 
response and after randomization. The significance level for 
efficacy will be 0.006 and it will be reached if the difference in 
CR is larger than 12.8%. The significance level for futility is 0.21 
and it will be reached if the difference in CR is less than 4.9%. 
Based on each of these interim analyses, if the CR difference is 
not sufficiently promising, consideration will be given to stopping 
the trial; otherwise, the trial will proceed. 
The final analysis will be performed when 500 patients are 
evaluable for response. This analysis will take place 
approximately 36 months after the first randomization. 
The number of events (deaths) required for secondary analysis is 
394. For OS, the re-randomization will use a stratified Cox 
proportional hazard test-statistic. For CR+CRh, the CMH 
test-statistic will be used. 
A Data Monitoring Committee will review safety periodically 
during the study. 
Cornerstone Pharmaceuticals Inc.
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            AML003
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Phase III Multicenter Open-Label Randomized Trial to Evaluate Efficacy and Safety of CPI-613® (devimistat) in Combination with 
High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) therapy and control 
sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
Filgrastim (FLAG) in Older Patients (≥ 50 years) with Relapsed/Refractory Acute Myeloid Leukemia (AML)  
Protocol AML003 
Version 8.00
October 19, 2020 
Page 43 of 198
  Copyright © 2020. Rafael Pharmaceuticals, Inc. Confidential and Proprietary. 
Figure 1 Schematic of Study Design 
Abbreviations: CHAM: CPI-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone; CR: complete 
remission; CRh: complete remission with partial hematologic recovery; ECOG PS: Eastern Cooperative Oncology Group Performance 
Score; EU: European Union; HAM: High Dose Cytarabine and Mitoxantrone; HiDAC: High Dose Cytarabine; HMA: High Dose 
Cytarabine + Mitoxantrone + Asparaginase; NA: North American; OS: overall survival; ROW; Rest of the World; Mitoxantrone, 
Etoposide and Cytarabine (MEC); Fludarabine, Cytarabine and Filgrastim (FLAG). 
Acute Myelold 
Leukemia (AML) 
Relapsed or 
Refractory, 
Ageo!:50 m, 
.. .!~fOG PS 0-2 
1:1 randomization 
Stratification factors: 
ANALYSIS 1 
(N• 125)" 
Jndkatlon for control therapy: HAM vs. MEC vs. 
FLAG; Prior Tho,.py (HDAC vs. HMA 7+3); 
Relapsed vs. Refractory AML; Cytogenetlc risk 
category; Ag• (50-59 vs. ~60 years old}; 
Perfonnanc• status (0-1 vs. 2); TrNting 
Institution. 
Continue 
final 1naly1l1 
CR difference 
does not reach 
1tatlstlcal 
slgniflcance 
CR difference 
reaches statlstlcal 
algniflcance 
Apply for 
Accelerated approval 
and continue flnal 
anaty1l1 
Control: High Dose 
Cytarablne + 
Mltoxantrone (HAM) 
Control aub• 
groups-: MEC and 
FLAG (Ann 2) 
Primary Endpoint: CR 
5-ndwy ondpolnr.: 
0$; CR + 
S.fety 
CPl-613 + High Dose 
Cytarablne + 
Mitoxantrone 
(CHAM) 
(Ann 1) 
Control: High Dose 
Cytarablne + 
Mltoxantrone {HAM) 
Control 1ub• 
groupa--: MEC and 
FLAG (Ann 2) 
Primary Endpoint: 
CR 
CP1~13 + High 
Dose Cytarablne 
Mltoxantrone 
(CHAM) 
(Ann 1) 
flliAL 
AtiALYlilli ... 
(N• SOO)" 
STOP ... 
Trial 
CR difference 11 NOT 
1ufflclently proml1lng 
CR difference 11 
aufflc5entty promising 
CR difference la 
sufficiently promising 
CR difference Is NOT 
sufficktntty promising 
... STOP 
Trial 
... 
INTERIM ANALYSIS 2 
(N• 250)" 
Primary Endpoint: CR 
Control: High 
OOH Cytarablne 
+ Mltoxantrone 
(HAM) 
Control aub-
groupt": MEC 
and FLAG 
(Ann2) 
CPl~13 + High 
Dote Cytarablne + 
Mltoxantrone 
(CHAM) 
(Ann1) 
• When these number of patients are evaluable for response 
•• Number of patients on this sub-group will be capped at 100. 
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            AML003
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