Conditions: Acute Myeloid Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
Tamibarotene is being studied as a treatment for participants with a type of leukemia called acute myeloid leukemia, or AML for short. Tamibarotene is being studied as a treatment for participants with AML whose cancer has a specific genetic abnormality characterized by the overexpression of the retinoic acid receptor alpha (RARA) gene. This genetic profile is found in about 3 of every 10 people with AML.

During the trial, tamibarotene will be given with 2 other drugs that are already used together to treat people who have AML and who cannot start treatment with standard chemotherapy.

Detailed description:
This study consists of 3 parts. In Part 1, the safety, tolerability, and pharmacokinetic (PK) evaluation of tamibarotene/venetoclax/azacitidine combination will inform the appropriate tamibarotene dose to be combined with the standard of care (SOC) venetoclax/azacitidine in Part 2 and Part 3. In Part 2, participants will be randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to compare the clinical activity of the 2 combinations. In Part 3, tamibarotene will be added to the venetoclax/azacytidine regimen of a subset of Part 2 participants who experience progressive disease, relapse after initial complete remission (CR) or CR with incomplete blood count recovery (CRi) response, or treatment failure.

Arms:
arm 1: Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination as follows: Azacitidine (intravenously or subcutaneously) at 75 milligrams (mg)/square meter (m\^2) once daily, on Days 1 through 7 of each 28-day therapy cycle (per VIDAZA USPI). Alternative dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study.

Venetoclax (orally) daily on Days 1 through 28 per standard of care. Standard of care daily dosing is 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and beyond.

Tamibarotene 6 mg twice daily (BID) orally, on Days 8 through 28 of each 28-day therapy cycle. Tamibarotene will only be administered to participants who have been confirmed as RARA-positive. arm 2: Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1. arm 3: Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1. arm 4: Part 2 participants treated with venetoclax/azacitidine who experience progressive disease, relapse after initial CR or CRi response, or treatment failure may begin subsequent treatment in Part 3, where tamibarotene will be added to their regimen.

Interventions: intervention 1: Tamibarotene intervention 2: Venetoclax intervention 3: Azacitidine
Intervention descriptions: intervention 1: Tamibarotene tablets will be administered per dose and schedule specified in the arm. intervention 2: Venetoclax tablets will be administered per dose and schedule specified in the arm. intervention 3: Azacitidine injection will be administered per dose and schedule specified in the arm.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
1 
CLINICAL STUDY PROTOCOL 
Protocol Title: Tamibarotene in Combination with Venetoclax and Azacitidine in Previously 
Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard 
Induction Therapy  
Protocol Number: SY-1425-202 
Amendment Number: 5 
Compound: Tamibarotene (formerly SY-1425) 
Brief Title: Tamibarotene/Venetoclax/Azacitidine in Previously Untreated Patients Selected for 
RARA-positive AML (SELECT-AML-1) 
Study Phase: 2 
Sponsor Name: Syros Pharmaceuticals, Inc. 
Legal Registered Address:  Syros Pharmaceuticals, Inc 
35 CambridgePark Drive, 4th Floor 
Cambridge, MA 02140 
USA 
Regulatory Agency Identifier Number(s): 
IND: 129755 
EudraCT: 2021-003910-38 
EU CT Number: 2024-510939-21-00 
DOCUMENT HISTORY 
Document 
Date 
Amendment 5 (Version 6.0) 
04 June 2024 
Amendment 4 (Version 5.0) 
16 November 2022 
Amendment 3 (Version 4.0) 
14 April 2022 
Amendment 2 FRA (Version 3.1) 
11 November 2021 
Amendment 1 FRA2 (Version 2.2) 
07 October 2021 
Amendment 1 FRA (Version 2.1) 
27 September 2021 
Amendment 2 (Version 3.0) 
16 September 2021 
Amendment 1 (Version 2.0) 
14 July 2021 
Original Protocol (Version 1.0) 
21 January 2021 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of Syros 
Pharmaceuticals, Inc. The protocol is for use by the Principal Investigator and his/her designated 
representatives participating in this investigational study. This protocol may not be copied or 
made available for review by an unauthorized person or firm without the prior written 
authorization of Syros Pharmaceuticals, Inc. 
NCT04905407


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
2 
INVESTIGATOR PROTOCOL APPROVAL 
I agree to the terms of this study protocol. I will conduct the study according to the procedures 
specified herein, and according to principles of Good Clinical Practice and all applicable 
regulations and requirements. 
 
Institution/Clinic:  
______________________________________ 
 
Principal Investigator 
Print Name:  
______________________________________ 
Signature: 
______________________________________ 
Date (DD MMM YYYY): 
______________________________________ 
 
 


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Protocol SY-1425-202, Version 6.0 
 
3 
SPONSOR PROTOCOL APPROVAL 
I have read this protocol and I approve the design of this study: 
 
 
 
 
 
 
 
Syros Pharmaceuticals, Inc. 
 
Date 
(DD MMM YYYY) 
PPD


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Protocol SY-1425-202, Version 6.0 
 
4 
CONTACT INFORMATION 
Sponsor: 
Syros Pharmaceuticals, Inc. 
35 CambridgePark Drive, 4th Floor 
Cambridge, MA 02140 
USA 
 
 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
5 
TABLE OF CONTENTS 
1 
Protocol Summary ......................................................................................................9 
1.1 
Synopsis ...................................................................................................................9 
1.2 
Schema ..................................................................................................................24 
1.3 
Schedules of Activities .........................................................................................25 
2 
Introduction...............................................................................................................33 
2.1 
Study Rationale ....................................................................................................33 
2.2 
Background ..........................................................................................................34 
2.2.1 
Disease Under Study ......................................................................................34 
2.2.2 
Tamibarotene .................................................................................................35 
2.2.3 
Venetoclax .......................................................................................................36 
2.2.4 
Azacitidine ......................................................................................................36 
2.3 
Benefit/Risk Assessment ......................................................................................36 
3 
Objectives and Endpoints ........................................................................................37 
4 
Study Design ..............................................................................................................40 
4.1 
Overall Design ......................................................................................................40 
4.2 
Scientific Rationale for Study Design .................................................................45 
4.3 
Rationale for Dose and Regimen ........................................................................46 
4.4 
End of Study Definition .......................................................................................47 
5 
Study Population .......................................................................................................47 
5.1 
Inclusion Criteria .................................................................................................47 
5.2 
Exclusion Criteria ................................................................................................49 
5.3 
Lifestyle Considerations ......................................................................................51 
5.4 
Screen Failures .....................................................................................................51 
5.5 
Criteria for Temporarily Delaying Randomization ..........................................51 
6 
Study Drugs and Concomitant Therapy.................................................................51 
6.1 
Study Drugs Administered ..................................................................................51 
6.1.1 
Study Procedures at the time of Response Assessment ..............................53 
6.2 
Preparation/Handling/Storage/Accountability .................................................54 
6.2.1 
Tamibarotene .................................................................................................54 
6.2.2 
Venetoclax .......................................................................................................55 
6.2.3 
Azacitidine ......................................................................................................55 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................55 
6.4 
Study Drug Compliance ......................................................................................55 
6.5 
Dose Modification and Management of Toxicities ............................................56 
6.5.1 
Dose Delay or Toxicity-related Discontinuation of One or More Study 
Drugs ...............................................................................................................58 
6.5.2 
Hypertriglyceridemia ....................................................................................58 
6.5.3 
Sensitivity to Sodium Hydrosulfite ...............................................................59 
6.5.4 
Interstitial Lung Disease................................................................................59 
6.6 
Continued Access to Study Drug After the End of the Study ..........................59 
6.7 
Treatment of Overdose ........................................................................................59 
6.7.1 
Tamibarotene .................................................................................................59 
6.7.2 
Venetoclax .......................................................................................................60 
6.7.3 
Azacitidine ......................................................................................................60 
6.8 
Concomitant Therapy ..........................................................................................60 


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Protocol SY-1425-202, Version 6.0 
 
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6.8.1 
Cytotoxic or Investigational Therapy ..........................................................60 
6.8.2 
Growth Factors ..............................................................................................60 
6.8.3 
Oral Hydroxyurea ..........................................................................................60 
6.8.4 
Platelet Transfusions .....................................................................................60 
6.8.5 
Red Blood Cell Transfusions.........................................................................60 
6.8.6 
 
...............................................................................................61 
6.8.7 
Antifibrinolytic ...............................................................................................61 
6.8.8 
Retinoic Acid Syndrome ................................................................................61 
6.8.9 
Multivitamin and Supplements ....................................................................61 
6.8.10 
Antacids and Proton Pump Inhibitors .........................................................61 
7 
Discontinuation of Study Drug and Patient Discontinuation/Withdrawal .........61 
7.1 
Discontinuation of Study Drug Administration ................................................61 
7.2 
Discontinuation of Study Participation by Patient’s Withdrawal of 
Informed Consent ................................................................................................62 
7.3 
Lost to Follow-up .................................................................................................63 
8 
Study Assessments and Procedures ........................................................................63 
8.1 
Efficacy Assessments ...........................................................................................64 
8.1.1 
Response Assessment .....................................................................................64 
8.1.2 
Bone Marrow Sample Collection ..................................................................64 
8.1.3 
Blood Product Transfusions..........................................................................65 
8.1.4 
Overall Survival .............................................................................................65 
8.2 
Safety Assessments ...............................................................................................65 
8.2.1 
Prior, Concomitant, and Subsequent Medication Review .........................65 
8.2.2 
ECOG Performance Status ...........................................................................66 
8.2.3 
Physical Examinations ...................................................................................66 
8.2.4 
Vital Signs .......................................................................................................66 
8.2.5 
Electrocardiograms........................................................................................66 
8.2.6 
Clinical Safety Laboratory Assessments ......................................................67 
8.2.7 
Pregnancy Testing ..........................................................................................67 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .........67 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information.....68 
8.3.2 
Method of Detecting AEs and SAEs .............................................................68 
8.3.3 
Follow-up of AEs and SAEs ..........................................................................68 
8.3.4 
Regulatory Reporting Requirements for SAEs ...........................................68 
8.3.5 
Pregnancy .......................................................................................................69 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs ....................................................................69 
8.4 
Pharmacokinetics .................................................................................................70 
8.5 
Genetics and Pharmacogenomics .......................................................................70 
8.6 
Biomarkers ...........................................................................................................70 
8.6.1 
RARA Biomarker Assessment ......................................................................70 
8.6.2 
Companion Diagnostic Assay Development ................................................71 
8.6.3 
Molecular Markers of Tumor Response and Resistance ...........................71 
9 
Statistical Considerations .........................................................................................71 
9.1 
Statistical Hypothesis for Part 2 .........................................................................71 
CCI


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Protocol SY-1425-202, Version 6.0 
 
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9.2 
Sample Size Determination .................................................................................71 
9.3 
Analysis Sets .........................................................................................................72 
9.4 
Statistical Analyses...............................................................................................72 
9.4.1 
General Considerations .................................................................................72 
9.4.2 
Primary Endpoint ..........................................................................................73 
9.4.3 
Secondary Endpoints .....................................................................................73 
9.4.4 
Exploratory Endpoints ..................................................................................75 
9.5 
Interim Analysis ...................................................................................................75 
10 Supporting Documentation and Operational Considerations ..............................76 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........76 
10.1.1 
Regulatory and Ethical Considerations .......................................................76 
10.1.2 
Informed Consent Process ............................................................................77 
10.1.3 
Confidentiality and Data Protection ............................................................77 
10.1.4 
Committees Structure ....................................................................................78 
10.1.5 
Dissemination of Clinical Study Data ..........................................................78 
10.1.6 
Data Quality Assurance .................................................................................78 
10.1.7 
Source Documents ..........................................................................................78 
10.1.8 
Study and Site Start and Closure .................................................................79 
10.1.9 
Publication Policy...........................................................................................80 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................80 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...............................................................82 
10.3.1 
Definition of AE..............................................................................................82 
10.3.2 
Definition of SAE ...........................................................................................83 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................83 
10.3.4 
Reporting of SAEs..........................................................................................85 
10.3.5 
Reporting of Serious Adverse Events to Regulatory Authorities, Ethics 
Committees, and Institutional Review Board .............................................86 
10.4 
Appendix 4: Contraceptive and Barrier Guidance...........................................87 
10.4.1 
Definitions .......................................................................................................87 
10.4.2 
Contraception Guidance ...............................................................................89 
10.5 
Appendix 5: ECOG Performance Status ...........................................................90 
10.6 
Appendix 6: Response Criteria for AML ..........................................................91 
10.7 
Appendix 7: Abbreviations and Definitions ......................................................92 
11 References ..................................................................................................................95 
 


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Protocol SY-1425-202, Version 6.0 
 
8 
LIST OF TABLES 
Table 1: 
Part 1 and Part 2 Schedule of Activities ................................................25 
Table 2: 
Part 3 Schedule of Activities ...................................................................30 
Table 3: 
Study Drugs ..............................................................................................52 
Table 4: 
Venetoclax Dosing ....................................................................................53 
Table 5: 
Dose Modifications ...................................................................................56 
Table 6: 
Dose Reductions of Tamibarotene ..........................................................58 
Table 7: 
Estimands..................................................................................................74 
 


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Protocol SY-1425-202, Version 6.0 
 
9 
1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: Tamibarotene in Combination with Venetoclax and Azacitidine in Previously 
Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard 
Induction Therapy 
Brief Title: Tamibarotene/Venetoclax/Azacitidine in Previously Untreated Patients Selected for 
RARA-positive AML (SELECT-AML-1) 
Rationale: 
Tamibarotene (formerly SY-1425) is a potent and selective agonist of retinoic acid receptor 
alpha (RARα) being developed in combination with azacitidine in a novel genomically defined 
subset of patients with non-acute promyelocytic leukemia (non-APL) acute myeloid leukemia 
(AML), characterized by overexpression of RARA (McKeown 2017). Approximately 30% of 
patients with newly diagnosed (ND) AML are expected to be positive for RARA overexpression 
(de Botton 2020).  
Currently, ND AML patients who are ineligible for standard induction therapy are increasingly 
receiving venetoclax/azacitidine combination as initial treatment. In a randomized study of such 
AML patients, the combination of azacitidine with venetoclax has demonstrated a high 
composite complete remission (CR) rate and a survival benefit compared to treatment with 
azacitidine monotherapy (DiNardo 2020). However, approximately one-third of patients failed to 
respond to the venetoclax/azacitidine combination (DiNardo 2020), supporting the existing need 
to improve upon the outcomes in this subpopulation.  
In RARA-positive ND AML patients who are ineligible for standard induction therapy, 
tamibarotene plus azacitidine is associated with high CR rates and a rapid onset of response 
(de Botton 2020). Further, recent data demonstrate that monocytic features associated with 
resistance to venetoclax are significantly present in those RARA-positive patients who achieve a 
complete response with tamibarotene plus azacitidine (Section 4.2, Fiore 2020, Pei 2020). 
Consequently, adding venetoclax to the tamibarotene plus azacitidine combination may address 
an unmet need in RARA-positive AML, allowing for the treatment of both primitive AML that 
may be sensitive to venetoclax and more mature monocytic subpopulations that may respond to 
treatment with tamibarotene plus azacitidine. Given that tamibarotene, venetoclax, and 
azacitidine have distinct adverse event (AE) profiles, it is anticipated that the 3 drugs can be 
administered safely in combination. 
This open-label Phase 2 study in adult RARA-positive, previously untreated AML patients who 
are ineligible for standard induction therapy will consist of 3 parts. In Part 1, the safety and 
tolerability of the tamibarotene/venetoclax/azacitidine combination will be evaluated, 
pharmacokinetics (PK) of tamibarotene will be assessed when co-administered with 
venetoclax/azacitidine, and the dosing regimen of the combination for evaluation in Part 2 will 
be selected. In Part 2, patients who are ineligible for standard induction therapy will be 
randomized to tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine. In Part 3, patients 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
10 
treated with venetoclax/azacitidine in Part 2 who experience progressive disease, relapse after 
initial CR or complete remission with incomplete blood count recovery (CRi) response, or 
treatment failure (defined as failure to achieve a bone marrow blast count of <5% following at 
least 2 cycles of therapy, as determined by the investigator) may receive tamibarotene in addition 
to venetoclax/azacitidine. 
Inclusion Criteria: 
Note: all inclusion/exclusion criteria should be met prior to the first dose of 
venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result 
referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue 
treatment on study. 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Patients must be at least 18 years old at the time of signing of an informed consent. 
2. All patients must have obtained a blood sample for RARA biomarker investigational 
assay testing prior to starting treatment on Cycle 1 Day 1. The results of the 
investigational biomarker assay for all patients must be confirmed as RARA-positive 
by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study. 
3. Patients must have ND, previously untreated non-APL AML with a bone marrow or 
peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive 
chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or 
comorbidities based on at least one of the following criteria (Ferrara 2013):  
a. age ≥75 years old 
 
OR 
b. age <75 years old, with at least one of the following: 
o Eastern Cooperative Oncology Group (ECOG) performance status of 3 
o cardiac history of congestive heart failure (CHF) or documented ejection 
fraction (EF) ≤50% 
o pulmonary disease with diffusing capacity of the lungs for carbon 
monoxide (DLCO) ≤65% or forced expiratory volume in one 
second (FEV1) ≤65% 
o creatinine clearance ≥30 mL/min to <45 mL/min based on the Cockcroft-Gault 
glomerular filtration rate estimation 
o hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of 
normal (ULN) 


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Protocol SY-1425-202, Version 6.0 
 
11 
o any other comorbidity that the investigator judges to be incompatible with 
intensive chemotherapy, and reviewed and approved by the sponsor 
4. Patients must have ECOG of 0 to 3 (if <75 years old) or 0 to 2 (if ≥75 years old). 
5. Patients must have a white blood cell (WBC) count <25,000/µL at the time of initiation 
of study drug (leukapheresis may be performed and/or hydroxyurea may be 
administered to decrease the WBC count to <25,000/µL). 
6. Patients must have minimum baseline organ function, as defined by: 
a. total bilirubin ≤3.0 × ULN (if <75 years old) or ≤1.5 × ULN (if ≥75 years old) 
b. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN 
or ≤5 × ULN (if documented liver infiltration with leukemia cells) 
c. creatinine clearance ≥30 mL/min (if <75 years old) or ≥45 mL/min (if ≥75 years 
old) based on the Cockcroft-Gault glomerular filtration rate estimation  
7. Patients must have a high-sensitivity urine or serum pregnancy test (for females of 
childbearing potential) that is negative at the Screening Visit and immediately prior to 
initiation of treatment (first dose of study drug). 
8. Patients must be willing and able to comply with the scheduled study visits, treatment 
plans, laboratory tests, use of 2 methods of birth control (including a barrier method) 
for women of childbearing potential (WOCBP) and male patients (as described in 
Appendix 4), and other procedures. 
9. Patients must be capable of giving signed and dated Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) approved informed consent. 
Exclusion Criteria  
Note: all inclusion/exclusion criteria should be met prior to the first dose of 
venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result 
referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue 
treatment on study. 
Patients are excluded from the study if any of the following criteria apply: 
1. Patients have APL. 
2. Patients have known active central nervous system involvement with AML. 
3. Participants with a history of other cancers must not be receiving active treatment (with 
radiation or chemotherapy) and must be free of disease for 2 years prior to the 
Screening Visit with the exception of localized prostate cancer treated with hormone 


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12 
therapy, breast cancer treated with hormone therapy, localized basal cell carcinoma, 
non-melanoma skin cancer, or cervical carcinoma in situ. 
4. Patients have an active, life-threatening, or clinically-significant uncontrolled systemic 
infection requiring hospitalization. 
5. Patients have a known malabsorption syndrome or other condition that may impair 
absorption of study medication (e.g., gastrectomy). 
6. Immunocompromised patients with increased risk of opportunistic infections, including 
known human immunodeficiency virus (HIV)-positive patients with CD4 counts 
≤350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To 
ensure that effective anti-retroviral therapy (ART), when used in eligible HIV-positive 
patients, is tolerated and that toxicities are not confused with investigational drug 
toxicities, patients should be on an established ART for at least 4 weeks and have an 
HIV viral load less than 400 copies/mL prior to the Screening Visit. 
7. Patients have a known active or chronic hepatitis B or active hepatitis C virus (HCV) 
infection. Patients with a history of HCV infection who have completed curative 
therapy for HCV at least 12 weeks before the Screening Visit and have a documented 
undetectable viral load at the Screening Visit are eligible for enrollment. 
8. Patients have other severe acute or chronic medical conditions (and/or psychiatric 
conditions or laboratory abnormalities) that may increase the expected risk to the 
patient (i.e., the risk associated with the study participation or study drug 
administration) or that may interfere with the interpretation of study results or, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study. 
9. Patients received prior treatment with all-trans retinoic acid (ATRA) or systemic 
retinoid for a hematologic malignancy. 
10. Patients have not adequately recovered from a major surgery within 4 weeks of starting 
study drug administration. 
11. Prior treatment (before Cycle 1 Day 1) for the diagnosis of AML, MDS, or antecedent 
hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, 
or hematopoietic stem cell transplantation (HSCT), with the exception of prior 
treatment with hydroxyurea.  
12. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A 
supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to 
the first dose of the study drug.  
13. Patients received any other investigational agents within 4 weeks of the Screening Visit 
or <5 half-lives since completion of previous investigational therapy have elapsed, 
whichever is shorter. 


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Protocol SY-1425-202, Version 6.0 
 
13 
14. Patients require concurrent treatment with any investigational or approved oncology 
agent, except for hydroxyurea. 
15. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (Common 
Terminology Criteria for Adverse Events [CTCAE], version 5). 
16. QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc 
>480 msec in male or female patients with bundle branch block based on triplicate 
electrocardiogram (ECG) readings at the Screening Visit. NOTE: The QTc in this 
study should be the QT interval corrected for heart rate according to Fridericia formula 
(QTcF).  
17. Pregnant females, breastfeeding females, and males not willing to comply with 
contraceptive requirements (as described in Appendix 4) or females of childbearing 
potential not willing to comply with contraceptive requirements (as described in 
Appendix 4). 
18. Patients who have a hypersensitivity to tamibarotene, azacitidine, venetoclax or to any 
of their excipients. 
19. Patients for whom treatment with tamibarotene, azacitidine, or venetoclax is 
contraindicated. 
20. Protected persons (legally protected adults [under judicial protection, guardianship, or 
supervision] and persons deprived of their liberty). 
Objectives and Endpoints: 
OBJECTIVES 
ENDPOINTS 
Part 1 
Primary 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine combination 
in RARA-positive, previously untreated AML 
patients to inform Part 2 dose and regimen of the 
tamibarotene/venetoclax/azacitidine therapy 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 
Secondary 
• 
Characterize the ORR of 
tamibarotene/venetoclax/azacitidine combination 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 
• 
Characterize PK of tamibarotene when 
administered as a part of 
tamibarotene/venetoclax/azacitidine therapy  
• 
Tamibarotene PK parameters  
Exploratory 
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 


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Protocol SY-1425-202, Version 6.0 
 
14 
OBJECTIVES 
ENDPOINTS 
Part 2 
Primary 
• 
Characterize and compare the CR/CRi rate of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine  
• 
CR/CRi assessment; CR/CRi rate is estimated by 
the proportion of patients who achieve CR/CRi (as 
determined by the investigatora)  
Secondary 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine in RARA-positive, 
previously untreated AML patients 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 
• 
Characterize and compare CR rate and CR/CRh 
rate of tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
CR assessment; CR rate is estimated by the 
proportion of patients who achieve CR (as 
determined by the investigatora) 
• 
CR/CRh assessment; CR/CRh rate is estimated by 
the proportion of patients who achieve CR/CRh (as 
determined by the investigatora) 
• 
Characterize duration of CR, duration of CR/CRi, 
and duration of CR/CRh of 
tamibarotene/venetoclax/azacitidine combination 
versus venetoclax/azacitidine 
• 
Duration of CR, defined as duration from the date 
of first documented evidence of CR to the date of 
relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 
• 
Duration of CR/CRi, defined as duration from the 
date of first documented evidence of CR/CRi to 
the date of relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 
• 
Duration of CR/CRh, defined as duration from the 
date of first documented evidence of CR/CRh to 
the date of relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 
• 
Characterize time to CR, time to CR/CRi, and time 
to CR/CRh of tamibarotene/venetoclax/azacitidine 
combination versus venetoclax/azacitidine 
• 
Time to CR, defined as the duration from the date 
of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR as determined by the 
investigatora 
• 
Time to CR/CRi, defined as the duration from the 
date of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR/CRi as determined by 
the investigatora 
• 
Time to CR/CRh, defined as the duration from the 
date of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR/CRh as determined by 
the investigatora 
• 
Characterize and compare the ORR of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 


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OBJECTIVES 
ENDPOINTS 
Exploratory 
• 
Characterize and compare EFS of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
EFS, defined as the duration from the date of 
Cycle 1 Day 1 Visit to the date of progressive 
disease, relapse after CR or CRi, treatment failureb, 
or death from any cause 
• 
Characterize and compare OS of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Duration from the date of Cycle 1 Day 1 Visit to 
the date of death due to any cause  
• 
Characterize and compare MRD-negative response 
rate of tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Assessment of MRD; MRD-negative response rate 
estimated by the proportion of patients achieving 
an MRD-negative CR by multiparameter flow 
cytometry, qPCR, or next generation sequencing, 
as determined by the investigatora 
• 
Characterize time to MRD-negative response of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Time to MRD-negative response, defined as the 
duration from the date of Cycle 1 Day 1 Visit to 
the date of achieving an MRD-negative CR by 
multiparameter flow cytometry, qPCR, or next 
generation sequencing, as determined by the 
investigatora 
• 
Characterize and compare the TI rate of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
TI rate, defined as the proportion of patients who 
achieve TI. TI is a period of at least 56 days with 
no RBC or platelet transfusion since the date of 
Cycle 1 Day 1 Visit to the last dose of study drug 
+30 days, the initiation of post-treatment therapy, 
or death, whichever occurs first 
• 
Characterize PK of tamibarotene when 
co-administered with venetoclax and azacitidine  
• 
Plasma tamibarotene PK parameters  
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 
Part 3 
Exploratory 
• 
Characterize the ORR after treatment with 
tamibarotene/venetoclax/azacitidine for patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine in patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 
• 
Characterize the OS of 
tamibarotene/venetoclax/azacitidine in patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Duration from the date of first dose in Part 3 to the 
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OBJECTIVES 
ENDPOINTS 
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 
Abbreviations: AE = adverse event; AML = acute myeloid leukemia; CR = complete remission; CRh = CR with 
partial hematologic recovery; CRi = CR with incomplete blood count recovery; ECG = electrocardiogram; 
EFS = event-free survival; ELN = European LeukemiaNet; MLFS = morphologic leukemia-free state; 
MRD = minimal residual disease; OS = overall survival; ORR = objective response rate; PK = pharmacokinetic(s); 
PR = partial remission; qPCR = quantitative polymerase chain reaction; RBC = red blood cell; TI = transfusion 
independence. 
a 
Determination of response will be made by the investigator in alignment with ELN AML criteria (Döhner 2017) 
and Bloomfield 2018 for CRh. 
b 
Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 2 cycles 
of therapy, as determined by the investigator.  
Overall Design: 
This is a Phase 2, open-label, 3-part, multi-center study evaluating 
tamibarotene/venetoclax/azacitidine combination therapy in RARA-positive, previously 
untreated, non-APL AML patients who are unlikely to tolerate standard intensive chemotherapy 
at the time of study entry.  
In Part 1, tamibarotene will be administered at 6 mg twice per day (BID) starting dose in 
combination with venetoclax/azacitidine, which will be administered at the approved dose and 
schedule (VIDAZA United States Prescribing Information [USPI]/VIDAZA Summary of 
Product Characteristics [SmPC] and VENCLEXTA USPI/VENCLYXTO SmPC). Tamibarotene 
dose modifications for AEs will follow guidelines outlined in the protocol (Section 6.5); 
venetoclax/azacitidine dose modifications will follow the standard dose modifications for AEs 
(VIDAZA USPI/VIDAZA SmPC and VENCLEXTA USPI/VENCLYXTO SmPC). 
The safety, tolerability, and PK evaluation of tamibarotene/venetoclax/azacitidine combination 
will inform the appropriate tamibarotene dose to be combined with the standard of care (SOC) 
venetoclax/azacitidine (Döhner 2022) in Part 2 and Part 3. In Part 2, patients will be 
randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to 
compare the clinical activity of the 2 combinations. In Part 3, tamibarotene will be added to the 
venetoclax/azacitidine regimen of a subset of Part 2 patients who experience progressive disease, 
relapse after initial CR or CRi response, or treatment failure (see Part 3 Design section below). 
Enrollment is planned in the United States (US) and France. 
Start of Venetoclax/Azacitidine Therapy 
Currently, ND AML patients who are ineligible for standard induction therapy are increasingly 
receiving venetoclax/azacitidine combination as the SOC therapy. Since AML is an acute disease 
and prompt treatment may be required, in Part 1 and Part 2 of the study, the treating investigator 
may choose one of the two options below.  
• Begin SOC venetoclax/azacitidine treatment on Cycle 1 Day 1 using protocol-defined 
regimen and doses while awaiting pre-treatment screening RARA biomarker test result.  


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• Begin venetoclax/azacitidine treatment on Cycle 1 Day 1 after the patient is confirmed to 
be RARA-positive. 
All eligibility requirements must be met prior to dosing on Cycle 1 Day 1, with the exception of 
RARA test results (inclusion criterion 2).  
Pre-screening/Screening and Enrollment (Part 1)/Randomization (Part 2) Procedures 
The sample for RARA biomarker testing must be collected and sent for assessment prior to 
starting venetoclax/azacitidine administration on Cycle 1 Day 1. Patients who meet all eligibility 
criteria (except for RARA-positive status confirmation; inclusion criterion 2) can begin 
venetoclax/azacitidine treatment on Cycle 1 Day 1 and are considered to be enrolled 
(Part 1)/randomized (Part 2) upon confirmation of RARA-positive status by Cycle 1 Day 8. 
 
Abbreviations: AE = adverse event; I/E = inclusion/exclusion [criteria]; C1DX = Cycle 1 Day X; RARA = retinoic 
acid receptor alpha. 
a 
If the patient discontinues treatment or study participation prior to confirmation of screening RARA results and 
RARA-positivity is confirmed by C1D8, the patient will be enrolled (Part 1)/randomized (Part 2), and the data 
from C1D1 until the time of study discontinuation will be captured (including AEs and the reason for 
discontinuation of treatment). 
Part 1 Design 
In total, up to approximately 
 patients may be enrolled in Part 1. Enrolled RARA-positive 
patients will receive the tamibarotene/venetoclax/azacitidine triplet combination as follows: 
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18 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 through 7 
of each 28-day therapy cycle (per VIDAZA USPI and VIDAZA SmPC). Alternative 
dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study.  
• Venetoclax (orally) at a dose described in the most current VENCLEXTA USPI and 
VENCLYXTO SmPC (including ramp-up and appropriate dosing for patients receiving 
concomitant 
 and P-gp inhibitors [Table 4]), daily on Days 1 through 28. 
• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy cycle. 
Tamibarotene will only be administered to patients who have been confirmed as 
RARA-positive. 
If needed to manage toxicity, the study drugs will be modified as outlined in Section 6.5. After 
Cycle 1 data for at least 6 patients become available, the totality of data (including study drug 
administration record, dose modifications, and available PK data) will be evaluated to support 
advancing to Part 2 of the study. The ongoing enrollment of 6 to 9 additional patients to further 
characterize the dosing regimen or a modified regimen may occur in Part 1 of the study. A 
modified regimen may be evaluated if the starting dose of tamibarotene (6 mg BID) is not 
tolerated in combination with venetoclax/azacitidine or if the 6 mg BID dose of tamibarotene 
does not allow for patients to tolerate the approved regimen of venetoclax/azacitidine. A 
modified regimen would consist of a reduced dose of tamibarotene (Table 6) in combination with 
the approved regimen of venetoclax/azacitidine.  
The dose and regimen of tamibarotene administered in combination with venetoclax/azacitidine 
in Part 2 and Part 3 will be informed by the totality of available data from all patients enrolled in 
Part 1, including the incidence of treatment-emergent AEs, the study drug administration record 
(including dose modifications and interruptions), safety laboratory data, physical examination 
and vital signs findings, and PK data.  
Part 2 Design  
In total, approximately 
 patients will be randomized in Part 2 of the study. RARA-positive 
patients will be randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or 
venetoclax/azacitidine dosing as follows: 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 through 7 
of each 28-day therapy cycle (per VIDAZA USPI and VIDAZA SmPC). Alternative 
dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study.  
• Venetoclax (orally) at a dose described in the most current VENCLEXTA USPI and 
VENCLYXTO SmPC (including ramp-up and appropriate dosing for patients receiving 
concomitant 
 and P-gp inhibitors [Table 4]) daily beginning on Day 1 for a 
minimum of 14 days and a maximum of 28 days for Cycle 1, with the duration of 
venetoclax determined by early response assessment conducted between Days 14 and 21 
of the cycle (Section 6.1.1). If bone marrow blasts are <5%, venetoclax administration 
will be stopped and held for up to 14 days prior to proceeding with Cycle 2. If bone 
marrow blasts are ≥5%, venetoclax administration will continue through Day 28 of 
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Cycle 1. For Cycle 2 and beyond, patients will receive venetoclax daily beginning on Day 
1 through Day 28 for each cycle, with dose modifications as needed for toxicity, as 
outlined in Table 5 (Döhner 2022; Maiti 2022). 
• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy cycle. 
Tamibarotene will only be administered to patients who have been confirmed as 
RARA-positive. 
PK evaluation of tamibarotene will be conducted using samples collected from patients receiving 
the triplet combination only. 
Part 3 Design 
Part 2 patients treated with venetoclax/azacitidine who experience progressive disease, relapse 
after initial CR or CRi response, or treatment failure may begin subsequent treatment in Part 3, 
where tamibarotene will be added to their regimen. Participation in Part 3 will begin as soon as 
possible, but within 30 days of the decision to stop participation in Part 2. Treatment failure is 
defined as a failure to achieve a bone marrow blast count of <5% following at least 2 cycles of 
therapy, as determined by the investigator. No PK evaluation will be performed in Part 3. 
Parts 1 through 3 Assessments and Follow-up 
Patients will undergo safety and response evaluations throughout their study participation as 
detailed in the Schedules of Activities (Section 1.3). Response will be assessed by the 
investigator in alignment with European LeukemiaNet (ELN) AML criteria (Döhner 2017), with 
complete remission with partial hematologic recovery (CRh) assessed according to Bloomfield 
2018.  
In Part 1, bone marrow aspirates will be collected to measure response at the End of Cycle (EoC) 
Visits of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), with bone marrow 
aspirates collected at other times as clinically determined based upon clinical findings or changes 
in peripheral blood counts. If a patient achieves a CR/CRi at the Cycle 1 EoC Visit, the Cycle 2 
EoC bone marrow aspirate is not required. 
In Part 2 and Part 3, Cycle 1 response will initially be assessed between Days 14 and 21 of 
Cycle 1, as recommended by ELN guidelines (Döhner 2022), with venetoclax administration 
proceeding in alignment with these recommendations. For those with blast clearance 
(<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For 
patients with ≥5% blasts at that initial assessment, Cycle 1 EoC bone marrow aspirate will be 
completed. Subsequent bone marrow aspirates for all patients will be collected at the EoC Visit 
of Cycles 2 and 3, followed by every third cycle (6, 9, 12, etc.), with bone marrow aspirates 
collected at other times as clinically determined. If a patient achieves a CR/CRi within Cycle 1 
response assessment(s), the Cycle 2 EoC bone marrow aspirate is not required. 
The AE profiles of tamibarotene and venetoclax/azacitidine combination are well-documented 
and largely do not overlap (tamibarotene Investigator’s Brochure [IB], VENCLEXTA USPI, 
VENCLYXTO SmPC). Consequently, in this study, it is recommended that hematologic 
toxicities and non-hematologic toxicities typically associated with the venetoclax/azacitidine 


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Protocol SY-1425-202, Version 6.0 
 
20 
combination (VENCLEXTA USPI, VENCLYXTO SmPC) should be managed with adjustments 
to venetoclax/azacitidine administration. AEs that have been identified as tamibarotene adverse 
drug reactions (ADRs; tamibarotene IB) should be managed via modification to tamibarotene 
administration (Section 6.5). In patients receiving triplet combination therapy, if improvements 
in blood counts or relevant toxicities are not observed with recommended adjustments to 
venetoclax/azacitidine, an adjustment to the tamibarotene dose should be considered.  
All patients who remain on study may continue to receive study drug until experiencing an 
unacceptable toxicity, disease progression, relapse, decision to pursue post-remission therapy 
(such as HSCT) or an alternative anticancer therapy, patient withdraws consent, or the 
investigator determines it is in the best interest of the patient to discontinue study drug. Note: 
Part 2 patients assigned to venetoclax/azacitidine treatment may continue on study in Part 3 
following progressive disease, relapse after initial CR or CRi response, or treatment failure as 
noted in section Part 3 Design above. 
For all enrolled (Part 1)/randomized (Part 2) patients, an End of Treatment (EoT) Visit should 
occur within 3 days of the last dose of study drug (or within 3 days of decision to permanently 
stop drug treatment, if this decision directly follows a period when study drug has been on hold) 
and before the start of any subsequent anticancer therapy. A Safety Follow-up Visit should occur 
30 days (±3 days) after the EoT Visit and before the start of any subsequent anticancer therapy. 
After the EoT Visit, patients who have not progressed/relapsed will enter the Disease Follow-up 
period, during which response assessments will be performed for up to 3 years after 
discontinuation of study drug, or until disease progression/relapse, whichever occurs first. 
Patients who progress/relapse will enter Survival Follow-up and will be followed to document 
the start of subsequent anticancer therapy, the date of disease progression/relapse, and overall 
survival status for up to 3 years after discontinuation of study drug. 
There will be no formal Independent Data Monitoring Committee (IDMC). The sponsor will 
provide oversight of safety and tolerability at regularly scheduled intervals (and ad hoc if 
needed) via Safety Review Team (SRT) meetings as detailed in the SRT Charter. In addition, 
regularly scheduled reviews of safety and tolerability will be performed by the sponsor in 
collaboration with the study investigators in Part 1 of the study. These reviews will inform the 
dose of tamibarotene to be combined with venetoclax/azacitidine in Part 2 of the study. 
Administrative interim analyses will be performed by the sponsor personnel or designee. 
Number of Patients: 
• Part 1: approximately 
 patients will be screened with up to approximately 
 patients 
enrolled to receive study drug 
• Part 2: approximately 
 patients will be screened with approximately 
 patients 
randomized to receive study drug 
• Part 3: approximately 
 patients treated with venetoclax/azacitidine in Part 2 will be 
enrolled 
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21 
Intervention Groups and Duration: 
• Part 1: tamibarotene/venetoclax/azacitidine 
• Part 2: tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine 
• Part 3: tamibarotene/venetoclax/azacitidine 
Patients will receive treatment until they meet study drug discontinuation criteria, as described in 
the Overall Design. Patients will be followed for up to 3 years after discontinuation of study 
drug. 
Statistical Methods: 
Sample Size 
Up to approximately 
 patients will be treated in Part 1. The actual number of tamibarotene 
dose levels explored in combination with venetoclax/azacitidine, and the number of patients 
treated at each dose regimen, will vary depending on the totality of evaluated data (including 
safety, dose modifications, and tamibarotene PK data) from patients treated with the 
tamibarotene/venetoclax/azacitidine combination. With 
 patients treated, there is 
approximately 
% probability of observing at least 1 AE with an event rate of 
%. With 
 patients treated, there is approximately 
% probability of observing at least 1 AE with an 
event rate of 
%. 
Approximately 
 patients will be randomized in Part 2, which provides approximately 
% power to detect a difference in CR/CRi rates between tamibarotene/venetoclax/azacitidine 
and venetoclax/azacitidine, with assumed CR/CRi rates of 
% versus 
% in the 2 groups, 
respectively, a 1:1 randomization, and a 1-sided alpha of 
.  
Part 3 of the study is exploratory in nature and the number of patients who will receive 
tamibarotene in addition to venetoclax/azacitidine will vary depending on the number of patients 
who experienced disease progression, relapse after initial CR or CRi response, or treatment 
failure when randomized and treated with venetoclax/azacitidine in Part 2.  
Statistical Analysis 
Part 1 Primary Endpoint Analysis 
The number and percentage of patients with AEs, including AEs leading to dose modifications or 
discontinuations, and serious AEs (SAEs) will be summarized. Laboratory values and changes in 
values from baseline will be summarized descriptively by visit, and shift tables will be provided 
showing changes in National Cancer Institute (NCI) CTCAE (version 5) grade from baseline to 
worst grade postbaseline. Descriptive summaries will be provided for ECG and vital sign values, 
changes in values from baseline, and categorical summaries. The number and percentage of 
patients with dose modifications will be summarized. 
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22 
Part 1 Secondary Endpoint Analysis 
The estimated objective response rate (ORR) will be provided with corresponding 95% exact 
binomial confidence intervals (CIs). 
Part 2 Primary Endpoint Analysis 
CR/CRi rate and 95% exact binomial CIs will be calculated by treatment group. The Fisher’s 
exact test will be applied to compare the CR/CRi rates between the 2 treatment groups.  
Part 2 Secondary Endpoint Analyses 
The number and percentage of patients with AEs, including AEs leading to dose modifications or 
discontinuations, and SAEs will be summarized. Laboratory values and changes in values from 
baseline will be summarized descriptively by visit, and shift tables will be provided showing 
changes in NCI CTCAE (version 5) grade from baseline to worst grade postbaseline. Descriptive 
summaries will be provided for ECG and vital sign values, changes in values from baseline, and 
categorical summaries. The number and percentage of patients with dose modifications will be 
summarized. 
The difference in CR/CRi rate between the 2 treatment groups and corresponding 95% CIs will 
be calculated. 
CR rate and 95% exact binomial CIs will be calculated by treatment group. The Fisher’s exact 
test will be applied to compare the CR rates between the 2 treatment groups.  
CR/CRh rate and 95% exact binomial CIs will be calculated by treatment group. The Fisher’s 
exact test will be applied to compare the CR/CRh rates between the 2 treatment groups.  
Kaplan-Meier estimation of median duration of CR, median duration of CR/CRi, and median 
duration of CR/CRh and respective 95% CIs will be presented by treatment group. 
Time to CR, time to CR/CRi, and time to CR/CRh will be summarized descriptively for the 
2 treatment groups. 
ORR rate and 95% exact binomial CIs will be calculated by treatment group. The Fisher’s exact 
test will be applied to compare the ORR rates between the 2 treatment groups.  
Part 2 Interim Analysis 
An interim futility analysis of the CR/CRi rates is planned in Part 2 for the first 40 treated 
RARA-positive patients and will be performed after the 40th randomized patient has received 
approximately 3 months of study drug or has discontinued treatment due to disease progression, 
withdrawal of consent, or death. The study may be terminated at this interim analysis for futility 
if the 1-sided p-value from the Fisher’s exact test comparing the CR/CRi rates 
(tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine) is 
. The non-binding 
futility bound is derived using a Hwang-Shih-DeCani (HSD) spending function with gamma = ‑2 
(Hwang 1990). 
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23 
Administrative interim analyses may be performed after approximately 25%, 50%, and 75% (
 
) patients have had 3 cycles of treatment. No multiplicity adjustments are needed since 
the study will not be stopped for efficacy until the primary analysis. 
Data Monitoring/Other Committee: There will be no formal IDMC. The sponsor will provide 
oversight of safety and tolerability at regularly scheduled intervals (and ad hoc if needed) via 
SRT meetings as detailed in the SRT Charter. In addition, regularly scheduled reviews of safety 
and tolerability will be performed by the sponsor in collaboration with the study investigators in 
Part 1 of the study. These reviews will inform the dose of tamibarotene to be combined with 
venetoclax/azacitidine in Part 2 of the study. Administrative interim analyses will be performed 
by the sponsor personnel or designee. 
 
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24 
1.2 
Schema 
 
Abbreviations: aza = azacitidine; b/w = between; C1DX = Cycle 1 Day X; tami = tamibarotene; ven = venetoclax.  
a 
Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 2 cycles 
of therapy, as determined by the investigator.  
 


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25 
1.3 
Schedules of Activities 
Table 1: 
Part 1 and Part 2 Schedule of Activities 
 
Pre-
screening 
(a) 
Day -30 to 
C1D1 
Screening 
(a) 
Day -30 to 
C1D1 
Cycle 1,  
28 Days 
Cycle 2, 3 
28 Days 
Cycles 4+  
28 Days (b) 
EoT 
(c) 
Safety 
Follow-
up (d) 
30d post 
EoT 
(±3d) 
Disease 
Follow-
up (e) 
q3mo 
post EoT 
(±30d) 
Survival 
Follow-
up (f) 
q3mo 
post  
EoT 
(±30d) 
Study Day (D/d) 
D1 
(g) 
D2-7 
±2d 
D8 
±1d 
 
D15 
±1d  
D22 
±1d 
EoC 
(h) 
D28 
±3d 
D1 
(i) 
D2-7 
±2d 
D15 
±1d 
EoC 
(h) 
D28 
±3d 
D1 
±3d 
(i) 
D2-7 
±2d 
D15 
±2d  
(j)  
EoC 
(h) 
D28 
±3d 
 
Prescreening Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review (k) 
 
X 
X (k) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment (Part 1) / 
Randomization (Part 2) (l) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History (m) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Status 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Vital Signs (n) 
 
X 
X 
X (n) 
X 
X 
X 
 
X X (n) 
X 
 
X 
X (n) 
X 
 
X 
X 
 
 
Physical Examination (o) 
 
X (o) 
X (o) 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X (o) X (o) 
X 
 
Hematology (p), (q) 
 
X 
X 
 
X 
X 
X 
X (q) X 
 
X X (q) X 
 
 
X (q) X 
X 
X 
 
Serum Chemistries (p) 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
Coagulation (p) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Triglycerides, Total  
Cholesterol (p) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Urinalysis (p) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Pregnancy Test (r) 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Triplicate ECG (s) 
 
X 
 
 
X (s) 
 
X (s) 
 
 
 
X (s) 
 
 
 
X (s) 
 
 
 
 
 
AE Monitoring (t) 
 
 
X  
X 
X  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior/Concomitant 
Medication Review (u) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
RBC and Platelet 
Transfusions Recorded (v) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dosing Compliance/Diary 
Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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26 
 
Pre-
screening 
(a) 
Day -30 to 
C1D1 
Screening 
(a) 
Day -30 to 
C1D1 
Cycle 1,  
28 Days 
Cycle 2, 3 
28 Days 
Cycles 4+  
28 Days (b) 
EoT 
(c) 
Safety 
Follow-
up (d) 
30d post 
EoT 
(±3d) 
Disease 
Follow-
up (e) 
q3mo 
post EoT 
(±30d) 
Survival 
Follow-
up (f) 
q3mo 
post  
EoT 
(±30d) 
Study Day (D/d) 
D1 
(g) 
D2-7 
±2d 
D8 
±1d 
 
D15 
±1d  
D22 
±1d 
EoC 
(h) 
D28 
±3d 
D1 
(i) 
D2-7 
±2d 
D15 
±1d 
EoC 
(h) 
D28 
±3d 
D1 
±3d 
(i) 
D2-7 
±2d 
D15 
±2d  
(j)  
EoC 
(h) 
D28 
±3d 
 
Subsequent Anticancer 
Therapies (w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Response  
Assessment (q), (x)  
 
 
 
 
 
 
 
X 
(q), (x) 
 
 
 
X 
(q), 
(x) 
 
 
 
X 
(q), (x) 
X 
 
X 
 
Part 1: Bone Marrow 
Aspirate 
 
X  
(y) 
 
 
 
 
 
X (i), 
(z) 
 
 
 
X (i), 
(z) 
 
 
 
X (i), 
(z) 
X (z) 
 
X 
(z) 
 
Part 2: Bone Marrow 
Aspirate 
 
X  
(y) 
 
 
 
X 
D14-D21 
(aa)  
X (i), 
(aa), 
(bb) 
 
 
 
X (i), 
(aa) 
 
 
 
X (i), 
(aa) 
X 
(aa) 
 
X 
(aa) 
 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tamibarotene (i), (cc) 
 
 
 
 
Dosing D8-D28 of each Cycle (i), (cc) 
 
 
 
 
 
Azacitidine (i), (dd), (ee) 
 
 
X X (ee) 
 
 
 
 
X (i) X (ee) 
 
 
X (i) X (ee) 
 
 
 
 
 
 
Venetoclax (i), (ff) 
 
 
X 
X 
X (ff) X (ff) X (ff) 
X X (i) X 
X (ff) 
X X (i) 
X 
X 
X 
 
 
 
 
Blood Sample for RARA 
Biomarker Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood Sample for 
Exploratory Research (gg) 
X 
 
X 
 
 
 
 
X (gg) 
 
 
 
X 
(gg) 
 
 
 
X 
(gg) 
X 
 
 
 
Blood Sample for CDx 
Development 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1 Blood for PK (hh) 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Part 2 Blood for PK (ii) 
 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AML = acute myeloid leukemia; CDx = companion diagnostic; CR = complete remission; CRi = CR with incomplete blood 
count recovery; CXDX = Cycle X, Day X; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; EDC = electronic data 
capture [system]; ELN = European LeukemiaNet; EoC = End of Cycle; EoT = End of Treatment; HSCT = hematopoietic stem cell transplantation; 
MRD = minimal residual disease; PK = pharmacokinetic(s); q3mo = every 3 months; RBC = red blood cell; RARA = retinoic acid receptor alpha; SAE = serious 
adverse event; SOC = standard of care. 
(a) Pre-screening (to evaluate RARA status) and screening assessments will be performed within 30 days of C1D1. Pre-screening and Screening Visits may be 
combined. If the Pre-screening and Screening Visits are not combined, Screening assessments may occur on C1D1 but must be completed and results 
reviewed prior to dosing on C1D1. 
(b) Cycle 4 schedule should be followed for all subsequent cycles. 


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Protocol SY-1425-202, Version 6.0 
 
27 
(c) An EoT Visit should occur within 3 days of the last dose of study drug (or within 3 days of decision to permanently stop study drug treatment, if this 
decision directly follows a period when study drug has been on hold) and before the start of any subsequent anticancer therapy. If the EoT Visit occurs 
≥30 days after the last dose of study drug, it may be combined with the Safety Follow-up Visit.  
(d) A Safety Follow-up Visit should occur 30 days (±3 days) after the EoT Visit and before the start of any subsequent anticancer therapy. If the EoT Visit 
occurs ≥30 days after the last dose of study drug, it may be combined with the Safety Follow-up Visit. 
(e) Patients who have not progressed/relapsed will enter the Disease Follow-up period. Visits should occur every 3 months for response assessment for up to 
3 years after discontinuation of study drug or until disease progression/relapse, whichever occurs first. Disease Follow-up Visit window is ±30 days. 
(f) Patients who progress/relapse will be followed to document the start of subsequent anticancer therapy, the date of disease progression/relapse, and overall 
survival status by telephone (or another appropriate method) for up to 3 years after discontinuation of study drug. Survival Follow-up Visit contact window 
is ±30 days. 
(g) C1D1 assessments must be performed prior to study drug administration.  
(h) EoC Visit should occur on Day 28 (±3 days) of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.).  
(i) Response assessment results must be evaluated prior to start of Cycles 2, 3, and 4, followed by every third cycle (7, 10, 13, etc.). The timing of cycle start for 
these cycles will be determined as outlined in Section 6.1.1 and Table 5. In Part 2 of the study only, patients being treated with venetoclax/azacitidine who 
experience progressive disease, relapse after initial CR or CRi response, or treatment failure (failure to achieve a bone marrow blast count of <5% following 
at least 2 cycles of therapy, as determined by the investigator) will begin subsequent treatment cycle in Part 3, where tamibarotene will be added to their 
regimen (see Table 2). 
(j) Cycle 4 only. 
(k) All eligibility requirements (with exception of RARA test results [inclusion criterion 2]) must be met prior to venetoclax/azacitidine dosing on C1D1. 
Confirmation of all eligibility requirements (including confirmation of RARA-positive status) is required for enrollment (Part 1)/randomization (Part 2) and 
must occur by C1D8. Eligibility is based on meeting the inclusion/exclusion criteria on C1D1. While RARA results from screening may not become 
available until after C1D1, any patient confirmed to be RARA-positive by C1D8 will be enrolled (Part 1)/randomized (Part 2), even if the patient 
discontinues treatment and/or discontinues the study prior to receiving RARA results. 
(l) Enrollment (Part 1)/randomization (Part 2) can occur between C1D1 Visit and C1D8 Visit (inclusive) as soon as all eligibility requirements are met, 
including confirmation of patient’s RARA-positive status (inclusion criterion 2). For Part 2 patients who are confirmed RARA-positive prior to C1D1, 
randomization can occur within 72 hours prior to the first dose of venetoclax/azacitidine to accommodate operational needs. 
(m) For all enrolled (Part 1)/randomized (Part 2) patients, any untoward medical occurrences that happen before the first dose of venetoclax/azacitidine on 
C1D1 should be captured as a part of medical history.  
(n) If administration of the 6th and 7th doses of azacitidine of the cycle is delayed to Days 8 and 9 (see footnote (dd)), the vital sign evaluation will shift from 
Days 6 and 7 to Days 8 and 9 to parallel azacitidine administration. C1D8 vital sign evaluation is required for all patients. 
(o) Full physical examination will be performed at the Screening Visit, C1D1, EoT, and the Safety Follow-up Visit; abbreviated physical examination will be 
performed at other visits indicated (see Section 8.2.3). 
(p) Safety laboratory assessments will be performed locally. 
(q) Additional unscheduled hematology evaluations may be performed prior to commencement of the next treatment cycle to reflect the best AML response 
achieved. 
(r) A pregnancy test (high-sensitivity urine or serum) must be performed for women of childbearing potential. 
(s) ECG should be performed after an approximately 10-minute rest period, 2 to 4 hours after tamibarotene and/or venetoclax administration. 
(t) For all enrolled (Part 1)/randomized (Part 2) patients, AEs and SAEs will be captured from the time of the first dose of venetoclax/azacitidine on C1D1 
through the Safety Follow-up Visit. This will require collecting safety data for all treated patients from C1D1 onward (until RARA status is confirmed) to 
enable timely reporting (SAEs) and capture in the eCRF (AEs) upon enrollment (Part 1)/randomization (Part 2). 


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Protocol SY-1425-202, Version 6.0 
 
28 
(u) For all enrolled (Part 1)/randomized (Part 2) patients, every medication within 30 days of C1D1 or at any time during the course of the study treatment, up 
to the Safety Follow-up Visit, must be documented. 
(v) For all enrolled (Part 1)/randomized (Part 2) patients, all RBC and platelet transfusions received by the patient from 8 weeks prior to first dose of study 
drug on C1D1 through the Safety Follow-up period will be recorded. 
(w) Subsequent anticancer therapies (including allogeneic HSCT) following EoT will be recorded.  
(x) Response assessments will be performed at EoC Visit of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), at the EoT Visit, and at each 
Disease Follow-up Visit, with additional assessments performed if clinically determined. If a patient achieves a CR/CRi at Cycle 1 EoC, the Cycle 2 EoC 
bone marrow aspirate is not required. Response assessments during Disease Follow-up visits where the bone marrow aspirates are not performed are based 
on hematology evaluation and physical examination findings. 
(y) A screening bone marrow aspirate will be performed, with samples collected for local assessment of blast count, cytogenetics, immunophenotype, and 
AML-associated gene mutations. An additional aspirate sample should be collected if possible and sent to the Central Laboratory for exploratory 
analyses. Bone marrow samples collected within 30 days of C1D1 as a part of SOC are acceptable and in that setting a marrow would not need to be 
repeated for the sole purpose of gathering the exploratory sample; however, collection of the exploratory sample is encouraged. Anonymized reports will be 
uploaded to the EDC.  
(z) Part 1: The bone marrow aspirate samples for local assessment of response (blast count, cytogenetics, and assessment of MRD) will be collected at the 
EoC Visit of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), at the EoT Visit, and at every other visit during the Disease Follow-up period 
(every 6 months), with bone marrow aspirates collected at other times as clinically determined. If a patient achieves a CR/CRi at the Cycle 1 EoC Visit, the 
Cycle 2 EoC bone marrow aspirate is not required. Anonymized reports will be uploaded to the EDC. At each bone marrow aspirate draw, an additional 
aspirate sample will be collected and sent to the Central Laboratory for exploratory analyses. 
(aa) Part 2: The bone marrow aspirate samples for local assessment of response (blast count, cytogenetics, and assessment of MRD) will be collected between 
Days 14 and 21 of Cycle 1, with venetoclax administration proceeding in alignment with ELN 2022 recommendations (Döhner 2022). For those with blast 
clearance (<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For patients with ≥5% blasts at that initial assessment, 
Cycle 1 EoC bone marrow aspirate will be completed. Subsequent bone marrow aspirates for all patients will be collected at the EoC Visit of Cycles 2 and 3, 
followed by every third cycle (6, 9, 12, etc.); at the EoT Visit; and at every other visit during the Disease Follow-up period (every 6 months), with bone 
marrow aspirates collected at other times as clinically determined. If a patient achieves a CR/CRi within Cycle 1 response assessment(s), the Cycle 2 EoC 
bone marrow aspirate is not required. Anonymized reports will be uploaded to the EDC. At each bone marrow aspirate draw, an additional aspirate sample 
will be collected and sent to the Central Laboratory for exploratory analyses. 
(bb) For those with blast clearance (<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For patients with ≥5% blasts at that 
initial assessment, Cycle 1 EoC bone marrow aspirate will be completed. 
(cc) Tamibarotene will only be administered to patients who have been confirmed as RARA-positive. For patients receiving tamibarotene/venetoclax/azacitidine, 
tamibarotene will be administered on Days 8 through 28 of each 28-day therapy cycle. On visit days when PK samples are collected, venetoclax and 1 dose 
of tamibarotene should be administered at the same time.  
(dd) Patients may begin C1D1 using SOC treatment with venetoclax/azacitidine while awaiting RARA biomarker results to confirm eligibility (inclusion 
criterion 2). Azacitidine will be administered intravenously or subcutaneously as described in the most current VIDAZA USPI/VIDAZA SmPC.  
(ee) Azacitidine will be administered each day on Days 1 through 7 of each 28-day therapy cycle. If dosing on Days 6 and 7 is not possible due to logistical 
limitations, these doses may be delayed to Days 8 and 9. Tamibarotene is permitted to overlap with azacitidine on Days 8 through 9 of this alternative 
schedule. 
(ff) Patients may begin C1D1 using SOC treatment with venetoclax/azacitidine while awaiting RARA biomarker results to confirm eligibility (inclusion 
criterion 2). Venetoclax will be administered daily, as described in the most current VENCLEXTA USPI/VENCLYXTO SmPC with SOC modifications 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
29 
consistent with ELN 2022 guidelines (Döhner 2022; Section 6.1.1; Table 5). On visit days when PK samples are collected, venetoclax and 1 dose of 
tamibarotene should be administered at the same time. 
(gg) Blood samples will be collected for exploratory research at pre-screening, C1D1, at EoC Visit of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, 
etc.), and at EoT. If a patient achieves a CR/CRi at the Cycle 1 EoC Visit, the Cycle 2 EoC blood sample is not required. 
(hh) At C1D8 and C1D22 Visits, PK samples will be obtained: pre-dose, and at 0.5, 1, 2, 4, and 6 hours after tamibarotene dose. At C2D15 and C3D15, 1 sample 
will be collected and collection time/date recorded. The dose, time, and date of the 2 immediate prior doses (if applicable) of tamibarotene taken before the 
PK collection will be recorded. On visit days when PK samples are collected, venetoclax and the dose of tamibarotene should be administered at the same 
time. Additional details are provided in Section 8.4. 
(ii) PK samples will be obtained only from patients receiving triplet combination therapy. At each applicable visit, 1 sample will be collected and collection 
time/date recorded. The dose, time, and date of the 2 immediate prior doses of tamibarotene taken before the PK collection will be recorded. On visit days 
when PK samples are collected, venetoclax and the dose of tamibarotene should be administered at the same time. 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
30 
Table 2: 
Part 3 Schedule of Activities 
 
Cycle 1,  
28 Days (a) 
Cycle 2, 3 
28 Days 
Cycles 4+  
28 Days (b) 
EoT 
(c) 
Safety 
Follow-up (d) 
30d post EoT 
(±3d) 
Disease 
Follow-up (e) 
q3mo post 
EoT (±30d) 
Survival 
Follow-up (f) 
q3mo post  
EoT (±30d) 
Study Day (D/d) 
D1 
(g) 
D2-7 
±2d 
D8 
±1d 
D15 
±1d 
D22 
±1d 
EoC 
(h) 
D28 
±3d 
D1  
(i) 
 
D2-7 
±2d 
D15 
±2d 
EoC 
(h) 
D28 
±3d 
D1  
±3d (i) 
D2-7 
±2d 
D15 
±2d  
(j) 
EoC 
(h) 
D28 
±3d 
 
ECOG Status 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Weight 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Vital Signs (k) 
X X (k) 
X 
X 
X 
 
X X (k) X 
 
X 
X (k) 
X 
 
X 
X 
 
 
Physical Examination (l) 
X (l) 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X (l) 
X (l) 
X 
 
Hematology (m), (n) 
X  
 
X 
X 
X X (n) X 
 
 
X (n) 
X 
 
 
X (n) 
X 
X 
X 
 
Serum Chemistries (m) 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Coagulation (m) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Triglycerides, Total Cholesterol 
(m) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Urinalysis (m) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Pregnancy Test (o) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Triplicate ECG (p) 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
AE Monitoring (q) 
X  
X 
X  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior/Concomitant Medication 
Review (r) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
RBC and Platelet Transfusions 
Recorded (s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dosing Compliance/Diary 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Subsequent Anticancer 
Therapies (t) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Response Assessment (n), (u) 
 
 
 
 
 
X 
(n), (u) 
 
 
 
X 
(n), (u) 
 
 
 
X 
(n), (u) 
X 
 
X 
 
Bone Marrow Aspirate 
 
 
 
X 
D14-D21 
(v) 
X 
 (i), 
(v), (w) 
 
 
 
X 
(i), (v) 
 
 
 
X 
(i), (v) 
X (v) 
 
X 
(v)  
 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tamibarotene (i), (x) 
 
 
Dosing D8-D28 of each Cycle (i), (x) 
 
 
 
 
 
Azacitidine (i), (y) 
X X (y) 
 
 
 
 
X (i) X (y) 
 
 
X 
X (y) 
 
 
 
 
 
 
Venetoclax (i), (z) 
X 
X 
X 
X 
X 
X X (i) X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blood Sample for Exploratory 
Research (aa) 
X 
 
 
 
 
X 
(aa) 
 
 
 
X (aa) 
 
 
 
X 
(aa) 
X 
 
 
 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
31 
Abbreviations: AE = adverse event; AML = acute myeloid leukemia; CR = complete remission; CRi = CR with incomplete blood count recovery; 
CXDX = Cycle X, Day X; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; EDC = electronic data capture [system]; 
ELN = European LeukemiaNet; EoC = End of Cycle; EoT = End of Treatment; HSCT = hematopoietic stem cell transplantation; MRD = minimal residual 
disease; q3mo = every 3 months; RBC = red blood cell; RARA = retinoic acid receptor alpha; SAE = serious adverse event. 
(a) Part 2 patients randomized to venetoclax/azacitidine treatment will begin their subsequent cycle in Part 3 as Part 3 Cycle 1, if they experience progressive 
disease, relapse after initial CR or CRi response, or treatment failure (failure to achieve a bone marrow blast count of <5% following at least 2 cycles of 
therapy, as determined by the investigator).  
(b) Cycle 4 schedule should be followed for all subsequent cycles. 
(c) An EoT Visit should occur within 3 days of the last dose of study drug (or within 3 days of decision to permanently stop study drug treatment, if this 
decision directly follows a period when study drug has been on hold) and before the start of any subsequent anticancer therapy. If the EoT Visit occurs 
≥30 days after the last dose of study drug, it may be combined with the Safety Follow-up Visit. 
(d) A Safety Follow-up Visit should occur 30 days (±3 days) after the EoT Visit and before the start of any subsequent anticancer therapy. If the EoT Visit 
occurs ≥30 days after the last dose of study drug, it may be combined with the Safety Follow-up Visit. 
(e) Patients who have not progressed/relapsed will enter the Disease Follow-up period. Visits should occur every 3 months for response assessment for up to 
3 years after discontinuation of study drug or until disease progression/relapse, whichever occurs first. Disease Follow-up Visit window is ±30 days. 
(f) Patients who progress/relapse will be followed to document the start of subsequent anticancer therapy, the date of disease progression/relapse, and overall 
survival status by telephone (or another appropriate method) for up to 3 years after discontinuation of study drug. Survival Follow-up Visit contact window 
is ±30 days. 
(g) Participation in Part 3 will begin as soon as possible, but within 30 days of the decision to stop participation in Part 2. C1D1 assessments must be performed 
prior to study drug administration.  
(h) EoC Visit should occur on Day 28 (±3 days) of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.) 
(i) EoC response assessment results must be evaluated prior to start of Cycles 2, 3, and 4, followed by every third cycle (7, 10, 13, etc.). The timing of cycle 
start for these cycles will be determined as outlined in Section 6.1.1. 
(j) Cycle 4 only. 
(k) If administration of the 6th and 7th doses of azacitidine of the cycle is delayed to Days 8 and 9 (see footnote (y)), the vital sign evaluation will shift from 
Days 6 and 7 to Days 8 and 9 to parallel azacitidine administration. C1D8 vital sign evaluation is required for all patients. 
(l) Full physical examination will be performed at C1D1, EoT, and the Safety Follow-up Visit; abbreviated physical examination will be performed at other 
visits indicated (see Section 8.2.3). 
(m) Safety laboratory assessments will be performed locally. 
(n) Additional unscheduled hematology evaluations may be performed prior to commencement of the next treatment cycle to reflect the best AML response 
achieved. 
(o) A pregnancy test (high-sensitivity urine or serum) must be performed for women of childbearing potential. 
(p) ECG should be performed after an approximately 10-minute rest period, 2 to 4 hours after tamibarotene and/or venetoclax administration.  
(q) For all patients continuing on to Part 3, AEs and SAEs will be captured from Part 2 C1D1 through the Safety Follow-up Visit.  
(r) For all patients continuing on to Part 3, every medication within 30 days of Part 2 C1D1 or at any time during the course of the study treatment, up to the 
Safety Follow-up Visit, must be documented. 
(s) For all patients continuing on to Part 3, all RBC and platelet transfusions received by the patient from 8 weeks prior to Part 2 C1D1 through the Safety 
Follow-up period will be recorded. 
(t) Subsequent anticancer therapies (including allogeneic HSCT) following EoT will be recorded.  


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
32 
(u) Response assessments will be performed at EoC Visit of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), at the EoT Visit, and at each 
Disease Follow up Visit, with additional assessments performed if clinically determined. If a patient achieves a CR/CRi at the Cycle 1 EoC, the Cycle 2 EoC 
bone marrow aspirate is not required. Response assessments during Disease Follow-up visits where the bone marrow aspirates are not performed are based 
on hematology evaluation and physical examination findings. 
(v) The bone marrow aspirate samples for local assessment of response (blast count, cytogenetics, and assessment of MRD) will be collected between Days 
14 and 21 of Cycle 1, with venetoclax administration proceeding in alignment with ELN 2022 recommendations (Döhner 2022). For those with blast 
clearance (<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For patients with ≥5% blasts at that initial assessment, 
Cycle 1 EoC bone marrow aspirate will be completed. Subsequent bone marrow aspirates for all patients will be collected at the EoC Visit of Cycles 2 and 3, 
followed by every third cycle (6, 9, 12, etc.); at the EoT Visit; and at every other visit during the Disease Follow-up period (every 6 months), with bone 
marrow aspirates collected at other times as clinically determined. If a patient achieves a CR/CRi within Cycle 1 response assessment(s), the Cycle 2 EoC 
bone marrow aspirate is not required. Anonymized reports will be uploaded to the EDC. At each bone marrow aspirate draw, an additional aspirate sample 
will be collected and sent to the Central Laboratory for exploratory analyses. 
(w) For those with blast clearance (<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For patients with ≥5% blasts at that 
initial assessment, Cycle 1 EoC bone marrow aspirate will be completed.  
(x) Tamibarotene will be administered on Days 8 through 28 of each 28-day therapy cycle. 
(y) Azacitidine will be administered intravenously or subcutaneously as described in the most current VIDAZA USPI/VIDAZA SmPC. Azacitidine will be 
administered each day on Days 1 through 7 of each 28-day therapy cycle. If dosing on Days 6 and 7 is not possible due to logistical limitations, these doses 
may be delayed to Days 8 and 9. Tamibarotene is permitted to overlap with azacitidine on Days 8 through 9 of this alternative schedule. 
(z) Venetoclax will be administered daily, as described in the most current VENCLEXTA USPI/VENCLYXTO SmPC with SOC modifications consistent with 
ELN 2022 guidelines (Döhner 2022; Section 6.1.1; Table 5). 
(aa) Blood samples will be collected for exploratory research at C1D1, at EoC Visit of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), and at 
EoT. If a patient achieves a CR/CRi at the Cycle 1 EoC, the Cycle 2 EoC blood sample is not required. 
 


CONFIDENTIAL 
Protocol SY-1425-202, Version 6.0 
 
 
33 
2 INTRODUCTION 
2.1 
Study Rationale 
Tamibarotene is a potent and selective agonist of RARα being developed in combination with 
azacitidine in a novel genomically defined subset of patients with non-APL AML, characterized 
by overexpression of RARA (McKeown 2017). Approximately 30% of patients with ND AML 
are expected to be positive for RARA overexpression (de Botton 2020).  
Currently, ND AML patients who are ineligible for standard induction therapy are increasingly 
receiving venetoclax/azacitidine combination as initial treatment. In a randomized study of such 
AML patients, the combination of azacitidine with venetoclax has demonstrated a high 
composite CR rate and a survival benefit compared to treatment with azacitidine monotherapy 
(DiNardo 2020). However, approximately one-third of patients failed to respond to the 
venetoclax/azacitidine combination (DiNardo 2020), supporting the existing need to improve 
upon the outcomes in this subpopulation.  
In RARA-positive ND AML patients who are ineligible for standard induction therapy, 
tamibarotene plus azacitidine is associated with high CR rates and a rapid onset of response 
(de Botton 2020). Further, recent data demonstrate that monocytic features associated with 
resistance to venetoclax are significantly present in those RARA-positive patients who achieve a 
complete response with tamibarotene plus azacitidine (Section 4.2; Fiore 2020; Pei 2020). 
Consequently, adding venetoclax to the tamibarotene plus azacitidine combination may address 
an unmet need in RARA-positive AML, allowing for the treatment of both primitive AML that 
may be sensitive to venetoclax and more mature monocytic subpopulations that may respond to 
treatment with tamibarotene plus azacitidine. Given that tamibarotene, venetoclax, and 
azacitidine have distinct AE profiles, it is anticipated that the 3 drugs can be administered safely 
in combination. 
This open-label Phase 2 study in adult RARA-positive, previously untreated AML patients who 
are ineligible for standard induction therapy will consist of 3 parts. In Part 1, the safety and 
tolerability of the tamibarotene/venetoclax/azacitidine combination will be evaluated, PK of 
tamibarotene will be assessed when co-administered with venetoclax/azacitidine, and the dosing 
regimen of the combination for evaluation in Part 2 will be selected. In Part 2, patients who are 
ineligible for standard induction therapy will be randomized to 
tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine. In Part 3, patients treated with 
venetoclax/azacitidine in Part 2 who experience progressive disease, relapse after initial CR or 
CRi response, or treatment failure (defined as failure to achieve a bone marrow blast count of 
<5% following at least 2 cycles of therapy, as determined by the investigator) may receive 
tamibarotene in addition to venetoclax/azacitidine. 


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2.2 
Background 
2.2.1 
Disease Under Study 
AML is the most common leukemia in adults, with an estimated 20,000 individuals diagnosed 
with AML each year in the US. Current treatment paradigms in younger patients (<60 years) 
include induction regimens of standard cytotoxic chemotherapy (cytarabine and an 
anthracycline) and consolidation with additional chemotherapy and/or HSCT (Shallis 2019). 
However, the majority of ND AML patients are “unfit” for intensive induction chemotherapy, 
based on advanced age, comorbidities, and other factors (Ferrara 2013). For these patients, the 
combination of venetoclax and azacitidine has become the SOC (VENCLEXTA USPI, 
VENCLYXTO SmPC).  
2.2.1.1 
Venetoclax/Azacitidine Combination 
Clinical efficacy of venetoclax/azacitidine was demonstrated in a randomized trial that compared 
the combination to placebo/azacitidine regimen. Venetoclax/azacitidine treatment was associated 
with a CR/CRi rate of 66.4% and an improvement in overall survival (OS) (14.7 months versus 
9.6 months in placebo/azacitidine group) (DiNardo 2020). Despite this progress, there remains a 
high unmet need for new, effective, and well-tolerated therapies. From the tolerability 
perspective, myelosuppression is a known adverse reaction of venetoclax and venetoclax 
combination therapies (VENCLEXTA USPI, VENCLYXTO SmPC). Over 80% of patients 
treated have high grade (NCI CTCAE Grade 3 or 4) hematologic AEs, including various 
cytopenias and febrile neutropenia. From the efficacy perspective, one-third of patients treated 
with venetoclax/azacitidine do no respond (DiNardo 2020). The patients who are refractory to or 
relapse after venetoclax/hypomethylating agent (HMA) therapy have a shorter median OS 
(2.4 months) than the overall relapsed/refractory (R/R) AML patient population (Maiti 2020).  
Markers of response and resistance to venetoclax treatment in the ND unfit setting have begun to 
emerge, with poor response associated with mutations in TP53, NRAS, and DNMT3A genes and 
with an AML monocytic phenotype (Pei 2020, Kuusanmäki 2020, Zhang 2018). Similarly, the 
loss of BCL2 expression and concomitant overexpression of MCL1 have been linked with 
primary and acquired resistance to venetoclax (Wang 2020, Knight 2019, Campos 2019). Further 
research is needed to fully characterize the drivers of resistance to venetoclax/azacitidine 
treatment. 
2.2.1.2 
Tamibarotene/Azacitidine Combination 
RARA-positive AML is a novel patient subset with an actionable target for treatment with 
tamibarotene, an oral selective RARα agonist. RARA-positive AML is characterized by 
overexpression of the RARA gene in blasts. RARA-positive patients are identified with an 
investigational assay that assesses RARA expression in peripheral blood mononuclear cell blasts 
with quantitative polymerase chain reaction. Approximately 30% of AML patients are 
RARA-positive (de Botton 2020). 
In a Phase 2 study evaluating tamibarotene plus azacitidine in ND unfit AML patients (Study 
SY-1425-201; N = 51), the combination was well tolerated. Additive myelosuppression was not 
observed when tamibarotene was combined with azacitidine, and the majority of non-


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hematologic AEs were low grade and reversible. The combination of tamibarotene plus 
azacitidine was associated with a high CR/CRi rate (61%), CR rate (50%), and a rapid onset of 
response (median time to composite CR 1.2 months). Responses were observed irrespective of 
cytogenetic risk or the presence of AML-associated genetic mutations. A majority of patients 
achieved transfusion independence, and the median OS of those achieving CR/CRi was 18 
months (de Botton 2020). Additional data from this study are provided in the IB. 
2.2.1.3 
Triplet (Tamibarotene/Venetoclax/Azacitidine) Combination 
Currently, ND AML patients who are ineligible for standard induction therapy are increasingly 
receiving venetoclax plus azacitidine combination as initial treatment. In a randomized study of 
such AML patients, the combination of azacitidine with venetoclax has demonstrated a high 
composite CR rate and a survival benefit compared to treatment with azacitidine monotherapy 
(DiNardo 2020). However, approximately one-third of patients failed to respond to the 
venetoclax/azacitidine combination (DiNardo 2020), supporting the existing need to improve 
upon the outcomes in this subpopulation.  
Several reports have shown that primary venetoclax resistance is associated with monocytic 
features in AML and that low-level monocytic clones present at diagnosis expand at relapse on 
venetoclax plus azacitidine treatment (Pei 2020, Kuusanmäki 2020, Zhang 2018). Syros recently 
reported that RARA positivity significantly enriched for ND unfit AML patients with monocytic 
gene expression features associated with venetoclax resistance (Fiore 2020), including low BCL2 
expression and high MCL1 expression. A majority (80%) of RARA-positive ND unfit AML 
patients enrolled in Study SY-1425-201 had monocytic expression features in blasts collected at 
study entry, which included patients with CR/CRi responses to tamibarotene plus azacitidine. 
Collectively, these findings suggest that patient selection based on the RARA biomarker test 
identifies a distinct AML patient subset who may be likely to respond to tamibarotene plus 
azacitidine, but not to venetoclax plus azacitidine. Considering the non-overlapping toxicity 
profiles of tamibarotene, venetoclax, and azacitidine, the use of the triplet combination may be 
tolerable and improve outcomes in RARA-positive ND unfit AML patients by inducing deeper 
and more durable responses through inhibition of distinct blast cell populations: 
1) RARA-positive mature monocytic blasts sensitive to tamibarotene plus azacitidine but 
resistant to venetoclax plus azacitidine; 2) subclonal RARA-negative primitive blasts sensitive to 
venetoclax plus azacitidine but not tamibarotene plus azacitidine. 
2.2.2 
Tamibarotene 
Tamibarotene is an orally available, synthetic retinoid approved in Japan (AMNOLAKE® 
Tablets) since April 2005 for the treatment of relapsed or refractory APL, characterized by 
t(15;17), which results in the PML-RARA fusion. Tamibarotene was designed to be a more potent 
and selective RARα agonist with significantly improved in vivo pharmacologic properties 
compared to ATRA, a component of the current first-line treatment of APL. In vitro, 
tamibarotene is approximately 10-fold more potent than ATRA.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of tamibarotene is 
provided in the IB. 


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2.2.3 
Venetoclax 
Venetoclax is an orally bioavailable small molecule that is a potent and selective inhibitor of an 
anti-apoptotic protein BCL-2. BCL-2 over-expression prevents death of AML cells, with high 
levels associated with resistance to chemotherapy and poor survival (Konopleva 2006, 
Tsao 2012).  
Venetoclax in combination with azacitidine is approved in the US and European Union (EU) for 
the treatment of newly diagnosed AML in adults who are age 75 years or older or who have 
comorbidities that preclude use of intensive induction chemotherapy.  
Additional information is available in the venetoclax label (VENCLEXTA USPI, 
VENCLYXTO SmPC). 
2.2.4 
Azacitidine 
Azacitidine is a pyrimidine analogue that exerts antineoplastic effects on abnormal 
hematopoietic bone marrow cells through multiple mechanisms including deoxyribonucleic 
acid (DNA) hypomethylation. Cytotoxicity may also result from incorporation into DNA and 
ribonucleic acid (RNA), with inhibition of DNA, RNA, and protein synthesis. Azacitidine is 
approved in the US and EU for treatment of MDS. Azacitidine is also approved for use in AML 
in the EU and is widely accepted as the SOC for treatment of AML in the US.  
Additional information is available in the azacitidine label (VIDAZA USPI, VIDAZA SmPC). 
2.3 
Benefit/Risk Assessment 
Despite an improvement in outcomes compared to historical treatment with HMA monotherapy 
in the recent studies of tamibarotene plus azacitidine and venetoclax plus azacitidine in ND AML 
patients (de Botton 2020, DiNardo 2020), approximately one-third of patients do not achieve a 
response after treatment with either combination.  
In the SY-1425-201 study, Syros has explored the safety, PK, pharmacodynamic, and clinical 
activity of tamibarotene in combination with azacitidine in RARA-positive AML. Clinical 
activity data from that study (de Botton 2020) and from the study exploring clinical activity of 
the venetoclax plus azacitidine combination (DiNardo 2020) support the rationale for further 
development of the triplet combination of tamibarotene/venetoclax/azacitidine in a genomically 
defined subset of patients characterized by overexpression of RARA in blasts. The triplet 
combination of tamibarotene/venetoclax/azacitidine may improve response in RARA-positive 
AML patients by treating both primitive AML that may be sensitive to venetoclax and more 
mature monocytic subpopulations that may be resistant to venetoclax, but respond to treatment 
with tamibarotene plus azacitidine. 
The AE profile of the tamibarotene plus azacitidine combination was consistent with what has 
been previously reported for single agent tamibarotene or single agent azacitidine in treatment of 
AML/MDS patients (see IB, VIDAZA USPI, VIDAZA SmPC) and supports potential 
tolerability of the triplet regimen. Notably, the AE profile of tamibarotene plus azacitidine is 
distinct from the AE profile of the venetoclax plus azacitidine combination (DiNardo 2020) and 


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does not suggest overlapping toxicity. In particular, whereas hematologic toxicities are 
frequently observed with venetoclax effects (VENCLEXTA USPI, VENCLYXTO SmPC), the 
rates of myelosuppression with the tamibarotene plus azacitidine combination were comparable 
to single-agent azacitidine, without evidence for additive hematologic toxicity from the 
combination. To minimize the known myelosuppression from venetoclax (with a goal of 
improving patient safety and tolerability of treatment), the duration of venetoclax administration 
in Cycle 1 will be guided by blast clearance status at a response assessment performed between 
Days 14 and 21. For Cycle 2 and beyond, patients will receive venetoclax daily beginning on 
Day 1 through Day 28 for each cycle, with dose modifications based on time to recovery of 
blood counts, as recommended in ELN 2022 guidelines (Döhner 2022). 
The majority of nonhematologic AEs observed with tamibarotene plus azacitidine therapy were 
low grade and reversible. The safety profile of tamibarotene plus azacitidine is further supported 
by the Japanese marketing experience with tamibarotene (AMNOLAKE®), in which more than 
1000 patients have been treated for R/R APL.  
Overall, the expected safety profile of the tamibarotene/venetoclax/azacitidine combination is 
predicted to be acceptable, with the potential for improved response rate in RARA-positive 
patients when treated with the triplet combination. All patients in the study will receive 
venetoclax and azacitidine, which is the current best practice for treating ND AML. 
The risks of the underlying condition evaluated in this study are significant and represent areas 
of high unmet medical need. Patients undergoing treatment for AML undergo the procedural risk 
of repeated bone marrow aspirations, which are also required assessments in this study. There is 
a significant risk of complications due to leukemia and its treatment, including bleeding and life-
threatening infections. The treatment-related mortality is historically high in clinical trials in 
AML (Estey 2018). The clinical activity of the individual venetoclax plus azacitidine 
combination, coupled with that of the tamibarotene plus azacitidine combination, suggest that the 
triplet combination has the potential to provide a valuable treatment option for RARA-positive 
patients with AML. 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs for tamibarotene may be found in the IB. 
3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Part 1 
Primary 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine combination 
in RARA-positive, previously untreated AML 
patients to inform Part 2 dose and regimen of the 
tamibarotene/venetoclax/azacitidine therapy 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 


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OBJECTIVES 
ENDPOINTS 
Secondary 
• 
Characterize the ORR of 
tamibarotene/venetoclax/azacitidine combination 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 
• 
Characterize PK of tamibarotene when 
administered as a part of 
tamibarotene/venetoclax/azacitidine therapy  
• 
Tamibarotene PK parameters  
Exploratory 
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 
Part 2 
Primary 
• 
Characterize and compare the CR/CRi rate of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine  
• 
CR/CRi assessment; CR/CRi rate is estimated by 
the proportion of patients who achieve CR/CRi (as 
determined by the investigatora)  
Secondary 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine in RARA-positive, 
previously untreated AML patients 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 
• 
Characterize and compare CR rate and CR/CRh 
rate of tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
CR assessment; CR rate is estimated by the 
proportion of patients who achieve CR (as 
determined by the investigatora) 
• 
CR/CRh assessment; CR/CRh rate is estimated by 
the proportion of patients who achieve CR/CRh (as 
determined by the investigatora) 
• 
Characterize duration of CR, duration of CR/CRi, 
and duration of CR/CRh of 
tamibarotene/venetoclax/azacitidine combination 
versus venetoclax/azacitidine 
• 
Duration of CR, defined as duration from the date 
of first documented evidence of CR to the date of 
relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 
• 
Duration of CR/CRi, defined as duration from the 
date of first documented evidence of CR/CRi to 
the date of relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 
• 
Duration of CR/CRh, defined as duration from the 
date of first documented evidence of CR/CRh to 
the date of relapse of disease (as determined by the 
investigatora), or death due to any cause, 
whichever occurs first 


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OBJECTIVES 
ENDPOINTS 
• 
Characterize time to CR, time to CR/CRi, and time 
to CR/CRh of tamibarotene/venetoclax/azacitidine 
combination versus venetoclax/azacitidine 
• 
Time to CR, defined as the duration from the date 
of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR as determined by the 
investigatora 
• 
Time to CR/CRi, defined as the duration from the 
date of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR/CRi as determined by 
the investigatora 
• 
Time to CR/CRh, defined as the duration from the 
date of Cycle 1 Day 1 Visit to the date of the first 
documented evidence of CR/CRh as determined by 
the investigatora 
• 
Characterize and compare the ORR of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 
Exploratory 
• 
Characterize and compare EFS of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
EFS, defined as the duration from the date of 
Cycle 1 Day 1 Visit to the date of progressive 
disease, relapse after CR or CRi, treatment failureb, 
or death from any cause 
• 
Characterize and compare OS of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Duration from the date of Cycle 1 Day 1 Visit to 
the date of death due to any cause  
• 
Characterize and compare MRD-negative response 
rate of tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Assessment of MRD; MRD-negative response rate 
estimated by the proportion of patients achieving 
an MRD-negative CR by multiparameter flow 
cytometry, qPCR, or next generation sequencing, 
as determined by the investigatora 
• 
Characterize time to MRD-negative response of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
Time to MRD-negative response, defined as the 
duration from the date of Cycle 1 Day 1 Visit to 
the date of achieving an MRD-negative CR by 
multiparameter flow cytometry, qPCR, or next 
generation sequencing, as determined by the 
investigatora 
• 
Characterize and compare the TI rate of 
tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine 
• 
TI rate, defined as the proportion of patients who 
achieve TI. TI is a period of at least 56 days with 
no RBC or platelet transfusion since the date of 
Cycle 1 Day 1 Visit to the last dose of study drug 
+30 days, the initiation of post-treatment therapy, 
or death, whichever occurs first 
• 
Characterize PK of tamibarotene when 
co-administered with venetoclax and azacitidine  
• 
Plasma tamibarotene PK parameters  
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 


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OBJECTIVES 
ENDPOINTS 
Part 3 
Exploratory 
• 
Characterize the ORR after treatment with 
tamibarotene/venetoclax/azacitidine for patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Overall response assessment, comprised of CR, 
CRi, CRh, MLFS, or PR (as determined by the 
investigatora); ORR is estimated by the proportion 
of patients who achieve overall response 
• 
Characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine in patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Incidence of AEs, changes in clinical laboratory 
values, ECGs, and vital sign measurements 
• 
Characterize the OS of 
tamibarotene/venetoclax/azacitidine in patients 
who have experienced progressive disease, relapse, 
or treatment failureb on venetoclax/azacitidine 
• 
Duration from the date of first dose in Part 3 to the 
date of death due to any cause  
• 
Evaluate AML molecular features associated with 
response and with loss of response to treatment 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, on treatment, 
and/or at time of loss of response 
Abbreviations: AE = adverse event; AML = acute myeloid leukemia; CR = complete remission; CRh = CR with 
partial hematologic recovery; CRi = CR with incomplete blood count recovery; ECG = electrocardiogram; 
EFS = event-free survival; ELN = European LeukemiaNet; MLFS = morphologic leukemia-free state; 
MRD = minimal residual disease; OS = overall survival; ORR = objective response rate; PK = pharmacokinetic(s); 
PR = partial remission; qPCR = quantitative polymerase chain reaction; RBC = red blood cell; TI = transfusion 
independence. 
a 
Determination of response will be made by the investigator in alignment with ELN AML criteria (Döhner 2017) 
and Bloomfield 2018 for CRh. 
b 
Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 2 cycles 
of therapy, as determined by the investigator. 
4 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2, open-label, 3-part, multi-center study evaluating 
tamibarotene/venetoclax/azacitidine combination therapy in RARA-positive, previously 
untreated, non-APL AML patients who are unlikely to tolerate standard intensive chemotherapy 
at the time of study entry.  
In Part 1, tamibarotene will be administered at 6 mg BID starting dose in combination with 
venetoclax/azacitidine, which will be administered at the approved dose and schedule (VIDAZA 
USPI/VIDAZA SmPC and VENCLEXTA USPI/VENCLYXTO SmPC). Tamibarotene dose 
modifications for AEs will follow guidelines outlined in the protocol (Section 6.5); 
venetoclax/azacitidine dose modifications will follow the standard dose modifications for AEs 
(VIDAZA USPI/VIDAZA SmPC and VENCLEXTA USPI/VENCLYXTO SmPC). 
The safety, tolerability, and PK evaluation of tamibarotene/venetoclax/azacitidine combination 
will inform the appropriate tamibarotene dose to be combined with the SOC 
venetoclax/azacitidine (Döhner 2022) in Part 2 and Part 3. In Part 2, patients will be 


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randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to 
compare the clinical activity of the 2 combinations. In Part 3, tamibarotene will be added to the 
venetoclax/azacitidine regimen of a subset of Part 2 patients who experience progressive disease, 
relapse after initial CR or CRi response, or treatment failure (see Part 3 Design section below). 
Enrollment is planned in the United States (US) and France. 
Start of Venetoclax/Azacitidine Therapy 
Currently, ND AML patients who are ineligible for standard induction therapy are increasingly 
receiving venetoclax/azacitidine combination as the SOC therapy. Since AML is an acute disease 
and prompt treatment may be required, in Part 1 and Part 2 of the study, the treating investigator 
may choose one of the two options below.  
• Begin SOC venetoclax/azacitidine treatment on Cycle 1 Day 1 using protocol defined 
regimen and doses while awaiting pre-treatment screening RARA biomarker test result.  
• Begin venetoclax/azacitidine treatment on Cycle 1 Day 1 after the patient is confirmed to 
be RARA-positive. 
All eligibility requirements must be met prior to dosing on Cycle 1 Day 1, with the exception of 
RARA test results (inclusion criterion 2). 
Pre-screening/Screening and Enrollment (Part 1)/Randomization (Part 2) Procedures 
The sample for RARA biomarker testing must be collected and sent for assessment prior to 
starting venetoclax/azacitidine administration on Cycle 1 Day 1. Patients who meet all eligibility 
criteria (except for RARA-positive status confirmation; inclusion criterion 2) can begin 
venetoclax/azacitidine treatment on Cycle 1 Day 1 and are considered to be enrolled 
(Part 1)/randomized (Part 2) upon confirmation of RARA-positive status by Cycle 1 Day 8. 


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Abbreviations: AE = adverse events; I/E = inclusion/exclusion [criteria]; C1DX = Cycle 1 Day X; RARA = retinoic 
acid receptor alpha. 
a 
If the patient discontinues treatment or study participation prior to confirmation of screening RARA results and 
RARA-positivity is confirmed by C1D8, the patient will be enrolled (Part 1)/randomized (Part 2), and the data 
from C1D1 until the time of study discontinuation will be captured (including AEs and the reason for 
discontinuation of treatment). 
Part 1 Design 
In total, up to approximately 
 patients may be enrolled in Part 1. Enrolled RARA-positive 
patients will receive the tamibarotene/venetoclax/azacitidine triplet combination as follows: 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 through 7 
of each 28-day therapy cycle (per VIDAZA USPI, VIDAZA SmPC). Alternative dosing 
of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study.  
• Venetoclax (orally) at a dose described in the most current VENCLEXTA 
USPI/VENCLYXTO SmPC (including ramp-up and appropriate dosing for patients 
receiving concomitant 
 and P-gp inhibitors [Table 4]), daily on Days 1 
through 28. 
CCI
CCI


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• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy cycle. 
Tamibarotene will only be administered to patients who have been confirmed as 
RARA-positive. 
If needed to manage toxicity, the study drugs will be modified as outlined in Section 6.5. After 
Cycle 1 data for at least 6 patients become available, the totality of data (including study drug 
administration record, dose modifications, and available PK data) will be evaluated to support 
advancing to Part 2 of the study. The ongoing enrollment of 6 to 9 additional patients to further 
characterize the dosing regimen or a modified regimen may occur in Part 1 of the study. A 
modified regimen may be evaluated if the starting dose of tamibarotene (6 mg BID) is not 
tolerated in combination with venetoclax/azacitidine or if the 6 mg BID dose of tamibarotene 
does not allow for patients to tolerate the approved regimen of venetoclax/azacitidine. A 
modified regimen would consist of a reduced dose of tamibarotene (Table 6) in combination with 
the approved regimen of venetoclax/azacitidine.  
The dose and regimen of tamibarotene administered in combination with venetoclax/azacitidine 
in Part 2 and Part 3 will be informed by the totality of available data from all patients enrolled in 
Part 1, including the incidence of treatment-emergent AEs, the study drug administration record 
(including dose modifications and interruptions), safety laboratory data, physical examination 
and vital signs findings, and PK data.  
Part 2 Design 
In total, approximately 
 patients will be randomized in Part 2 of the study. RARA-positive 
patients will be randomized 1:1 to receive either tamibarotene/venetoclax/azacitidine or 
venetoclax/azacitidine dosing as follows: 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 through 7 
of each 28-day therapy cycle (per VIDAZA USPI and VIDAZA SmPC). Alternative 
dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study.  
• Venetoclax (orally) at a dose described in the most current VENCLEXTA USPI and 
VENCLYXTO SmPC (including ramp-up and appropriate dosing for patients receiving 
concomitant 
 and P-gp inhibitors [Table 4]) daily beginning on Day 1 for a 
minimum of 14 days and a maximum of 28 days for Cycle 1, with the duration of 
venetoclax determined by early response assessment conducted between Days 14 and 21 
of the cycle (Section 6.1.1). If bone marrow blasts are <5%, venetoclax administration 
will be stopped and held for up to 14 days prior to proceeding with Cycle 2. If bone 
marrow blasts are ≥5%, venetoclax administration will continue through Day 28 of 
Cycle 1. For Cycle 2 and beyond, patients will receive venetoclax daily beginning on Day 
1 through Day 28 for each cycle, with dose modifications as needed for toxicity, as 
outlined in Table 5 (Döhner 2022; Maiti 2022). 
• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy cycle. 
Tamibarotene will only be administered to patients who have been confirmed as 
RARA-positive. 
CCI
CCI


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PK evaluation of tamibarotene will be conducted using samples collected from patients receiving 
the triplet combination only. 
Part 3 Design 
Part 2 patients treated with venetoclax/azacitidine who experience progressive disease, relapse 
after initial CR or CRi response, or treatment failure may begin subsequent treatment in Part 3, 
where tamibarotene will be added to their regimen. Participation in Part 3 will begin as soon as 
possible, but within 30 days of the decision to stop participation in Part 2. Treatment failure is 
defined as a failure to achieve a bone marrow blast count of <5% following at least 2 cycles of 
therapy, as determined by the investigator. No PK evaluation will be performed in Part 3. 
Parts 1 through 3 Assessments and Follow-up 
Patients will undergo safety and response evaluations throughout their study participation as 
detailed in the Schedules of Activities (Section 1.3). Response will be assessed by the 
investigator in alignment with ELN AML criteria (Döhner 2017), with CRh assessed according 
to Bloomfield 2018.  
In Part 1, bone marrow aspirates will be collected to measure response at the EoC Visits of 
Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), with bone marrow aspirates 
collected at other times as clinically determined based upon clinical findings or changes in 
peripheral blood counts. If a patient achieves a CR/CRi at the Cycle 1 EoC Visit, the Cycle 2 
EoC bone marrow aspirate is not required. 
In Part 2 and Part 3, Cycle 1 response will initially be assessed between Days 14 and 21 of 
Cycle 1, as recommended by ELN guidelines (Döhner 2022), with venetoclax administration 
proceeding in alignment with these recommendations. For those with blast clearance 
(<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is required. For 
patients with ≥5% blasts at that initial assessment, Cycle 1 EoC bone marrow aspirate will be 
completed. Subsequent bone marrow aspirates for all patients will be collected at the EoC Visit 
of Cycles 2 and 3, followed by every third cycle (6, 9, 12, etc.), with bone marrow aspirates 
collected at other times as clinically determined. If a patient achieves a CR/CRi within Cycle 1 
response assessment(s), the Cycle 2 EoC bone marrow aspirate is not required.  
The AE profiles of tamibarotene and venetoclax/azacitidine combination are well-documented 
and largely do not overlap (tamibarotene IB, VENCLEXTA USPI, VENCLYXTO SmPC). 
Consequently, in this study, it is recommended that hematologic toxicities and non-hematologic 
toxicities typically associated with the venetoclax/azacitidine combination (VENCLEXTA USPI, 
VENCLYXTO SmPC) should be managed with adjustments to venetoclax/azacitidine 
administration. AEs that have been identified as tamibarotene ADRs (tamibarotene IB) should be 
managed via modification to tamibarotene administration (Section 6.5). In patients receiving 
triplet combination therapy, if improvements in blood counts or relevant toxicities are not 
observed with recommended adjustments to venetoclax/azacitidine, an adjustment to the 
tamibarotene dose should be considered.  
All patients who remain on study may continue to receive study drug until experiencing an 
unacceptable toxicity, disease progression, relapse, decision to pursue post-remission therapy 


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(such as HSCT) or an alternative anticancer therapy, patient withdraws consent, or the 
investigator determines it is in the best interest of the patient to discontinue study drug. Note: 
Part 2 patients assigned to venetoclax/azacitidine treatment may continue on study in Part 3 
following progressive disease, relapse after initial CR or CRi response, or treatment failure as 
noted in section Part 3 Design above. 
For all enrolled (Part 1)/randomized (Part 2) patients, an EoT Visit should occur within 3 days of 
the last dose of study drug (or within 3 days of decision to permanently stop drug treatment, if 
this decision directly follows a period when study drug has been on hold) and before the start of 
any subsequent anticancer therapy. A Safety Follow-up Visit should occur 30 days (±3 days) 
after the EoT Visit and before the start of any subsequent anticancer therapy. After the EoT Visit, 
patients who have not progressed/relapsed will enter the Disease Follow-up period, during which 
response assessments will be performed for up to 3 years after discontinuation of study drug or 
until disease progression/relapse, whichever occurs first. Patients who progress/relapse will enter 
Survival Follow-up and will be followed to document the start of subsequent anticancer therapy, 
the date of disease progression/relapse, and OS status for up to 3 years after discontinuation of 
study drug. 
There will be no formal IDMC. The sponsor will provide oversight of safety and tolerability at 
regularly scheduled intervals (and ad hoc if needed) via SRT meetings as detailed in the SRT 
Charter. In addition, regularly scheduled reviews of safety and tolerability will be performed by 
the sponsor in collaboration with the study investigators in Part 1 of the study. These reviews 
will inform the dose of tamibarotene to be combined with venetoclax/azacitidine in Part 2 of the 
study. Administrative interim analyses will be performed by the sponsor personnel or designee. 
4.2 
Scientific Rationale for Study Design 
This study is evaluating the addition of tamibarotene, a targeted therapy for RARA-positive 
AML patients who are not candidates for treatment with intensive chemotherapy, to the 
established venetoclax/azacitidine regimen. 
The design of the study follows an accepted approach for initiating study of a novel combination, 
in that it will begin with a small cohort of patients in Part 1 (approximately 
) to identify any 
safety issues and determine a tolerable regimen of tamibarotene in combination with 
venetoclax/azacitidine before proceeding to Part 2, where a larger number of patients 
(approximately 
) will be treated. Part 2 has been structured to characterize and compare 
clinical activity of tamibarotene/venetoclax/azacitidine with that of venetoclax/azacitidine 
through 1:1 randomization of approximately 
 patients between the 2 treatment arms. Part 3 is 
designed to allow exploration of the activity of the tamibarotene addition to the 
venetoclax/azacitidine combination in patients who have failed to respond to 
venetoclax/azacitidine (Section 4.1) by adding tamibarotene to venetoclax/azacitidine in these 
patients and following them for response. 
The inclusion criteria ensure enrollment of only RARA-positive patients and those who are not 
candidates for intensive treatment using standard criteria (Ferrara 2013). Treatment with prior 
cycles of HMA or other chemotherapy for AML is not permitted to ensure the enrollment of only 
ND patients.  
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The primary endpoint of Part 1 is safety to appropriately characterize the tolerability and safety 
of this novel combination. The primary endpoint of Part 2 is the CR/CRi rate. This outcome is 
accepted as a clinically meaningful outcome to investigators. CR is a surrogate for OS in AML. 
Achievement of CRi reflects the clearance of blasts from the bone marrow (and therefore anti-
leukemic activity) in the context of an incomplete recovery of peripheral blood counts. 
Composite CR/CRi rates are well characterized for the venetoclax/azacitidine combination to 
which the tamibarotene/venetoclax/azacitidine combination will be compared. 
In Part 3 of the study, the ORR for patients refractory to venetoclax/azacitidine will be explored 
following treatment with tamibarotene/venetoclax/azacitidine. 
4.3 
Rationale for Dose and Regimen 
Tamibarotene 
The selection of the 6 mg BID regimen of tamibarotene administered on Days 8 to 28 of a 
28-day cycle is based on the totality of safety, efficacy, and PK data available for tamibarotene to 
date, including from the Phase 2 study of tamibarotene in adults with AML or MDS 
(Study SY-1425-201) and the Japanese clinical trial and marketing experience.  
The dose and regimen used in Study SY-1425-201 (6 mg/m2/day in 2 divided doses) were based 
on the dose and regimen approved in Japan for the treatment of APL. Population PK analysis 
from Study SY-1425-201 indicated that body size was not significantly associated with 
clearance; therefore, a body surface area-based adjustment to tamibarotene dosing is not 
necessary. Based on this analysis, the 6 mg BID flat dosing regimen is expected to provide 
similar PK exposures compared to the 6 mg/m2/day (in 2 divided doses) regimen used in the 
SY-1425-201 study. 
In Part 1, tamibarotene will be administered at 6 mg BID starting dose in combination with 
venetoclax/azacitidine. Tamibarotene dose modifications for AEs will follow guidelines outlined 
in the protocol (Section 6.5). Evaluation of tamibarotene/venetoclax/azacitidine combination in 
Part 1 will inform the appropriate tamibarotene dose to be combined with SOC 
venetoclax/azacitidine in Part 2. 
A modified regimen may be evaluated if the starting dose of tamibarotene (6 mg BID) is not 
tolerated in combination with venetoclax/azacitidine or if the 6 mg BID dose of tamibarotene 
does not allow for patients to tolerate the SOC regimen of venetoclax/azacitidine. A modified 
regimen would consist of a reduced dose of tamibarotene (Table 6) in combination with the SOC 
regimen of venetoclax/azacitidine.  
The dose and regimen of tamibarotene administered in combination with venetoclax/azacitidine 
in Part 2 and Part 3 will be informed by the totality of available data from all patients enrolled in 
Part 1, including the incidence of treatment-emergent AEs, the study drug administration record 
(including dose modifications and interruptions), safety laboratory data, physical examination 
and vital signs findings, and PK data. 


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Venetoclax and Azacitidine 
In Part 1 of the study, when administered as a part of the triplet combination, venetoclax and 
azacitidine will be given as described in VIDAZA USPI/VIDAZA SmPC and 
VENCLEXTA USPI/VENCLYXTO SmPC, respectively.  
In Part 2 and Part 3 of the study, response assessment and SOC modifications will be consistent 
with ELN guidelines (Döhner 2022; Maiti 2022). Utilization of the ELN 2022 venetoclax dosing 
guidelines allows to minimize the known myelosuppression from venetoclax with a goal of 
improving patient safety and tolerability of treatment. Cycle 1 response will initially be assessed 
between Days 14 and 21, with Cycle 1 and subsequent venetoclax administration proceeding in 
alignment with ELN 2022 recommendations (Döhner 2022; Section 6.1.1; Table 5). 
Venetoclax/azacitidine dose modifications will follow the standard dose modifications for AEs 
(VIDAZA USPI/VIDAZA SmPC and VENCLEXTA USPI/VENCLYXTO SmPC), with SOC 
modifications consistent with ELN 2022 guidelines in Part 2 and Part 3 (Döhner 2022; 
Maiti 2022). 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedules of Activities (SoAs) (Section 1.3) for the last patient in the study.  
A patient is considered to have completed the study if he/she has completed all phases of the 
study, including the last scheduled procedure shown in the SoA. 
5 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Note: all inclusion/exclusion criteria should be met prior to the first dose of 
venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result 
referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue 
treatment on study. 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Patients must be at least 18 years old at the time of signing of an informed consent. 


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2. All patients must have obtained a blood sample for RARA biomarker investigational 
assay testing prior to starting treatment on Cycle 1 Day 1. The results of the 
investigational biomarker assay for all patients must be confirmed as RARA-positive 
by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study. 
3. Patients must have ND, previously untreated non-APL AML with a bone marrow or 
peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive 
chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or 
comorbidities based on at least one of the following criteria (Ferrara 2013):  
a. age ≥75 years old 
 
OR 
b. age <75 years old, with at least one of the following: 
o ECOG performance status of 3 
o cardiac history of CHF or documented EF ≤50% 
o pulmonary disease with DLCO ≤65% or FEV1 ≤65% 
o creatinine clearance ≥30 mL/min to <45 mL/min based on the Cockcroft-Gault 
glomerular filtration rate estimation 
o hepatic impairment with total bilirubin >1.5 to ≤3.0 × ULN 
o any other comorbidity that the investigator judges to be incompatible with 
intensive chemotherapy, and reviewed and approved by the sponsor  
4. Patients must have ECOG of 0 to 3 (if <75 years old) or 0 to 2 (if ≥75 years old). 
5. Patients must have a WBC count <25,000/µL at the time of initiation of study drug 
(leukapheresis may be performed and/or hydroxyurea may be administered to decrease 
the WBC count to <25,000/µL). 
6. Patients must have minimum baseline organ function, as defined by: 
a. total bilirubin ≤3.0 × ULN (if <75 years old) or ≤1.5 × ULN (if ≥75 years old) 
b. ALT and AST ≤3 × ULN or ≤5 × ULN (if documented liver infiltration with 
leukemia cells) 
c. creatinine clearance ≥30 mL/min (if <75 years old) or ≥45 mL/min (if ≥75 years 
old) based on the Cockcroft-Gault glomerular filtration rate estimation  


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7. Patients must have a high-sensitivity urine or serum pregnancy test (for females of 
childbearing potential) that is negative at the Screening Visit and immediately prior to 
initiation of treatment (first dose of study drug). 
8. Patients must be willing and able to comply with the scheduled study visits, treatment 
plans, laboratory tests, use of 2 methods of birth control (including a barrier method) 
for WOCBP and male patients (as described in Appendix 4), and other procedures. 
9. Patients must be capable of giving signed and dated IRB- or IEC-approved informed 
consent. 
5.2 
Exclusion Criteria 
Note: all inclusion/exclusion criteria should be met prior to the first dose of 
venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result 
referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue 
treatment on study. 
Patients are excluded from the study if any of the following criteria apply: 
1. Patients have APL. 
2. Patients have known active central nervous system involvement with AML. 
3. Participants with a history of other cancers must not be receiving active treatment (with 
radiation or chemotherapy) and must be free of disease for 2 years prior to the 
Screening Visit with the exception of localized prostate cancer treated with hormone 
therapy, breast cancer treated with hormone therapy, localized basal cell carcinoma, 
non-melanoma skin cancer, or cervical carcinoma in situ. 
4. Patients have an active, life-threatening, or clinically-significant uncontrolled systemic 
infection requiring hospitalization. 
5. Patients have a known malabsorption syndrome or other condition that may impair 
absorption of study medication (e.g., gastrectomy). 
6. Immunocompromised patients with increased risk of opportunistic infections, including 
known HIV-positive patients with CD4 counts ≤350 cells/mm3 or history of 
opportunistic infection in the last 12 months. Note: To ensure that effective ART, when 
used in eligible HIV-positive patients, is tolerated and that toxicities are not confused 
with investigational drug toxicities, patients should be on an established ART for at 
least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the 
Screening Visit. 
7. Patients have a known active or chronic hepatitis B or active HCV infection. Patients 
with a history of HCV infection who have completed curative therapy for HCV at least 


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12 weeks before the Screening Visit and have a documented undetectable viral load at 
the Screening Visit are eligible for enrollment. 
8. Patients have other severe acute or chronic medical conditions (and/or psychiatric 
conditions or laboratory abnormalities) that may increase the expected risk to the 
patient (i.e., the risk associated with the study participation or study drug 
administration) or that may interfere with the interpretation of study results or, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study. 
9. Patients received prior treatment with ATRA or systemic retinoid for a hematologic 
malignancy. 
10. Patients have not adequately recovered from a major surgery within 4 weeks of starting 
study drug administration. 
11. Prior treatment (before Cycle 1 Day 1) for the diagnosis of AML, MDS, or antecedent 
hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, 
or HSCT, with the exception of prior treatment with hydroxyurea.  
12. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A 
supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to 
the first dose of the study drug.  
13. Patients received any other investigational agents within 4 weeks of the Screening Visit 
or <5 half-lives since completion of previous investigational therapy have elapsed, 
whichever is shorter. 
14. Patients require concurrent treatment with any investigational or approved oncology 
agent, except for hydroxyurea. 
15. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, 
version 5). 
16. QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc 
>480 msec in male or female patients with bundle branch block based on triplicate 
ECG readings at the Screening Visit. NOTE: The QTc in this study should be the QT 
interval corrected for heart rate according to QTcF formula. 
17. Pregnant females, breastfeeding females, and males not willing to comply with 
contraceptive requirements (as described in Appendix 4) or females of childbearing 
potential not willing to comply with contraceptive requirements (as described in 
Appendix 4). 
18. Patients who have a hypersensitivity to tamibarotene, azacitidine, venetoclax or to any 
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19. Patients for whom treatment with tamibarotene, azacitidine, venetoclax is 
contraindicated. 
20. Protected persons (legally protected adults [under judicial protection, guardianship, or 
supervision] and persons deprived of their liberty). 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
A screen failure occurs when a patient who has consented to participate in the clinical study is 
not subsequently enrolled (Part 1)/randomized (Part 2) in the study. In particular, patients 
determined to be RARA-negative or who do not have a RARA biomarker result by Cycle 1 
Day 8 will be classified as screen failures. 
A minimal set of information will be collected and is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE that occurs after the 
first dose of venetoclax/azacitidine on Cycle 1 Day 1 and prior to screen failure. 
Individuals who do not meet the criteria for participation in this study may be rescreened.  
5.5 
Criteria for Temporarily Delaying Randomization 
Not applicable. 
6 STUDY DRUGS AND CONCOMITANT THERAPY 
Study drug is defined as any investigational intervention(s), marketed product(s), or placebo 
intended to be administered to a patient according to the study protocol beginning on Cycle 1 
Day 1. 
6.1 
Study Drugs Administered 
Study drugs described in Table 3 will be administered. All patients will receive 
venetoclax/azacitidine from Cycle 1 Day 1 to Cycle 1 Day 7 in Part 1 and Part 2 of the study.  
• Part 1 patients who meet all eligibility criteria and are enrolled by Cycle 1 Day 8 (once 
RARA-positive status has been confirmed) will receive 
tamibarotene/venetoclax/azacitidine combination therapy.  
• Part 2 patients who meet all eligibility criteria and are randomized by Cycle 1 Day 8 
(once RARA-positive status has been confirmed) will receive either 
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• In Part 3, tamibarotene will be added to venetoclax/azacitidine regimen of a subset of 
Part 2 patients.  
In each part of the study, the decision to begin Cycles 2, 3, 4, followed by every third cycle (7, 
10, 13, etc.) will be made as described in Section 6.1.1. 
Table 3: 
Study Drugs 
Intervention Name 
Tamibarotene 
Venetoclax 
Azacitidine 
Type  
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Reconstituted as solution or 
suspension 
Unit Dose Strength(s) 
2-mg tablets 
10-mg, 50-mg, 100-mg 
tablets 
100-mg single-use vials 
Dosage Level and 
Regimen 
6 mg twice per day; 
Days 8 through 28 of 
each 28-day treatment 
cycle. 
See Section 6.2.1 for 
details of dose 
administration.  
Daily, Days 1 through 28, as 
described in Table 4 
(adapted from 
VENCLEXTA USPI/ 
VENCLYXTO SmPC). 
See Section 6.2.2 for details 
of dose administration. 
75 mg/m2 once per day; 
Days 1 through 7 of each 
28-day treatment cycle (per 
VIDAZA USPI/ 
VIDAZA SmPC). 
If dosing on Days 6 and 7 is 
not possible due to logistical 
limitations, these doses may 
be delayed to Days 8 and 9. 
See Section 6.2.3 for details 
of dose administration. 
Route of 
Administration 
Oral 
Oral 
Intravenous or subcutaneous 
Use 
Experimental 
Background intervention 
Background intervention 
Investigational 
Medicinal Product 
(IMP) and Non-
Investigational 
Medicinal Product 
(NIMP) 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by 
the sponsor  
As regionally applicable  
Sourced by the site 
Packaging and 
Labeling 
Study drug will be 
provided in bottles. 
Each bottle will be 
labeled as required per 
country requirement. 
Study drug is commercially 
available and will be 
provided in the commercial 
packaging. Each container 
will be labeled as required 
per country requirement. 
Study drug is commercially 
available and will be 
provided in the commercial 
packaging. Each container 
will be labeled as required 
per country requirement. 


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Table 4: 
Venetoclax Dosing  
Day 
Standard 
Ven Dosing 
Drug Interaction Management 
Ven + 
Posaconazole 
Ven + Other
 
 
 
 or P-gp 
Inhibitor 
Daily Ven Dose 
Day 1 
100 
10 
10 
Reduce standard 
venetoclax dose by at 
least 50% 
Day 2 
200 
20 
20 
Day 3 
400 
50 
50 
Day 4 and beyond 
400 
70 
100 
Source: adapted from VENCLEXTA USPI 2020 
Note: Resume the venetoclax dosage that was used prior to concomitant use of a 
 
 or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. 
Abbreviations: P-gp = P-glycoprotein; ven = venetoclax 
6.1.1 
Study Procedures at the time of Response Assessment  
Part 1 
Patients will undergo a response assessment at the end of Cycles 1, 2, and 3, followed by every 
third cycle (6, 9, 12, etc.). The start of the next treatment cycle will be determined as follows:  
• If a patient achieves CR at the EoC response assessment, the patient will begin the next 
treatment cycle. 
• If a patient achieves CRi or has a morphologically leukemia-free state (MLFS) at the EoC 
response assessment, without absolute neutrophil count (ANC) recovery, the start of the 
next treatment cycle will be held to allow for ANC recovery until ANC is ≥500/µL or up 
to 14 days. Granulocyte colony stimulating growth factor (G-CSF) may be administered 
if clinically indicated for neutropenia. If ANC recovery does not occur within 14 days of 
the EoC response assessment, the next treatment cycle may begin in the absence of 
recovery of peripheral blood counts. 
• If a patient is NOT in CR, CRi, or MLFS at the EoC response assessment, the start of the 
next treatment cycle should begin with supportive care, without modifications to the 
regimen, regardless of peripheral blood count recovery. 
Part 2 and Part 3 
Patients will undergo a response assessment between Days 14 and 21 of Cycle 1 and at the EoC 
of Cycles 1 (only for patients with ≥5% blasts when assessed between Days 14 and 21), 2, and 3, 
followed by every third cycle (6, 9, 12, etc.). The start of the next treatment cycle will be 
determined as follows:  
Cycle 1 Assessments: 
• If a patient has <5% bone marrow blasts at the response assessment conducted between 
Days 14 and 21 of Cycle 1, stop venetoclax for up to 14 days prior to proceeding to 
Cycle 2 to allow for count recovery to ≥CRh (ANC ≥500/µL and platelets ≥50,000/µL; 
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Döhner 2022). For these patients with blast clearance (<5% blasts) at that initial 
assessment, no Cycle 1 EoC bone marrow aspirate is required. 
• If a patient has ≥5% bone marrow blasts at the response assessment conducted between 
Days 14 and 21 of Cycle 1, venetoclax administration will continue for the remainder of 
the cycle, and another bone marrow aspirate will be performed at Cycle 1 EoC. If blast 
clearance (<5% blasts) is documented, Cycle 2 will be held to allow for peripheral blood 
count recovery to ≥CRh. 
• If a patient has ≥5% blasts at the EoC response assessment, the start of the next treatment 
cycle should begin on schedule with supportive care, without modifications to the 
regimen, regardless of peripheral blood count recovery. 
Cycle 2 and Beyond: 
• If a patient has bone marrow blasts <5% at the EoC response assessment, without count 
recovery, the start of the next treatment cycle will be held to allow for count recovery to 
≥CRh. G-CSF may be administered as clinically indicated for neutropenia. See Table 5 to 
guide venetoclax schedule adjustment for cytopenia management (Döhner 2022). 
Cytopenias and dose adjustments should be managed per the guidance in the most current 
VENCLEXTA USPI/ VENCLYXTO SmPC (e.g., Table 5) in conjunction with Döhner 2022. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Tamibarotene 
A total of 6 tablets (12 mg total) will be taken each day, 3 tablets (6 mg) in the morning and 
3 tablets (6 mg) in the evening. Patients will be instructed to take the dose with a glass of water 
after their morning meal and after their evening meal. Tablets should not be crushed, broken, or 
split. Dosing should not be repeated if a patient vomits. A dose missed by greater than 4 hours 
should be skipped.  
Until dispensed to the patients, the study drug will be stored in a securely locked area, accessible 
to authorized personnel only. Tablets should be stored at room temperature (15°C [59°F] to 30°C 
[86°F]) and should not be removed from bottles until immediately before administration. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all tamibarotene received, and any discrepancies are reported and 
resolved before its use. 
Only patients enrolled in the study may receive tamibarotene and only authorized site staff may 
supply or administer it. All tamibarotene must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff. 


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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for tamibarotene accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused tamibarotene are provided 
in the Pharmacy Manual. 
6.2.2 
Venetoclax 
Venetoclax is commercially available as 10-mg, 50-mg, and 100-mg tablets.  
Tablets must be stored at room temperature (15°C [59°F] to 25°C [77°F]). Refer to the 
venetoclax package insert for complete details, as applicable (VENCLEXTA USPI, 
VENCLYXTO SmPC). 
6.2.3 
Azacitidine 
Azacitidine is commercially available as a lyophilized powder. The product is reconstituted as a 
suspension for subcutaneous injection or as a solution with further dilution for intravenous 
infusion. 
Unreconstituted vials must be stored at room temperature (15°C [59°F] to 25°C [77°F]). Refer to 
the azacitidine package insert for complete details, as applicable (VIDAZA USPI, VIDAZA 
SmPC). 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; no blinding will occur.  
Parts 1 and 3 of the study are not randomized.  
Randomization in Part 2 will be performed using an interactive response system. Approximately 
 patients will be randomized 1:1 to receive tamibarotene/venetoclax/azacitidine or 
venetoclax/azacitidine. Randomization can occur between Cycle 1 Day 1 Visit and Cycle 1 
Day 8 Visit (inclusive), as soon as all eligibility requirements are met, including confirmation of 
patient’s RARA-positive status (inclusion criterion 2). For patients who are confirmed 
RARA-positive prior to Cycle 1 Day 1, randomization can occur within 72 hours prior to the first 
dose of venetoclax/azacitidine to accommodate operational needs. 
6.4 
Study Drug Compliance 
Tamibarotene and venetoclax may be administered at the site or self-administered at home. 
Azacitidine (subcutaneous or intravenous) will be administered under the supervision of the 
study site staff or trained designee (as needed).  
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When the study drug is administered at the site, patients will receive study drug directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. 
Compliance with tamibarotene will be assessed at each applicable study visit (Section 1.3). 
Patients will maintain diaries to include the date and time each dose of study drug is taken, 
including hour and minute. Patients are required to return the bottle(s) and unused study drug at 
each study visit. If a tablet is damaged (broken, crushed, split, etc.), the patient should record the 
information in the diary and bring the damaged tablet to the next study visit. The diaries, unused 
study drug, and study drug bottle will be used to assess study drug compliance and 
accountability.  
A record of the quantity of study drug dispensed to and administered by each patient must be 
maintained and reconciled with study drug accountability records. Study drug start and stop 
dates, including dates for study drug delays and/or dose reductions, will also be recorded. 
6.5 
Dose Modification and Management of Toxicities 
The instructions provided in Table 5 and Table 6 must be followed to adjust tamibarotene, 
azacitidine, or venetoclax dosing for management of toxicities. 
It is not anticipated that tamibarotene dose modifications would be needed for hematologic 
events (i.e., cytopenias, complications associated with cytopenias [including infection], or 
bleeding). Consideration for relatedness should be given to the timing of the AE, the temporal 
association between the onset of the AE and the administration of azacitidine (Days 1 through 7) 
and tamibarotene (Days 8 through 28), and the known adverse reactions for tamibarotene (see 
IB) and venetoclax/azacitidine (see most current VIDAZA USPI/VIDAZA SmPC, 
VENCLEXTA USPI, VENCLYXTO SmPC).  
Table 5: 
Dose Modifications  
Adverse Events (AEs) 
Dosage Modification  
Grade 4 hematologic 
toxicity  
Part 1  
Occurrence of Grade 4 neutropenia (with or without fever or infection) or 
Grade 4 thrombocytopenia prior to achieving remission: 
In most instances, do not interrupt venetoclax in combination with 
azacitidine due to cytopenias prior to achieving remission. 
First occurrence of Grade 4 neutropenia (with or without fever or infection) 
or Grade 4 thrombocytopenia after achieving remission and lasting at least 
7 days: 
Delay subsequent cycle of venetoclax in combination with azacitidine and 
monitor blood counts. Upon resolution to Grade 1 or 2, resume venetoclax 
at the same dose in combination with azacitidine.a 
Subsequent occurrences of Grade 4 neutropenia (with or without fever or 
infection) or Grade 4 thrombocytopenia in cycles after achieving remission 
and lasting 7 days or longer: 
Delay subsequent cycle of venetoclax in combination with azacitidine and 
monitor blood counts. Upon resolution to Grade 1 or 2, resume venetoclax 
at the same dose in combination with azacitidine and reduce venetoclax 


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Adverse Events (AEs) 
Dosage Modification  
duration by 7 days during each of the subsequent cycles, such as 21 days 
instead of 28 days.a 
If Grade 4 hematologic toxicity does not resolve after 
venetoclax/azacitidine dose modifications have been attempted, the dose 
of tamibarotene may be reduced by 1 Dose Reduction Level (Table 6). 
Part 2 and Part 3 
Occurrence of Grade 4 neutropenia (with or without fever or infection) or 
Grade 4 thrombocytopenia prior to achieving remission: 
In most instances, do not interrupt venetoclax in combination with 
azacitidine due to cytopenias prior to achieving remission. 
Subsequent Grade 4 neutropenia/thrombocytopenia after achieving remission 
(<5% blasts) and lasting 7 days or longer Döhner 2022): 
Delay subsequent cycle of venetoclax in combination with azacitidine and 
monitor blood counts. Upon resolution to Grade 1 or 2, resume venetoclax 
at the same dose in combination with azacitidine but reduce the 
venetoclax duration by 7 days during subsequent cycle (first occurrence 
reduce from 28 to 21 days, second occurrence reduce from 21 to 14 days, 
third occurrence reduce from 14 to 7 days). 
For severe marrow hypoplasia, azacitidine dosing may be modified as outlined in 
the most current VIDAZA USPI/VIDAZA SmPC.  
If Grade 4 hematologic toxicity does not resolve after venetoclax adjustments 
above, the dose of tamibarotene may be reduced by 1 Dose Reduction Level 
(Table 6). 
Retinoic acid syndrome 
(RAS)b 
Hold tamibarotene until RAS is considered controlled and Grade ≤2.  
See Section 6.8.8 for additional information on monitoring and treatment of RAS. 
Grade 4 
hypertriglyceridemia  
Hold tamibarotene until AE resolves to Grade ≤1 or baseline. Tamibarotene 
treatment may resume at the previous dose level once the AE has resolved to 
Grade ≤1 or baseline. Should the same AE recur, the dose of tamibarotene will be 
reduced by 1 Dose Reduction Level (Table 6). Dosing may be increased to a prior 
dose level if the AE remains Grade ≤1 or at baseline for 14 days. 
Serum electrolyte and 
renal toxicity  
The dose of azacitidine should be modified as described in the most current 
VIDAZA USPI/VIDAZA SmPC or applicable locally approved labeling. 
If serum electrolyte and renal toxicity does not resolve after azacitidine dose 
modifications have been attempted, the dose of tamibarotene may be reduced by 
1 Dose Reduction Level (Table 6). 


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Adverse Events (AEs) 
Dosage Modification  
Grade ≥3 non-
hematologic toxicity 
(excluding 
hypertriglyceridemia and 
renal toxicity) 
Hold venetoclax, if deemed related to venetoclax and not resolved with supportive 
care. Upon resolution of AE to Grade ≤1 or baseline, resume venetoclax at the 
same dose. 
Hold tamibarotene, if deemed related to tamibarotene and not resolved with 
supportive care, until AE resolves to Grade ≤1 or baseline. Tamibarotene treatment 
may resume at the previous dose level once the event has resolved to Grade ≤1 or 
baseline. Should the same AE recur, the dose of tamibarotene will be reduced by 
1 Dose Reduction Level (Table 6). Dosing may be increased to a prior dose level if 
the AE remains Grade ≤1 or at baseline for 14 days. 
If attribution is unclear, follow tamibarotene dose modification first. If AE does not 
resolve, next attempt venetoclax modifications. 
Note: Tamibarotene administration should not be resumed in the case of ≥28-day dose delay due to treatment-related 
AEs. 
a 
Venetoclax will be discontinued for patients with ≥21-day delay in starting the next cycle; treatment with 
azacitidine and tamibarotene may continue. 
b 
Also referred to as differentiation syndrome. 
Table 6: 
Dose Reductions of Tamibarotene 
Dose Level 
Tamibarotene Dose 
Initial Dose: Level 0 
6 mg twice per day (BID) 
 
 
 
 
6.5.1 
Dose Delay or Toxicity-related Discontinuation of One or More Study 
Drugs  
If criteria for hold of 1 study drug in the combination regimen are met (Table 5), the 
administration of the other drug(s) in the regimen may continue, unless hold criteria for the other 
drug(s) are met. If azacitidine is held, then Day 1 of the next treatment cycle is delayed until 
azacitidine dosing may resume. 
If implementation of the dose modification guidelines described in Table 5 (including dose holds 
and reductions) was not sufficient to adequately manage toxicity, the relevant study drug(s) 
should be discontinued. Discontinuation of 1 or 2 of the 3 drugs, while continuing administration 
of the other study drug(s), may occur. If only azacitidine is permanently discontinued, Day 1 of 
the next treatment cycle may resume within 3 days of the decision to discontinue azacitidine. 
If implementation of dose modifications described in Table 5 is insufficient to adequately 
manage toxicity and discontinuation of all study drugs in the patient's regimen is required, the 
patient should have an EoT Visit. 
6.5.2 
Hypertriglyceridemia 
Significant increases in both cholesterol and triglycerides have been reported with tamibarotene 
in patients with APL. Similarly, increases in triglycerides have been reported in patients with 
AML. Based upon these findings, tamibarotene should be cautiously administered to patients 
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with a disposition of hypertriglyceridemia such as those with diabetes mellitus, obesity, 
alcoholism, or abnormal lipid metabolism. 
6.5.3 
Sensitivity to Sodium Hydrosulfite 
It is possible that tamibarotene drug substance may contain a small amount of sodium 
hydrosulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms 
and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall 
prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite 
sensitivity is seen more frequently in individuals with asthma. 
6.5.4 
Interstitial Lung Disease 
Interstitial lung disease has been reported in patients with APL and hepatocellular carcinoma 
treated with tamibarotene (frequency lower than 5%). Patients must be carefully monitored 
(including chest X-rays as appropriate) for interstitial lung disease. If abnormalities are observed, 
tamibarotene should be discontinued and appropriate treatment administered (i.e., adrenocortical 
steroids). 
6.6 
Continued Access to Study Drug After the End of the Study 
At the time of study termination, if there are patients benefitting from treatment in the opinion of 
the investigator, the investigator should contact the medical monitor to discuss the possibility of 
treatment continuation. 
6.7 
Treatment of Overdose 
In the event of an overdose, the investigator should do the following: 
• Contact the medical monitor immediately. 
• Evaluate the patient to determine, in consultation with the medical monitor, whether 
study drug should be interrupted, reduced, or remain unchanged. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Closely monitor the patient for any AE/SAE and laboratory abnormalities. Note: while 
overdose itself is not considered to be an AE or SAE, any overdose complication will be 
reported as an AE or SAE.  
6.7.1 
Tamibarotene 
There has been no experience with acute overdose of tamibarotene in humans. However, 
overdose with other retinoids has been associated with transient headache, facial flushing, 
cheilosis, abdominal pain, dizziness, and ataxia. These symptoms have resolved quickly without 
apparent residual effects. The sponsor does not recommend specific treatment for an overdose. 
Management of overdose with tamibarotene should focus on monitoring target organ function to 
preserve their viability and prevent complications. 


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6.7.2 
Venetoclax 
Overdose of venetoclax should be managed as described in the product label (VENCLEXTA 
USPI, VENCLYXTO SmPC). For patients who experience overdose of venetoclax, closely 
monitor and provide appropriate supportive treatment; during ramp-up phase, interrupt 
venetoclax and monitor carefully for signs and symptoms of tumor lysis syndrome along with 
other toxicities. Based on venetoclax large volume of distribution and extensive protein binding, 
dialysis is unlikely to result in significant removal of venetoclax. There is no specific antidote for 
venetoclax.  
6.7.3 
Azacitidine 
Overdose of azacitidine should be managed as described in the product label (VIDAZA USPI, 
VIDAZA SmPC). One case of overdose with azacitidine was reported during clinical trials. A 
patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of 
approximately 290 mg/m2, almost 4 times the recommended starting dose. In the event of 
overdose, the patient should be monitored with appropriate peripheral blood count tests and 
should receive supportive treatment, as necessary. There is no known antidote for azacitidine 
overdose. 
6.8 
Concomitant Therapy 
Concomitant therapy must be documented as described in Section 8.2.1. 
6.8.1 
Cytotoxic or Investigational Therapy 
No concomitant cytotoxic or investigational therapy is allowed during the study.  
6.8.2 
Growth Factors 
G-CSF may be administered if clinically indicated for neutropenia. 
6.8.3 
Oral Hydroxyurea 
Concomitant hydroxyurea treatment is permitted during the study, as clinically determined. 
Treatment with hydroxyurea for greater than 7 consecutive days requires medical monitor 
approval. 
6.8.4 
Platelet Transfusions 
Administration of platelet transfusions may be utilized throughout the study, as clinically 
determined.  
6.8.5 
Red Blood Cell Transfusions 
Administration of red blood cell (RBC) transfusions may be utilized throughout the study, as 
clinically determined.  


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6.8.6 
 and 
P-gp Inhibitors 
Though the in vitro 
 metabolism of tamibarotene appears to be primarily due to 
, a clinical drug-drug interaction study with 
; 
Study SY-1425-102) in healthy adult study participants showed that there was no clinically 
significant change in tamibarotene plasma PK exposure when co-administered with itraconazole. 
These results demonstrate that 
 is not a major enzyme involved in the clearance of 
tamibarotene, and therefore, 
 should not have a clinically 
significant impact on tamibarotene PK exposure. 
6.8.7 
Antifibrinolytic 
Investigators should be advised of the potential for thrombosis observed when drugs similar to 
tamibarotene (e.g., ATRA/tretinoin) have been combined with an antifibrinolytic. 
Antifibrinolytic medicines should be used with caution while on study drug.  
6.8.8 
Retinoic Acid Syndrome 
Patients should be carefully monitored for the development of retinoic acid syndrome (RAS). 
High-dose dexamethasone (i.e., 10 mg/m2 intravenous twice daily), and supportive measures 
(e.g., diuretics, dialysis, mechanical ventilation) as needed, should be implemented at the earliest 
suspicion of RAS. Glucocorticoid therapy should continue until complete disappearance of 
symptoms and then tapered. Tamibarotene therapy should be temporarily discontinued until RAS 
is considered controlled and Grade ≤2.  
6.8.9 
Multivitamin and Supplements 
Vitamin A supplements (>10,000 IU/day) are not allowed while on study drug. 
6.8.10 
Antacids and Proton Pump Inhibitors 
Antacids, H2-receptor antagonists such as cimetidine, and proton pump inhibitors such as 
omeprazole should be used with caution while on study drug, as exposure to tamibarotene may 
be increased when these products are used concomitantly. Patients must be monitored for AEs, 
with dose adjustments for toxicity as described in Section 6.5. 
7 DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Drug Administration 
If the patient discontinues treatment or study participation prior to confirmation of screening 
RARA results and RARA-positivity is confirmed by Cycle 1 Day 8, the patient will be enrolled 
(Part 1)/randomized (Part 2), and the data from Cycle 1 Day 1 until the time of study 
discontinuation will be captured (including AEs and the reason for discontinuation of treatment). 
CCI
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Enrolled (Part 1)/randomized (Part 2) patients will continue to receive study drug until they meet 
one of the following criteria: 
• An unacceptable toxicity (AEs that would result in permanent discontinuation of study 
drug) 
• An AE related to study drug that requires ≥28 days (1 cycle) of dose interruption of all 
study drugs (i.e., tamibarotene, venetoclax, and azacitidine) 
• Failure to achieve a minimum response of PR following the completion of the Cycle 3 
EoC response assessment 
• Disease progression/relapse and not eligible for transition to Part 3 
• Decision to pursue post-remission therapy (such as HSCT) or an alternative anticancer 
therapy  
• Patient withdraws consent for further study drug (interventional therapy) administration. 
The site should clarify with the patient if they maintain consent to follow-up visits and 
calls after the end of study drug administration 
• Investigator determines it is in the best interest of the patient to discontinue study drug 
(interventional therapy) administration 
An EoT Visit should occur within 3 days of the last dose of study drug (or within 3 days of 
decision to permanently stop study drug treatment, if this decision directly follows a period when 
study drug has been on hold) and before the start of any subsequent anticancer therapy. A Safety 
Follow-up Visit should occur 30 days (±3 days) after the EoT Visit and before the start of any 
subsequent anticancer therapy. If the EoT Visit occurs ≥30 days after the last dose of study drug, 
it may be combined with the Safety Follow-up Visit. 
Patients will continue participation in all applicable follow-up assessments according to the SoAs 
(Section 1.3). 
7.2 
Discontinuation of Study Participation by Patient’s Withdrawal of 
Informed Consent 
• If a patient withdraws consent to study participation, study drug administration will be 
terminated and no additional follow-up will occur. Public sources may be searched for 
vital status information. 
• The sponsor may retain and use any data collected before withdrawal of consent for study 
participation. 
• If a patient withdraws his/her informed consent, he/she may request destruction of any 
samples taken and not yet tested, and the investigator must document this in the patient’s 
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7.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to comply with the 
protocol and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit schedule, 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
• Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
discontinued from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital status of the 
patient within legal and ethical boundaries for all patients randomized. Public sources 
may be searched for vital status information. If vital status is determined as deceased, this 
will be documented, and the patient will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
8 STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoAs (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
drug. 
• Adherence to the study design requirements, including those specified in the 
SoAs (Section 1.3), is essential and required for study conduct. 
• All pre-screening and screening evaluations must be completed by Cycle 1 Day 1 and all 
results reviewed by Cycle 1 Day 1, with the exception of RARA results, which must be 
reviewed by Cycle 1 Day 8. Minimal details of all patients screened will be captured to 
confirm eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) and obtained before signing of the informed consent form (ICF) may be utilized 


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for screening purposes, provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoAs (Section 1.3).  
• The maximum amount of blood collected from each patient over the duration of the study 
is specified in the ICF. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• For all enrolled (Part 1)/randomized (Part 2) patients, any untoward medical occurrences 
that happen before the first dose of venetoclax/azacitidine on Cycle 1 Day 1 should be 
captured as a part of medical history.  
8.1 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoAs (Section 1.3). 
Unscheduled efficacy assessments during the study will also be collected in the electronic data 
capture (EDC) system. 
8.1.1 
Response Assessment  
Responses are evaluated in alignment with ELN AML criteria (Döhner 2017) and Bloomfield 
2018 for CRh (Appendix 6). Additional unscheduled hematology evaluations may be performed 
prior to commencement of the next treatment cycle to reflect the best AML response achieved.  
In addition to on-treatment assessments, after the EoT visit, patients who have not 
progressed/relapsed will enter the Disease Follow-up period, during which response assessments 
will be performed for up to 3 years after discontinuation of study drug or until disease 
progression/relapse, whichever occurs first. Response assessments during Disease Follow-up 
visits where the bone marrow aspirates are not performed are based on hematology evaluation 
and physical examination findings. 
Patients who progress/relapse will enter Survival Follow-up and will be followed to document 
the start of subsequent anticancer therapy, the date of disease progression/relapse, and OS status 
for up to 3 years after discontinuation of study drug.  
8.1.2 
Bone Marrow Sample Collection 
A screening bone marrow aspirate will be performed, with samples collected for local 
assessment of blast count, cytogenetics, immunophenotype, and AML-associated gene 
mutations. An additional aspirate sample should be collected if possible and sent to the Central 
Laboratory for exploratory analyses. Bone marrow samples collected within 30 days of Cycle 1 
Day 1 as a part of SOC are acceptable and in that setting a marrow would not need to be repeated 
for the sole purpose of gathering the exploratory sample; however, collection of the exploratory 
sample is encouraged. Anonymized reports will be uploaded to the EDC. 
Part 1: The bone marrow aspirate samples for local assessment of response (blast count, 
cytogenetics, and assessment of minimal residual disease) will be collected at the EoC Visit of 


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Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), at the EoT Visit, and at every 
other visit during the Disease Follow-up period (every 6 months), with bone marrow aspirates 
collected at other times as clinically determined. If a patient achieves a CR/CRi at the Cycle 1 
EoC Visit, the Cycle 2 EoC bone marrow aspirate is not required. Anonymized reports will be 
uploaded to the EDC. At each bone marrow aspirate draw, an additional aspirate sample will be 
collected and sent to the Central Laboratory for exploratory analyses. 
Part 2 and Part 3: The bone marrow aspirate samples for local assessment of response (blast 
count, cytogenetics, and assessment of MRD) will be collected between Days 14 and 21 of 
Cycle 1, with venetoclax administration proceeding in alignment with ELN 2022 
recommendations (Döhner 2022). For those with blast clearance (<5% blasts) at that initial 
assessment, no Cycle 1 EoC bone marrow aspirate is required. For patients with ≥5% blasts at 
that initial assessment, Cycle 1 EoC bone marrow aspirate will be completed. Subsequent bone 
marrow aspirates for all patients will be collected at the EoC Visit of Cycles 2 and 3, followed by 
every third cycle (6, 9, 12, etc.); at the EoT Visit; and at every other visit during the Disease 
Follow-up period (every 6 months), with bone marrow aspirates collected at other times as 
clinically determined. If a patient achieves a CR/CRi within Cycle 1 response assessment(s), the 
Cycle 2 EoC bone marrow aspirate is not required. Anonymized reports will be uploaded to the 
EDC. At each bone marrow aspirate draw, an additional aspirate sample will be collected and 
sent to the Central Laboratory for exploratory analyses. 
Instructions for the collection and handling of the bone marrow samples will be provided 
separately in the Laboratory Manual. 
8.1.3 
Blood Product Transfusions 
For all enrolled (Part 1)/randomized (Part 2) patients, all RBC and platelet transfusions received 
by the patient from 8 weeks prior to Cycle 1 Day 1 through the Safety Follow-up period will be 
recorded. 
8.1.4 
Overall Survival 
All patients will be followed for OS every 3 months for up to 3 years after discontinuation of 
study drug. If the patient withdraws consent for study participation (Section 7.2) or is lost to 
follow-up (Section 7.3), public sources may be searched for vital status information. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoAs (Section 1.3). 
8.2.1 
Prior, Concomitant, and Subsequent Medication Review 
For all enrolled (Part 1)/randomized (Part 2) patients, every medication (including 
over-the-counter or prescription medicines, recreational drugs, vitamins, and/or herbal 
supplements), vaccine, and blood product used by the patient within 30 days of Cycle 1 Day 1 or 
at any time during the course of the study treatment, up to the Safety Follow-up Visit, must be 
documented, including:  


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• reason for use; 
• dates of administration, including start and end dates; 
• dosage information, including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Subsequent anticancer therapies (including HSCT) following EoT will be recorded. 
8.2.2 
ECOG Performance Status 
A copy of the ECOG Performance Status criteria is provided in Appendix 5. 
8.2.3 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems. 
• An abbreviated physical examination will include, at a minimum, assessments of the 
skin, lungs, Cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.4 
Vital Signs 
• Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements should be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the patient in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs should be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.  
8.2.5 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Fridericia formula should be used 
to calculate QTc. Three individual ECG tracings should be obtained as closely as possible in 
succession, but no more than 2 minutes apart. 
ECGs should be performed after an approximately 10-minute rest period. 


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8.2.6 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed. 
• The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
• Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the patient’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the investigator or medical monitor, 
or until the Safety Follow-up Visit, whichever is first. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified, and the sponsor 
should be notified. 
• All protocol-required local laboratory tests, as defined in Appendix 2, will be conducted 
in accordance with local laboratory practices. 
• If laboratory values from unscheduled laboratory tests performed at the institution’s local 
laboratory require a change in patient health management or are considered clinically 
significant by the investigator (e.g., SAE, AE, or dose modification), then the results 
must be recorded in the EDC as Unscheduled Labs. 
8.2.7 
Pregnancy Testing 
A pregnancy test (high-sensitivity urine or serum) must be performed for WOCBP at the time 
points listed in the SoAs (Section 1.3). 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy 
test is required. In such cases, the patient must be excluded from participation if the serum 
pregnancy result is positive. 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs; the method of recording, evaluating, and assessing causality of 
AEs and SAEs; and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative [LAR]). 


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
For all enrolled (Part 1)/randomized (Part 2) patients, AEs and SAEs will be captured from the 
time of the first dose of venetoclax/azacitidine on Cycle 1 Day 1 through the Safety Follow-up 
Visit. This will require collecting safety data for all treated patients from Cycle 1 Day 1 onward 
(until RARA status is confirmed) to enable timely reporting (SAEs) and capture in the eCRF 
(AEs) upon enrollment (Part 1)/randomization (Part 2). 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.  
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
the sponsor. 
Contact information for the Pharmacovigilance group is provided in Appendix 3. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient should be used to inquire about AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study drug under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 


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• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5 
Pregnancy 
• Details of all pregnancies in female patients and, if indicated, female partners of male 
patients will be collected after the start of study drug and until 90 days after the last dose 
of study drug. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
pregnancy notification form and submit it to the sponsor’s designee via email at 
SyrosPV@primevigilance.com or Fax #: 1-855-234-6419 within 24 hours of learning of 
the female patient’s or female partner’s of male patient (after obtaining the necessary 
signed informed consent from the female partner) pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The patient/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the patient/pregnant 
female partner and the infant and the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study drug 
by the investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study 
patients/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study drug(s). 
8.3.6 Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs 
8.3.6.1 
Disease Progression 
Progression of the underlying disease, including death from progression of the underlying 
disease, is considered an efficacy outcome parameter and should not be captured as an AE/SAE. 
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If a patient dies of their disease during the reporting period, progressive disease (PD) and/or PD 
with a fatal outcome does not need to be reported as an SAE. The applicable protocol electronic 
case report form (eCRF) page(s) pertaining to death (End of Treatment, End of Study, Death 
pages) should be completed per eCRF completion guidelines. 
8.3.6.2 
New Cancers 
The development of a new primary cancer in enrolled (Part 1)/randomized (Part 2) patients 
should be regarded as an AE and will generally meet at least one of the seriousness criteria 
(Section 10.3.2). New primary cancers are those that are not the primary reason for the 
administration of study drug and have developed after the patient has received at least 1 dose of 
study drug upon enrollment/randomization in the study. They do not include metastases of the 
original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
8.4 
Pharmacokinetics 
Samples will be collected from all patients in Part 1 and patients receiving triplet therapy in 
Part 2. Samples will be analyzed using a validated bioanalytical assay. 
• Whole blood samples will be collected for measurement of plasma concentrations of 
tamibarotene. 
• It is important that the actual date and time of each sample should be recorded.  
• If a PK sample is collected outside of the schedule specified for Part 1 in the SoA 
(Section 1.3), this will not qualify as a protocol deviation, as long as the exact date and 
times of PK sample and applicable dosing are recorded. 
• Unscheduled samples may be collected at additional time points during the study, if 
warranted (e.g., safety event evaluation) and agreed upon between the investigator and 
the sponsor.  
• Instructions for the collection and handling of the PK samples will be provided 
separately. 
8.5 
Genetics and Pharmacogenomics 
Germline genetics and pharmacogenomics are not evaluated in this study. 
8.6 
Biomarkers 
8.6.1 
RARA Biomarker Assessment 
This study will be evaluating the presence of a biomarker based on the expression levels of 
RARA messenger RNA in peripheral blood mononuclear cells. The biomarker will be assessed as 


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“RARA-positive” or “RARA-negative” based on an investigational assay, conducted at the 
Almac Diagnostics Laboratory. This investigational assay will also be used to explore potential 
changes in the RARA biomarker associated with treatment. 
8.6.2 
Companion Diagnostic Assay Development  
Blood samples will be used for development of companion diagnostic assays for the RARA 
biomarker. Samples with residual material following completion of companion diagnostic assay 
development may also be used for exploratory research to evaluate AML molecular features 
associated with response to drug treatment and loss of response to drug treatment (Section 8.6.3). 
8.6.3 
Molecular Markers of Tumor Response and Resistance  
Blood samples will be collected for exploratory research to evaluate AML molecular features 
associated with response to drug treatment and loss of response to drug treatment. Bone marrow 
aspirates (Section 8.1.2) may also be analyzed centrally for exploratory research to evaluate 
genetic mutations and/or gene expression markers associated with response and loss of response.  
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis for Part 2 
Null hypothesis (H0): In RARA-positive patients with previously untreated AML who are 
ineligible for standard induction therapy, the CR/CRi rate in the 
tamibarotene/venetoclax/azacitidine arm is the same as the CR/CRi rate in the 
venetoclax/azacitidine arm. 
Alternative hypothesis (H1): In RARA-positive patients with previously untreated AML who are 
ineligible for standard induction therapy, the CR/CRi rate in the 
tamibarotene/venetoclax/azacitidine arm is higher than the CR/CRi rate in the 
venetoclax/azacitidine arm. 
The level of significance for the analysis of the primary endpoint is 1-sided at 0.05. 
Adjustments for multiplicity will not be performed. 
9.2 
Sample Size Determination 
Up to approximately 
 patients will be treated in Part 1. The actual number of tamibarotene 
dose levels explored in combination with venetoclax/azacitidine, and the number of patients 
treated at each dose regimen, will vary depending on the totality of evaluated data (including 
safety, dose modifications, and tamibarotene PK data) from patients treated with the 
tamibarotene/venetoclax/azacitidine combination. With 
 patients treated, there is 
approximately 
% probability of observing at least 1 AE with an event rate of 
%. With 
 patients treated, there is approximately 
% probability of observing at least 1 AE with an 
event rate of 
%. 
CCI
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Approximately 
 patients will be randomized in Part 2, which provides approximately 
% power to detect a difference in CR/CRi rates between tamibarotene/venetoclax/azacitidine 
and venetoclax/azacitidine, with assumed CR/CRi rates of 
% versus 
% in the 2 groups, 
respectively, a 1:1 randomization, and a 1-sided alpha of 
.  
Part 3 of the study is exploratory in nature and the number of patients who will receive 
tamibarotene in addition to venetoclax/azacitidine will vary depending on the number of patients 
who experienced disease progression, relapse after initial CR or CRi response, or treatment 
failure when randomized and treated with venetoclax/azacitidine in Part 2.  
9.3 
Analysis Sets 
For the purposes of the analyses, the following analysis sets are defined: 
Part 2 Modified Intent-to-treat 
(mITT) Population 
All RARA-positive patients who are randomized in Part 2 starting treatment 
from Cycle 1 Day 1. Treatment groups for this analysis set will be 
determined according to the treatment assignment at the time of 
randomization.  
Part 1 Safety Population 
All enrolled RARA-positive patients who have received any amount of study 
drug (tamibarotene, venetoclax, or azacitidine) 
Part 2 Safety Population 
All randomized RARA-positive patients who have received any amount of 
study drug (tamibarotene, venetoclax, or azacitidine). Treatment groups for 
this population will be determined according to the actual treatment the 
patients received.  
Part 2 Per-protocol Population 
All patients in Part 2 mITT Population who are considered to be sufficiently 
compliant with the protocol. Specific criteria for this population will be 
defined in the statistical analysis plan.  
PK Evaluable Population 
All patients who are have received at least 1 dose of tamibarotene and have 
at least 1 quantifiable PK concentration comprise the PK evaluable analysis 
population.  
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and secondary endpoints. 
9.4.1 
General Considerations 
The level of significance for the analysis of the Part 2 primary endpoint is 1-sided at 5%. All 
secondary and exploratory endpoints for Part 1 and Part 2 will be tested using a 2-sided, 
5% significance level. Two (2)-sided 95% CIs will be reported for all endpoints/analyses, when 
appropriate, unless otherwise specified. 
Frequency distributions will be used for categorical variables and appropriate summary statistics 
(i.e., mean, median, and range) for quantitative/continuous variables.  
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Additional details of the analyses will be provided in the SAP.  
9.4.2 
Primary Endpoint 
Part 1 
The number and percentage of patients with AEs, including AEs leading to dose modifications or 
discontinuations, and SAEs will be summarized. Laboratory values and changes in values from 
baseline will be summarized descriptively by visit, and shift tables will be provided showing 
changes in NCI CTCAE (version 5) grade from baseline to worst grade postbaseline. Descriptive 
summaries will be provided for ECG and vital sign values, changes in values from baseline, and 
categorical summaries. The number and percentage of patients with dose modifications will be 
summarized. 
Part 2  
Patients will be assessed for the primary endpoint of CR/CRi from the time of Cycle 1 Day 1 
until the initiation of non-study drug therapy or until time of disease progression/relapse. CR/CRi 
rate and 95% exact binomial CIs will be calculated by treatment group in the mITT Population. 
Patients who do not have a post-baseline response assessment will be considered non-responders 
and included in the denominator when calculating the response rate analysis. In addition, patients 
who do not achieve a response and 1) die, 2) have a transplant, 3) experience prolonged 
treatment interruption requiring permanent withdrawal of study drug, and/or 4) start a new 
systemic therapy will also be considered non-responders. The Fisher’s exact test will be applied 
to compare the CR/CRi rates between the 2 treatment groups. The analysis of the CR/CRi rate is 
planned for the time when the last patient has completed the Cycle 3 EoC response assessment or 
discontinued treatment earlier. 
9.4.3 
Secondary Endpoints 
Part 1 
The estimated ORR will be provided with corresponding 95% exact binomial CIs. Patients who 
do not have a post-baseline response assessment will be considered non-responders and will be 
included in the denominator. 
Part 2 
The number and percentage of patients with AEs, including AEs leading to dose modifications or 
discontinuations, and SAEs will be summarized. Laboratory values and changes in values from 
baseline will be summarized descriptively by visit, and shift tables will be provided showing 
changes in NCI CTCAE (version 5) grade from baseline to worst grade postbaseline. Descriptive 
summaries will be provided for ECG and vital sign values, changes in values from baseline, and 
categorical summaries. The number and percentage of patients with dose modifications will be 
summarized. 


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Table 7: 
Estimands 
Objective 
Estimand 
Category  
Estimand 
Variable 
Analysis Set  Intercurrent Event Strategy 
Population Level 
Summary Measure 
Primary Objective:  
To demonstrate the superiority of 
tamibarotene/venetoclax/azacitidine 
compared to venetoclax/azacitidine 
in CR/CRi in newly diagnosed 
RARA-positive AML patients 
Primary 
CR/CRi 
mITT 
• 
New anti-cancer therapy: while on 
treatment 
• 
Treatment discontinuation: treatment 
policy 
CR/CRi percentage by 
treatment arm 
Supplementary 
CR/CRi 
PP 
• 
New anti-cancer therapy: while on 
treatment 
• 
Treatment discontinuation: treatment 
policy 
CR/CRi percentage by 
treatment arm 
Abbreviations: AML = acute myeloid leukemia; CR = complete remission; CRi = CR with incomplete blood count recovery; mITT = modified intent-to-treat; 
PP = per protocol; RARA = retinoic acid receptor alpha. 


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The difference in CR/CRi rate between the 2 treatment groups and corresponding 95% CIs will 
be calculated. 
CR rate and 95% exact binomial CIs will be calculated by treatment group. Patients who do not 
have any post-baseline response assessment will be considered as non-responders and will be 
included in the denominator. The Fisher’s exact test will be applied to compare the CR rates 
between the 2 treatment groups.  
CR/CRh rate and 95% exact binomial CIs will be calculated by treatment group. Patients who do 
not have any post-baseline response assessment will be considered as non-responders and will be 
included in the denominator. The Fisher’s exact test will be applied to compare the CR/CRh rates 
between the 2 treatment groups.  
Kaplan-Meier estimation of median duration of CR, median duration of CR/CRi, and median 
duration of CR/CRh and respective 95% CIs will be presented by treatment group. 
Time to CR, time to CR/CRi, and time to CR/CRh will be summarized descriptively for the 
2 treatment groups. 
ORR rate and 95% exact binomial CIs will be calculated by treatment group. Patients who do not 
have a post-baseline response assessment will be considered as non-responders and will be 
included in the denominator. The Fisher’s exact test will be applied to compare the ORR rates 
between the 2 treatment groups. 
9.4.4 
Exploratory Endpoints 
Concentration-time data for tamibarotene will be included in the Clinical Study Report as 
listings; no formal non-compartmental analysis will be performed. 
Analyses of the other exploratory endpoints will be described in the SAP. 
9.5 
Interim Analysis 
An interim futility analysis of the CR/CRi rates is planned in Part 2 for the first 40 treated 
RARA-positive patients and will be performed after the 40th randomized patient has received 
approximately 3 months of study drug or has discontinued treatment due to disease progression, 
withdrawal of consent, or death. The study may be terminated at this interim analysis for futility 
if the 1-sided p-value from the Fisher’s exact test comparing the CR/CRi rates 
(tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine) is >0.428. The non-binding 
futility bound is derived using an HSD spending function with gamma = ‑2 (Hwang 1990).  
Administrative interim analyses may be performed after approximately 25%, 50%, and 75% (20, 
40, and 60) patients have had 3 cycles of treatment. No multiplicity adjustments are needed since 
the study will not be stopped for efficacy until the primary analysis. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the currently approved protocol and any 
other study agreements and the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines 
− (EU) No 536/2014 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to patients.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to the safety and welfare of patients. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study and adherence to all applicable 
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10.1.2 
Informed Consent Process 
• A Pre-screening ICF and a Main ICF will be used in this study, as shown in the SoAs 
(Section 1.3). Patients who begin Cycle 1 Day 1 prior to enrollment 
(Part 1)/randomization (Part 2) must use the Main ICF. 
• The investigator or his/her representative will explain the nature of the study to the 
patient/LAR and answer all questions regarding the study. 
• Patients must be informed that their participation is voluntary. Patients/LARs will be 
required to sign an IRB/IEC-approved ICF that meets the requirements of 21 CFR 50 and 
56, local regulations, ICH guidelines, and Health Insurance Portability and 
Accountability Act requirements, where applicable. 
• The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF(s). 
• Patients must be re-consented to the most current IRB/IEC-approved version of the 
ICF(s) during their participation in the study. 
• A copy of the ICF(s) must be provided to the patient/LAR. 
10.1.3 
Confidentiality and Data Protection 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Syros. However, authorized regulatory officials, IRB/IEC personnel, and Syros 
and its authorized representatives are allowed full access to the records. 
• Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient names 
or any information that would make the patient identifiable will not be transferred. 
• The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient, who will be required to give consent for their data to be used as 
described in the informed consent. 
• The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 


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10.1.4 
Committees Structure 
10.1.4.1 
Independent Data Monitoring Committee 
There will be no formal IDMC. The sponsor will provide oversight of safety and tolerability at 
regularly scheduled intervals (and ad hoc if needed) via SRT meetings as detailed in the SRT 
Charter. In addition, regularly scheduled reviews of safety and tolerability will be performed by 
the sponsor in collaboration with the study investigators in Part 1 of the study. These reviews 
will inform the dose of tamibarotene to be combined with venetoclax/azacitidine in Part 2 of the 
study. Administrative interim analyses will be performed by the sponsor personnel or designee. 
10.1.5 
Dissemination of Clinical Study Data 
Dissemination of the clinical study data will occur in alignment with Syros policies and any 
applicable local regulations.  
10.1.6 
Data Quality Assurance 
• All patient data relating to the study will be recorded/uploaded in eCRFs via EDC. The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the eCRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The site shall retain all study documentation and any other documents required to be 
retained by applicable law for the longer of (i) 2 years after the marketing authorization 
approval or termination of the program or (ii) such longer period as required by 
applicable law. After the end of such period, if the site desires to destroy any study 
documentation or such other documents, the site shall notify the sponsor of such desire 
and the sponsor shall have 30 days after receipt of such notice to, at its option, either take 
custody of any study documentation or other documents the site proposes to destroy or 
allow the site to destroy such study documentation or other documents. 
10.1.7 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, based on what is required in 
the SoA. Also, current medical records must be available for monitoring. 


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• The source records are typically the patient’s medical chart and other sources, such as 
tamibarotene dosing diary. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable 
compared to the source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted as outlined in Section 10.1.1. 
10.1.8 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first patient pre-screened. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion at that site. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• For study termination: 
− Discontinuation of further study drug development 
• For site termination: 
− Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
− Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients 
by the investigator 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigators shall promptly inform the patients and should assure 
appropriate patient therapy and/or follow-up. 


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10.1.9 
Publication Policy 
The sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. The publication 
of study results will be governed by the applicable clinical trial agreement between the sponsor 
and the study site and investigator (as applicable). 
10.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in the table below will be performed by the local laboratory as 
specified in the SoAs (Section 1.3) and Section 8.2.6. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 


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Protocol-Required Safety Laboratory Tests 
Lab Tests 
Parameters 
Hematology 
Platelet Count  
Hemoglobin 
White blood cell (WBC) (leukocyte count 
including differential): 
Neutrophils (absolute neutrophil count, 
calculated from the leukocyte count and WBC 
differential count) 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
% Blasts 
Clinical 
Chemistry 
Blood urea nitrogen/urea 
Creatinine 
Bicarbonate (CO2) 
Uric acid 
Albumin 
Sodium 
Phosphorus 
Triglycerides 
Total cholesterol 
Magnesium  
Calcium 
Potassium 
Chloride 
Glucose  
Amylase 
Lipase 
Total protein 
Alkaline phosphatase 
Lactate dehydrogenase 
Total and direct bilirubin  
Aspartate aminotransferase/serum 
glutamic-oxaloacetic transaminase 
Alanine aminotransferase/serum 
glutamic-pyruvic transaminase  
Coagulation 
International normalized ratio or prothrombin 
time  
Activated partial thromboplastin time/ 
partial thromboplastin time  
Routine 
Urinalysis 
• Specific gravity 
• pH, protein, red and white blood cells, leukocyte esterase, ketones, and nitrite  
Pregnancy testing 
• Highly sensitive serum or urine human chorionic gonadotropin pregnancy test (as needed 
for women of childbearing potential)a 
Other Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing 
potential only) 
NOTES: 
a 
Local high-sensitivity urine pregnancy testing will be standard for the protocol unless serum testing is 
required by local regulation or Institutional Review Board/Independent Ethics Committee. 
 
 


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10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study patient, temporally 
associated with the use of study drug, whether or not considered related to the study 
drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug whether or not related to the study drug. An AE 
can arise from any use of the study drug, and from any route of administration, 
formulation, or dose, including an overdose. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease). 
• Medical conditions present prior to the first dose of study drug that are being treated at 
baseline will be captured as medical history unless the frequency, severity, or character 
of the condition worsens during the study (after the first dose of any study drug), for 
which the condition would then be captured as an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 


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10.3.2 
Definition of SAE 
An SAE is defined as any serious AE that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. Similarly, any planned hospitalization, such as 
for blood sampling for PK assessments, is not considered an AE or criterion for 
seriousness. Note: Complications that occur during hospitalization are AEs and if a 
complication prolongs hospitalization, then the event is serious. 
d. Results in persistent or significant disability/incapacity 
e. 
Is a congenital anomaly/birth defect 
f. 
Other important medical events: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as important medical 
events that may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  
• Examples of such events include intensive treatment for allergic bronchospasm, blood 
dyscrasias, convulsions, or development of drug dependency or drug abuse. 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 


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• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the Pharmacovigilance group in lieu of completion of the SAE required 
form. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Severity 
The investigator will make an assessment of severity (Grades 1 through 5) for each AE and 
SAE reported during the study using NCI CTCAE, version 5.  
Note: It is important to distinguish between SAEs and severe AEs. Severity is a measure of 
intensity, whereas seriousness is classified by the criteria based on the regulatory definitions as 
described in Section 10.3.2. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
• Related assessment is reported when a “reasonable possibility” of a relationship 
between study drug administration and AE exists. “Reasonable possibility” conveys 
that there are facts, evidence, and/or arguments to suggest a causal relationship, rather 
than a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration, 
will be considered and investigated. 
• The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Pharmacovigilance group. 
However, it is very important that the investigator always makes an assessment of 
causality for every event before the initial transmission of the SAE data to the 
Pharmacovigilance group. It is helpful if the investigator includes the rationale for the 
assessment as being causally related, or not causally related, in the transmission of the 
SAE data.  


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• The investigator may change his/her opinion of causality based upon follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a patient dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Pharmacovigilance group with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor’s designee via email 
at SyrosPV@primevigilance.com or Fax #: 1-855-234-6419 within 24 hours of receipt 
of the information. The investigator may also be asked by the sponsor to provide 
clarification or additional information. 
10.3.4 
Reporting of SAEs 
SAE Reporting to Pharmacovigilance Group 
• An SAE Report form will be completed and submitted to the sponsor’s designee via 
email at SyrosPV@primevigilance.com or Fax #: 1-855-234-6419 within 24 hours of 
the investigator’s first knowledge of the event, even if the experience does not appear 
to be related to study drug. 
• The initial SAE Report form must be as complete as possible, including details of the 
current illness and SAE and an assessment of the relationship between the event and 
the study drug. Additional information relating to a previously reported SAE must also 
be reported within 24 hours of the investigator’s first knowledge of information. The 
investigator may also be asked by the sponsor to provide clarification or additional 
information. 
• If the investigator becomes aware of an SAE considered related to study drug by the 
investigator occurring more than 30 days after the last dose of study drug, the SAE 
must be reported as described above. 


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10.3.5 
Reporting of Serious Adverse Events to Regulatory Authorities, Ethics 
Committees, and Institutional Review Board 
The sponsor will determine the expectedness for each reported SAE based on the appropriate 
reference safety information per local requirements. The sponsor or designee shall notify 
regulatory authorities of serious, unexpected, and related AEs or other AEs per local 
requirements. The sponsor or designee shall notify the investigator of serious, related, and 
unexpected AE(s) per local country requirements. 
The investigator will notify the appropriate IRB/IEC of serious, related, and unexpected 
AE(s), or significant risks to patients, per local country requirements. The investigator must 
keep records of all AE information on file, including correspondence with the sponsor and 
IRBs/IECs. 
 
 


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10.4 Appendix 4: Contraceptive and Barrier Guidance 
Contraceptive use by men and women should be consistent with description below or with local 
requirements (as defined in local informed ICF) for those participating in clinical studies. 
Tamibarotene has been reported to cause abnormalities in spermatogenesis in nonclinical studies 
in rats and dogs. Patients who are fertile must agree to use 2 methods of birth control including a 
barrier method (e.g., latex condom, diaphragm, or cervical cap) combined with an intrauterine 
device (IUD) or birth control pills while taking tamibarotene. Contraception use must be 
continued for at least 90 days after the last dose of study drug for men and 6 months for women. 
Men/women should not donate sperm or ova during this timeframe. Male patients should 
consider banking sperm before tamibarotene is administered. 
10.4.1 
Definitions 
Woman of Childbearing Potential 
Women in the following categories are considered to be of childbearing potential (fertile): 
1. Following menarche. 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below). 
a. A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
i. A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than 1 FSH measurement is 
required.  
ii. Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before Cycle 1 Day 1. 
b. Permanent sterilization methods (for the purpose of this study) include: 
i. Documented hysterectomy 
ii. Documented bilateral salpingectomy 
iii. Documented bilateral oophorectomy 


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iv. For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
c. If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of study drug, additional evaluation 
should be considered. 
Woman of Nonchildbearing Potential 
Women in the following categories are considered NOT to be of childbearing potential: 
1. Premenopausal female with permanent infertility due to one of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
2. Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
 A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than 1 FSH measurement is required. 
 Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before Cycle 1 Day 1. 


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10.4.2 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing systemc 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male patient can come from the site personnel’s review of the 
patient’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
− 
oral 
− 
intravaginal 
− 
transdermal 
− 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− 
oral 
− 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the patient. 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which 
inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study. 
Male condom and female condom should not be used together (due to risk of failure from friction). 


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10.5 Appendix 5: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
As published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
 
 


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10.6 Appendix 6: Response Criteria for AML 
Responses are evaluated as summarized below, in alignment with ELN AML criteria 
(Döhner 2017) and Bloomfield 2018 for CRh. 
Response Category  
Definition  
 
ANC 
(/µL) 
Platelets 
(/µL) 
Bone 
Marrow 
Blasts (%) 
Comment 
CR without MRD 
(CRMRD-) 
≥1,000  
≥100,000  
<5 
All CR criteria met and absence of MRD as 
accessed by multiparameter flow cytometry, 
qPCR, or next generation sequencing 
Complete Remission 
(CR)  
≥1,000  
≥100,000  
<5 
Absence of circulating blasts and blasts with 
Auer rods; absence of EMD 
CR with incomplete 
hematologic recovery 
(CRi) 
<1,000  
-or  
<100,000  
 
<5 
All CR criteria met except either neutrophils 
or platelets not recovered 
CR with partial 
hematologic recovery 
(CRh) 
>500 
>50,000 
<5 
All CR criteria met except ANC and platelets 
with partial recovery of peripheral counts 
Morphologic leukemia-
free state (MLFS) 
NA 
NA 
<5 
Absence of blasts with Auer rods and <5% 
blasts in marrow sample with a count of at 
least 200 nucleated cells or cellularity ≥10%. 
Absence of EMD. No hematologic criteria 
required. 
Partial Remission (PR) 
≥1,000  
≥100,000   
≥50% decrease from baseline, with decrease 
to 5-25  
 
Stable disease 
Absence of CR, MLFS, PR; and criteria for PD not met 
Progressive disease 
(PD) 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute 
blast counts in the blood:  
• >50% increase in marrow blasts over baseline (a minimum 15% point increase is 
required in cases with <30% blasts at baseline; or persistent marrow blast percentage 
of >70% over at least 3 months; without at least a 100% improvement in ANC to 
>500 and/or platelet count to >50,000 non-transfused); or  
• >50% increase in peripheral blasts (WBC x % blasts) to >25,000 µL (in the absence 
of differentiation syndrome a); or  
• New extramedullary disease  
Treatment failure 
Failure to achieve blast count of <5% following at least 2 cycles of therapy, as 
determined by the investigator. 
Relapse 
Bone marrow blasts ≥5%; or reappearance of blasts in blood; or development of 
EMD. If studied pre-treatment, reoccurrence of MRD. 
Abbreviations: ANC = absolute neutrophil count; EMD = extramedullary disease; MRD = minimal residual disease; 
qPCR = quantitative polymerase chain reaction; WBC = white blood cell. 
a 
Differentiation syndrome, i.e., a transient increase in the percentage of bone marrow blasts and an absolute 
increase in blood blasts, may be observed with targeted therapies; in this setting, an increase in blasts may not 
necessarily indicate progressive disease. 
 
 


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10.7 Appendix 7: Abbreviations and Definitions 
Abbreviation 
Definition 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia  
ANC 
Absolute neutrophil count 
APL 
Acute promyelocytic leukemia 
ART 
Anti-retroviral therapy 
AST 
Aspartate aminotransferase 
ATRA 
All-trans retinoic acid  
BID 
Twice daily 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CR 
Complete remission 
CRh 
CR with partial hematologic recovery 
CRi 
CR with incomplete blood count recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI 
Drug-drug interaction 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EF 
Ejection fraction 
ELN 
European LeukemiaNet 
EoC 
End of Cycle 
EoT 
End of Treatment  
EU 
European Union 
FEV1 
Forced expiratory volume in one second 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
G-CSF 
Granulocyte colony stimulating growth factor 
HCV 
Hepatitis C virus 


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Abbreviation 
Definition 
HIV 
Human immunodeficiency virus  
HMA 
Hypomethylating agent 
HRT 
Hormonal replacement therapy 
HSCT 
Hematopoietic stem cell transplantation 
HSD 
Hwang-Shih-DeCani 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LAR 
Legally authorized representative 
mITT 
Modified intent-to-treat 
MLFS 
Morphologically leukemia-free state 
NCI 
National Cancer Institute 
ND 
Newly diagnosed 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PK 
Pharmacokinetic 
QTcF 
QTc interval calculated using Fridericia formula 
RARα 
Retinoic acid receptor alpha 
RAS 
Retinoic acid syndrome 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
R/R 
Relapsed/refractory 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SOC 
Standard of care 
SRT 
Safety Review Team 
ULN 
Upper limit of normal 
US 
United States 


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Abbreviation 
Definition 
USPI 
United States Prescribing Information 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential  


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11 REFERENCES 
AMNOLAKE (Tamibarotene) [Package Insert]. Tokyo, Japan: Toko Pharmaceutical Industrial 
Co. Ltd. 2005. 
Bloomfield CD, Estey E, Pleyer L, Schuh AC, Stein EM, Tallman MS, Wei A. Time to repeal 
and replace response criteria for acute myeloid leukemia? Blood Rev. 2018 Sep;32(5):416-425.  
de Botton S, Cluzeau T, Vigil CE, et al. SY-1425, a potent and selective RARα agonist, in 
combination with azacitidine demonstrates high response rates and a rapid onset of response in 
RARA-positive newly diagnosed unfit acute myeloid leukemia. Abstract 112. American Society 
of Hematology. 5-8 December 2020. 
Campos EDV, Pinto R. Targeted therapy with a selective BCL-2 inhibitor in older patients with 
acute myeloid leukemia. Hematol Transfus Cell Ther. 2019;41(2):169-177. 
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated 
Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129(4):424-447.  
Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 
recommendations from an international expert panel on behalf of the ELN. Blood. 
2022;140(12):1345-1377.  
Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J 
Hematol. 2018;93(10):1267-1291. 
Ferrara F, Barosi G, Venditti A, et al. Consensus-based definition of unfitness to intensive and 
non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO 
group on a new tool for therapy decision making. Leukemia. 2013;27(5):997-999. 
Fiore C, Kelly M, Volkert A, et al. Selection of RARA-Positive Newly Diagnosed Unfit AML 
Patients with Elevated RARA Gene Expression Enriches for Features Associated with Primary 
Resistance to Venetoclax and Clinical Response to SY-1425, a Potent and Selective RAR 
Agonist, Plus Azacitidine. Abstract 2862. American Society of Hematology. 5-8 December 2020. 
Hwang IK, Shih WJ, DeCani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990; 9(12):1439-45. 
Knight T, Edwards H, Taub JW, Ge Y. Evaluating venetoclax and its potential in treatment-naïve 
acute myeloid leukemia. Cancer Manag Res. 2019;11:3197-3213. 
Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to 
the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375-88. 


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Kuusanmäki H, Leppä AM, Pölönen P, et al. Phenotype-based drug screening reveals association 
between venetoclax response and differentiation stage in acute myeloid leukemia. 
Haematologica. 2020;105(3):708-720.  
Maiti A, Konopleva MY. How We Incorporate Venetoclax in Treatment Regimens for Acute 
Myeloid Leukemia. Cancer J. 2022;28(1):2-13. 
Maiti A, Rausch CR, Cortes JE, et al. Outcomes of relapsed or refractory acute myeloid 
leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 
2020;252569. 
McKeown MR, Corces MR, Eaton ML, et al. Superenhancer Analysis Defines Novel 
Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by 
SY-1425, a Potent and Selective RARα Agonist. Cancer Discov. 2017 Oct;7(10):1136-1153. 
Pei S, Pollyea DA, Gustafson A, et al. Monocytic Subclones Confer Resistance to Venetoclax-
Based Therapy in Patients with Acute Myeloid Leukemia. Cancer Discov. 2020;10(4):536-551.  
Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: 
Recent progress and enduring challenges. Blood Rev. 2019;36:70-87. 
Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 
protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia 
cells. Ann Hematol. 2012;91(12):1861-70. 
VIDAZA (azacitidine) Summary of Product Characteristics. Celgene Europe B.V. 2021. 
Available from: https://www.ema.europa.eu/en/documents/product-information/vidaza-epar-
product-information_en.pdf. Accessed 23 June 2021. 
VIDAZA (azacitidine) US Prescribing Information. Celgene Corporation. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/050794s032lbl.pdf.  
VENCLEXTA (venetoclax) US Prescribing Information. AbbVie Inc. 2020. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208573s023lbl.pdf 
VENCLYXTO (venetoclax) Summary of Product Characteristics. AbbVie Deutschland GmbH 
Co. KG. Available from: https://www.ema.europa.eu/en/documents/product-
information/venclyxto-epar-product-information_en.pdf. Accessed 23 June 2021. 
Wang YW, Tsai CH, Lin CC, et al. Cytogenetics and mutations could predict outcome in 
relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax. 
Ann Hematol. 2020;99(3):501-511. 
Zhang H, Wilmot B, Bottomly D, et al. Biomarkers Predicting Venetoclax Sensitivity and 
Strategies for Venetoclax Combination Treatment. Blood. 2018;132(Supplement 1):175. 

SAP_001.pdf: 
Syros Pharmaceuticals, Inc. 
Statistical Analysis Plan
SY-1425-202 
Version 4.0
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Page 1 of 60 
STATISTICAL ANALYSIS PLAN 
Syros Pharmaceuticals, Inc. 
SY-1425-202 
Protocol Title: 
Tamibarotene in Combination with Venetoclax and Azacitidine 
in Previously Untreated Adult Patients Selected for RARA-
positive AML Who Are Ineligible for Standard Induction 
Therapy 
Protocol Version 
and Date: 
Version 5.0; 16 November 2022 
Sponsor: 
Syros Pharmaceuticals, Inc. 
35 CambridgePark Drive, 4th Floor 
Cambridge, MA 02140 
USA 
Prepared By: 
 
Document Version 
and Date: 
Version 4.0; 18 March 2024 
NCT04905407
PPD


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Statistical Analysis Plan
SY-1425-202 
 
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1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Syros Pharmaceuticals, Inc. 
Clinical Protocol Number: SY-1425-202 
Protocol Title: 
Tamibarotene in Combination with Venetoclax and 
Azacitidine in Previously Untreated Adult Patients 
Selected for RARA-positive AML Who Are Ineligible 
for Standard Induction Therapy 
Document File Name: 
SY-1425-202_SAP_V4.0_18MAR2024 
Document Version and 
Effective Date: 
Version 4.0; 18 March 2024 
Approved By: 
 
 
  
  
Syros Pharmaceuticals, Inc. 
 Date 
 
  
 
Syros Pharmaceuticals, Inc. 
 Date 
PPD
PPD


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Syros Pharmaceuticals, Inc. 
 Date 
PPD


Syros Pharmaceuticals, Inc. 
Statistical Analysis Plan
SY-1425-202 
 
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2 TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................4 
3 
List of Abbreviations ..................................................................................................6 
4 
Introduction.................................................................................................................7 
5 
Study Objectives .........................................................................................................8 
5.1 
Primary Study Objectives .....................................................................................8 
5.2 
Secondary Study Objectives..................................................................................8 
5.3 
Exploratory Study Objectives ...............................................................................9 
6 
Investigational Plan ..................................................................................................10 
6.1 
Overall Study Design ...........................................................................................10 
6.2 
Schedule of Assessments ......................................................................................15 
6.3 
Treatments ............................................................................................................15 
6.3.1 
Treatments Administered .............................................................................15 
6.3.2 
Method of Assigning Participants to Treatment Groups ...........................17 
6.4 
Efficacy and Safety Endpoints ............................................................................18 
6.4.1 
Efficacy Endpoints .........................................................................................18 
6.4.2 
Safety Endpoints ............................................................................................24 
6.4.3 
Pharmacokinetic Endpoints ..........................................................................26 
7 
Statistical Methods ....................................................................................................26 
7.1 
General Methodology ..........................................................................................26 
7.1.1 
Reporting Conventions ..................................................................................27 
7.1.2 
Summarization by Visit .................................................................................28 
7.1.3 
Data Handling Rules ......................................................................................28 
7.1.4 
Standard Calculations ...................................................................................32 
7.2 
Analysis Populations ............................................................................................32 
7.3 
Study Participants ................................................................................................34 
7.3.1 
Disposition of Participants ............................................................................34 
7.3.2 
Protocol Deviations ........................................................................................35 
7.3.3 
Demographic and Baseline Characteristics .................................................36 
7.3.4 
AML Disease History .....................................................................................36 
7.3.5 
Medical History ..............................................................................................37 
7.3.6 
Prior and Post-treatment Cancer Therapies ...............................................37 
7.3.7 
Prior and Concomitant Medications ............................................................38 
7.3.8 
Prior and Concomitant Blood Transfusions................................................38 
7.3.9 
Other Therapies, Treatments, and Procedures ...........................................39 
7.3.10 
Extent of Study Drug Exposure ....................................................................39 
7.4 
Efficacy Evaluation ..............................................................................................40 
7.4.1 
Datasets Analyzed ..........................................................................................40 
7.4.2 
Primary Efficacy Endpoint Analysis Methods ............................................41 
7.4.3 
Secondary Efficacy Endpoint Analysis Methods ........................................41 
7.4.4 
Exploratory Efficacy Endpoint Analysis Methods .....................................44 
7.4.5 
Statistical/Analytical Issues ...........................................................................47 
7.5 
Pharmacokinetic Evaluation ...............................................................................49 


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7.6 
Safety Evaluation .................................................................................................49 
7.6.1 
Adverse Events ...............................................................................................49 
7.6.2 
Clinical Laboratory Evaluation ....................................................................53 
7.6.3 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety ...............................................................................................................55 
7.7 
Determination of Sample Size .............................................................................56 
7.8 
Changes in the Conduct of the Study or Planned Analyses .............................57 
8 
Amendment History .................................................................................................57 
9 
Reference List ............................................................................................................60 
 
TABLE OF TABLES 
Table 1 
List of Abbreviations .................................................................................6 
Table 2 
Study Treatments .....................................................................................15 
Table 3 
Venetoclax Dosing ....................................................................................17 
Table 4 
Estimands..................................................................................................19 
Table 5 
Response Criteria for AML ....................................................................23 
Table 6 
Protocol-Required Safety Laboratory Tests .........................................25 
Table 7 
Date Imputation Rules for AEs ..............................................................29 
Table 8 
Date Imputation Rules for Medical History/Prior and Concomitant 
Medications/Prior Cancer Therapy .......................................................30 
Table 9 
Assignments for Event and Censoring Dates for Duration of CR 
Analysis .....................................................................................................42 
Table 10 
Assignments for Primary and Alternative Event and Censoring Dates 
for EFS Analysis .......................................................................................44 
Table 11 
Search Strategy for Selected TEAE Groups .........................................49 
Table 12 
Vital Signs ACC/AHA Blood Pressure Categories ...............................55 
Table 13 
CTCAE Grading Criteria for Temperature ..........................................55 
 
TABLE OF FIGURES 
Figure 1 
Study Design .............................................................................................15 
 


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3 LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
ATC 
Anatomical Therapeutic Chemical 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
CMQ 
Custom MedDRA Query 
CO2 
bicarbonate 
CR 
complete remission 
CRh 
CR with partial hematologic recovery 
CRi 
CR with incomplete blood count recovery 
CSR 
clinical study report 
DS 
Differentiation syndrome 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EFS 
event-free survival 
ELN 
European LeukemiaNet 
EMD 
extramedullary disease 
EoC 
End of Cycle 
EoT 
End of Treatment 
FAB 
French-American-British 
G-CSF 
granulocyte colony stimulating growth factor 
HLT 
High Level Term 
HSCT 
hematopoietic stem cell transplantation 
HSD 
Hwang-Shi-DeCani 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MLFS 
morphologically leukemia-free state 
MPN 
myeloproliferative neoplasm 
MRD 
minimal residual disease 


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Abbreviation 
Definition  
NCI 
National Cancer Institute 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PP 
Per Protocol 
PR 
partial remission 
PT 
preferred term 
Q1 
25th percentile 
Q3 
75th percentile 
qPCR 
quantitative polymerase chain reaction 
RARA 
retinoic acid receptor alpha 
RBC 
red blood cell 
RE 
Response evaluable 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
Système International 
SMQ 
Standardized MedDRA Query 
SOC 
system organ class/standard of care 
TEAE 
treatment-emergent adverse event 
TI 
transfusion independence 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for Syros 
Pharmaceuticals, Inc.’s Protocol SY-1425-202 (Tamibarotene in Combination with 
Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for 
RARA-positive AML Who Are Ineligible for Standard Induction Therapy). Descriptions 
of planned analyses are provided in order to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. The statistical methods applied in the design and 
planned analyses of this study are consistent with the International Council for 
Harmonisation (ICH) guideline Statistical Principles for Clinical Trials (E9) (1998).  


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This SAP will be finalized prior to data analysis and database lock to provide full details 
to be presented in the clinical study report (CSR). Any changes between the statistical 
methods provided in the clinical study protocol and this SAP will be explained herein; 
any changes or deviations from this SAP relative to the final analysis will be fully 
documented in the CSR. Minor changes or deviations from the templates for tables, 
figures, and listings need not be documented in the CSR. In this SAP, patients will 
hereafter be referred to as participants, with the exception of the study objectives. The 
interim CSR will use a subset of the analyses specified in this SAP. 
5 STUDY OBJECTIVES 
5.1 
Primary Study Objectives 
Part 1 
The primary objective of Part 1 is to characterize the safety and tolerability of 
tamibarotene/venetoclax/azacitidine combination in retinoic acid receptor alpha (RARA)-
positive, previously untreated acute myeloid leukemia (AML) patients to inform Part 2 
dose and regimen of the tamibarotene/venetoclax/azacitidine therapy. 
Part 2 
The primary objective of Part 2 is to characterize and compare the complete 
remission/complete remission with incomplete hematologic recovery (CR/CRi) rate of 
tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine. 
5.2 
Secondary Study Objectives 
Part 1 
The secondary objectives of Part 1 are to 
• characterize the overall response rate (ORR) of 
tamibarotene/venetoclax/azacitidine combination and 
• characterize the pharmacokinetics (PK) of tamibarotene when administered as a 
part of tamibarotene/venetoclax/azacitidine therapy. 
Part 2 
The secondary objectives of Part 2 are to 
• characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine 
versus venetoclax/azacitidine in RARA-positive, previously untreated AML 
patients, 
• characterize and compare CR rate and CR/CR with partial hematologic recovery 
(CRh) rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 


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• characterize duration of CR, duration of CR/CRi, and duration of CR/CRh of 
tamibarotene/venetoclax/azacitidine combination and venetoclax/azacitidine, 
• characterize time to CR, time to CR/CRi, and time to CR/CRh of 
tamibarotene/venetoclax/azacitidine combination and venetoclax/azacitidine, and 
• characterize and compare the ORR of tamibarotene/venetoclax/azacitidine versus 
venetoclax/azacitidine. 
5.3 
Exploratory Study Objectives 
Part 1 
The exploratory objective of Part 1 is to evaluate AML molecular features associated 
with response and with loss of response to treatment. 
Part 2 
The exploratory objectives of Part 2 are to 
• characterize and compare event-free survival (EFS) of 
tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 
• characterize and compare overall survival (OS) of 
tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 
• characterize and compare minimal residual disease (MRD)-negative response rate 
of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 
• characterize time to MRD-negative response of 
tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 
• characterize and compare the transfusion independence (TI) rate of 
tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine, 
• characterize PK of tamibarotene when co-administered with venetoclax and 
azacitidine, and 
• evaluate AML molecular features associated with response and with loss of 
response to treatment. 
Part 3 
The exploratory objectives of Part 3 are to 


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• characterize the ORR after treatment with tamibarotene/venetoclax/azacitidine for 
patients who have experienced progressive disease, relapse, or treatment failurea 
on venetoclax/azacitidine, 
• characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine in 
patients who have experienced progressive disease, relapse, or treatment failurea 
on venetoclax/azacitidine, 
• characterize the OS of tamibarotene/venetoclax/azacitidine in patients who have 
experienced progressive disease, relapse, or treatment failureb on 
venetoclax/azacitidine, and 
• evaluate AML molecular features associated with response and with loss of 
response to treatment. 
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
This is a Phase 2, open-label, 3-part, multi-center study evaluating 
tamibarotene/venetoclax/azacitidine combination therapy in RARA-positive, previously 
untreated, non-acute promyelocytic leukemia (APL) AML participants who are unlikely 
to tolerate standard intensive chemotherapy at the time of study entry. 
 
In Part 1, tamibarotene will be administered at 6 mg BID starting dose in combination 
with venetoclax/azacitidine, which will be administered at the approved dose and 
schedule (VIDAZA USPI/VIDAZA SmPC and VENCLEXTA USPI/VENCLYXTO 
SmPC). Tamibarotene dose modifications for AEs will follow guidelines outlined in the 
protocol (Section 6.5); venetoclax/azacitidine dose modifications will follow the standard 
dose modifications for AEs (VIDAZA USPI/VIDAZA SmPC and VENCLEXTA 
USPI/VENCLYXTO SmPC). 
 
The safety, tolerability, and PK evaluation of tamibarotene/venetoclax/azacitidine 
combination will inform the appropriate tamibarotene dose to be combined with the 
standard of care (SOC) venetoclax/azacitidine (Döhner 2022) in Part 2 and Part 3. In Part 
2, participants will be randomized 1:1 to receive either 
tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine to compare the clinical 
activity of the 2 combinations. In Part 3, tamibarotene will be added to the 
venetoclax/azacitidine regimen of a subset of Part 2 participants who experience 
progressive disease, relapse after initial CR or CRi response, or treatment failure. 
Enrollment is planned in the United States and France. 
 
 
a Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 
2 cycles of therapy, as determined by the investigator. 
b Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 
2 cycles of therapy, as determined by the investigator. 


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Start of Venetoclax/Azacitidine Therapy 
Currently, ND AML participants who are ineligible for standard induction therapy are 
increasingly receiving venetoclax/azacitidine combination as the SOC therapy (DiNardo 
2020; NCCN Guidelines). Since AML is an acute disease and prompt treatment may be 
required, in Part 1 and Part 2 of the study, the treating investigator may choose one of the 
two options below. 
• Begin SOC venetoclax/azacitidine treatment on Cycle 1 Day 1 using protocol 
defined regimen and doses while awaiting pre-treatment screening RARA 
biomarker test result. 
• Begin venetoclax/azacitidine treatment on Cycle 1 Day 1 after the participant is 
confirmed to be RARA-positive. 
 
All eligibility requirements must be met prior to dosing on Cycle 1 Day 1, with the 
exception of RARA test results (inclusion criterion 2). 
 
Pre-screening/Screening and Enrollment (Part 1)/Randomization (Part 2) Procedures 
 
The sample for RARA biomarker testing must be collected and sent for assessment prior 
to starting venetoclax/azacitidine administration on Cycle 1 Day 1. Participants who meet 
all eligibility criteria (except for RARA-positive status confirmation; inclusion criterion 
2) can begin venetoclax/azacitidine treatment on Cycle 1 Day 1 and are considered to be 
enrolled (Part 1)/randomized (Part 2) upon confirmation of RARA-positive status by 
Cycle 1 Day 8. 
 


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a If the participant discontinues treatment or study participation prior to confirmation of screening RARA 
results and RARA-positivity is confirmed by C1D8, the participant will be enrolled (Part 1)/randomized 
(Part 2), and the data from C1D1 until the time of study discontinuation will be captured (including AEs 
and the reason for discontinuation of treatment). 
Part 1 Design 
In total, up to approximately 
 participants may be enrolled in Part 1. Enrolled RARA-
positive participants will receive the tamibarotene/venetoclax/azacitidine triplet 
combination as follows: 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 
through 7 of each 28-day therapy cycle (per VIDAZA USPI, VIDAZA SmPC). 
Alternative dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted 
throughout the study. 
• Venetoclax (orally) at a dose described in the most current VENCLEXTA 
USPI/VENCLYXTO SmPC (including ramp-up and appropriate dosing for 
participants receiving concomitant 
 and P-glycoprotein (P-gp) inhibitors), 
daily on Days 1 through 28. 
• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy 
cycle. Tamibarotene will only be administered to participants who have been 
confirmed as RARA-positive.  
 
If needed to manage toxicity, the study drugs will be modified as outlined in Section 6.5 
of the protocol. After Cycle 1 data for at least 6 participants become available, the totality 
of data (including study drug administration record, dose modifications, and available PK 
data) will be evaluated to support advancing to Part 2 of the study. The ongoing 
enrollment of 6 to 9 additional participants to further characterize the dosing regimen or a 
modified regimen may occur in Part 1 of the study. A modified regimen may be 
evaluated if the starting dose of tamibarotene (6 mg BID) is not tolerated in combination 
with venetoclax/azacitidine or if the 6 mg BID dose of tamibarotene does not allow for 
participants to tolerate the approved regimen of venetoclax/azacitidine. A modified 
regimen would consist of a reduced dose of tamibarotene in combination with the 
approved regimen of venetoclax/azacitidine. 
 
The dose and regimen of tamibarotene administered in combination with 
venetoclax/azacitidine in Part 2 and Part 3 will be informed by the totality of available 
data from all participants enrolled in Part 1, including the incidence of treatment-
emergent AEs, the study drug administration record (including dose modifications and 
interruptions), safety laboratory data, physical examination and vital signs findings, and 
PK data.  
Part 2 Design 
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In total, approximately 
 participants will be randomized in Part 2 of the study, RARA-
positive participants will be randomized 1:1 to receive either 
tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine dosing as follows: 
• Azacitidine (intravenously or subcutaneously) at 75 mg/m2 each day on Days 1 
through 7 of each 28-day therapy cycle (per VIDAZA USPI and VIDAZA 
SmPC). Alternative dosing of azacitidine (Days 1 through 5, 8, and 9) will be 
permitted throughout the study.  
• Venetoclax (orally) at a dose described in the most current VENCLEXTA USPI 
and VENCLYXTO SmPC (including ramp-up and appropriate dosing for 
participants receiving concomitant 
 and P-gp inhibitors) daily beginning 
on Day 1 for a minimum of 14 days and a maximum of 28 days for Cycle 1, with 
the duration of venetoclax determined by early response assessment conducted 
between Days 14 and 21 of the cycle. If bone marrow blasts are <5%, venetoclax 
administration will be stopped and held for up to 14 days prior to proceeding with 
Cycle 2. If bone marrow blasts are ≥5%, venetoclax administration will continue 
through Day 28 of Cycle 1. For Cycle 2 and beyond, participants will receive 
venetoclax daily beginning on Day 1 through Day 28 for each cycle, with dose 
modifications as needed for toxicity (Döhner 2022; Maiti 2022). 
• Tamibarotene (orally) 6 mg BID on Days 8 through 28 of each 28-day therapy 
cycle. Tamibarotene will only be administered to participants who have been 
confirmed as RARA-positive. 
PK evaluation of tamibarotene will be conducted using samples collected from 
participants receiving the triplet combination only. 
Part 3 Design 
Part 2 participants treated with venetoclax/azacitidine who experience progressive 
disease, relapse after initial CR or CRi response, or treatment failure may begin 
subsequent treatment in Part 3, where tamibarotene will be added to their regimen. 
Participation in Part 3 will begin as soon as possible, but within 30 days of the decision to 
stop participation in Part 2. Treatment failure is defined as a failure to achieve a bone 
marrow blast count of <5% following at least 2 cycles of therapy, as determined by the 
investigator. No PK evaluation will be performed in Part 3. 
Parts 1 through 3 Assessments and Follow-up 
Participants will undergo safety and response evaluations throughout their study 
participation as detailed in the Schedules of Activities. Response will be assessed by the 
investigator in alignment with European LeukemiaNet (ELN) AML criteria (Döhner 
2017), with CRh assessed according to Error! No bookmark name given. 2018. 
In Part 1, bone marrow aspirates will be collected to measure response at the End of 
Cycle (EoC) Visits of Cycles 1, 2, and 3, followed by every third cycle (6, 9, 12, etc.), 
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with bone marrow aspirates collected at other times as clinically determined based upon 
clinical findings or changes in peripheral blood counts. If a participant achieves CR/CRi 
at the Cycle 1 EoC Visit, the Cycle 2 EoC bone marrow aspirate is not required. 
In Part 2 and Part 3, Cycle 1 response will initially be assessed between Days 14 and 21 
of Cycle 1, as recommended by ELN guidelines (Döhner 2022), with venetoclax 
administration proceeding in alignment with these recommendations. For those with blast 
clearance (<5% blasts) at that initial assessment, no Cycle 1 EoC bone marrow aspirate is 
required. For participants with ≥5% blasts at that initial assessment, Cycle 1 EoC bone 
marrow aspirate will be completed. Subsequent bone marrow aspirates for all participants 
will be collected at the EoC Visit of Cycles 2 and 3, followed by every third cycle (6, 9, 
12, etc.), with bone marrow aspirates collected at other times as clinically determined. If 
a participant achieves a CR/CRi within Cycle 1 response assessment(s), the Cycle 2 EoC 
bone marrow aspirate is not required. 
All participants who remain on study may continue to receive study drug until 
experiencing an unacceptable toxicity, disease progression, relapse, decision to pursue 
post-remission dose anticancer therapy, participant withdraws consent, or the investigator 
determines it is in the best interest of the participant to discontinue study drug. Note: Part 
2 participants assigned to venetoclax/azacitidine treatment may continue on study in Part 
3 following progressive disease, relapse after initial CR or CRi response, or treatment 
failure as noted in section Part 3 Design above. 
For all enrolled (Part 1)/randomized (Part 2) participants, an End of Treatment (EoT) 
Visit should occur within 3 days of the last dose of study drug (or within 3 days of 
decision to permanently stop drug treatment, if this decision directly follows a period 
when study drug has been on hold) and before the start of any subsequent anticancer 
therapy. A Safety Follow-up Visit should occur 30 days (±3 days) after the EoT Visit and 
before the start of any subsequent anticancer therapy. After the EoT Visit, participants 
who have not progressed/relapsed will enter the Disease Follow-up period, during which 
response assessments will be performed for up to 3 years after discontinuation of study 
drug, or until disease progression/relapse, whichever occurs first. Participants who 
progress/relapse will enter Survival Follow-up and will be followed to document the start 
of subsequent anticancer therapy, the date of disease progression/relapse, and OS status 
for up to 3 years after discontinuation of study drug. 


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Figure 1 
Study Design 
  
Abbreviations: aza = azacitidine; b/w = between; C1DX = Cycle 1 Day X; tami = tamibarotene; ven = 
venetoclax. 
a Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 2 
cycles of therapy, as determined by the investigator. 
6.2 
Schedule of Assessments 
Refer to the protocol (Section 1.3) for the complete Schedule of Assessments. 
 
6.3 
Treatments 
6.3.1 
Treatments Administered 
The study drugs described in Table 2 will be administered. All participants enrolled will 
receive venetoclax/azacitidine from Cycle 1 Day 1 to Cycle 1 Day 7 in Part 1 and Part 2 
of the study. 
• Part 1 participants who meet all eligibility criteria and are enrolled by Cycle 1 
Day 8 (once RARA-positive status has been confirmed) will receive 
tamibarotene/venetoclax/azacitidine combination therapy. 
• Part 2 participants who meet all eligibility criteria and are randomized by Cycle 1 
Day 8 (once RARA-positive status has been confirmed) will receive either 
tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine. 
• In Part 3, tamibarotene will be added to venetoclax/azacitidine regimen of a 
subset of Part 2 participants. 
Table 2 
Study Treatments 
Intervention Name  
Tamibarotene 
Venetoclax 
Azacitidine 
Type 
Drug 
Drug 
Drug 


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Dose Formulation 
Tablet 
Tablet 
Reconstituted as solution or 
suspension 
Unit Dose Strength(s) 
2-mg tablets 
10-mg, 50-mg, 100-
mg tablets 
100-mg single-use vials 
Dosage Level and 
Regimen 
6 mg twice per 
day; Days 8 
through 28 of each 
28-day treatment 
cycle. 
Daily, Days 1 
through 28, as 
described in Table 3 
(adapted from 
VENCLEXTA 
USPI/ 
VENCLYXTO 
SmPC). 
75 mg/m2 once per day; Days 1 
through 7 of each 28-day 
treatment cycle (per VIDAZA 
USPI/VIDAZA SmPC). 
If dosing on Days 6 and 7 is not 
possible due to logistical 
limitations, these doses may be 
delayed to Days 8 and 9. 
Route of 
Administration 
Oral 
Oral 
Intravenous or subcutaneous 
Use 
Experimental 
Background 
intervention 
Background intervention 
 
 
 


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Table 3 
Venetoclax Dosing 
Day  
Standard 
Ven Dosing 
Drug Interaction Management 
Ven + 
Posaconazole 
Ven + Other 
 
 
 
or P-gp 
Inhibitor 
Daily Ven Dose 
Day 1 
100 
10 
10 
Reduce standard 
venetoclax dose by at 
least 50% 
Day 2 
200 
20 
20 
Day 3 
400 
50 
50 
Day 4 and beyond 
400 
70 
100 
Source: adapted from VENCLEXTA USPI 2020 
Note: Resume the venetoclax dosage that was used prior to concomitant use of a 
 
 or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. 
Abbreviations: P-gp = P-glycoprotein; ven = venetoclax 
In each part of the study, the decision to begin Cycles 2, 3, 4, followed by every third 
cycle (7, 10, 13, etc.) will be made based on the response assessment. Participants will 
undergo a response assessment at the end of Cycles 1, 2, and 3, followed by every third 
cycle (6, 9, 12, etc.). The start of the next treatment cycle will be determined as follows: 
• If a participant achieves CR at the EoC response assessment, the participant will 
begin the next treatment cycle. 
• If a participant achieves CRi or has a morphologically leukemia-free state 
(MLFS) at the EoC response assessment, without absolute neutrophil count 
(ANC) recovery, the start of the next treatment cycle will be held to allow for 
ANC recovery until ANC is ≥500/μL or up to 14 days. Granulocyte colony 
stimulating growth factor (G-CSF) may be administered if clinically indicated for 
neutropenia. If ANC recovery does not occur within 14 days of the EoC response 
assessment, the next treatment cycle may begin in the absence of recovery of 
peripheral blood counts. 
• If a participant is NOT in CR, CRi, or MLFS at the EoC response assessment, the 
start of the next treatment cycle should begin with supportive care, without 
modifications to the regimen, regardless of blood count recovery. 
6.3.2 
Method of Assigning Participants to Treatment Groups 
This is an open-label study; no blinding will occur. Parts 1 and 3 of the study are not 
randomized. Randomization in Part 2 will be performed using an interactive response 
system. Randomization can occur between Cycle 1 Day 1 Visit and Cycle 1 Day 8 Visit 
(inclusive), as soon as all eligibility requirements are met, including confirmation of 
participant’s RARA-positive status (inclusion criterion 2). For participants who are 
confirmed RARA-positive prior to Cycle 1 Day 1, randomization can occur within 72 
hours prior to the first dose of venetoclax/azacitidine to accommodate operational needs. 
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6.4 
Efficacy and Safety Endpoints 
6.4.1 
Efficacy Endpoints 
6.4.1.1 
Primary Efficacy Endpoint 
Part 2 
The primary efficacy endpoint of Part 2 is:  
• 
CR/CRi assessment; CR/CRi rate is estimated by the proportion of participants 
who achieve CR/CRi (as determined by the investigatora). 
Participants will be assessed for the primary endpoint of CR/CRi from the time of the 
index date until the initiation of non-study drug therapy or until time of disease 
progression/relapse. The index date is defined as the earlier of the (date of randomization 
and the date of Cycle 1 Day 1 Visit) for Part 2 and the date of Cycle 1 Day 1 Visit for 
Parts 1 and 3. The calculation of the primary efficacy endpoint is: 
CR/CRi rate (%) = number of CR/CRi responders / number of participants in the 
modified Intent-to-Treat (mITT) Population × 100. The denominator is the mITT 
Population in each treatment group. 
Non-responders are participants who do not achieve a CR/CRi response or meet any of 
the following criteria: 
1. Do not have any post-baseline response assessments. 
2. All response assessment results are missing or not done. 
3. Discontinue prior to having a post-baseline assessment. 
4. Withdraw consent before achieving a response. 
5. Die before achieving a response. 
6. Start a new systemic therapy before achieving a response. 
7. Receive a transplant before achieving a response. 
8. Experience prolonged treatment interruption requiring permanent withdrawal of 
study drug before achieving a response. 
 
 
 
 
a Determination of response will be made by the investigator in alignment with ELN AML criteria (Döhner 
2017) and Bloomfield 2018 for CRh. 


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Table 4 
Estimands 
Objective 
Treatment 
Estimand Category 
Variable  
Population 
(Based on 
mITT 
Population) 
Intercurrent 
Event Strategy 
Population 
Level 
Summary 
Measure 
Primary 
Objective:  
To demonstrate 
the superiority of 
tamibarotene/ 
venetoclax/ 
azacitidine 
compared to 
venetoclax/ 
azacitidine in 
CR/CRi in newly 
diagnosed 
RARA-positive 
AML 
participants 
Tamibarotene/ 
venetoclax/ 
azacitidine 
versus 
venetoclax/ 
azacitidine 
CR/CRi as 
determined 
by the 
investigator 
in alignment 
with ELN 
AML 
criteria 
(Döhner 
2017) and 
Bloomfield 
2018 for 
CRh. 
Adult 
RARA-
positive, 
previously 
untreated 
AML 
participants 
who are 
ineligible 
for standard 
induction 
therapy 
• Treatment 
discontinuation: 
treatment 
policy 
• Composite 
strategy: 
Participants 
who die, 
withdraw 
consent, or start 
a new 
anticancer 
treatment 
before 
achieving a 
response  
• CR/CRi rate 
by treatment 
arm 
• Difference 
in proportion 
of CR/CRi 
rate between 
the 2 
treatment 
arms 
Abbreviations: AML = acute myeloid leukemia; CR = complete remission; CRi = CR with incomplete 
blood count recovery; mITT = modified Intent-to-Treat; RARA = retinoic acid receptor alpha. 
6.4.1.2 
Secondary Efficacy Endpoints 
Part 1 
The secondary efficacy endpoint of Part 1 is:  
• 
Overall response assessment, comprised of CR, CRi, CRh, MLFS, or PR (as 
determined by the investigatora); ORR is estimated by the proportion of participants 
who achieve overall response. 
ORR will be calculated as: 
ORR (%) = number of overall responders / number of participants in the Safety 
Population × 100. 
Non-responders are participants who do not achieve an overall response or meet any 
of the non-response criteria listed for the primary efficacy endpoint in Section 6.4.1.1.  
Part 2 
The secondary efficacy endpoints of Part 2 are: 
 
a Determination of response will be made by the investigator in alignment with ELN AML criteria 
(Döhner 2017) and Bloomfield 2018 for CRh. 


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• 
CR assessment; CR rate is estimated by the proportion of participants who achieve 
CR (as determined by the investigatora). CR rate will be calculated as: 
CR rate (%) = number of CR responders / number of participants in the mITT 
Population × 100. The denominator is the mITT Population in each treatment group. 
Non-responders are participants who do not achieve a CR response or meet any of the 
non-response criteria listed for the primary efficacy endpoint in Section 6.4.1.1. 
• 
CR/CRh assessment; CR/CRh rate is estimated by the proportion of participants who 
achieve CR/CRh (as determined by the investigatora). CR/CRh rate will be calculated 
as: 
CR/CRh rate = number of CR/CRh responders / number of participants in the mITT 
Population × 100. The denominator is the mITT Population in each treatment group. 
Non-responders are participants who do not achieve a CR/CRh response or meet any 
of the non-response criteria listed for the primary efficacy endpoint in Section 6.4.1.1. 
• 
Duration of CR, defined as the duration from the date of first documented evidence of 
CR to the date of relapse of disease, as determined by the investigatora, or death due 
to any cause, whichever occurs first. Among CR responders, DOCR will be 
calculated in days as: 
Duration of CR (days) = first date of documented relapse of disease or death due to 
any cause - date of first documented evidence of CR + 1. 
• 
Duration of CR/CRi, defined as the duration from the date of first documented 
evidence of CR/CRi to the date of relapse of disease as determined by the 
investigatora, or death due to any cause, whichever occurs first. Among CR/CRi 
responders, duration will be calculated in days as: 
Duration of CR/CRi (days) = first date of documented relapse of disease or death due 
to any cause - date of first documented evidence of CR/CRi + 1. 
• 
Duration of CR/CRh, defined as the duration from the date of first documented 
evidence of CR/CRh to the date of relapse of disease as determined by the 
investigatora, or death due to any cause, whichever occurs first. Among CR/CRh 
responders, duration will be calculated in days as: 
Duration of CR/CRh (days) = first date of documented relapse of disease or death 
due to any cause - date of first documented evidence of CR/CRh + 1. 
• Time to CR, defined as the duration from the index date to the date of the first 
documented evidence of CR as determined by the investigatora. The date of the bone 
 
a Determination of response will be made by the investigator in alignment with ELN AML criteria 
(Döhner 2017) and Bloomfield 2018 for CRh. 


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marrow aspirate will be used for determining the date of response. Among CR 
responders, this endpoint will be calculated as: 
Time to CR (days) = date of the first documented evidence of CR – index date + 1. 
• Time to CR/CRi, defined as the duration from the index date to the date of the first 
documented evidence of CR/CRi as determined by the investigatora. Among CR/CRi 
responders, this endpoint will be calculated as: 
Time to CR/CRi (days) = date of the first documented evidence of CR/CRi – index 
date + 1. 
• Time to CR/CRh, defined as the duration from the index date to the date of the first 
documented evidence of CR/CRh as determined by the investigatora. Among CR/CRh 
responders, this endpoint will be calculated as: 
Time to CR/CRh (days) = date of the first documented evidence of CR/CRh – index 
date + 1. 
• 
Overall response assessment, comprised of CR, CRi, CRh, MLFS, or PR (as 
determined by the investigatora); ORR is estimated by the proportion of participants 
who achieve overall response. 
ORR will be calculated as: 
ORR (%) = number of overall responders / number of participants in the mITT 
Population × 100. The denominator is the mITT Population in each treatment group. 
Non-responders are participants who do not achieve an overall response or meet any 
of the non-response criteria listed for the primary efficacy endpoint in Section 6.4.1.1. 
6.4.1.3 
Exploratory Efficacy Endpoints 
Part 1 
The exploratory endpoint of Part 1 is to assess for correlation between both molecular 
mutation profile and MES (monocytic expression score) and ORR/CR/CRi rate and 
evaluate changes to molecular mutation profile and MES score on treatment and/or at the 
time of loss of response. 
Part 2 
The exploratory efficacy endpoints of Part 2 are: 
 
a Determination of response will be made by the investigator in alignment with ELN AML criteria (Döhner 
2017) and Bloomfield 2018 for CRh. 


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• EFS, defined as the duration from the index date to the date of progressive disease, 
relapse after CR/CRi, treatment failurea, or death from any cause. 
EFS (months) = (date of progressive disease, relapse after CR/CRi, treatment failure, 
or death due to any cause – index date + 1) / 30.4375. 
• OS, defined as the duration from the index date to the date of death due to any cause. 
OS will be calculated in months as: 
OS (months) = (date of death – index date + 1) / 30.4375. 
• 
MRD-negative response rate, comprised of achieving an MRD-negative CR by 
multiparameter flow cytometry, quantitative polymerase chain reaction (qPCR), or 
next-generation sequencing, as determined by the investigatorb; MRD-negative rate is 
estimated by the proportion of participants who achieve MRD-negative CR. 
MRD-negative response rate will be calculated as: 
MRD-negative response rate (%) = number of overall participants with MRD-
negative CR / number of participants in the mITT Population × 100. The 
denominator is the mITT Population in each treatment group. 
• Time to MRD-negative response, defined as the duration from the index date to the 
date of achieving an MRD-negative CR by multiparameter flow cytometry, 
quantitative polymerase chain reaction (qPCR), or next generation sequencing, as 
determined by the investigatorb. Among participants with MRD-negative CR, this 
endpoint will be calculated as: 
Time to MRD-negative CR (days) = earliest date of MRD-negative CR – index date 
+ 1. 
• TI rate, defined as the proportion of participants who achieve TI. TI is a period of at 
least 56 consecutive days with no RBC or platelet transfusion since the date of Cycle 
1 Day 1 Visit to the last dose of study drug + 30 days, the initiation of post-treatment 
therapy, or death, whichever occurs first. Among participants who achieved TI, this 
endpoint will be calculated as: 
TI rate (%) = number of participants who achieve TI / number of participants in the 
mITT Population × 100. The denominator is the mITT Population in each treatment 
group. 
• Clinical response and genetic mutations and/or gene expression markers at baseline, 
on treatment, and/or at time of loss of response. 
 
a Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 
2 cycles of therapy, as determined by the investigator. 
b Determination of response will be made by the investigator in alignment with ELN AML criteria 
(Döhner 2017) and Bloomfield 2018 for CRh. 


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Part 3 
The exploratory efficacy endpoints of Part 3 are: 
• 
Overall response assessment, comprised of CR, CRi, CRh, MLFS, or PR (as 
determined by the investigatora); ORR is estimated by the proportion of participants 
who achieve overall response. 
ORR will be calculated as: 
ORR (%) = number of overall responders / number of participants in the Safety 
Population × 100. 
Non-responders are participants who do not achieve an overall response or meet any 
of the non-response criteria listed for the primary efficacy endpoint in Section 6.4.1.1. 
• OS, defined as the duration from the index date to the date of death due to any cause. 
OS will be calculated in months as: 
OS (months) = (date of death – index date + 1) / 30.4375. 
• Clinical response and genetic mutations and/or gene expression markers at baseline, 
on treatment, and/or at time of loss of response. 
Response types (i.e., CR, CRi, CRh, etc.) included in the efficacy endpoints are defined 
in Table 5 below in alignment with ELN AML criteria (Döhner 2017) and Bloomfield 
2018 for CRh. 
Response definitions for participants with marrow blast clearance (<5%) may be adjusted 
to reflect the best hematologic response achieved prior to commencement of the next 
treatment cycle (Döhner 2022). 
Table 5 
Response Criteria for AML 
Response 
Category 
Definition 
ANC 
(/μL) 
Platelets 
(/μL) 
Bone 
Marrow 
Blasts(%) 
Comment 
CR 
≥1,000 
≥100,000 
<5 
Absence of circulating blasts and blasts with 
Auer rods; absence of extramedullary disease 
(EMD) 
CRi 
<1,000 
-or 
<100,000 
<5 
All CR criteria met except either neutrophils or 
platelets not recovered 
CRh 
>500 
>50,000 
<5 
All CR criteria met except ANC and platelets 
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MRD-
negative CR 
≥1,000 
≥100,000 
<5 
All CR criteria met and absence of MRD as 
accessed by multiparameter flow cytometry, 
qPCR, or next generation sequencing 
MLFS 
NA 
NA 
<5 
Absence of blasts with Auer rods and <5% 
blasts in marrow sample with a count of at least 
200 nucleated cells or cellularity ≥10%. 
Absence of EMD. No hematologic criteria 
required. 
PR 
≥1,000 
≥100,000 
 
≥50% decrease from baseline, with decrease to 
5-25 
Stable 
disease (SD) 
Absence of CR, MLFS, PR; and criteria for PD not met 
Progressive 
disease 
(PD) 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute 
blast counts in the blood: 
• 
>50% increase in marrow blasts over baseline (a minimum 15% point increase is 
required in cases with <30% blasts at baseline; or persistent marrow blast 
percentage of >70% over at least 3 months; without at least a 100% improvement in 
ANC to >500 and/or platelet count to >50,000 non-transfused); or 
• 
>50% increase in peripheral blasts (white blood cells (WBC) x % blasts) to >25,000 
μL (in the absence of differentiation syndromea); or 
• 
New extramedullary disease 
Treatment 
failure 
Failure to achieve blast count of <5% following at least 2 cycles of therapy, as 
determined by the investigator. 
Relapse 
Bone marrow blasts ≥5%; or reappearance of blasts in blood; or development of EMD. 
If studied pre-treatment, reoccurrence of MRD. 
a Differentiation syndrome, i.e., a transient increase in the percentage of bone marrow blasts and an 
absolute increase in blood blasts, may be observed with targeted therapies; in this setting, an increase in 
blasts may not necessarily indicate progressive disease. 
6.4.2 
Safety Endpoints 
The safety endpoints for this study are incidence of AEs, changes in clinical laboratory 
values, electrocardiograms (ECGs), and vital sign measurements. 
6.4.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study drug, whether or not considered related to the study drug. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study drug whether or not related to the study drug. An AE can arise from any 
use of the study drug, and from any route of administration, formulation, or dose, 
including an overdose. 
AEs will be captured from the time of the first dose of venetoclax/azacitidine on Cycle 1 
Day 1 through the Safety Follow-up Visit. 
6.4.2.2 
Laboratory Parameters 
All protocol-required local laboratory tests, as defined in Table 6, will be conducted in 
accordance with local laboratory practices. 


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Table 6 
Protocol-Required Safety Laboratory Tests 
Lab Tests 
Parameters 
Hematology 
Platelet Count 
Hemoglobin 
WBC (leukocyte count including differential): 
Neutrophils (absolute neutrophil count, calculated from the leukocyte count and WBC 
differential count) 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
% Blasts 
Clinical 
Chemistry 
Blood urea nitrogen/urea 
Creatinine 
Bicarbonate (CO2) 
Uric acid 
Albumin 
Sodium 
Phosphorus 
Triglycerides 
Total cholesterol 
Magnesium 
Calcium 
Potassium 
Chloride 
Glucose 
Amylase 
Lipase 
Total protein 
Alkaline phosphatase 
Lactate dehydrogenase 
Total and direct bilirubin 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
Alanine aminotransferase/serum glutamic-pyruvic transaminase 
Coagulation 
International normalized ratio or prothrombin time 
Activated partial thromboplastin time/partial thromboplastin time 
Routine 
Urinalysis 
Specific gravity 
pH 
Protein 
Red blood cell 
White blood cell 
Leukocyte esterase 
Ketones 
Nitrite 
Pregnancy 
testing 
Highly sensitive serum or urine human chorionic gonadotropin pregnancy test (as 
needed for women of childbearing potential)a 
a Local urine pregnancy testing will be standard for the protocol unless serum testing is required by local 
regulation or Institutional Review Board/Independent Ethics Committee. 


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6.4.2.3 
Other Safety Endpoints 
6.4.2.3.1 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
6.4.2.3.2 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals (utilizing 
Fredericia’s correction for QTc). Central and/or local overreads may be performed by a 
cardiologist in the event calculations made by the machine do not appear to be accurate. 
6.4.3 
Pharmacokinetic Endpoints 
 
The PK endpoints will be provided in a separate report and is outside the scope of this 
SAP. 
7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Syros Pharmaceuticals, Inc. biostatistics personnel or designee. 
Statistical analyses will be reported with tables, figures, and listings, presented in rich 
text format, and using recommended ICH numbering. Output specifications for all tables, 
figures, and listings will be in conformance with guidelines specified by the ICH in 
Appendix 7 of the Electronic Common Technical Document Specification (Apr 2003).  
There are 4 planned analyses for this study: 
• An interim futility analysis of the CR/CRi rates is planned in Part 2 for the first 
 randomized RARA-positive participants and will be performed after 
approximately 
 randomized participants have been on treatment for 
approximately 3 months or discontinued treatment earlier than 3 months. If any 
additional analyses are performed at this time other than the futility, they will be 
based on the mITT, Response Evaluable (RE), and/or Per Protocol (PP) 
Populations, as deemed appropriate. 
• Two administrative interim analyses may be performed after approximately 25% 
and 75% (
) of participants have had approximately 3 cycles of 
treatment. All interim analyses in Part 2 will be conducted on the mITT, RE, 
and/or PP Populations, as deemed necessary. No multiplicity adjustments are 
needed since the study will not be stopped for efficacy until the primary analysis. 
• A final analysis when all participants are off study will be performed based on the 
mITT, RE, and/or PP Populations. 
CCI
CCI
CCI


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All relevant data from Parts 1, 2, and 3 of the study will be included as a part of the 
interim and final analyses. 
7.1.1 
Reporting Conventions 
Tables and figures will be summarized separately by study part (Parts 1, 2, and 3) and 
treatment group (tamibarotene/venetoclax/azacitidine and venetoclax/azacitidine). 
Non-efficacy tables in Part 2 will also include a column for all participants combined. In 
general, all data collected and any derived data will be presented in participant data 
listings, for all enrolled participants. Listings will be ordered by study part, treatment 
group, site, participant number, and assessment or event date. The treatment group 
presented in listings will be based on the planned assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the number of 
participants with available data (n), mean, SD, median, minimum, and maximum values. 
Categorical variables, unless otherwise specified, will be summarized by the number of 
participants with available data (n), and number and percentage of participants in each 
category. If there is a subcategory under a categorical variable, this subcategory will be 
summarized by the number and percentage of participants based on the number of 
participants under this categorical variable. A category for “Missing” will be added and 
populated to make the total percentage of each category equal to 100%. Select ordinal 
data may be summarized using both descriptive statistics and counts and percentages of 
participants in each category, as appropriate. 
Non-zero percentages will be rounded to 2 decimal places. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the electronic case report form 
[eCRF] or as provided within an external file) and are outlined as follows: 
• The mean and median will be rounded to 1 more decimal place than the precision 
of the variable of summarization and up to 3 decimal places. 
• Measures of variability (e.g., SD, SE) will be rounded to 2 more decimal places 
than the precision of the variable of summarization and up to 4 decimal places. 
• Minimum and maximum values will be presented using the same precision as the 
variable of summarization and up to 2 decimal places.   
Other statistics (e.g., CIs) will be presented using the same general rules outlined above 
or assessed for the most appropriate presentation based on the underlying data. 
The level of significance for the analysis of the Part 2 primary endpoint is 1-sided at 5%. 
Secondary efficacy endpoints for Part 1 and Part 2 may be tested using a 2-sided, 5% 
significance level. Two (2)-sided 95% CIs will be reported for all endpoints/analyses, 
when appropriate, unless otherwise specified. P-values will be rounded to four decimal 
places. P-values less than 0.0001 will be displayed as “<0.0001”; p-values greater than 
0.9999 will be displayed as “>0.9999”. 


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7.1.2 
Summarization by Visit 
Data summarized by study visit will be based on the nominal, scheduled visit label as 
reported on the eCRF. For safety analysis, in the case of multiple observations at a 
specific visit, the observation which is the latest will be used. If more than one 
observation is made on the same day, an average value if continuous or the worst value if 
categorical will be included in the analysis. 
Data collected at unscheduled visits will not be included in by-visit summaries but will be 
considered when endpoint derivations potentially include multiple visits (e.g., 
determination of baseline value, determination of worst post-baseline value, etc.). All 
data will be included in participant listings. 
7.1.3 
Data Handling Rules 
7.1.3.1 
Threshold Values 
Unless otherwise noted, values that include a threshold sign (i.e., “<” or “>”) will be 
imputed for summary tables in the following manner: 
 
• A value that is 1 unit less than the limit of quantitation will be used for the 
calculation of descriptive statistics if the datum is reported in the form of “<x” 
(where x is considered the limit of quantitation). For example, if the values are 
reported as <50 and <5.0, values of 49 and 4.9, respectively, will be used for 
calculation of summary statistics. An exception to this rule is any value reported 
<1. For the values reported as <1 or <0.1, a value of 0.9 or 0.09 will be used for 
calculation of summary statistics.  
• A value that is 1 unit above the limit of quantitation will be used for the 
calculation of descriptive statistics if the datum is reported in the form of “>x” 
(where x is considered the limit of quantitation). Values with decimal points will 
follow the same logic as above.  
• The limit of quantitation will be used for the calculation of descriptive statistics if 
the datum is reported in the form of “≤x” or “≥x” (where x is considered the limit 
of quantitation).  
The original data including the threshold signs will be displayed in the listings. 
7.1.3.2 
Baseline Definition 
 
For all endpoints, unless otherwise specified, the baseline value will be the latest pre-dose 
assessment with a non-missing value, including those from unscheduled visits. If time is 
not collected, Cycle 1 Day 1 assessments are assumed to be taken prior to first dose and 
used as baseline. When scheduled assessments and unscheduled assessments occur on the 
same day as the first dose and the time of assessment or the time of the first dose is not 
available, the following convention to determine baseline will be used:  


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• If both a scheduled visit and an unscheduled visit are available on the day of the 
first dose, and time is missing, the scheduled assessment will be used as baseline.  
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, the unscheduled assessment will be used as 
baseline.  
For participants who did not receive study treatment during the study, baseline will be 
defined as the latest, non-missing collected value. Unless otherwise stated, if baseline 
data is missing no derivation will be performed and baseline will be set to missing. For 
purposes of defining “pre-dose”, reference should be made to the first dose of 
tamibarotene, azacitidine, or venetoclax, whichever comes first. 
 
For ECG analyses, if the latest, non-missing pre-dose value is from triplicate, the 
participant level baseline is defined as the mean of the triplicate baseline assessments. 
 
For all analyses in Part 3, the visit corresponding to Part 3 Cycle 1 Day 1 will be used as 
baseline.  
7.1.3.3 
Imputation of Partial or Missing AE Dates for Analysis 
 
Rules for imputing partial or missing AE dates for analysis are provided in Table 7. 
 
Table 7 
Date Imputation Rules for AEs 
Adverse Events 
Partial/missing AE dates recorded in the CRF will be imputed using the 
following conventions: 
Missing start day 
First of the month will be used unless it is before the start date of study 
treatment; in this case, the study treatment start date will be used and hence the 
event is considered treatment emergent. 
Missing start day and 
month 
No imputation. 
Missing end day 
Last day of the month will be used. 
Missing end day and 
month 
No imputation. 
Completely missing 
start/end day 
No imputation. 
7.1.3.4 
Imputation of Partial or Missing Medical History/Concomitant 
Medication Dates for Analysis 
 
Rules for imputing partial or missing medical history or concomitant dates for analysis 
are provided in Table 8. 


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Table 8 
Date Imputation Rules for Medical History/Prior and Concomitant 
Medications/Prior Cancer Therapy 
Medical History/Prior and 
Concomitant 
Medications/Prior Cancer 
Therapy 
Partial/Missing Medical History/Prior and Concomitant 
Medication/Prior Cancer Therapy Dates Recorded in the 
CRF Will Be Imputed Using the Following Conventions: 
Missing start day 
“01” will be used for the day. 
Missing start day and month 
“01” will be used for the day and “Jan” will be used for the 
month. 
Missing end day 
“28/29/30/31” will be used for the day (dependent on the 
month and year) and the earlier of last day of the month and 
the end of study date will be used as the imputed value 
except in the following 2 cases: 
1) For prior cancer therapy 
2) If it is not ongoing and the start date is prior to the study 
treatment start date 
For these 2 cases, the end date will be imputed as (study 
treatment start date - 1). 
Missing end day and month 
“31” will be used for the day and “Dec” will be used for the 
month, and the earlier of 31 Dec of the given year and the 
end of study date will be used as the imputed value except in 
the following 2 cases: 
1) For prior cancer therapy 
2) If it is not ongoing and the start date is prior to the study 
treatment start date 
For these 2 cases, the end date will be imputed as (study 
treatment start date - 1). 
Completely missing start/end 
day 
No imputation. 
7.1.3.5 
Imputation of Partial or Missing New Anticancer Dates for Efficacy 
Evaluation 
 
Start dates for follow-up anticancer therapy will be temporarily imputed in order to 
define event and censoring rules for event-free survival, response rate, time to event, 
duration of response or time to response (e.g., start date for new anticancer therapy). The 
imputed dates will be stored in the systemic therapy derived dataset. 
 
• If missing start day, month, and year, then no imputation. 
• If missing start day and month, then no imputation. 
• If missing start day only, then do the following: 


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o If partial date falls in the same month as the last dose of study treatment, 
then assign to earlier of (date of last dose of study treatment + 1, last day 
of month). 
o If partial date falls in the same month as the participant’s last assessment 
and the participant’s last assessment is progressive disease, relapse after 
CR/CRi, or treatment failurea, then assign to earlier of (date of progressive 
disease, relapse after CR/CRi, or treatment failure + 1, last day of month). 
o If both rules above apply, then assign to latest of the 2 dates. 
o Otherwise, impute missing day to the first of the month. 
• If missing end date, then no imputation should be done. 
7.1.3.6 
Imputation of Partial or Missing Date of Birth and the Calculation of Age  
Age in years will be calculated as (date of main informed consent – date of birth + 1) / 
365.25 and will be stored in the adsl dataset.  
• If missing day, month, and year of birth, then no imputation.  
• If missing day and month of birth, then impute date of birth to June 30.  
• If missing day only, then impute date of birth to 15th of the month.  
 
7.1.3.7 
Imputation of Partial or Missing Date of Death  
Date of death will be temporarily imputed in order to define event and censoring rules for 
time to event endpoints. The imputed dates will be stored in the adsl dataset.  
• If missing day, month, and year, then no imputation.  
• If missing day and month, then impute to later of January 1st or (last known alive 
date + 1). 
• If missing day only, then impute to later of first date of the month or (last known 
alive date + 1).  
7.1.3.8 
Calculation of ECG Data  
Three reads are taken during ECG at each visit. The average of the available reads will be 
used as the ECG data at the corresponding visit. If none of the three reads are available, 
then the observation will be considered as missing, and no imputation will be performed. 
7.1.3.9 
Post-baseline Missing Values  
 
• If post-baseline Common Terminology Criteria for Adverse Events (CTCAE) 
grade for laboratory parameters is missing, there will be no imputation for 
missing values, and in the shift from baseline to worst post-baseline CTCAE 
 
a Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 
2 cycles of therapy, as determined by the investigator. 


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grade by parameter tables, a missing category will be added in order to have the 
total number of post-baseline participants equal to the total number at baseline.  
• Missing category for post-baseline values will be added to ECG shift table, 
similar to the bullet above. The same rules will be applied for vital sign shift 
tables and ECOG shift tables.  
• If AE grade is missing, the previous worst grade under the same preferred 
term (PT) will be assigned if it is available, otherwise a grade of 4 will be 
assigned for classification purpose in the tables, figures, and listings.  
• If the transfusion eCRF page is missing or if the blood product received 
information is missing, then there will be no imputation, and the participants will 
be classified as having missing transfusion dependence status. If the date of the 
transfusion is missing, then the transfusion dependence status at baseline and 
post-baseline will both be missing.  
7.1.4 
Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on participant data listings, where study day 
will be determined as: 
• The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose of study drug, plus one, if 
the assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated as the 
later date – the earlier date + 1. 
• Months: A duration expressed in months will be calculated by dividing the 
duration in days by (30.4375). 
• Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25. 
• Change from Baseline: Change from baseline will be calculated as the 
post-baseline value minus the baseline value. 
• Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
7.2 
Analysis Populations 
The analysis populations are defined as follows:  


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• Part 1 Safety Population: Includes all enrolled participants who have received any 
amount of study drug (tamibarotene, venetoclax, or azacitidine).  
• Part 1 RE Population: Includes all RARA-positive participants enrolled in Part 1 
who have received any amount of study drug (tamibarotene, venetoclax, or 
azacitidine) and have either completed at least 1 response assessment or have 
discontinued treatment due to clinical progression/progressive disease prior to any 
response assessments.  
• Part 2 ITT Population: Includes all participants who are randomized in Part 2. 
Treatment groups for this population will be determined according to the 
treatment assignment at the time of randomization. 
• Part 2 mITT Population: Includes all RARA-positive participants who are 
randomized in Part 2 and start dosing from Cycle 1 Day 1. Treatment groups for 
this population will be determined according to the treatment assignment at the 
time of randomization. 
• Part 2 RE Population: Includes all mITT participants who have either completed 
at least 1 response assessment or have discontinued treatment due to clinical 
progression/progressive disease prior to any response assessments. Treatment 
groups for this population will be determined according to the treatment 
assignment at the time of randomization.  
• Part 2 PP Population: Includes all mITT participants who are considered to be 
sufficiently compliant with the protocol as determined by the sponsor before 
database lock. Treatment groups for this population will be determined according 
to the treatment assignment at the time of randomization.              
• Part 2 Safety Population: Includes all randomized participants who have received 
any amount of study drug (tamibarotene, venetoclax, or azacitidine). Treatment 
groups for this population will be determined according to the actual treatment the 
participants received. Participants who have only received venetoclax and/or 
azacitidine will be assigned to the doublet treatment group. 
• Part 3 Safety Population: Includes all enrolled participants who have received any 
amount of study drug (tamibarotene, venetoclax, or azacitidine). 
• Part 3 RE Population: Includes all RARA-positive participants enrolled in Part 3 
who have received any amount of study drug (tamibarotene, venetoclax, or 
azacitidine) and have either completed at least 1 response assessment or have 
discontinued treatment due to clinical progression/progressive disease prior to any 
response assessments. 
• PK Evaluable Population: Includes all participants who have received at least 
1 dose of tamibarotene and have at least 1 quantifiable PK concentration. 


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Treatment groups for this population will be determined according to the actual 
treatment the participants received.  
Data summaries to be presented for multiple populations will only be produced for each 
separate population if there is a difference between the population group counts. 
All data collected from participants who received venetoclax and azacitidine in Part 2 but 
were not randomized will be listed separately. 
All efficacy analyses in Part 2 of the interim CSR will be based on the RE Population, 
and all efficacy analyses in the final CSR will be based on the mITT and/or RE 
Populations. 
7.3 
Study Participants 
7.3.1 
Disposition of Participants 
7.3.1.1 
Part 1 
Participant disposition in Part 1 will be summarized for all enrolled participants. The 
summary will include  
• the number and percentage of participants in the Safety Population 
• the number and percentage of participants completing and discontinuing each 
study treatment 
• the number and percentage of participants by primary reason for discontinuation 
of each study treatment 
• the number and percentage of participants by primary reason for study 
termination.  
7.3.1.2 
Part 2 
Participant disposition in Part 2 will be summarized for all randomized participants by 
treatment group (venetoclax/azacitidine or tamibarotene/venetoclax/azacitidine) and for 
all participants combined (total). Summaries will include 
• the number and percentage of participants in ITT Population 
• the number and percentage of participants by primary reason for exclusion from 
the PP Population 
• the number and percentage of participants completing and discontinuing each 
study treatment 
• the number and percentage of participants by primary reason for discontinuation 
of each study treatment 
• the number and percentage of participants by primary reason for study 
termination 
• the number and percentage of participants enrolling in Part 3 
• the number and percentage of participants by reason for enrolling in Part 3. 


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The primary reasons for exclusion from the PP Population will be identified by the 
Sponsor prior to database lock. 
7.3.1.3 
Part 3 
Participant disposition in Part 3 will be summarized for all participants enrolled in Part 3. 
The summary will include 
• the number and percentage of participants in the Safety Population 
• the number and percentage of participants completing and discontinuing each 
study treatment 
• the number and percentage of participants by primary reason for discontinuation 
of each study treatment 
• the number and percentage of participants by primary reason for study 
termination. 
Listings of participant disposition by study part and treatment group will be provided. 
Participants from Part 2 who continue to Part 3 will be flagged. 
Additionally, listings of randomization schemes and codes (Part 2 only), discontinuation 
from study treatments, and study eligibility will be provided. Screen failures will be 
included in the study eligibility listing but will not be included in any summary tables for 
analysis. 
7.3.2 
Protocol Deviations 
Major protocol deviations will be summarized separately by study part for all enrolled 
participants in Parts 1 and 3 and by treatment group and over all participants combined 
for the ITT Population in Part 2. Major protocol deviations are protocol deviations, 
including non-compliance with the protocol, captured on study that are be deemed by the 
Sponsor to potentially impact the efficacy or safety conclusions of the study.  
Protocol deviation review will be conducted and agreed upon by the sponsor and CRO 
stakeholders regularly throughout the study. All protocol deviations including major 
protocol deviations will be determined and appropriately categorized (as specified in the 
study Protocol Deviation Assessment Plan) prior to database lock. The number and 
percentage of participants with protocol deviations that impact the efficacy or safety 
conclusions, as well as the number and percentage of participants with deviations within 
all categories will be presented. 
The reasons for protocol deviations will be summarized for the PP Population. 
By-participant listings of all protocol deviations, including those related to Covid-19, will 
be provided for each study part.  


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7.3.3 
Demographic and Baseline Characteristics 
Demographic variables and baseline characteristics will be summarized separately by 
study part, for all participants in the Safety Populations for Parts 1 and 3, and by 
treatment group and total in the ITT Population for Part 2. Additional tables for the Part 2 
mITT Populations will be presented if the population counts are different from the ITT 
Population. 
Continuous variables will be summarized using descriptive statistics (mean, standard 
deviation, and median, as well as the minimum and maximum values). 
Categorical variables will be summarized with the number and percentage of participants 
in each category by treatment group and overall. The number of participants with missing 
information will also be summarized. 
The demographic variables include: 
• 
Age (years) 
• 
Age categories (≥18 to <65, ≥65 to <75, ≥75) 
• 
Sex (male, female) 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) 
• 
Body Surface Area (BSA) 
• 
ECOG Performance Status (0, 1, 2, 3) 
BMI will be calculated as: weight (kg) / [height (cm) / 100]2. BSA will be calculated as 
(height (cm) × weight (kg)) / 3600)1/2. The demographic and baseline data listed above as 
well as female child-bearing potential will be presented in listings for each study part. 
Participants from Part 2 who continue to Part 3 will be flagged. 
7.3.4 
AML Disease History 
AML disease history characteristics include: 
• 
Time since initial diagnosis of AML 
• 
AML type (de novo, AML associated with treatment from prior malignancy, 
myelodysplastic syndrome and/or MPN if AML evolved from antecedent 
hematologic malignancy 
• 
ELN risk status (Favorable, Intermediate, Adverse) 
• 
FAB classification (M0-M7) 
• 
RARA status (positive, negative) 
• 
Bone marrow blast category (≤30%, >30 - ≤50%, >50%) 
• 
Molecular mutation status (e.g., FLT3, CEBPA, TP53, etc.) 
• 
WBC count (low (<4 109/L), normal (4-11 109/L), high (>11 109/L)) 
• 
Low hemoglobin (<10 g/dL) 
• 
Low platelets (<100 109/L) 


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• 
Low ANC (<1.0 109/L) 
The above AML disease characteristics will be summarized separately by study part 
(excluding Part 3), treatment group and total (Part 2 only) for the Part 1 Safety Population 
and Part 2 ITT Population. 
Time since initial diagnosis in months will be calculated as: (Index Date - Date of Initial 
Diagnosis of AML + 1) / 30.4375. Index date is defined as date of Cycle 1 Day 1 visit for 
Parts 1 and 3, and the earlier of the date of randomization and the date of Cycle 1 Day 1 
Visit for Part 2. Time since initial diagnosis will be summarized using descriptive 
statistics and the remaining characteristics will be summarized with the number and 
percentage of participants in each category. The number of participants with missing 
information will also be summarized. 
A listing of AML disease history will be provided for Parts 1 and 2. Participants from 
Part 2 who continue to Part 3 will be flagged. 
7.3.5 
Medical History 
Medical History is collected prior to dosing and will be summarized by study part 
(excluding Part 3), treatment group, and total (Part 2 only) for the Part 1 Safety 
Population and Part 2 ITT Population. Verbatim terms on case report forms will be 
mapped to preferred terms and system organ classes using the Medical Dictionary for 
Regulatory Activities (MedDRA), version 23.1 or higher.   
Summaries will be ordered by descending incidence of system organ class and 
descending incidence of preferred term within each system organ class for all 
participants. A listing of medical history will be provided for Parts 1 and 2. Participants 
from Part 2 who continue to Part 3 will be flagged. 
7.3.6 
Prior and Post-treatment Cancer Therapies 
All prior cancer therapy data, including regimen number, indication, drug/agent name, 
and start/end dates, will be collected prior to dosing. Any systemic therapy that is started 
after the end of study treatment will also be recorded. Medications will be coded using 
the World Health Organization (WHO) Drug Dictionary Global B3 01 September 2020 
version or a more recent version and will be mapped to Anatomic Therapeutic Chemical 
(ATC) drug class (level 4) and drug name. Prior and post-treatment cancer therapies will 
be summarized separately by study part (excluding Part 3 for prior cancer therapies), 
treatment group, and total (Part 2 only) for the Part 1 Safety Population, Part 2 ITT 
Population, and Part 3 Safety Population. Summaries will be ordered by descending 
incidence of ATC class and descending incidence of drug name within ATC class for all 
participants. 
 
Separate by-participant listings of prior and post-treatment cancer therapies will be 
provided for each study part (excluding Part 3 for prior cancer therapies, for which 
participants from Part 2 who continue to Part 3 will be flagged). 


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7.3.7 
Prior and Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary Global B3 01 September 
2020 version or a more recent version. Medications entered on the eCRF will be mapped 
to ATC drug class (level 4) and drug name.  
Prior and concomitant medications will be summarized separately, and the study phase of 
each medication will be determined programmatically based on medication start and end 
dates. A prior medication is defined as any medication that was used by the participant 
within 30 days of Cycle 1 Day 1. A concomitant medication is defined as any medication 
that (1) started before the first dose of study drug and was continuing at the time of the 
first dose of study drug, or (2) started on or after the date of the first dose of study drug 
through 30 days after the participant’s last dose of study drug.  
For both prior and concomitant medication summaries, the number and percentage of 
participants receiving any medication will be summarized by study part (excluding Part 3 
for prior medications), treatment group and total (Part 2 only) as will the number and 
percentage receiving any medication by ATC drug class and generic drug name. 
Participants reporting use of more than one medication at each level of summarization 
(any medication received, ATC class, and generic drug name) will be counted only once. 
ATC class terms will be displayed by descending order of incidence for all participants, 
as will generic drug names within each ATC class. Whether the medication is prior or 
concomitant will be presented on the listings of prior and concomitant medications 
(excluding Part 3 for prior medications, for which participants from Part 2 who continue 
to Part 3 will be flagged). Prior and concomitant medications will be summarized 
separately by study part (excluding Part 3 for prior medications), treatment group, and 
total (Part 2 only) for the Part 1 Safety Population, Part 2 ITT Population (mITT for 
concomitant medications), and Part 3 Safety Population. 
7.3.8 
Prior and Concomitant Blood Transfusions 
For all enrolled (Part 1)/randomized (Part 2) participants, any transfusions from 8 weeks 
(or 56 days) prior to first dose of study drug on Cycle 1 Day 1 through the Safety Follow-
up period will be recorded. Transfusions will be classified as prior or concomitant based 
on the start date. A prior transfusion is defined as any transfusion that started up to 
8 weeks prior to the date of the Cycle 1 Day 1 Visit. A concomitant transfusion is defined 
as any transfusion that started on or after the date of the Cycle 1 Day 1 Visit through the 
Safety Follow-up period. Prior and concomitant blood transfusions will be summarized 
separately by study part (excluding Part 3 for prior transfusions), treatment group, and 
total (Part 2 only) for the Part 1 Safety Population, Part 2 ITT Population (mITT for 
concomitant transfusions), and Part 3 Safety Population. 
Separate by-participant listings of prior and concomitant blood transfusions will be 
provided for each study part (excluding Part 3 for prior blood transfusions, for which 
participants from Part 2 who continue to Part 3 will be flagged). 


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7.3.9 
Other Therapies, Treatments, and Procedures 
Any other therapies, treatments or procedures that occur during the study will be 
provided in a by-participant listing for each study part. 
7.3.10 
Extent of Study Drug Exposure 
The total number of cycles will be summarized using descriptive statistics for the Part 1, 
2, and 3 Safety Populations for each study drug (tamibarotene, venetoclax, and 
azacitidine) and treatment group (for Part 2 only). Additionally, the number and 
percentage of participants will be summarized for each study treatment group (for Part 2 
only), separately for each study drug, by the total number of cycles in which they were 
treated, according to the following categories: <1, 1-2, 3-4, >4 cycles. 
Actual and planned total dose, duration of exposure, and actual, planned, and relative 
dose intensity will be summarized using descriptive statistics for the Part 1, 2 and 3 
Safety Populations for each study drug. 
The duration of exposure in months will be calculated as: 
duration of exposure (months) = (date of last dose of study drug – date of first dose of 
study drug + 1) / 30.4375. 
Actual dose intensity in dose units (mg for tamibarotene and venetoclax and mg/m2 for 
azacitidine) per month will be calculated as: 
actual dose intensity (units/month) = total dose received (units) / duration of exposure 
(months). 
The planned total dose of tamibarotene will be calculated as 12 mg × 21 days for each 
cycle. The planned total dose of azacitidine will be calculated as 75 mg/m2 × 7 days for 
each cycle. 
For the planned total dose of venetoclax for each cycle, refer to Table 4 in the protocol. 
For example, the planned total dose for standard venetoclax dosing during Cycle 1 will 
be calculated as 100 mg (Day 1) + 200 mg (Day 2) + 400 mg × (the remaining days on 
treatment (between 12 and 26)). For standard venetoclax dosing during Cycles 2 and 
above, the planned total dose will be calculated as 100 mg (Day 1) + 200 mg (Day 2) + 
400 mg × (26 days) for Cycles 2 and above. The planned total dose calculation for 
venetoclax in combination with other drugs will be modified using the dose amounts 
indicated in Table 4 of the protocol. 
For each study drug, the planned total dose will be calculated as two steps: 
1) Sum of the doses in each cycle (Cycle 1 (unit) = X1 dose, Cycle 2 (unit)= X2 dose, ... 
Cycle n (unit)= Xn dose) 


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2) Sum of non-zero dosing in all cycles (Cycle 1 (unit) + Cycle 2 (unit) + … + Cycle n 
(unit)) 
Planned dose intensity in dose units (mg for tamibarotene and venetoclax and mg/m2 for 
azacitidine) per month will be calculated as: 
planned dose intensity (units/month) = planned total dose (units) / duration of exposure 
(months). 
Relative dose intensity will be calculated as: 
relative dose intensity = actual dose intensity (units/month) / planned dose intensity 
(units/month).  
Summary of duration of exposure to study treatment will include categorical summaries. 
Duration of exposure will be categorized into time intervals (i.e., <1 month, ≥1 - <2 
months, ≥2 - <3 months, ≥3 - <4 months, and ≥4 months); frequency counts and 
percentages will be presented for the number and percentage of participants in each 
interval.  
Additionally, the total number of delayed, interrupted/held, missed/incorrect, 
discontinued, increased, decreased, and Part 2 discontinued doses will be summarized 
separately using descriptive statistics for the Part 1, 2 and 3 Safety Populations by study 
drug. 
All study treatment administration data will be listed for each study drug. 
7.4 
Efficacy Evaluation 
7.4.1 
Datasets Analyzed 
All efficacy summaries will be based on the mITT and/or RE Population for Part 2 and 
the Safety Population for Parts 1 and 3. An additional summary of the primary endpoint 
will be based on the PP and RE Populations for Part 2 and on the RE Population for Parts 
1 and 3. Time to response and duration of response in Part 2 will be analyzed using the 
RE Population. Listings and descriptive summaries of AML disease response 
assessments, bone marrow sample results, detection of MRD and EMD, cytogenetics and 
molecular abnormalities and post-treatment survival follow-up will be provided to 
support the efficacy analyses. 
All efficacy analyses in Part 2 of the interim CSR will be based on the RE Population and 
all efficacy analyses in the final CSR will be based on the mITT and/or RE Populations. 


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7.4.2 
Primary Efficacy Endpoint Analysis Methods 
7.4.2.1 
Part 2 
Participants will be assessed for the primary endpoint of CR/CRi from the time of the 
index date until the initiation of non-study drug therapy or until time of disease 
progression/relapse in Part 2 of the study. Further details of the calculation of the primary 
endpoint are provided in Section 6.4.1.1. The analysis of the CR/CRi rate is planned for 
the time when all participants have completed the Cycle 3 EoC response assessment or 
discontinued treatment earlier. 
The primary estimand is the CR/CRi rate, which is estimated by the proportion of 
participants who achieve CR/CRi (as determined by the investigatora). 
The null hypothesis (H0) to be tested is: 
 
In RARA-positive participants with previously untreated AML who are ineligible for 
standard induction therapy, the CR/CRi rate after treatment with 
tamibarotene/venetoclax/azacitidine is the same as the CR/CRi rate after treatment with 
venetoclax/azacitidine. 
 
The alternate hypothesis (HA) to be tested is: 
In RARA-positive participants with previously untreated AML who are ineligible for 
standard induction therapy, the CR/CRi rate after treatment with 
tamibarotene/venetoclax/azacitidine is higher than the CR/CRi rate after treatment with 
venetoclax/azacitidine. 
The number (%) of participants and 95% exact binomial CIs of the percentage of 
responders and non-responders (along with criteria for non-response) will be summarized 
by treatment group for the mITT Population, based on the Clopper-Pearson method. A p-
value from a Fisher’s exact test comparing the CR/CRi rates (%) between the two 
treatment groups with a 1-sided 5% level of significance will also be presented. The 
primary analysis will be repeated for the PP Population as a sensitivity analysis. 
A by-participant listing of the derived efficacy data used for the CR/CRi rate will be 
provided. Sensitivity analyses based on the RE Population may also be performed. 
7.4.3 
Secondary Efficacy Endpoint Analysis Methods 
7.4.3.1 
Part 1 
7.4.3.1.1 
Overall Response Rate 
 
 
a Determination of response will be made by the investigator in alignment with ELN AML criteria 
(Döhner 2017) and Bloomfield 2018 for CRh. 


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The number (%) of participants and 95% exact binomial CIs of the percentage of overall 
responders and non-overall responders (along with criteria for non-response), based on 
the Clopper-Pearson method, will be summarized for the Part 1 Safety Population. The 
number (%) of participants and 95% exact binomial CIs for the individual and combined 
rates of CR, CRi, CRh, MLFS, and PR will also be summarized based on the Clopper-
Pearson method. A by-participant listing of the derived efficacy data used for 
determining the ORR will be provided. A sensitivity analysis based on the RE Population 
may also be conducted. 
7.4.3.2 
Part 2 
7.4.3.2.1 
CR and CR/CRh Rates 
The CR and CR/CRh rates will be analyzed separately using the same statistical 
methodologies applied to the primary efficacy endpoint for the mITT Population, as 
described in Section 7.4.2. A by-participant listing of the derived efficacy data used for 
determining the CR and CR/CRh rates will be provided. 
7.4.3.2.2 
Duration of CR, CR/CRi, CR/CRh 
The duration of CR, CR/CRi, and CR/CRh will be estimated using Kaplan-Meier 
product-limit estimates and will be presented in separate summaries by treatment group 
for the mITT Population and only for participants who are responders as defined in 
Section 6.4.1 for the respective categories.  
The median estimate of duration of CR, CR/CRi, and CR/CRh and corresponding 95% 
CIs based on the Brookmeyer and Crowley method will be provided for each treatment 
group. The analysis will only be for participants who are CR, CR/CRi, and CR/CRh 
responders, respectively, or who are censored after achieving response. Event and 
censoring rules for duration of CR, CR/CRi, and CR/CRh are provided in Table 9. A 
sensitivity analysis of the duration of CR, CR/CRi, and CR/CRh will also be performed 
using the alternative censoring rule identified in situation number 5. A sensitivity analysis 
based on the RE Population may also be conducted for duration of CR/CRi. 
Table 9 
Assignments for Event and Censoring Dates for Duration of CR 
Analysis 
Situation 
# 
Situation (Occurring on or 
After First Date of CR 
Response) 
Date of Event or Censoring  
Outcome  
1 
No post-baseline response 
assessments after the first 
CR/CRi/CRh and the 
participant has not died or 
developed disease 
progression/ relapse (if the 
participant has died or 
developed disease 
First date of CR, CR/CRi, CR/CRh response 
Censored 


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Situation 
# 
Situation (Occurring on or 
After First Date of CR 
Response) 
Date of Event or Censoring  
Outcome  
progression/relapse follow the 
rules for death indicated in 
situations #6-7) 
2 
Disease progression / relapse 
documented at scheduled 
visits within extended loss-to-
follow-up time [1] 
Date of assessment of disease progression / 
relapse 
Event 
3 
Disease progression / relapse 
documented between 
scheduled (unscheduled) visits 
within extended loss-to-
follow-up time [1] 
Date of assessment of disease progression/ 
relapse 
Event 
4 
No disease progression / 
relapse (or death)  
Date of last adequate response assessment [2] 
Censored 
5 
HSCT and/or systemic therapy 
started prior to documented 
disease progression / relapse 
or death 
Date of last adequate response assessment 
occurring prior to documented disease 
progression/relapse or death, irrespective of 
HSCT/systemic therapy date[2] 
Censored  
Date of assessment of disease progression/ 
relapse or death [SA] 
Event 
6 
Death within extended loss-to-
follow-up time [1] 
Date of death 
Event 
7 
Death or disease progression / 
relapse after an extended loss-
to-follow-up time [1]   
Date of last adequate response assessment [2] 
prior to the ≥2 missed consecutive 
assessments 
Censored 
[SA] Alternative rule for handling of events for duration of CR.  
[1] Extended loss-to-follow-up time is defined as the last non-missing adequate response assessment and 
event (death or disease relapse). Extended loss-to-follow-up time is 240 days. This cutoff is calculated 
based on the protocol scheduled procedure: the 28-day treatment cycle has ± 3 days window, response 
assessment is expected to be conducted every 3 months (with ± 30 days window). Thus, 2 consecutive 
scheduled assessments window is 2 × [30 × 3 + 30] = 240 days. Within extended loss-to-follow up time is 
defined as ≤240 days; after an extended loss-to-follow-up time is defined as: >240 days. 
[2] An adequate response assessment is defined as an assessment where the investigator performed all the 
procedures required for assessment and documented the outcome. 
7.4.3.2.3 
Time to CR, CR/CRi, CR/CRh 
 
Time to CR, CR/CRi, and CR/CRh will be summarized separately using descriptive 
statistics by treatment group and only for participants who are responders for the mITT 
Population. A sensitivity analysis based on the RE Population may also be conducted for 
time to CR/CRi. 
7.4.3.2.4 
Overall Response Rate 
 
The ORR will be analyzed using the same statistical methodologies applied to the 
primary efficacy endpoint, described in Section 7.4.2, for the mITT Population. A by-


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participant listing of the derived efficacy data used for determining the ORR will be 
provided. Sensitivity analyses of ORR based on the RE Population may also be 
conducted. 
7.4.4 
Exploratory Efficacy Endpoint Analysis Methods 
7.4.4.1 
Part 1 
Analysis of clinical response and genetic mutations and/or gene expression markers at 
baseline, on treatment, and/or at time of loss of response will be detailed in a separate 
document and is outside the scope of this SAP. 
7.4.4.2 
Part 2 
7.4.4.2.1 
Event-Free Survival 
EFS is defined as the duration from the index date to the date of progressive disease, 
relapse after CR/CRi, treatment failurea, or death from any cause. EFS will be estimated 
using Kaplan-Meier product-limit estimates for the mITT Population and will be 
presented for each treatment group. The number and percentage of participants with an 
event or who were censored will be summarized by treatment group. The 25th percentile, 
median and 75th percentile (along with corresponding 95% CIs based on the Brookmeyer 
and Crowley method), will also be presented. Landmark analyses (EFS rates, 95% CI, 
and number of participants at risk) will occur at 6, 12, and 18 months from the index date. 
An unstratified log rank test will be used to analyze the difference in EFS between 
treatment groups and a 2-sided p-value with 5% level significance will be presented. A 
sensitivity analysis of EFS will also be performed using the alternative censoring rules 
identified in situation numbers 4, 6, 8, and 10 in Table 10. 
Additionally, a separate summary of reasons for censoring, plots of the Kaplan-Meier 
estimates a by-participant listing of the derived efficacy data used for the EFS analysis, 
and a listing of reasons for censoring will be provided. 
Table 10 
Assignments for Primary and Alternative Event and Censoring Dates 
for EFS Analysis 
Situation 
# 
Situation 
Date of Event or Censoring  
Outcome  
1 
No (or inadequate) baseline disease 
assessments [1] and the participant has 
not died (if the participant has died 
follow the rules for death indicated in 
situations #7-9). 
Index Date 
Censored 
2 
No post-baseline response assessments 
and the participant has not died (if the 
Index Date 
Censored 
 
a Treatment failure is defined as failure to achieve a bone marrow blast count of <5% following at least 
2 cycles of therapy, as determined by the investigator. 


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Situation 
# 
Situation 
Date of Event or Censoring  
Outcome  
participant has died follow the rules for 
death indicated in situations #7-9) 
3 
Progressive disease, relapse after 
CR/CRi, or treatment failure 
documented at scheduled visits without 
extended loss-to-follow-up time [2] 
Date of assessment of Progressive 
disease, relapse after CR/CRi, or 
treatment failure 
Event 
4 
Progressive disease, relapse after 
CR/CRi, or treatment failure 
documented between scheduled visits 
without extended loss-to-follow-up 
time [2] 
Date of assessment of Progressive 
disease, relapse after CR/CRi, or 
treatment failure 
Event 
Date of next scheduled response 
assessment [SA] 
Event [SA] 
5 
No progressive disease, relapse after 
CR/CRi, or treatment failure (or death).  
Date of last adequate response 
assessment [3] 
Censored 
6 
New systemic therapy and/or HSCT 
started (prior to documented 
progressive disease, relapse after 
CR/CRi, treatment failure, or death).  
Date of last adequate response 
assessment irrespective of new 
systemic therapy and/or HSCT 
date [3] 
Censored 
Date of assessment of progressive 
disease, relapse after CR/CRi, 
treatment failure, or death [SA] 
Event [SA] 
7 
Death without extended loss-to-follow-
up time [2] 
Date of death 
Event 
8 
Death, progressive disease, relapse 
after CR/CRi, or treatment failure after 
an extended loss-to-follow-up time [2]   
Date of last adequate response 
assessment [3] prior to event (prior 
to missed assessments) 
Censored 
Date of death or event [SA] 
Event [SA] 
9 
Death, progressive disease, relapse 
after CR/CRi, or treatment failure after 
an extended loss-to-follow-up time [2] 
from index date 
Index Date 
Censored 
10 
Treatment discontinuation due to 
progressive disease, relapse after 
CR/CRi, or treatment failure before 
progressive disease, relapse after 
CR/CRi, treatment failure or death [SA] 
Date of treatment discontinuation 
[SA] 
Event [SA] 
[SA] Alternative rule for handling of events for supplementary estimand of EFS.  
[1] Adequate baseline assessments are defined as at least one non-missing bone marrow sample or peripheral 
blood (ANC, platelets, and blasts) result at baseline. 
[2] Extended loss-to-follow-up time is defined as the last non-missing adequate response assessment and 
event (death or disease relapse). Extended loss-to-follow-up time is 240 days. This cutoff is calculated 
based on the protocol scheduled procedure: the 28-day treatment cycle has ± 3 days window, response 
assessment is expected to be conducted every 3 months (with ± 30 days window). Thus, 2 consecutive 
scheduled assessments window is 2 × [30 × 3 + 30] = 240 days. Within extended loss-to-follow up time is 
defined as ≤240 days; after an extended loss-to-follow-up time is defined as: >240 days. 
[3] An adequate response assessment is defined as an assessment where the investigator performed all the 
procedures required for assessment and documented the outcome. 


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7.4.4.2.2 
Overall Survival 
Overall Survival is defined as the time from the index date to the date of death due to any 
cause. Participants who do not die by the end of the study and participants lost to follow-
up before data cutoff will be censored at the date that the participant was last known to be 
alive. OS will be estimated using Kaplan-Meier product-limit estimates for the mITT 
Population. The number and percentage of participants with an event or who were 
censored will be presented along with the range of values (including and excluding 
censored participants). The 25th percentile, median and 75th percentile along with 
corresponding 95% CIs based on the Brookmeyer and Crowley method will also be 
presented. Landmark analyses (OS rates, 95% CI, and number of participants at risk) will 
occur at 6, 12, 18, and 24 months from the index date. Additionally, plots of the Kaplan-
Meier estimates will be provided. A by-participant listing of the derived efficacy data 
used for determining OS will be provided. 
7.4.4.2.3 
MRD-negative Response Rates 
The MRD-negative response rate will be analyzed using the same statistical 
methodologies as applied to the primary efficacy endpoint, as described in Section 7.4.2, 
for the mITT Population. A by-participant listing of the derived efficacy data used for 
determining the MRD-negative CR rate will be provided. 
7.4.4.2.4 
Time to MRD-negative Response 
 
Time to MRD-negative response will be summarized using descriptive statistics by 
treatment group and only for participants who are responders for the mITT Population. 
7.4.4.2.5 
TI Rate 
The TI rate will be analyzed using the same statistical methodologies as applied to the 
primary efficacy endpoint for the mITT Population, described in Section 7.4.2. A by-
participant listing of the derived efficacy data used for determining the TI rate will be 
provided. 
7.4.4.2.6 
Clinical Response and Genetic Mutations and/or Gene Expression 
Markers 
Analysis of clinical response and genetic mutations and/or gene expression markers at 
baseline, on treatment, and/or at time of loss of response will be detailed in a separate 
document and is outside the scope of this SAP. 
7.4.4.3 
Part 3 
7.4.4.3.1 
Overall Response Rate 
 
The number (%) of participants and 95% exact binomial CIs of the percentage of overall 
responders and non-overall responders (along with criteria for non-response) will be 
summarized for the Part 3 Safety Population. The number (%) of participants and 95% 


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exact binomial CIs for overall response, comprised of the combined rates of CR, CRi, 
CRh, MLFS, and PR will be summarized. A by-participant listing of the ORR will be 
provided. A sensitivity analysis based on the RE Population may also be conducted. 
7.4.4.3.2 
Overall Survival 
 
Overall Survival is defined as the time from the index date to death due to any cause. 
Participants who do not die by the end of the study will be censored at the date that the 
participant was last known to be alive. OS will be estimated using Kaplan-Meier product-
limit estimates for the Part 3 Safety Population. Participants who do not die by the end of 
the study will be censored at the last date the participant is known to be alive. 
 
The number and percentage of participants with an event or who were censored will be 
summarized. The 25th percentile, median and 75th percentile (along with corresponding 
95% CIs), will also be presented. Landmark analyses (OS rates, 95% CI, and number of 
participants at risk) will occur at 6, 12, 18, and 24 months post-first dose. Additionally, a 
plot of the Kaplan-Meier estimates will be provided. A by-participant listing of the 
derived efficacy data used for determining OS will be provided. 
7.4.4.3.3 
Clinical Response and Genetic Mutations and/or Gene Expression 
Markers 
 
Analysis of clinical response and genetic mutations and/or gene expression markers at 
baseline, on treatment, and/or at time of loss of response will be detailed in a separate 
document and is outside the scope of this SAP. 
7.4.5 
Statistical/Analytical Issues 
7.4.5.1 
Interim Analysis 
An interim futility analysis of the CR/CRi rates is planned in Part 2 for the first 
 
randomized RARA-positive participants and will be performed after approximately 
 
randomized participants have been on treatment for approximately 3 months or 
discontinued treatment earlier than 3 months. The study may be terminated at this interim 
analysis for futility if the 1-sided p-value from the Fisher’s exact test comparing the 
CR/CRi rates (tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine) is 
. The non-binding futility bound is derived using a Hwang-Shi-DeCani (HSD) 
spending function with gamma = ‑2 (Hwang 1990). Refer to Section 7.4.2 for a 
description of the analysis of the CR/CRi rate. 
 
Administrative interim analyses may be performed after approximately 25% and 75% (
 
) of participants have had approximately 3 cycles of treatment. All interim 
analyses in Part 2 will be conducted on mITT, RE, and/or PP Populations, as deemed 
necessary. No multiplicity adjustments are needed since the study will not be stopped for 
efficacy until the primary analysis. 
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7.4.5.2 
Multiplicity Adjustments 
Multiplicity adjustment is not applicable. The formal hypothesis testing is only performed 
on the primary efficacy endpoint CR/CRi rate on the mITT Population. CR/CRi rate will 
be formally tested at the 5% level (one-sided). No formal hypotheses testing will be 
performed for the secondary endpoints. 
7.4.5.3 
Examination of Subgroups 
To determine whether the treatment effect is consistent across various subgroups, 
subgroup analyses of the CR/CRi rate in Part 2 will be performed based on the participant 
subgroup categories listed below.  
• Age Group: 
- 
≥18 to <65 
- 
≥65 to <75 
- 
≥75 
• Gender: 
- 
Female 
- 
Male 
• Race: 
- 
Asian 
- 
Black or African American 
- 
White 
- 
Other/Multiple 
• Geographical Region: 
- 
North America 
- 
France 
• ECOG Performance Status: 
- 
0 or 1 
- 
2 
- 
3 
• TP53: 
- 
Mutated 
- 
Wild type 
• IDH1/IDH2:  
- 
IDH1 mutated/IDH2 wild type 
- 
IDH1 wild type/IDH2 mutated  
- 
IDH1 wild type/IDH2 wild type 
IDH1 mutated/IDH2 mutated 


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• FLT3, ITD, or TKD: 
- 
Any or all mutated 
- 
Other 
• NPM1: 
- 
Mutated 
- 
Wild type 
A forest plot of the estimated treatment effect along with 95% CIs of CR/CRi rate will be 
provided by the subgroup factors listed above. A subgroup analysis may not be 
performed if the number of participants in the subgroup in each treatment group is not 
sufficiently large (e.g., <10%). Additional subgroup analyses may be performed post-hoc, 
as appropriate. 
7.5 
Pharmacokinetic Evaluation 
 
The PK analyses will be provided in a separate report and is outside the scope of this 
SAP. 
7.6 
Safety Evaluation 
Safety analyses will be carried out for the Part 1, 2, and 3 Safety Populations. All safety 
data from participants in Part 2 who received venetoclax/azacitidine but were not 
randomized will be listed separately. For safety analyses presented by study visit, the 
baseline value will be defined as the last non-missing value reported prior to first study 
drug administration. 
7.6.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after 
the first dose of study drug or existing events that worsened after the first dose during the 
study up until the last dose of study drug + 30 days. TEAEs will be summarized by study 
part, treatment group and total (Part 2 only).  
Summaries of the number and fraction of participants with the Selected AEs in Table 11 
will be presented for Part 2. The searching strategy for Selected AE groups and their 
associated SMQ, HLT, or CMQ is listed in Table 11. 
Table 11 
Search Strategy for Selected TEAE Groups 
Selected TEAE Group 
Search Strategy 
Rash 
HLT Rashes, eruptions, and exanthems NEC 
Hypersensitivity (SMQ) broad search 
Pain 
HLT Pain and discomfort NEC 
HLT Bone Related Signs and Symptoms 
HLT Musculoskeletal and Connective Tissue Pain & 
Discomfort 
Hypertriglyceridemia 
HLT Elevated triglycerides 


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AEs with missing start and/or stop dates will be considered TEAEs. Imputation rules for 
partial and missing dates are described in Table 7.  
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using MedDRA, version 23.1 or higher. AEs are graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 5. If an AE grade is missing, the previous worst grade under the same PT will be 
assigned if it is available, otherwise a grade of 4 will be assigned for classification 
purposes in the TLFs. 
The CTCAE Grade will be summarized by grouping Grade 1 and Grade 2 together, then 
Grade 3 and Grade 4 together, as well as any grade for all relevant TEAE tables. 
• Overall summary of the number of TEAEs, TEAEs by relationship to study drug, 
TEAEs by CTCAE grade, serious AEs (SAEs), SAEs related to study drug, 
selected TEAEs, TEAEs requiring concomitant medications, TEAEs leading to 
dose interruption, TEAEs leading to dose reduction of study drug, TEAEs leading 
to discontinuation of study drug, TEAEs leading to death 
• TEAEs by SOC and PT 
PT Blood triglycerides increased 
PT Blood triglycerides abnormal 
Infections (all) 
SOC Infections and infestations 
Pneumonia/Respiratory infections 
Infective pneumonia (SMQ) narrow search 
Sepsis 
Sepsis (SMQ) narrow search 
Febrile neutropenia 
PT Febrile neutropenia 
Differentiation syndrome 
PT Differentiation syndrome 
Anemia/Red blood cell count decreased 
Hematopoietic erythropenia (SMQ) narrow search 
Thrombocytopenia/Platelet count decreased 
Hematopoietic thrombocytopenia (SMQ) narrow search 
Leukopenia/White blood cell count 
decreased 
Hematopoietic leukopenia (SMQ) narrow search 
Neutropenia/Neutrophil count decreased 
Hematopoietic leukopenia (SMQ) narrow search filtered 
for any PT with “neutro” 
Intracranial hypertension 
HLT Increased intracranial pressure disorders (in the 
SOC Nervous System Disorders) 
Elevated transaminases 
PT Transaminases elevated (in the investigations SOC) 
Arterial embolic and thrombotic events 
Embolic and thrombotic events (SMQ) Narrow search 
Venous embolic and thrombotic events 
Embolic and thrombotic events (SMQ) Narrow search 
Abbreviations: HLT = high-level term; MedDRA = Medical Dictionary for Regulatory Activities; 
NEC = not elsewhere classified; PT = preferred term; SMQ = Standardized MedDRA Query; 
SOC = system organ class; TEAE = treatment-emergent adverse event. 
Note: This list is based on MedDRA version 23.1 and will be updated based on the dictionary or relevant 
SMQ/HLT updates at the time of the analysis. 


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• TEAEs by PT 
• TEAEs occurring in ≥10% of participants in any treatment group by PT 
• TEAEs related to study drug by SOC and PT 
• TEAEs related to study drug by PT 
• TEAEs by CTCAE grade, SOC and PT 
• TEAEs by CTCAE grade and PT 
• SAEs by SOC and PT 
• SAEs by PT  
• SAEs occurring in ≥5% of participants in any treatment group by PT 
• SAEs related to study drug by SOC and PT 
• SAEs related to study drug by PT 
• Selected TEAEs by PT 
• Selected TEAEs related to study drug by PT 
• Selected TEAEs with CTCAE Grade 3 or 4 by PT 
• Selected TEAEs related to study drug with CTCAE Grade 3 or 4 by PT 
• TEAEs requiring concomitant medications by SOC and PT 
• TEAEs requiring concomitant medications by PT 
• TEAEs related to study drug requiring concomitant medications by SOC and PT 
• TEAEs related to study drug requiring concomitant medications by PT 
• TEAEs leading to dose interruption of study drug by SOC and PT 
• TEAEs leading to dose interruption of study drug by PT 
• TEAEs leading to dose reduction of study drug by SOC and PT 
• TEAEs leading to dose reduction of study drug by PT 
• TEAEs leading to discontinuation of study drug by SOC and PT 
• TEAEs leading to discontinuation of study drug by PT 
• TEAEs leading to death by SOC and PT 
• TEAEs leading to death by PT 
Summaries by SOC and PT will be ordered by descending incidence of SOC and 
descending incidence of PT within each SOC. At each level of summarization (e.g., any 
AE, SOC, and PT), participants experiencing more than one TEAE will be counted only 
once. In the summary of TEAEs by CTCAE grade, participants will be counted once at 
the highest severity reported at each level of summarization; in the summary of TEAEs 
by relationship, participants will be counted once at the closest relationship to study drug. 
A TEAE will be considered related to study drug if it is related to at least one of the study 
drugs or relationship to all study drugs is missing. 
Additionally, a summary of all deaths will be provided, including the number and 
percentage of deaths, deaths occurring within 30 days of last dose, deaths occurring later 
than 30 days of last dose, treatment-related deaths, and primary reason for death.  
Adverse event data will be presented in data listings. SAEs, selected AEs, AEs requiring 
concomitant medications, AEs leading to dose interruption/dose 
reductions/discontinuation of study drug, AEs leading to death, and deaths will be 
presented in separate data listings.  


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For the Selected AE of (suspected) differentiation syndrome (DS), an additional table 
and/or listing for all cases of DS or suspected DS using the following algorithmic 
approach based on the Montesinos et al scoring system (Montesinos 2009) will be 
provided: 
a. This will include i) all participants with investigator-reported PT = Differentiation 
Syndrome and ii) additional participants with ≥2 different AE or Vital Sign (VS) 
abnormalities from the table below, if: 
• >2 of the AE or VS abnormalities started within 7 days of each other; 
• the events occurred in <90 days of study drug start. 
 
Criteria (Montesinos 
Sign/Symptom) 
Variable  
Variable  
≥1 of these (pulmonary 
infiltrates or pleuropericardial 
effusion) 
PT 
Acute pulmonary oedema 
Acute respiratory distress syndrome 
Non-cardiogenic pulmonary edema 
Pulmonary congestion 
Pulmonary oedema 
Pleural effusion 
Pericardial effusion 
Acute interstitial pneumonitis  
Acute lung injury 
Atypical pneumonia 
Lower respiratory tract infection 
Lower respiratory tract inflammation 
Lung infection 
Lung infiltration 
Pneumonia 
Pneumonitis 
Pulmonary toxicity 
≥1 of these (fever) 
PT 
Pyrexia 
Febrile neutropenia 
VS result 
Temperature (any value ≥38.3) 
≥1 of these (weight gain >5 kg) 
PT 
Capillary leak syndrome 
Fluid overload 
Fluid retention 
Generalized oedema 
Hydraemia 
Hypervolaemia 
Oedema 
Oedema peripheral 
VS result 
Weight (any value >5 kg from 
baseline) 
≥1 of these (hypotension) 
PT 
Hypotension 
VS result 
Systolic blood pressure 
(any value <90 mmHg) 


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≥1 of these (dyspnea) 
PT 
Acute respiratory failure 
Cardiopulmonary failure 
Cardio-respiratory distress 
Cough 
Dyspnoea 
Respiratory arrest 
Respiratory distress 
Respiratory failure 
≥1 of these (acute renal failure) 
PT 
Acute kidney injury 
Anuria 
Cardiorenal syndrome 
Hepatorenal failure 
Prerenal failure 
Renal failure 
Renal failure acute 
Renal impairment 
Renal injury 
Laboratory 
result 
Creatinine (any value >26.52 μmol/L 
or 1.5 × above baseline) 
(“catch-all”)  
PT 
Multi-organ failure 
Abbreviations: PT = preferred term; VS = vital sign. 
b. The DS listing will include for all cases found by the search strategy (a) above: 
Demographics, details of the AE including PTs, severity, start and end dates, onset 
and duration of AE, study drug held or decreased, and dates. 
The listing will also include whether an AE occurred with PT of Leukocytosis, 
Hyperleukocytosis, or White blood cell count increased, or laboratory results showing 
leukocyte count >10 Gi/L <7 days before or >7 days after AE of DS. For those 
participants, the maximum value of leukocyte count during <7 days before or >7 days 
after AE of DS (or grade if no laboratory value), and repeat cases of DS for 
participants who met the criteria more than once, separated by >14 days between 
recovery of earlier AE of DS and onset of new AE of DS, will be presented. 
7.6.2 
Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data analyzed by the 
local laboratory and presented in Système International (SI) units. All clinical laboratory 
data (hematology, serum chemistry, coagulation, urinalysis, and pregnancy test) will be 
listed. Laboratory measurements identified as abnormal (i.e., outside the normal range) 
will be flagged in the listings. 
Clinical laboratory measurements, including hematology, serum chemistry, and 
coagulation will be summarized by study part, treatment group and total (Part 2 only). 
Descriptive statistics will be presented for observed values and changes from baseline at 
each visit where parameters were scheduled to be collected per the clinical study 
protocol.  


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Urinalysis parameters will be summarized using the following categories: “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant”. A 3-by-3 
contingency table will be presented to summarize the shift from the baseline category to 
the worst post-baseline category. Summary results will include the count and percentage 
of participants within each shift category and treatment group. 
Where applicable, hematology and chemistry results for select parameters will be 
assigned a toxicity grade based on the NCI CTCAE, version 5.0. If the quantitative 
criteria for grading are equivalent for two grades and the differentiation is described by 
clinical interventions, the clinical intervention component will not be considered and the 
highest CTCAE grade will be assigned. Similarly, death related to AE (i.e., Grade 5) 
cannot be determined with available laboratory-based data collection and, thus, will not 
be summarized as a category. Laboratory parameters that include multiple sets of criteria 
for each direction (e.g., separate criteria for potassium measures to assess hyperkalemia 
and hypokalemia) will be summarized separately to reflect each set of criteria. 
Six-by-six contingency tables will be presented for lab tests where toxicity grading can 
be applied, to summarize the shift from the baseline grade to the worst post-baseline 
grade. Grades will be presented as none (Grade 0; i.e., measurements did not meet any 
CTCAE criteria for Grades 1 through 4), mild (Grade 1), moderate (Grade 2), severe 
(Grade 3), life-threatening (Grade 4), or missing grade. Summary results will include the 
count and percentage of participants within each shift category. 
In addition, non-CTCAE-graded hematology, chemistry, and coagulation parameters will 
be summarized using the following categories: low, normal, high, and missing. A 4-by-4 
contingency table will be presented to summarize the shift from the baseline category to 
the worst post-baseline category. Summary results will include the count and percentage 
of participants within each shift category and treatment group. 
Prothrombin time will not be summarized and will only be available in a listing. 
International normalized ratio (INR) will be summarized. 
7.6.2.1 
Liver Safety Assessment 
The following potentially clinically significant (PCS) criteria in liver function tests for 
alkaline phosphatase (ALP), alanine transaminase (ALT), total bilirubin (TB), aspartate 
transaminase (AST), International Normalized Ratio (INR), and their combination are 
defined as follows. The participant’s worst post-baseline value (highest for all parameters 
and lowest for ALP, for combination values where ALP <2 × upper limit of normal 
[ULN]) will be used. 
• 
ALT or AST >3 × ULN 
• 
ALT or AST >5 × ULN 
• 
ALT or AST >8 × ULN 
• 
ALT or AST >10 × ULN 
• 
ALT or AST >20 × ULN 
• 
TB >2 × ULN 


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• 
ALP >1.5 × ULN 
• 
INR >1.5 
• 
ALT or AST >3 × ULN and TB >2 × ULN (*) 
• 
ALT or AST >3 × ULN and INR >1.5 (*) 
• 
ALT or AST >3 × ULN and ALP <2 × ULN and TB >2 × ULN (*) 
(*) Combination of values measured within same day or within 1 day apart 
The number and percentage of participants with potentially clinically significant values in 
liver enzymes and total bilirubin will be presented by study part, treatment group, and 
total (Part 2 only). A listing of participants who met above PCS criteria will be provided.  
7.6.3 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.6.3.1 
Vital Signs 
Vital sign measurements will be summarized by study part, treatment group and total 
(Part 2 only). Descriptive statistics will be presented for results and change from baseline 
at each time point where vital signs were scheduled to be collected.  
A shift from baseline to the worst post-baseline blood pressure category (normal to stage 
2 hypertension) summary will be presented by treatment group and total (Part 2 only) 
according to each of the American College of Cardiology (ACC) and American Heart 
Association (AHA) 2017 guidelines as outlined in the table below. 
Table 12 
Vital Signs ACC/AHA Blood Pressure Categories 
Blood Pressure 
Category 
Systolic Blood 
Pressure 
 
Diastolic Blood 
Pressure 
Normal 
<120 mmHg 
and 
<80 mmHg 
Elevated 
120 - 129 mmHg 
and 
<80 mmHg 
Stage 1 Hypertension 
130 - 139 mmHg 
or 
80 - 89 mmHg 
Stage 2 Hypertension 
≥140 mmHg 
or 
≥90 mmHg 
Additionally, temperature will be summarized by treatment group and total (Part 2) for 
each visit according to CTCAE grading criteria guidelines as outlined in the table below.  
Table 13 
CTCAE Grading Criteria for Temperature 
CTCAE Grade 
Criteria 
Grade 0 
<38.0 degrees C (<100.4 degrees F) 
Grade 1 
38.0 – 39.0 degrees C (100.4 - 102.2 degrees F) 
Grade 2 
>39.0 – 40.0 degrees C (102.3 - 104.0 degrees F)  
Grade 3 
>40.0 degrees C (>104.0 degrees F) for ≤24 hrs 
Grade 4 
>40.0 degrees C (>104.0 degrees F) for >24 hrs 
All vital signs data including scheduled and unscheduled time points will be presented in 
the participant data listings. 


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7.6.3.2 
12-Lead Electrocardiogram 
Twelve-Lead ECG continuous parameters (heart rate, PR Interval, QT Interval, QRS 
Duration, QTcF Interval) as calculated automatically by machine will be summarized by 
study part, treatment group and total (Part 2 only). Descriptive statistics will be presented 
for observed values and changes from baseline at each visit where parameters were 
scheduled to be collected.  
ECG recordings will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” or “abnormal, clinically significant.” A 3-by-3 contingency table 
will be presented to summarize the shift from the baseline category to the worst post-
baseline value. Summary results will include the count and percentage of participants 
within each shift category and treatment group. 
Prolonged QTcF intervals will be summarized as QTcF measurements (msec) that are 
>450 msec, >480 msec, and >500 msec at each visit where ECG is routinely collected per 
the clinical study protocol. Change from baseline categories will also be summarized for 
measurements that represent a change >30 msec or >60 msec relative to the baseline 
value. Summary results will include the percentage of participants within each category 
and treatment group.  
All ECG data including scheduled and unscheduled time points will be listed. 
Abnormalities occurring at any point in the study post-baseline will also be included in 
the ECG listing. 
7.6.3.3 
Physical Examination 
Any abnormal clinically significant finding identified during the physical examination 
will be recorded as medical history or AE depending on when it started or worsened. 
Otherwise, no other physical examination data will be listed or summarized. 
7.6.3.4 
ECOG Performance Status 
ECOG performance scores will be summarized by study part, treatment group, and total 
(Part 2 only). The number and percentage of participants will be presented by ECOG 
performance score (ranging from 0 to 5) at each time point where ECOG performance 
scoring was scheduled to be collected. The change from baseline by visit will be 
summarized. Additionally, 4-by-6 contingency table will be presented to summarize the 
shift from the baseline category to the worst post-baseline score. Summary results will 
include the count and percentage of participants within each shift category and treatment 
group. By-participant ECOG performance status results will be provided in a listing. 
7.7 
Determination of Sample Size 
Up to approximately 
 participants will be treated in Part 1. The actual number of 
tamibarotene dose levels explored in combination with venetoclax/azacitidine, and the 
number of participants treated at each dose regimen, will vary depending on the totality 
of evaluated data (including safety, dose modifications, and tamibarotene PK data) from 
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participants treated with the tamibarotene/venetoclax/azacitidine combination. With 
 
participants treated, there is approximately 
% probability of observing at least 1 AE 
with an event rate of 
%. With  participants treated, there is approximately 
% 
probability of observing at least 1 AE with an event rate of 
%. 
Approximately 
 participants will be randomized in Part 2, which provides 
approximately 
% power to detect a difference in CR/CRi rates between 
tamibarotene/venetoclax/azacitidine and venetoclax/azacitidine, with assumed CR/CRi 
rates of 
% versus 
% in the 2 groups, respectively, a 1:1 randomization, and a 1-sided 
alpha of 
. 
Part 3 of the study is exploratory in nature and the number of participants who will 
receive tamibarotene in addition to venetoclax/azacitidine will vary depending on the 
number of participants who experienced disease progression, relapse after initial CR or 
CRi response, or treatment failure when randomized and treated with 
venetoclax/azacitidine in Part 2.  
7.8 
Changes in the Conduct of the Study or Planned Analyses 
The planned analyses outlined in this SAP include deviations from the protocol as 
outlined below: 
• The Estimands table in the protocol (Table 7) has been modified (see Table 4 in 
the SAP).  
8 AMENDMENT HISTORY 
 
Version 2.0 
The number of participants in Part 2 and the dosing regimen have been clarified. The 
timeline for response assessments, as well as the criteria have been detailed. The 
estimand framework for the primary objective in Part 2 has been added. The participant 
population used for the different analyses have been detailed. Clarification added that PK 
analyses are not in scope for this SAP. 
 
Version 3.0 
A Response Evaluable Population has been defined. Efficacy analyses for Part 2 may be 
conducted for the mITT, PP, and/or RE Populations, as appropriate. The definition of 
index date has been added, which is the date of randomization for Part 2 and the date of 
Cycle 1 Day 1 visit for Parts 1 and 3. TTE endpoints, such as EFS and OS, will be 
calculated from the index date, instead of the Cycle 1 Day 1 visit date. Additional details 
have been added to the subgroup analysis section. 
The definition of protocol deviations has been updated. The definition of concomitant 
medications has been updated, and a definition of transfusion burden has been added. 
Additional details have been added about liver assessments and on how to address 
CCI
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
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missing AE grades. A search strategy for selected AE groups and their associated 
SMQ/HLT or CMQ has been added as an appendix.  
 
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In Section 6.4.1, the following updates were made: 
• The index date for Part 2 was changed to earlier of (date of randomization, 
Cycle 1 Day 1) to accommodate for all scenarios.  
• Definitions of all response rates were clarified to represent the respective analysis 
population in the denominator. 
• All time to response and duration endpoints were changed from months to days. 
• It was specified that the date of the bone marrow aspirate will be used for 
determining the date of response.  
• MRD-negative rate has been added to align with the protocol. 
• Response definitions for participants with marrow blast clearance (<5%) were 
added based on Döhner 2022. 
In Section 7.1, the following updates were made: 
• Descriptions of the planned analyses for this study were added. 
• Deleted Q1 and Q3 from the standard summary of continuous variables. 
• Details of handling subcategories under a categorical variable were added.  
• Formatting of decimal places has been modified to align with pivotal 
Study SY-1425-301. 
• Testing and p-values for exploratory endpoints have been deleted. 
• In Section 7.1.3.4, Table 8 has been updated to ensure that proper imputation 
methods are used for both events that should end prior to the treatment start date 
(e.g., prior cancer therapy) and events that should end after the treatment start date 
(e.g., concomitant medications). 
• Section 7.1.3.6 was added to detail the imputation rules for missing date of birth 
and the calculation of age. Sections 7.1.3.7, 7.1.3.8, and 7.1.3.9 were added to 
detail the imputation rules for missing date of death, calculation of ECG data, and 
post-baseline missing values, respectively. For all analyses in Part 3, the baseline 
visit definition has been added.  
• Rules in threshold values and text regarding scheduled/unscheduled visits was 
also added. 
In Section 7.2, the following updates were made: 
• Part 2 ITT Population was changed to include all randomized participants not just 
RARA-positive participants. 
• Added PP Population to be aligned with the protocol. 
• Clarified that participants who received only venetoclax and/or azacitidine will be 
assigned to the doublet treatment group in the Safety Population. 


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• To account for participants who received venetoclax and azacitidine in Part 2 but 
were not randomized, listings were added. 
• It was specified that all efficacy analyses in Part 2 of the interim CSR will be 
based on the RE Population and in the final CSR will be based on the mITT and 
RE Populations. 
In Section 7.3, the following updates were made: 
• The populations to be used for various analyses of baseline data were updated 
and/or clarified.  
• Baseline ECOG status of 4 was deleted to be in alignment with the protocol 
eligibility criteria. 
• The bone marrow blast categories were updated for AML disease history. 
• Clarification was added that a separate listing of prior and concomitant blood 
transfusions will be provided for each study part. 
• Clarification was added to flag participants continuing in Part 3 in the Part 2 
listings, where applicable. 
In Section 7.4.1, time to response and duration of response based on the RE Population 
were added to be consistent with the response rate calculation. 
In Section 7.4.5.3, the following updates were made: 
• New subgroup analyses of CR/CRi rate based on additional mutation status have 
been added to find possible predictors. 
• Subgroup analyses of OS were removed. 
In Section 7.6, the following updates were made: 
• Additional TEAE groups based on FDA feedback were added to Table 11. 
• Detailed analysis of DS was added based on FDA feedback. 
• A listing of all safety data from participants in Part 2 who received 
venetoclax/azacitidine but were not randomized was added. 
• Details of the analyses that will be performed for urinalysis and prothrombin time 
were added. 
• Box and whisker plots of change from baseline for specific labs were removed. 
In addition to the changes noted above, updates were made throughout the document to 
note that MedDRA and WHO dictionaries will be using version 23.1 or higher to align 
with more current studies in the New Drug Application. 


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9 REFERENCE LIST 
 
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Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 
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VIDAZA (azacitidine) Summary of Product Characteristics. Celgene Europe B.V. 2021. 
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VIDAZA (azacitidine) US Prescribing Information. Celgene Corporation. Available 
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