Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard Induction Therapy
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: Syros Pharmaceuticals

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

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

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Protocol SY-1425-202, Version 6.0 
 
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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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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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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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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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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 

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Protocol SY-1425-202, Version 6.0 
 
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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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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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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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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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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 
date of death due to any cause  

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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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Protocol SY-1425-202, Version 6.0 
 
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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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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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 

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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. 

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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 
 
 
 

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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.  

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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. 
 

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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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34 
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 
tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine.  

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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 
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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 
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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 
CCI

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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
CCI
CCI
CCI
CCI
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. 
Documentation of the progression of disease must be obtained and recorded in the EDC. 

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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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