Clinical trial NCT03504410
Conditions: Relapsed/Refractory Acute Myeloid Leukemia
Sponsor: Cornerstone Pharmaceuticals
Start date: 2018-11-12; Completion date: 2022-01-19
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase III study to evaluate the safety and efficacy of CPI-613® (devimistat) in combination with High Dose Cytarabine and Mitoxantrone in comparison with high dose Cytarabine and Mitoxantrone and control sub-groups: combination of Mitoxantrone, Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and Filgrastim (FLAG) in older patients with relapsed/refractory Acute Myeloid Leukemia. CPI-613® (devimistat) targets the altered energy metabolism and processes for production of ATP and essential bio-intermediates unique to and characteristic of most cancer cell types. The addition of CPI-613® (devimistat) to high dose cytarabine and mitoxantrone (CHAM) will improve the complete remission (CR) rate in patients 50 years or older with relapsed or refractory AML when compared to HAM alone or other control sub groups.

Detailed description:
Subjects were randomized in 1:1 allocation ratio by IWRS according to the stratification factors. However, the control sub-groups (MEC and FLAG) were capped at 100 (50 per sub-group).

Subjects in both Arm 1 and Arm 2 were planned to receive induction cycle 1 treatment for at least 14 days. Subjects will receive follow-up therapy based on results of the bone marrow aspirate, and CR/complete remission with incomplete recovery (CRi) status.

Arms: arm 1: CPI-613 + High Dose Cytarabine and Mitoxantrone

CPI-613 at 2,000 mg/m2/day from day 1 to 5.

Cytarabine at 1gm/m2 (5 doses), every 12 hours starting day 3. Mitoxantrone at 6gm/m2 (3 doses), everyday following the 1st, 2nd and 5th doses of Cytarabine. arm 2: High Dose Cytarabine and Mitoxantrone

Cytarabine at 1gm/m2 (5 doses), every 12 hours starting day 3. Mitoxantrone at 6gm/m2 (3 doses), everyday following the 1st, 3rd and 5th doses of Cytarabine.

Mitoxantrone, Etoposide and Cytarabine

Etoposide 80mg/m 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

Fludarabine, Cytarabine and Filgrastim

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
Interventions: intervention 1: CPI-613 + High Dose Cytarabine and Mitoxantrone intervention 2: High Dose Cytarabine and Mitoxantrone intervention 3: Mitoxantrone, Etoposide and Cytarabine intervention 4: Fludarabine, Cytarabine, Filgrastim
Intervention descriptions: intervention 1: CPI-613 + High Dose Cytarabine and Mitoxantrone CPI-613: 2000mg/m2, 5 doses once a day, days 1-5 Cytarabine 1gm/m2, 5 doses every 12hrs starting day 3 through day 5 Mitoxantrone 6mg/m2, 3 doses, once a day following the first, third and fifth doses of Cytarabine intervention 2: Cytarabine 1gm/m2, 5 doses every 12hrs starting day 3 through day 5 Mitoxantrone 6mg/m2, 3 doses, once a day following the first, third and fifth doses of Cytarabine intervention 3: Mitoxantrone, Etoposide and Cytarabine

Etoposide 80mg/m 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 intervention 4: Fludarabine, Cytarabine and Filgrastim

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

Protocol documents:
Prot_000.pdf: 
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.
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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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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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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 
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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 
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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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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 
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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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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.
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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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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 
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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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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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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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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 
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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 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. 
 
 
 
 
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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 
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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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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 
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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%. 
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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 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. 
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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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SAP_001.pdf: 
 
 
 
Confidential 
 
 
 
Page 1 of 15 
 
Rafael Pharmaceuticals, Inc. 
Version: 1.2 
AML003 
Date: 03 Jun 2020 
 
 
Statistical Analysis Plan 
 
 
 
 
Sponsor:  
Rafael Pharmaceuticals, Inc. 
Protocol 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, 
C\WDUDELQH, DQG FLOJUDVWLP (FLAG) LQ OOGHU PDWLHQWV ( 
50 years) with Relapsed/Refractory Acute Myeloid 
Leukemia (AML) 
Study Code: 
AML003 
 
 


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The signatures on this form indicate approval of this document. 


 
 
 
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Table of Contents 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 4 
2. 
INTRODUCTION ........................................................................................... 6 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................ 6 
3.1 
Study Objectives...................................................................................... 6 
3.1.1 
Primary Objective .............................................................................. 6 
3.1.2 
Secondary Objectives ........................................................................ 6 
3.1.3 
Exploratory Objectives ....................................................................... 7 
3.2 
Study Design ........................................................................................... 7 
3.3 
Sample Size Justification ........................................................................... 8 
4. 
GENERAL ANALYSIS DEFINITIONS .............................................................. 8 
4.1 
Planned Analyses ..................................................................................... 9 
4.1.1 
First Interim Analysis ......................................................................... 9 
4.1.2 
Second Interim Analysis ..................................................................... 9 
4.1.3 
Final Analysis .................................................................................. 10 
4.2 
Definition of Populations ......................................................................... 10 
4.2.1 
Intention-To-Treat (ITT) Population ................................................... 10 
4.2.2 
Per-Protocol (PP) Population ............................................................. 10 
4.2.3 
Safety (SAF) Population ................................................................... 10 
4.3 
Subgroup Definitions .............................................................................. 10 
4.4 
Multiple Comparison/Multiplicity ............................................................... 10 
4.5 
Treatment Assignment and Treatment Arms .............................................. 11 
4.6 
Calculated Variables ............................................................................... 11 
4.7 
Methods to Be Used For Handling Missing Data .......................................... 12 
5. 
STUDY PATIENTS ....................................................................................... 12 
5.1 
Disposition of Patients ............................................................................ 12 
5.2 
Protocol Deviations ................................................................................ 12 
5.3 
Inclusion and Exclusion Criteria ............................................................... 12 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 12 
7. 
STATISTICAL ANALYSIS ............................................................................ 13 
7.1 
Primary Analysis .................................................................................... 13 
7.1.1 
Complete Remission (CR) ................................................................. 13 
7.2 
Secondary Analyses ............................................................................... 13 
7.2.1 
Overall Survival (OS) and Complete Remission + Complete Remission with 
Partial Hematologic Recovery (CR+CRh) .......................................................... 13 
7.2.2 
Safety ............................................................................................ 14 
7.2.3 
Patient-Reported Outcomes Analysis .................................................. 15 
7.3 
Exploratory Analyses .............................................................................. 15 
8. 
REFERENCES .............................................................................................. 15 


 
 
 
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1. List of Abbreviations and Definition of Terms 
 
AE 
Adverse Events 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Amino Transferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Amino Transferase 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
BILI 
Total Bilirubin 
CEBPĮ 
CCAAT Enhancer Binding Protein A 
CFR 
Code of Federal Regulations 
CHAM 
CPI-613 in Combination with High Dose Cytarabine and Mitoxantrone 
CL 
Clearance 
Cmax 
The Maximum (Peak) Plasma Concentration 
Cmin 
The Minimum (Trough) Plasma Concentration 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Remission 
CRc 
Cytogenetic Complete Response 
CRh 
CR (Complete Remission) with Partial Hematologic Recovery 
CRi 
CR (Complete Remission) with Incomplete Recovery 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
FLAG 
Fludarabine, Cytarabine, and Filgrastim 
Flt3 
FMS-Like Tyrosine Kinase 3 
HAM 
High Dose Cytarabine and Mitoxantrone 
HAMA or 
HM 
High Dose Cytarabine + Mitoxantrone + Asparaginase 
HiDAC 
High Dose Cytarabine 
HMA 
High Dose Cytarabine + Mitoxantrone + Asparaginase 
HR 
Hazard Ratio 
IDH1/2  
Isocitrate Dehydrogenase 1 and 2 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IHC 
Immunohistochemistry 
ITT 
Intent-To-Treat 
IxRS 
Interactive Voice/Web Response Systems 
KGDH 
Alpha-Ketoglutarate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEC 
Mitoxantrone, Etoposide and Cytarabine 


 
 
 
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Mito 
Mitoxantrone 
NCA 
Non-Compartmental Analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NPM 
Nucleophosmin 
OS 
Overall Survival 
PD 
Pharmacodynamic 
PDH 
Pyruvate Dehydrogenase 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient-Reported Outcome 
PS 
Performance Score 
QLQ 
Quality of Life Questionnaire 
QTc 
Corrected QT Interval 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
T1/2 
Elimination half-life 
Tmax 
Time to Reach the Maximum Plasma Concentration 
US 
United States 
Vd 
Volume of Distribution 
WBC 
White Blood Cells 
 
 


 
 
 
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2. Introduction 
This Statistical Analysis Plan was written for the clinical trial Rafael AML003. The ICH 
guidelines E3 ³SWUXFWXUH DQG CRQWHQW RI COLQLFDO SWXG\ RHSRUWV´ DQG E9 ³SWDWLVWLFDO 
PULQFLSOHV IRU COLQLFDO TULDOV´ ZHUH used as a guide to the writing of the plan. 
3. Study Design and Objectives 
3.1 
Study Objectives 
3.1.1 
PULPDU\ OEMHFWLYH 
The primary objective is: 
x 
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). 
3.1.2 
SHFRQGDU\ OEMHFWLYHV 
The main secondary objectives are: 
x 
To determine efficacy of CHAM in terms of 1. Overall Survival (OS) and 2. 
Complete Remission + Complete Remission with Partial Hematologic 
Recovery (CR+CRh) as the two key secondary objectives to compare with 
HAM [control]. OS and CR+CRh will be determined as per standard response 
criteria for AML (Döhner et al. 2017). 
x 
Safety: The assessment of safety will be based mainly on the frequency of 
adverse events based on the Common Terminology Criteria for Adverse 
Events (CTCAE [v5.0]) grade. Adverse events will be coded according to 
MedDRA version 21.0. The safety outcomes will include the occurrence of at 
least one serious adverse event, of at least one grade 3/4 adverse event, and 
of at least one adverse event requiring the discontinuation of study treatment. 
30-day mortality and 60-day mortality will be evaluated as part of the safety 
analysis. QTc intervals will be also evaluated as part of the safety analysis. 
Other secondary objectives: 
x 
Pharmacokinetic 
(PK): 
The 
goal 
of 
non-compartmental 
(NCA) 
pharmacokinetic analysis will be to evaluate Cmax, Cmin, AUC, T1/2, Tmax, 
CL and Vd for both CPI-613 and its metabolites CPI-2850 and CPI-1810. NCA 
PK analysis is out of the scope of this SAP and will not be performed by IDDI. 
Definitions of Pharmacokinetic Parameters: 
x 
Cmax: Maximum (peak) plasma drug concentration  
x 
Cmin: Minimum (trough) plasma drug concentration  
x 
AUC: Area under the plasma concentration-time curve 
x 
T1/2: Elimination half-life 
x 
Tmax: Time to reach maximum (peak) plasma concentration following 
drug administration 
x 
CL: Apparent total body clearance 
x 
Vd: Apparent volume of distribution 


 
 
 
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x 
Patient-Reported Outcome (PRO) by EORTC QLQ-C30: Administered at 
enrollment, at time of recovery marrow, at completion of consolidation 
therapy (when applicable), every 3 months following completion of 
consolidation therapy and at time of study discontinuation (when possible). 
3.1.3 
E[SORUDWRU\ OEMHFWLYHV 
Exploratory objectives are: 
x 
Efficacy and safety analyses per gene mutations (e.g. FLT3, IDH1/2, TP53, 
CEBPĮ, NPM1, etc.) 
x 
PK/PD analyses for dose/exposure-response on efficacy and safety  
x 
Gene expression analysis by RNA sequencing for baseline bone marrow 
samples to validate previously described response signature from the phase 
I study (CCCWFU 22112) 
x 
Slides from baseline and time of progression biopsies will be used for IHC 
staining for PDKs, PDH, KGDH, SOD2 and CD79a 
3.2 
Study Design 
This is a prospective, multicenter, open label, randomized Phase III study of 
CHAM compared to HAM and control sub-groups: combination of Mitoxantrone, 
Etoposide and Cytarabine (MEC) and combination of Fludarabine, Cytarabine, and 
FLOJUDVWLP (FLAG) LQ ROGHU SDWLHQWV ( 50 \HDUV) ZLWK UHODSVHG/UHIUDFWRU\ AML. 
There will be two study arms: 
 
x 
Arm 1: CHAM (i.e. CPI-613 + High Dose Cytarabine and Mitoxantrone) 
x 
Arm 2: HAM (i.e. High Dose Cytarabine and Mitoxantrone) 
o 
Control sub-group 1: Mitoxantrone, Etoposide and Cytarabine 
(MEC) 
o 
Control sub-group 2: Fludarabine, Cytarabine, and Filgrastim 
(FLAG) 
Subjects will be randomized in 1:1 allocation ratio to treatment and control groups, 
respectively, in an open-label manner using a dynamic minimization procedure 
(additional details in section 4.5). The randomization number will be provided by 
IxRS. The randomization will be stratified by: 
 
x 
Indication for control therapy: HAM vs. MEC vs. FLAG 
x 
Prior therapy: HiDAC based vs. hypomethylator (azacytidine or decitabine, 
HMA) vs. 7+3 (7 days of cytarabine + anthracycline on the first 3 days) 
x 
Relapsed vs. refractory AML 
x 
Cytogenetic risk category (historical data might be used to define risk 
factors) 
x 
Age (50-69 YV.  70 years old) 
x 
Performance status (0-1 vs. 2) 
x 
Treating Institution 
The strata for control therapies of MEC and FLAG will be capped at 100 each.  The 
overall study design is shown in Figure 1. 


 
 
 
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FLgXUe 1  RafaeO AML003 SchePa 
 
3.3 
Sample Size Justification 
The sample size calculation is based on an improvement in complete response rate 
(CR) from 26% in the control arm to 39% in the experimental arm (a 13% absolute 
increase, or a 50% relative increase), based on clinical efficacy data from Phase I 
study CCCWFU 22112 in AML patients. For a power of 80%, 500 patients need to be 
evaluated for response. This number allows for two interim analyses to be performed 
as detailed in the interim analysis plan. 
The study is also powered to detect a clinically meaningful difference in overall 
survival (OS), with an expected median overall survival equal to 5.2 months in the 
control arm vs. 6.9 months in the experimental arm, i.e. a hazard ratio equal to 0.75 
assuming exponential survival distributions. For a power of 80%, 394 events need 
to be observed. This number allows for one interim analysis but is merely added to 
safeguard the type I error as no interim analysis for OS is planned (as detailed in 
the interim analysis plan). Assuming an accrual rate of 15 patients per month and a 
common dropout rate of 10% at 3 years, a sample size of 500 patients will provide 
a power of 80% for the OS analysis 36 months after the first randomization. Note 
that all efficacy secondary endpoints will be analyzed at the final analysis after 394 
deaths are observed. 
Finally, the study has more than 86% power to detect a clinically meaningful 
difference in CR+CRh rate (complete remission with or without complete hematologic 
recovery) at the final analysis, with an expected rate equal to 33% in the control 
arm vs. 47% in the experimental arm. Similarly, as for OS, this sample size allows 
for 1 interim analysis although there is no intent to analyze CR+CRh at interim.  
4. General Analysis Definitions 
Data will be analyzed using SAS (Version 9.4 or higher).  


 
 
 
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Descriptive statistics will be tabulated as follows:  
x 
Categorical data will be summarized in contingency tables presenting 
frequencies and percentages. 
x 
Continuous data will be summarized using number of non-missing values (n), 
mean, standard deviation, median, minimum and maximum values.  
The baseline tables will be created by treatment arm and overall. Tables containing 
post-randomization information will be created by treatment arm, unless otherwise 
specified.  
Listings with individual values will be provided for all data presented in the tables, 
where noted. The listings will be presented by identifiers, such as treatment group, 
center and patient number.  
One-sided tests will be used at a significance level equal to 0.025. Two-sided Exact 
Clopper Pearson confidence intervals will be computed for a coverage of 0.95. 
TLPH WR HYHQW RXWFRPHV (³VXUYLYDO WLPHV´) ZLOO EH GHVFULEHG E\ WUHDWPHQW DUP XVLQJ 
the Kaplan-Meier method. Subjects who have not had the event of interest at the 
time of the analysis will be censored at the time of the last follow up. Summary 
statistics will be provided by treatment arm in terms of the number of events, 
number of censored observations, median and 95% confidence interval, and survival 
probabilities at specific time points (such as 1 year, 2 years, etc.). Survival curves 
will be plotted by treatment arm and compared with a log-rank test stratified by 
performance status, age and refractory versus relapsed disease. A stratified Cox 
regression model will be used to estimate the hazard ratio and its 95% CI, as well 
as to adjust the comparison for baseline covariates. 
Binary outcomes will be described by proportions by treatment arm and compared 
with a Cochran-Mantel-Haenszel (CMH) test stratified by performance status, age 
and refractory versus relapsed disease. A logistic regression model will be used to 
adjust the comparison for baseline covariates. 
4.1 
Planned Analyses 
4.1.1 
FLUVW IQWHULP AQDO\VLV 
The first interim analysis will be performed when 125 patients are evaluable for 
response (had time for count recovery and bone marrow biopsy was obtained to 
assess remission status). The only endpoint analyzed at this interim analysis will 
be CR. The significance level to be used for this interim analysis will be determined 
XVLQJ DQ O¶BULHQ-Fleming type Lan-DeMets boundary for efficacy, and a Pocock type 
Lan-DeMets boundary for futility. Assuming an information fraction of 33% for CR 
at this interim analysis, the significance level for efficacy will be 0.0001 and it will 
be reached if the absolute difference in CR is larger than 26.7%. The significance 
level for futility is 0.48 and it will be reached if the absolute difference in CR is 
smaller than 0.5%. If, based on this interim analysis, the CR difference crosses the 
futility boundary, consideration will be given to stopping the trial; otherwise, the 
trial will proceed. 
4.1.2 
SHFRQG IQWHULP AQDO\VLV 
The second interim analysis will be performed when 250 patients are evaluable 
(had time for count recovery and bone marrow biopsy was obtained to assess 
remission status) for response. The only endpoint analyzed at this interim analysis 
will be CR. The significance level to be used for this interim analysis will be 


 
 
 
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deterPLQHG XVLQJ DQ O¶BULHQ-Fleming type Lan-DeMets boundary for efficacy, and 
a Pocock type Lan-DeMets boundary for futility. Assuming an information fraction 
of 67% for CR at this interim analysis, the significance level for efficacy will be 
0.006 and it will be reached if the absolute difference in CR is larger than 12.8%. 
The significance level for futility is 0.21 and it will be reached if the absolute 
difference in CR is smaller than 4.9%. If, based on this interim analysis, the CR 
crosses the futility boundary, consideration will be given to stopping the trial; 
otherwise, the trial will proceed. 
4.1.3 
FLQDO AQDO\VLV 
The final analysis will be performed when 500 patients are evaluable (had time for 
count recovery and bone marrow biopsy was obtained to assess remission status) 
for response. At that time, the primary endpoint of CR will be analyzed first, with 
D VLJQLILFDQFH OHYHO GHWHUPLQHG XVLQJ DQ O¶BULHQ-Fleming type Lan-DeMets 
boundary for efficacy equal to 0.023, which it will be reached if the absolute 
difference in CR is larger than 8.3%. In case efficacy is declared for CR, it will be 
considered to file for accelerated approval based on CR while patients are further 
followed to collect OS data. 
4.2 
Definition of Populations 
4.2.1 
IQWHQWLRQ-TR-TUHDW (ITT) PRSXODWLRQ  
The intent-to-treat (ITT) population (defined as all randomized patients) will be used 
for all analyses of efficacy and baseline characteristics. Patients will be analyzed 
according to their randomly assigned treatment regardless of treatment actually 
received. 
4.2.2 
PHU-PURWRFRO (PP) PRSXODWLRQ  
The per-protocol (PP) population consists of randomized subjects who do not have 
any major protocol violation and received at least one dose of study treatment. The 
PP population will be used as a sensitivity analysis for efficacy endpoints. 
4.2.3 
SDIHW\ (SAF) PRSXODWLRQ  
The safety population (SAF) includes all patients who receive at least one dose of 
study treatment. Patients will be analyzed according to treatment actually received. 
The SAF population will be used for safety analyses. 
4.3 
Subgroup Definitions 
Subgroup analyses will be carried out with a descriptive intent. Treatment effects 
will be estimated and tested for important factors, including the factors used in the 
treatment allocation procedure (performance status, age and refractory versus 
relapsed disease), and displayed as forest plots. Interaction tests will be carried 
between treatment and each of these factors. 
4.4 
Multiple Comparison/Multiplicity 
The randomized treatment arms will first be compared in terms of CR, using a 
Hochberg procedure to evaluate CR separately in the add-on ITT subpopulation 
(CHAM vs. HAM) and in the full ITT population.  Then, conditional on the comparison 
of CR reaching statistical significance in either or both populations, the randomized 
treatment arms will be compared in terms of the two key secondary endpoints, OS 


 
 
 
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and CR+CRh, evaluated in the full ITT population.  A Hochberg procedure will again 
be used to adjust the significance level to allow for multiple comparisons. 
The Hochberg testing procedure will proceed as follows for the two populations (full 
ITT population and CHAM vs. HAM subpopulation): Let p1 and p2 be the p-values of 
the two populations.  The two p-values ZLOO EH DUUDQJHG VXFK WKDW S1  S2. II S2  
0.023, then both key secondary endpoints will be declared significant. If p2 > 0.023 
DQG S1  0.0115, then the significance of the endpoint corresponding to p1 will be 
claimed. 
The Hochberg testing procedure will proceed as follows (if applicable) for the two key 
secondary endpoints (OS and CR+CRh): Let p1 and p2 be the p-values of the two 
key secondary endpoints in the full ITT population.  The two p-values will be arranged 
VXFK WKDW S1  S2. 
x 
If statistical signiILFDQFH ZDV UHDFKHG LQ ERWK SRSXODWLRQV DQG LI S2  0.023, 
WKHQ ERWK HQGSRLQWV ZLOO EH GHFODUHG VLJQLILFDQW.  II S2 > 0.023 DQG S1  
0.0115, then the significance of the endpoint corresponding to p1 will be 
claimed. 
x 
If statistical significance was reached LQ RQO\ RQH SRSXODWLRQ DQG LI S2  
0.0115, then both endpoints will be declared significant.  If p2 > 0.0115 and 
S1  0.00575, WKHQ WKH VLJQLILFDQFH RI WKH HQGSRLQW FRUUHVSRQGLQJ WR S1 ZLOO 
be claimed. 
4.5 
Treatment Assignment and Treatment Arms 
Eligible patients will be randomized to receive either  
x 
Arm 1: CHAM (i.e. CPI-613 + High Dose Cytarabine and Mitoxantrone) 
x 
Arm 2: HAM (i.e. High Dose Cytarabine and Mitoxantrone) 
o 
Control sub-group 1: Mitoxantrone, Etoposide and Cytarabine (MEC) 
o 
Control sub-group 2: Fludarabine, Cytarabine, and Filgrastim (FLAG) 
Subjects will be randomized in 1:1 ratio to the experimental treatment or control, 
using a dynamic minimization procedure based on the methodology described by 
Pocock and Simon (Pocock and Simon, 1975). The minimization algorithm will use 
the variance range method to minimize overall imbalances between the treatment 
arms with respect to center and important prognostic factors (see below). A 
stochastic minimization will be used so that no treatment allocation is deterministic. 
The stratification factors include:  
x 
Indication for control therapy: HAM vs. MEC vs. FLAG 
x 
Prior therapy: HiDAC based vs. hypomethylator (azacytidine or decitabine, 
HMA) vs. 7+3 (7 days of cytarabine + anthracycline on the first 3 days) 
x 
Relapsed vs. refractory AML 
x 
Cytogenetic risk category (historical data might be used to define risk factors) 
x 
Age (50-69 YV.  70 years old) 
x 
Performance status (0-1 vs. 2) 
x 
Treating Institution 
4.6 
Calculated Variables 
x 
Study day 1 is defined as the first date of drug intake. For those randomized who 
did not receive any study drugs, the date of randomization will be used.  


 
 
 
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x 
The baseline is defined as the last non-missing assessment done before start of 
treatment. 
x 
Body Surface Area (m²) = ([height (cm) × weight (kg)] / 3600)0.5 
x 
Months= days/30.4167 
4.7 
Methods to Be Used For Handling Missing Data 
For the primary analyses, no imputations will be done, and data will be analyzed as 
observed, with patients without response assessment set to non-responder. Multiple-
imputation will be used in secondary or sensitivity analyses, whenever necessary, to 
impute the missing efficacy endpoint data. 
Missing Quality of Life (QOL) scales will be imputed as follows: 
The missing items are imputed based on the average of other items that are 
answered by a patient for multi-item scales. None of the single item measures can 
be imputed using this method of imputation. In the event of missing full 
assessments, none of the subscales will be scored or imputed. 
5. Study Patients 
5.1 
Disposition of Patients 
The number of patients in each population will be tabulated by treatment arm and 
overall. Number screened and screen failed will be tabulated. Reason for screen 
failure will also be tabulated and listed. 
The frequency of patients treated, of patients who discontinued the study treatment 
and of patients who terminated the study will be given for the ITT population. The 
primary reason for discontinuation of the study treatment and terminating the study 
will be summarized. The details of the SDWLHQW¶V RU LQYHVWLJDWRU¶V GHFLVLRQ will be 
included in a listing. The frequency of subjects on treatment, who completed 
treatment, and reason for discontinuation of treatment will be summarized by 
consolidation and maintenance therapy cycles. 
5.2 
Protocol Deviations 
Protocol deviations classified as major will be determined before database lock. The 
major protocol deviations will be categorized by type and summarized by treatment 
arm, for the ITT population.   
A listing of all major protocol deviations will be provided by treatment arm. 
5.3 
Inclusion and Exclusion Criteria 
Enrolled patients who violate inclusion/exclusion entry criteria (described in Section 
5 of protocol) will be summarized for those randomized.  
A listing of all inclusion and exclusion criteria not met will be provided by treatment 
arm. 
6. Demographic and other Baseline Characteristics 
Descriptive statistics with respect to patient characteristics at baseline will be 
displayed for the ITT population. Stratification information will be tabulated by 
treatment arm. 


 
 
 
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The summary of demographic and baseline characteristics data will present the 
following variables: 
x 
Age at Screening (years) and Age Category (50-55, 56-60, 61-65, 66-70, 71-
75, 76-80, 81-85, 86-90, 90+) 
x 
Race 
x 
Ethnicity 
x 
Sex 
x 
ECOG Performance Status 
x 
Height (cm) 
x 
Weight (kg) 
x 
BSA (m2) 
AML history including type, status, prior type of therapy, and time since diagnosis 
will be summarized by treatment arm and overall. Prior and concomitant medication 
will be summarized using WHODrug version 2018. Medical history and concomitant 
illness will be classified according to the terminology of CTCAE version 5.0 and coded 
using MedDRA version 21.0. Medical history will be tabulated by system organ class 
and preferred term for the ITT population.  
7.  Statistical Analysis  
The efficacy analyses will be performed on the ITT population. In addition, Complete 
Remission (CR), Overall Survival (OS) and Complete Remission + Complete 
Remission with Partial Hematologic Recovery (CR+CRh) will be analyzed on the PP 
population.  
7.1 
Primary Analysis 
7.1.1 
CRPSOHWH RHPLVVLRQ (CR)  
The treatment arm will be compared with control arm in terms of CR. The primary 
analysis will be a re-randomization test (Simon R., 1979) based on the CMH test-
statistic, stratified by performance status, age and refractory versus relapsed 
disease. The re-randomization approach fixes all data except the treatment labels 
at their observed values, regenerates the randomization sequence using the 
minimization algorithm (Buyse M., 2000), and computes the test statistic 
corresponding to those reshuffled assignments. This process is repeated a large 
number of times, and a p-value is calculated as the proportion of re-randomized 
trials whose test statistic is at least as extreme as the observed one from the 
original assignments. 
The trial design includes two interim analyses, and one final analysis. Both interim 
analyses are only performed for the primary endpoint CR rate with the intent to 
stop the trial if the difference in CR between arms is not sufficiently promising; 
there is no intention to stop the study early if efficacy is shown. The futility 
boundaries are conceived as non-binding boundaries allowing the DMC to decide 
independently at the timing of the interim analysis, taking all available data into 
account, whether the study should continue or stop. 
7.2 
Secondary Analyses 
7.2.1 
OYHUDOO SXUYLYDO (OS) DQG CRPSOHWH RHPLVVLRQ + CRPSOHWH RHPLVVLRQ ZLWK 
PDUWLDO HHPDWRORJLF RHFRYHU\ (CR+CRK) 


 
 
 
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The primary analysis of these secondary efficacy endpoints will be a re-
randomization test that calculates the p-value by re-randomizing and allocating 
patients to treatments. For OS, the re-randomization will use a stratified Cox 
proportional hazard test-statistic. For CR + CRh, the stratified CMH test-statistic 
will be used. The secondary endpoints will only be analyzed at the final analysis. 
Note that by design an interim analysis has been foreseen for OS, using an 
O¶BULHQ-Fleming type Lan-DeMets boundary for efficacy.  
When the number of required deaths is observed, all secondary endpoints will be 
analyzed at the time of final analysis. The number of required deaths for a final 
analysis of OS is 394. 
7.2.2 
SDIHW\ 
The assessment of safety will be based mainly on the frequency of adverse events, 
which will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
Version 21.0) and will be graded according to the National Centre Institute 
Common Terminology Criteria for AEs (NCI-CTCAE criteria [v5.0]). Uncoded terms 
ZLOO EH SUHVHQWHG XQGHU ³SOC XQFRGHG´, ZLWK WKHLU UHSRUWHG WHUP. 
Adverse events will be analyzed in terms of their type, incidence, severity and 
relationship to the study treatment.  
A summary table will present, by treatment arm, the number and percentage of 
patients with at least one: 
x 
AE 
x 
Related AE 
x 
AE leading to treatment discontinuation  
x 
AE leading to dose interruption 
x 
Grade 3/4 AE 
x 
Serious AE  
x 
AE leading to death 
In addition, tabulations of the number of AE events (same categories as above) as 
well as severity of the events will be presented by system organ class and preferred 
term. Patients will only be counted once for each preferred term. In case a patient 
experienced the same event more than once, the worst severity will be presented. 
Listings of all adverse events by treatment arm will be provided including the 
patient identifier, age, race, sex, verbatim, preferred term, severity, relationship 
to study treatment. 
30-day mortality and 60-day mortality will also be evaluated as a part of the safety 
analysis using Kaplan-Meier for overall survival. The number of deaths will be 
tabulated together with the primary cause of death. The detDLOV RI WKH µRWKHU FDXVH¶ 
will be included in the listing. 
Hematology [hemoglobin, leukocytes (WBC), neutrophil count (ANC), lymphocytes, 
platelets] 
and 
biochemistry 
[creatinine, 
AST/SGOT, 
ALT/SGPT, 
alkaline 
phosphatase (ALP), total bilirubin (BILI)] lab data will be presented in shift tables 
from baseline to worst post-baseline CTC grade, along with listings.  
Number and cause of death will be summarized and listed. 


 
 
 
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Version: 1.2 
AML003 
Date: 03 Jun 2020 
 
QTc interval at pre-infusion and at the end of infusion will be summarized by visit 
and treatment arm separately for induction, consolidation and maintenance 
therapies. 
7.2.3 
PDWLHQW-RHSRUWHG OXWFRPHV AQDO\VLV 
Changes over time in QLQ-C30 Global Health Status/Quality of Life (QOL) scores 
will be summarized and listed for all time points and by treatment group. Changes 
over time in QLQ-C30 Global Health Status/Quality of Life (QOL) scores will also be 
compared between treatment groups using a restricted maximum likelihood-based 
mixed model for repeated measures under the assumption of missing at random. 
The minimal clinical important difference (MID) will help to interpret any observed 
differences between treatment groups. The MID for between-group differences on 
the QLQ-C30 Global Health Scale/QoL is 5 points. 
 
Sensitivity analysis will be performed on PP population after imputations are made 
as per section 4.7. 
7.3 
Exploratory Analyses 
  
Bone marrow aspirate/biopsy samples are collected from patients at baseline and 
RNA sequencing analyses will performed to determine the positive and negative 
predictive value of the response signature. The response summary will be displayed 
per FLT3, IDH1/2, TP53, CEBPĮ, and NPM1 gene mutation. 
8. References 
1. 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 Jan 21; 115(3): 453-74. 
2. Pocock SJ, Simon R. Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics. 1975; 31: 103-5. 
3. Simon R. Restricted randomization designs in clinical trials. Biometrics. 1979; 
35(2): 503-12 
4. Buyse M. Centralized treatment allocation in comparative clinical trials. Applied 
Clinical Trials. 2000; 9(6): 32-37