A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Tamibarotene Plus Azacitidine Versus Placebo Plus Azacitidine in Newly Diagnosed, Adult Patients Selected for RARA-positive Higher-risk Myelodysplastic Syndrome (SELECT MDS-1)
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Sponsor: Syros Pharmaceuticals

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Protocol SY-1425-301, Version 4.1 
1 
Clinical Study Protocol 
Protocol Title: A Randomized, Double-blind, Placebo-controlled Phase 3 Study of 
Tamibarotene Plus Azacitidine Versus Placebo Plus Azacitidine in Newly Diagnosed Adult 
Patients Selected for RARA-positive Higher-risk Myelodysplastic Syndrome 
Protocol Number: SY-1425-301 
Amendment Number: 4.1 
Compounds: Tamibarotene (formerly SY-1425) and azacitidine 
Brief Title: Phase 3 Study of Tamibarotene Plus Azacitidine in Patients Selected for 
RARA-positive Higher-risk MDS (SELECT-MDS-1) 
Study Phase: 3 
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: 2020-004528-40; EU CT 
Number: 2023-510361-97-00 
DOCUMENT HISTORY 
Document 
Date 
Amendment 4.1 EU CTR (Version 4.1) 
04 June 2024 
Amendment 4 (Version 4.0) 
23 March 2023 
Amendment 3 CZE (Version 3.3) 
11 April 2022 
Amendment 3 UK (Version 3.2) 
08 April 2022 
Amendment 3 GER3 (Version 3.1) 
28 February 2022 
Amendment 1 GER2 (Version 1.6) 
27 September 2021 
Amendment 3 (Version 3.0) 
16 September 2021 
Amendment 2 (Version 2.0) 
30 July 2021 
Amendment 1 GER (Version 1.5) 
14 July 2021 
Amendment 1 BEL2 (Version 1.4) 
08 June 2021 
Amendment 1 BEL (Version 1.3) 
28 April 2021 
Amendment 1 FRA (Version 1.2) 
06 April 2021 
Amendment 1 (Version 1.1) 
06 January 2021 
Original Protocol (Version 1.0) 
23 October 2020 
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. 
NCT04797780

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Protocol SY-1425-301, Version 4.1 
 
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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-1425-301, Version 4.1 
 
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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-1425-301, Version 4.1 
 
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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-1425-301, Version 4.1 
 
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Table of Contents 
 
1 
PROTOCOL SUMMARY .........................................................................................8 
1.1 
Synopsis ...................................................................................................................8 
1.2 
Schema ..................................................................................................................19 
1.3 
Schedule of Activities ...........................................................................................20 
2 
INTRODUCTION ....................................................................................................25 
2.1 
Study Rationale ....................................................................................................25 
2.2 
Background ..........................................................................................................25 
2.2.1 
Disease Under Study ......................................................................................25 
2.2.2 
Tamibarotene .................................................................................................25 
2.2.3 
Azacitidine ......................................................................................................26 
2.3 
Benefit/Risk Assessment ......................................................................................26 
3 
OBJECTIVES AND ENDPOINTS .........................................................................27 
4 
STUDY DESIGN ......................................................................................................28 
4.1 
Overall Design ......................................................................................................28 
4.2 
Scientific Rationale for Study Design .................................................................30 
4.3 
Rationale for Dose and Regimen ........................................................................30 
4.4 
End of Study Definition .......................................................................................31 
5 
STUDY POPULATION ...........................................................................................31 
5.1 
Inclusion Criteria .................................................................................................31 
5.2 
Exclusion Criteria ................................................................................................32 
5.3 
Lifestyle Considerations ......................................................................................34 
5.4 
Screen Failures .....................................................................................................34 
5.5 
Criteria for Temporarily Delaying Randomization ..........................................34 
6 
STUDY DRUGS AND CONCOMITANT THERAPY .........................................34 
6.1 
Study Drugs Administered ..................................................................................34 
6.2 
Preparation/Handling/Storage/Accountability .................................................35 
6.2.1 
Tamibarotene/Placebo ...................................................................................35 
6.2.2 
Azacitidine ......................................................................................................36 
6.3 
Measures to Minimize Bias: Randomization and Blinding..............................36 
6.4 
Study Drug Compliance ......................................................................................37 
6.5 
Dose Modification and Management of Toxicities ............................................38 
6.5.1 
Dose Delay and Toxicity-related Discontinuation Guidelines ...................40 
6.5.2 
Phototoxicity ...................................................................................................40 
6.5.3 
Hypertriglyceridemia ....................................................................................40 
6.6 
Continued Access to Study Drug After the End of the Study ..........................40 
6.7 
Treatment of Overdose ........................................................................................40 
6.8 
Concomitant Therapy ..........................................................................................41 
6.8.1 
Cytotoxic or Investigational Therapy ..........................................................41 
6.8.2 
Growth Factors ..............................................................................................41 
6.8.3 
Thrombopoietin Receptor Agonists .............................................................41 
6.8.4 
Oral Hydroxyurea ..........................................................................................41 
6.8.5 
Platelet Transfusions .....................................................................................41 
6.8.6 
Red Blood Cell Transfusions.........................................................................42 
6.8.7 
 ................................................42 
6.8.8 
Antifibrinolytic ...............................................................................................42 
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6.8.9 
Retinoic Acid Syndrome ................................................................................42 
6.8.10 
Multivitamin and Supplements ....................................................................42 
6.8.11 
Antacids and Proton Pump Inhibitors .........................................................42 
7 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL ...............................................................43 
7.1 
Discontinuation of Study Drug Administration ................................................43 
7.2 
Discontinuation of Study Participation by Patient’s Withdrawal of Informed 
Consent..................................................................................................................43 
7.3 
Lost to Follow-up .................................................................................................44 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................44 
8.1 
Efficacy Assessments ...........................................................................................45 
8.1.1 
Response Assessment .....................................................................................45 
8.1.2 
Bone Marrow Sample Collection ..................................................................46 
8.1.3 
Hematologic Improvement ............................................................................46 
8.1.4 
Transformation to AML................................................................................46 
8.1.5 
Blood Product Transfusions..........................................................................47 
8.1.6 
Overall Survival .............................................................................................47 
8.2 
Safety Assessments ...............................................................................................47 
8.2.1 
Prior, Concomitant, and Subsequent Medication Review .........................47 
8.2.2 
ECOG Performance Status ...........................................................................47 
8.2.3 
Physical Examinations ...................................................................................47 
8.2.4 
Vital Signs .......................................................................................................48 
8.2.5 
Electrocardiograms........................................................................................48 
8.2.6 
Clinical Safety Laboratory Assessments ......................................................48 
8.2.7 
Pregnancy Testing ..........................................................................................49 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .........49 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information.....49 
8.3.2 
Method of Detecting AEs and SAEs .............................................................50 
8.3.3 
Follow-up of AEs and SAEs ..........................................................................50 
8.3.4 
Regulatory Reporting Requirements for SAEs ...........................................50 
8.3.5 
Pregnancy .......................................................................................................51 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs ...............................................................................................51 
8.4 
Pharmacokinetics .................................................................................................52 
8.5 
Genetics and Pharmacogenomics .......................................................................52 
8.6 
Biomarkers ...........................................................................................................52 
8.6.1 
RARA Biomarker Assessment ......................................................................52 
8.6.2 
Companion Diagnostic Assay Development ................................................53 
8.6.3 
Molecular Markers of Tumor Response and Resistance ...........................53 
8.7 
Health-related Quality of Life .............................................................................53 
9 
STATISTICAL CONSIDERATIONS ....................................................................53 
9.1 
Statistical Hypothesis ...........................................................................................53 
9.2 
Sample Size Determination .................................................................................54 
9.3 
Analysis Sets .........................................................................................................54 
9.4 
Statistical Analyses...............................................................................................55 
9.4.1 
General Considerations .................................................................................55 

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9.4.2 
Primary Endpoint ..........................................................................................55 
9.4.3 
Key Secondary Endpoint ...............................................................................55 
9.4.4 
Secondary Endpoints .....................................................................................58 
9.4.5 
Exploratory Endpoints ..................................................................................65 
9.4.6 
Timing of Efficacy Analysis ..........................................................................65 
9.5 
Interim Analyses ..................................................................................................65 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................66 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........66 
10.1.1 
Regulatory and Ethical Considerations .......................................................66 
10.1.2 
Informed Consent Process ............................................................................67 
10.1.3 
Confidentiality and Data Protection ............................................................68 
10.1.4 
Committees Structure ....................................................................................68 
10.1.5 
Dissemination of Clinical Study Data ..........................................................69 
10.1.6 
Data Quality Assurance .................................................................................69 
10.1.7 
Source Documents ..........................................................................................69 
10.1.8 
Study and Site Start and Closure .................................................................70 
10.1.9 
Publication Policy...........................................................................................70 
10.2 
Appendix 2: Clinical Laboratory Tests..............................................................71 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...............................................................73 
10.3.1 
Definition of AE..............................................................................................73 
10.3.2 
Definition of SAE ...........................................................................................74 
10.3.3 
Recording and Follow-up of AE and/or SAE ..............................................75 
10.3.4 
Reporting of SAEs..........................................................................................77 
10.3.5 
Reporting of Serious Adverse Events to Regulatory Authorities, Ethics 
Committees, and Institutional Review Board .............................................77 
10.4 
Appendix 4: Contraceptive and Barrier Guidance...........................................78 
10.4.1 
Definitions .......................................................................................................78 
10.4.2 
Contraception Guidance ...............................................................................80 
10.5 
Appendix 5: ECOG Performance Status ...........................................................81 
10.6 
Appendix 6: 
 ........................................................82 
10.7 
Appendix 7: Criteria for Determination of MDS IPSS-R Risk Category ......83 
10.8 
Appendix 8: IWG Response Criteria for MDS .................................................84 
10.9 
Appendix 9: European Organization for Research and Treatment of Cancer 
Quality of Life Core Questionnaire 30 (Sample) ..............................................86 
10.10 Appendix 10: EuroQol 5 Dimensions (Sample).................................................89 
10.11 Appendix 11: Abbreviations and Definitions ....................................................92 
11 REFERENCES .........................................................................................................95 
 
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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Randomized, Double-blind, Placebo-controlled Phase 3 Study of 
Tamibarotene Plus Azacitidine Versus Placebo Plus Azacitidine in Newly Diagnosed Adult 
Patients Selected for RARA-positive Higher-risk Myelodysplastic Syndrome 
Brief Title: Phase 3 Study of Tamibarotene Plus Azacitidine in Patients Selected for 
RARA-positive Higher-risk MDS (SELECT-MDS-1) 
Rationale: 
Tamibarotene (formerly SY-1425) is a potent and selective agonist of retinoic acid receptor 
alpha (RARα), approved for the treatment of relapsed/refractory acute promyelocytic leukemia 
(R/R APL) in Japan. Tamibarotene is being developed in a subset of non-APL acute myeloid 
leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS) patients who are 
RARA-positive, as identified by high levels of RARA expression in blasts. Initial clinical data in 
RARA-positive R/R AML and R/R HR-MDS patients treated with single agent tamibarotene 
demonstrated evidence of biological activity with myeloid differentiation and blast reductions 
(Jurcic 2017). In newly diagnosed, unfit AML patients, tamibarotene in combination with 
azacitidine showed high complete response (CR) rates and a rapid onset of action in 
RARA-positive patients (de Botton 2022). The adverse event (AE) profile of the combination 
was consistent with what has been previously reported for single agent tamibarotene or single 
agent azacitidine in treatment of AML/MDS patients (see Investigator’s Brochure [IB], 
VIDAZA United States Prescribing Information [USPI], VIDAZA Summary of Product 
Characteristics [SmPC]). Approximately 30% of AML patients (Jurcic 2017, Vigil 2017, 
de Botton 2022) and approximately 50% of MDS patients (data on file as of 27 May 2022) are 
RARA-positive. HR-MDS and AML are closely related biologically, with common cytogenetic 
abnormalities and gene mutations present in the blast populations in each condition (Arber 
2016). Historical precedent demonstrates that active agents in AML, specifically 
hypomethylating agents, are active in HR-MDS, supporting the rationale for further development 
of the combination of tamibarotene with azacitidine in the HR-MDS patient population. 
Azacitidine remains the standard of care for the treatment of HR-MDS (VIDAZA USPI, 
VIDAZA SmPC, National Comprehensive Cancer Network [NCCN] Guidelines for MDS, 
Malcovati 2013), however there is opportunity to improve upon the clinical outcomes of single-
agent azacitidine. In this study, newly diagnosed, RARA-positive HR-MDS patients will be 
randomized to therapy with tamibarotene plus azacitidine or placebo plus azacitidine. 
Inclusion Criteria: 
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. Patients must be RARA-positive based on the investigational assay (Section 8.6.1). 
3. Patients must be newly diagnosed with HR-MDS as follows: 

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Diagnosis of MDS according to the World Health Organization (WHO) classification 
(Arber 2016) and classified by the Revised International Prognostic Scoring 
System (IPSS-R) risk category as: 
a. 
Very High (risk score >6), 
b. 
High (risk score >4.5 to 6), OR 
c. 
Intermediate (risk score >3 to 4.5). 
4. Patients must have measurable disease with bone marrow blasts >5% at the Screening 
Visit. 
5. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 
≤2. 
6. Patients must have adequate organ function, as defined by: 
a. 
total bilirubin ≤3.0 × the upper limit of normal (ULN),  
b. 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN, 
and 
c. 
creatinine clearance ≥30 mL/min based on the Cockcroft-Gault Glomerular 
Filtration Rate estimation. 
7. Patients must have a serum/high-sensitivity urine 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 document. 
Exclusion Criteria:  
Patients are excluded from the study if any of the following criteria apply: 
1. Patients are suitable for and agree to undergo allogeneic hematopoietic stem cell 
transplantation (HSCT) at the time of screening. 
2. Patients received prior treatment for MDS with any hypomethylating agent, 
chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior 
treatment with growth factors or hydroxyurea. Growth factor treatment must be 

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discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be 
discontinued prior to starting study drug. 
3. Patients with history of cancer are excluded if they are in active treatment (with radiation, 
chemotherapy, antibodies, immunotherapies, or molecularly targeted therapies) or unless 
they are disease free for at least 2 years prior to the Screening Visit, following completion 
of a prior treatment. Exceptions include: localized prostate cancer treated with hormone 
monotherapy; localized breast cancer treated with adjuvant hormone monotherapy; or 
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 investigational product 
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. 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. 
12. Patients known to be refractory to platelet or packed red blood cell transfusions per 
Institutional Guidelines, or patients who refuse blood product support. 

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13. Patients received 
 (see 
 within 2 weeks prior to 
the first tamibarotene/placebo administration. 
14. 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. 
15. Patients require concurrent treatment with any investigational or approved oncology 
agent, other than the agents described in exclusion criterion #3. 
16. Patients with ≥20% blasts in peripheral blood or bone marrow or evidence of myeloid 
sarcoma (extramedullary AML). 
17. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (Common 
Terminology Criteria for Adverse Events [CTCAE], version 5). 
18. 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). 
19. 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). 
20. Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their 
excipients.  
21. Patients for whom treatment with tamibarotene or azacitidine is contraindicated. 
22. Patients with clinically significant cardiovascular disease, including unstable angina, 
acute myocardial infarction within 3 months prior to the start of study drug 
administration, or New York Heart Association Class III or IV congestive heart failure, 
cerebral vascular accident within 3 months prior to the start of study drug administration, 
or cardiac arrhythmia associated with hemodynamic instability.  
23. Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
• 
Characterize and compare the CR rate of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
CR, as determined by the investigator per the modified 
IWG MDS criteria (Cheson 2006) 
Key Secondary 
• 
Characterize and compare the OS of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
OS, defined as the time from the date of randomization to 
the date of death due to any cause 
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Objectives 
Endpoints 
Secondary 
• 
Characterize and compare the TI rate of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
TI, defined as a period of at least 56 days with no RBC or 
platelet transfusion since the date of randomization to the 
last dose of study drug +30 days, the initiation of post-
treatment therapy, or death, whichever occurs first 
• 
Characterize and compare the ORR of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
Overall response, defined as achieving CR, PR, mCR, or HI 
as determined by the investigator per the modified IWG 
MDS criteria (Cheson 2006) 
• 
Characterize the DOCR and duration of 
overall response of tamibarotene plus 
azacitidine or placebo plus azacitidine 
• 
DOCR, defined as the duration from the date of first 
documented evidence of CR to the date of documented 
relapse of disease, as determined by the investigator per the 
modified IWG MDS criteria (Cheson 2006), or death due to 
any cause, whichever occurs first 
• 
Duration of overall response defined as the duration from 
the date of first documented evidence of CR, PR, mCR, or 
HI, to the date of documented disease progression, relapse 
of disease as determined by the investigator per the 
modified IWG MDS criteria (Cheson 2006), or death due to 
any cause, whichever occurs first 
• 
Characterize the time to CR and time to 
initial response of tamibarotene plus 
azacitidine vs. placebo plus azacitidine 
• 
Time to CR, defined as the duration from the date of 
randomization to the date of the first documented evidence 
of CR as determined by the investigator per the modified 
IWG MDS criteria (Cheson 2006) 
• 
Time to initial response, defined as the duration from the 
date of randomization to the date of the first documented 
evidence of CR, PR, mCR, or HI as determined by the 
investigator per the modified IWG MDS criteria 
(Cheson 2006) 
• 
Characterize and compare the EFS of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
EFS, defined as the time from the date of randomization to 
the date of transformation to AML or death due to any 
cause, whichever occurs first 
• 
Compare changes in HRQOL of 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
Change in HRQOL as measured by the EORTC QLQ-30 
and EQ-5D-5L 
• 
Characterize the safety of tamibarotene 
plus azacitidine vs. placebo plus 
azacitidine 
• 
AEs and changes in clinical laboratory values, ECG results, 
and vital sign measurements 
Exploratory 
• 
Characterize and compare the cytogenetic 
CR rate of tamibarotene plus azacitidine 
vs. placebo plus azacitidine 
• 
Cytogenetic CR, defined as patients achieving cytogenetic 
CR (Cheson 2006), as determined by the investigator 
• 
Characterize and compare the molecular 
response rate of tamibarotene plus 
azacitidine vs. placebo plus azacitidine 
• 
Molecular response, defined as patients achieving a 
reduction in variant allele frequency by next generation 
sequencing 
• 
Characterize and compare the change in 
transfusion requirements of tamibarotene 
• 
Transfusion requirement, defined as the frequency and 
amount of blood products (RBC or platelet) received 

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Objectives 
Endpoints 
plus azacitidine vs. placebo plus 
azacitidine 
• 
Characterize and compare the rate of 
consolidation treatment with allogeneic 
HSCT following treatment with 
tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
The rate of consolidation with allogeneic HSCT defined as 
the proportion of patients who are treated with allogeneic 
HSCT 
• 
Characterize the PK of tamibarotene 
• 
Plasma concentrations of tamibarotene 
• 
Characterize MDS molecular features 
associated with response and with loss of 
response for tamibarotene plus azacitidine 
vs. placebo plus azacitidine 
• 
Clinical response and genetic mutations and/or gene 
expression markers at baseline, at the time of response, and 
loss of response 
Abbreviations: AE = adverse events; AML = acute myeloid leukemia; CR = complete remission; DOCR = duration 
of complete remission; ECG = electrocardiogram; EFS = event-free survival; EORTC QLQ30 = European 
Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30; EQ-5D-5L = EuroQol 5 
dimensions; HI = hematologic improvement; HRQOL = health-related quality of life; HSCT = hematopoietic stem 
cell transplantation; IWG = International Working Group; mCR = marrow CR; MDS = myelodysplastic syndrome; 
ORR = overall response rate; OS = overall survival; PK = pharmacokinetic(s); PR = partial remission; RBC = red 
blood cell; TI = transfusion independence; vs. = versus. 
Overall Design: 
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study comparing 
the activity of tamibarotene plus azacitidine to placebo plus azacitidine as first line of therapy in 
RARA-positive patients with newly diagnosed HR-MDS. Enrollment in countries in North 
America and Europe and in Israel is planned. 
At the Pre-screening Visit, blood samples will be collected and sent to the Almac Diagnostics 
Laboratory for assessment of RARA biomarker to determine study eligibility. Pre-screening 
assessments for the RARA biomarker will be performed within 45 days of Cycle 1 Day 1 and 
screening assessments for all other eligibility criteria will be performed within 30 days of 
Cycle 1 Day 1. 
Patients will be randomized 2:1 to receive either tamibarotene plus azacitidine or placebo plus 
azacitidine. Randomization will be stratified by the IPSS-R risk group (Intermediate, High, and 
Very High Risk) and by geographical region (North America, Western Europe, and Israel versus 
Eastern Europe); block randomization with a block size of 6 will be used. 
Response will be assessed by the investigator per the modified International Working 
Group (IWG) MDS criteria (Cheson 2006). Bone marrow aspirates will be collected to measure 
response on Day 1 of Cycles 2 and 4, followed by every third cycle (7, 10, 13, etc.), with bone 
marrow aspirates collected at other times as clinically determined based upon clinical findings or 
changes in peripheral blood counts. Following the response assessment on Day 1 of Cycle 7, 
those in CR may have the frequency of bone marrow aspirates for response assessment reduced 
to every 6 cycles. 

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Patients will undergo response and safety evaluations throughout their study participation as 
detailed in the Schedule of Activities (Section 1.3). Patients may continue to receive study drug 
until experiencing an unacceptable toxicity, disease progression (including transformation into 
AML), 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. 
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 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 if possible 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 5 years after discontinuation of study drug (irrespective of initiation 
of HSCT or other subsequent anticancer therapy) or until disease progression/relapse, death, or 
the occurrence of the expected number of overall survival (OS) events to support the final OS 
analysis, whichever occurs first. It is estimated that a final analysis of OS will occur 
approximately 70 months following the enrollment of the first patient. 
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, the date of 
transformation to AML, and OS status until the expected number of OS events to support the 
final OS analysis is observed. 
An independent data monitoring committee (IDMC) will be established and will review the data 
at the 2 planned interim futility analyses and the safety interims, as specified in the IDMC 
Charter. 
Number of Patients:  
Approximately 
 HR-MDS patients will be screened, with approximately 
 patients 
randomly assigned to tamibarotene plus azacitidine or placebo plus azacitidine. 
Intervention Groups and Duration: 
Patients will receive either tamibarotene plus azacitidine or placebo plus azacitidine. 
• Tamibarotene/placebo will be administered at 6 mg twice per day (BID) (orally) each day 
on Days 8 through 28 of each 28-day treatment cycle. 
• Azacitidine will be administered at 75 mg/m2 (intravenously or subcutaneously) each day 
on Days 1 through 7 of each 28-day treatment 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/placebo is permitted to overlap with azacitidine on Days 8 through 9 of 
this alternative schedule. 
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Patients will receive treatment until they meet study drug discontinuation criteria, as described in 
the Overall Design. Patients will be followed until the number of OS events is sufficient to 
enable the final analysis. 
Statistical Considerations 
Statistical Hypotheses 
Primary: CR Rate 
Null hypothesis (H0): In RARA-positive patients with newly diagnosed HR-MDS, CR rate for 
patients in the tamibarotene plus azacitidine treatment group is the same as the CR rate for 
patients in the placebo plus azacitidine treatment group. 
Alternative hypothesis (H1): In RARA-positive patients with newly diagnosed HR-MDS, CR 
rate for patients in the tamibarotene plus azacitidine treatment group is higher than the CR rate 
for patients in the placebo plus azacitidine treatment group. 
Key Secondary: OS 
Null hypothesis (H0): In RARA-positive patients with newly diagnosed HR-MDS, OS for 
patients in the tamibarotene plus azacitidine treatment group is the same as the OS for patients in 
the placebo plus azacitidine treatment group. 
Alternative hypothesis (H1): In RARA-positive patients with newly diagnosed HR-MDS, OS for 
patients in the tamibarotene plus azacitidine treatment group is superior to the OS for patients in 
the placebo plus azacitidine treatment group. 
Sample Size Determination 
 patients will provide 
 power to detect the difference in CR rates 
between the tamibarotene plus azacitidine treatment group and the placebo plus azacitidine 
treatment group, with assumed CR rates of 
 versus 
 in the 2 treatment groups, 
respectively, a 2:1 randomization, and 1-sided alpha of 
. 
A total of 
 death events will provide 
 power to detect the difference in OS between the 
tamibarotene plus azacitidine treatment group and the placebo plus azacitidine treatment group, 
with assumed median survival of 
 months versus 
 months (hazard ratio = 
) in the 
2 treatment groups, respectively, a 2:1 randomization, and 1-sided alpha of 
. 
A total of approximately 
 patients (
 in the tamibarotene plus azacitidine treatment group 
and 
 in the placebo plus azacitidine treatment group) are expected to be randomized in this 
study to obtain the 
 death events and final analysis time at approximately 70 months. 
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16 
Primary Endpoint Analysis 
CR Rate 
The CR rate will be evaluated in the Intent-to-Treat (ITT) population. CR rate and 95% exact 
binomial confidence intervals (CIs) will be calculated by treatment group. The stratified 
Cochran–Mantel–Haenszel (CMH) test will be applied to compare the CR rates between the 
2 treatment groups. 
The point estimate of the difference of the proportions for CR rate between the 2 treatment 
groups will also be provided along with 95% CI. 
Key Secondary Endpoint Analysis 
OS 
OS will be evaluated in the ITT population. The distribution of OS will be estimated for each 
treatment group using Kaplan-Meier methodology and compared between 2 treatment groups 
using the log-rank test stratified by IPSS-R risk group (Intermediate, High, and Very High Risk) 
and by geographical region (North America, Western Europe, and Israel versus Eastern Europe). 
The hazard ratio and the corresponding 95% CI between 2 treatment groups will be estimated 
using the stratified Cox proportional hazards model with the same stratification factors that are 
used for stratified log-rank test. 
Secondary Endpoint Analyses 
TI Rate 
TI rate (based on receiving neither red blood cell [RBC] nor platelet transfusion for a period of at 
least 56 days) with respective 95% exact binomial CIs will be calculated by treatment group. The 
stratified CMH test will be applied to compare the TI rates between the 2 treatment groups. 
ORR 
ORR and 95% exact binomial CIs will be calculated by treatment group. The stratified CMH test 
will be applied to compare the ORRs between the 2 treatment groups. The rates of CR or partial 
remission (PR); rates of CR, PR, or marrow CR; and the rates of hematologic improvement (HI) 
will also be summarized with 95% exact binomial CIs and compared between the treatment 
groups using the stratified CMH test. 
Duration of Complete Remission (DOCR) 
Kaplan-Meier estimation of median DOCR and corresponding 95% CIs will be presented by 
treatment group. 

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17 
Duration of Overall Response 
Kaplan-Meier estimation of median duration of overall response and corresponding 95% CIs will 
be presented by treatment group. 
Time to CR 
Time to CR will be summarized descriptively for the 2 treatment groups. 
Time to Initial Response 
Time to initial response will be summarized descriptively for the 2 treatment groups. 
Event-free Survival (EFS) 
Kaplan-Meier estimation of median EFS and 95% CI will be presented by treatment group. The 
stratified log rank test will be used to analyze the difference in EFS between treatment groups. 
Change in Health-related Quality of Life (HRQOL) 
The European Organization for Research and Treatment of Cancer Quality of Life Core 
Questionnaire 30 (EORTC QLQ-30) and EuroQol 5 dimensions (EQ-5D-5L) test results will be 
summarized separately by treatment group, parameter, and visit. Additionally, the change from 
baseline in each parameter will be analyzed using a mixed models for repeated 
measures (MMRM). A by-patient listing of all EORTC QLQ-30 and EQ-5D-5L results will be 
provided. 
Safety Analyses 
The number and percentage of patients with AEs or serious adverse events (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 change in National Cancer 
Institute CTCAE (version 5) grade from baseline to worst grade postbaseline. Descriptive 
summaries will be provided for ECG and vital sign values by each visit, changes in values from 
baseline, and shift from baseline category to the worst post-baseline values. Prolonged QTcF 
intervals (>450 msec, >480 msec, and >500 msec) will be summarized by each visit. Change 
from baseline categories will also be summarized for measurements that represent a change 
>30 msec or >60 msec relative to the baseline value. 
Pharmacokinetic Analysis 
Concentration-time data for tamibarotene will be included in the Clinical Study Report as 
listings; no formal non-compartmental analysis will be performed. 

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18 
Interim Futility Analyses 
There will be 2 planned interim futility analyses, one for the CR and one for OS, respectively; 
these will be non-binding and will be conducted by the IDMC. The IDMC may recommend 
terminating the study for unfavorable results at an interim analysis. 
Interim Futility Analysis for CR 
An interim futility analysis of the CR rate is planned when the 
 randomized patient has 
completed the Cycle 7 Day 1 assessment or discontinued treatment, whichever comes first. The 
study may be terminated at CR interim futility analysis, if the 1-sided p-value from the stratified 
CMH test comparing the CR rates (tamibarotene plus azacitidine treatment group versus placebo 
plus azacitidine treatment group) is 
. The non-binding futility bound is derived using a 
Hwang-Shih-DeCani (HSD) spending function with gamma = 4 (Hwang 1990). 
Interim Futility Analysis for OS 
If the CR rate is statistically significant at the time of the primary efficacy analysis of the CR 
rates between the 2 treatment groups, an interim OS futility analysis will be conducted when 
approximately 
 information fraction (
 of the total 
 events) has been observed. The 
study may be terminated at OS interim futility analysis if the 1-sided p-value from the stratified 
log rank test comparing the distribution of OS (tamibarotene plus azacitidine treatment group 
versus placebo plus azacitidine treatment group) is 
. The non-binding futility bound is 
derived using Lan-DeMets spending function. 
 
 
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19 
 
1.2 
Schema 
Abbreviations: MDS = myelodysplastic syndrome; N = number of patients; RARA = retinoic acid receptor alpha. 
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20 
1.3 
Schedule of Activities 
 
Pre-
screening 
(a) 
Day -45 to 
C1D1 
Screening 
(a) 
Day -30 to 
C1D1 
Cycle 1 
28 Days 
Cycles 2+  
28 Days Each (b) 
End of 
Treatment 
(EoT) (c) 
Safety 
Follow-
up (d) 
30d post 
EoT 
(±3d) 
Disease 
Follow-
up (e) 
q3mo 
post 
EoT 
(±14d) 
Survival 
Follow-
up (f) 
q3mo 
post EoT 
(±14d) 
Study Day 
 
 
D1 
(g) 
D2-7 
(±2d) 
D8 
(±1d) 
D22 
(±1d) 
D1 
(±3d) 
D2-7 
(±2d) 
D15 
(±2d) 
(h) 
 
 
 
 
Pre-screening Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Main Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review (i) 
 
X 
X 
(i) 
 
 
 
 
 
 
 
 
 
 
Eligibility Approval Form (i) 
 
X 
X 
(i) 
 
 
 
 
 
 
 
 
 
 
Randomization (j) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History (k) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Status 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
Vital Signs (l) 
 
X 
X 
X 
(l) 
X 
X 
X 
X 
(l) 
X 
X 
X 
 
 
Physical Examination (m) (n) 
 
X 
X 
 
X 
(n) 
X 
(n) 
X 
(n) 
 
 
X 
X 
X 
(n) 
 
Hematology (o), (p), (q) 
 
X 
(p) 
X 
 
X 
X 
X 
(q) 
 
 
X 
X 
X 
 

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21 
 
Pre-
screening 
(a) 
Day -45 to 
C1D1 
Screening 
(a) 
Day -30 to 
C1D1 
Cycle 1 
28 Days 
Cycles 2+  
28 Days Each (b) 
End of 
Treatment 
(EoT) (c) 
Safety 
Follow-
up (d) 
30d post 
EoT 
(±3d) 
Disease 
Follow-
up (e) 
q3mo 
post 
EoT 
(±14d) 
Survival 
Follow-
up (f) 
q3mo 
post EoT 
(±14d) 
Study Day 
 
 
D1 
(g) 
D2-7 
(±2d) 
D8 
(±1d) 
D22 
(±1d) 
D1 
(±3d) 
D2-7 
(±2d) 
D15 
(±2d) 
(h) 
 
 
 
 
Serum Chemistries (o) 
 
X 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
Coagulation (o) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Triglycerides, Total  
Cholesterol (o) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Hepatitis Panel (r) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (o) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Pregnancy Test (s)  
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Triplicate ECG (t) 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
AE Monitoring (u) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior/Concomitant Medication 
Review (v) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
RBC and Platelet Transfusions 
Recorded (w) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing Compliance/Diary 
Review 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
 
HRQOL (EORTC QLQ-C30, 
EQ-5D-5L) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Subsequent Anticancer 
Therapies (x) 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 

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22 
 
Pre-
screening 
(a) 
Day -45 to 
C1D1 
Screening 
(a) 
Day -30 to 
C1D1 
Cycle 1 
28 Days 
Cycles 2+  
28 Days Each (b) 
End of 
Treatment 
(EoT) (c) 
Safety 
Follow-
up (d) 
30d post 
EoT 
(±3d) 
Disease 
Follow-
up (e) 
q3mo 
post 
EoT 
(±14d) 
Survival 
Follow-
up (f) 
q3mo 
post EoT 
(±14d) 
Study Day 
 
 
D1 
(g) 
D2-7 
(±2d) 
D8 
(±1d) 
D22 
(±1d) 
D1 
(±3d) 
D2-7 
(±2d) 
D15 
(±2d) 
(h) 
 
 
 
 
Response Assessment (q), (y) 
 
 
 
 
 
 
X 
(q), 
(y) 
 
 
X 
(y) 
 
X 
(y) 
 
Bone Marrow Aspirate 
 
X 
(z) 
 
 
 
 
X 
(aa) 
 
 
X  
(aa) 
 
X  
(bb) 
 
Transformation into AML 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tamibarotene or Placebo (cc) 
 
 
 
 
Dosing D8-28 of each Cycle (cc) 
 
 
 
 
Azacitidine (dd) 
 
 
X 
X 
(dd) 
 
 
X 
X  
(dd) 
 
 
 
 
 
Blood Sample for RARA 
Biomarker Test (ee) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood Sample for Exploratory 
Research (ff) 
X 
  
X 
 
 
 
 
 
 
X 
 
 
 
Blood Sample for CDx 
Development 
X 
  
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood for PK (gg) 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AML = acute myeloid leukemia; CBC = complete blood count; CDx = companion diagnostic; CR = complete remission; 
CXDX = Cycle X, Day X; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; ECG = electrocardiogram; 
EDC = electronic data capture [system]; EORTC QLQ-30 = European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 
30; EoT = End of Treatment; EQ-5D-5L = EuroQol 5 dimensions; HRQOL = health-related quality of life; HSCT = Hematopoietic stem cell transplantation; 
IWG = International Working Group; MDS = myelodysplastic syndrome; OS = overall survival; PK = pharmacokinetic(s); q3mo = every 3 months; RBC = red 
blood cell; RARA = retinoic acid receptor alpha; SAE = serious adverse event. 

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23 
(a) Pre-screening assessments to ensure patients are RARA-positive will be performed within 45 days of Cycle 1 Day 1 and screening assessments for all other 
eligibility criteria will be performed within 30 days of C1D1. Screening assessments may occur on C1D1 but must be completed and results reviewed prior 
to dosing on C1D1. Screening assessments performed within 30 days of C1D1 as part of standard of care are acceptable to support eligibility review. 
(b) Cycle 2 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 after the EoT Visit and if possible, 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 until disease 
progression/relapse, death, or the occurrence of the expected number of OS events to support the final OS analysis, whichever occurs first. Disease 
Follow-up Visit window is ±14 days. 
(f) Patients who progress/relapse will be followed to document the start of subsequent anticancer therapy, the date of disease progression/relapse, the date of 
transformation to AML, and OS status by telephone (or another appropriate method) until the expected number of OS events to support the final OS analysis 
is observed. Survival Follow-up Visit contact window is ±14 days. 
(g) C1D1 assessments must be performed prior to study drug administration. 
(h) Cycles 2 through 4 only. 
(i) Eligibility review and approval by Sponsor or designee (via Eligibility Approval Form) must be completed prior to randomization. 
(j) Patients can be randomized earlier than C1D1, but within 72 hours of the first dose of study drug, to accommodate operational needs. 
(k) For all randomized patients, any untoward medical occurrences that happen before the first dose of the study drug should be captured as a part of medical 
history. 
(l) 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. 
(m) Definitions for the “full” and “abbreviated” physical examination are provided in Section 8.2.3; both must include an assessment for the presence of 
extramedullary AML. 
(n) Abbreviated physical examination will be performed at C1D8, C1D22, D1 of Cycles 2+, and at each Disease Follow-up Visit (see Section 8.2.3). 
(o) Laboratory assessments will be performed locally. 
(p) Screening hematology parameter evaluation must be performed prior to or at least 7 days following any blood product transfusion. 
(q) Additional unscheduled hematology evaluations may be performed up to 2 weeks after the bone marrow aspiration, for those patients in marrow CR without 
full peripheral blood count recovery at the time of the bone marrow aspirate, to assess whether they meet IWG criteria for CR. 
(r) See Section 10.2 for details. 
(s) A pregnancy test (high-sensitivity urine or serum) must be performed for women of childbearing potential. 
(t) ECGs should be performed after an approximately 10-minute rest period. 
(u) AEs and SAEs will be captured from the time of the first study drug administration through the Safety Follow-up Visit. 
(v) 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. 
(w) All RBC and platelet transfusions received by the patient from 16 weeks prior to randomization through the Disease Follow-up period will be recorded. Per 
the IWG 2006 response criteria, RBC transfusions entered into the corresponding eCRF in EDC should include only those administered for a hemoglobin 
level of ≤9 g/dL. 
(x) Subsequent anticancer therapies (including allogeneic HSCT) following EoT will be recorded. 

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24 
(y) Response assessments will be performed on D1 of Cycles 2 and 4, followed by every third cycle (7, 10, 13, etc.), at the EoT Visit and at each Disease 
Follow-up Visit, with additional assessments performed if clinically determined. Following the C7D1 response assessment, those in CR may have the 
frequency of bone marrow aspirates for response assessment reduced to every 6 cycles, with intervening response assessments based on hematology 
evaluation and physical examination findings. 
(z) A screening bone marrow aspirate will be performed, with samples for local assessment of blast count, cytogenetics, MDS-associated gene mutations, and 
immunophenotype. A bone marrow biopsy may be performed at investigator’s discretion to supplement the interpretation of the bone marrow aspirate. In 
addition, it is mandatory that an aspirate smear will be sent to the Central Laboratory for central morphologic review. An additional aspirate sample 
should be collected if possible and sent to the Central Laboratory for exploratory analyses. Bone marrow aspirate smears collected within 30 days of 
Cycle 1 Day 1 as a part of standard of care (pre-consent) are acceptable to support both local assessments and central review. 
(aa) Response assessment bone marrow aspirates will be collected on Day 1 of Cycles 2 and 4, followed by every third cycle (7, 10, 13, etc.), and at EoT, with 
bone marrow aspirates collected at other times as clinically determined. Following the C7D1 response assessment, those in CR may have the frequency of 
bone marrow aspirates for response assessment reduced to every 6 cycles. The samples for the local assessment of response (blast count and cytogenetics) 
are required. In addition, an aspirate smear will be collected and sent to the Central Laboratory for central review. At C4D1, C7D1, every 6 cycles 
thereafter, as well as at EoT, an additional aspirate sample will be collected and sent to the Central Laboratory for exploratory analyses (Section 8.6.3). A 
bone marrow biopsy may be performed at investigator’s discretion to supplement the interpretation of the bone marrow aspirate. 
(bb) Response assessment bone marrow aspirates will be collected every 3 months during the Disease Follow-up period, with bone marrow aspirates collected at 
other times as clinically determined. Patients in CR may have the frequency of bone marrow aspirates for response assessment reduced to every 6 months. 
The samples for the local assessment of response (blast count and cytogenetics) are required. In addition, an aspirate smear for central review will be 
collected and sent to the Central Laboratory. An additional aspirate sample should be collected if possible and sent to the Central Laboratory for exploratory 
analyses (Section 8.6.3). A bone marrow biopsy may be performed at investigator’s discretion to supplement the interpretation of the bone marrow aspirate. 
(cc) The morning dose of tamibarotene/placebo will be taken in the clinic on C1D8, C1D22, and D15 of Cycles 2 through 4; date/time of dose should be 
recorded. 
(dd) If dosing on Days 6 and 7 of a cycle is not possible due to logistical limitations, these doses may be delayed to Days 8 and 9. Tamibarotene/placebo is 
permitted to overlap with azacitidine on Days 8 through 9 of this alternative schedule. If criteria for azacitidine dose hold are met (Table 1), 
tamibarotene/placebo dosing may continue, unless criteria for tamibarotene/placebo hold are also met. D1 of the next treatment cycle is delayed until 
azacitidine dosing may resume. 
(ee) Peripheral blood samples will be sent to the Almac Diagnostics Laboratory for assessment of RARA biomarker to determine study eligibility. 
(ff) For evaluation of MDS molecular features associated with response to drug treatment and loss of response to drug treatment (Section 8.6.3). 
(gg) The morning dose of tamibarotene/placebo will be taken in the clinic on C1D8 and C1D22; date/time of dose should be recorded. The date/time of the 
C1D21 evening dose of tamibarotene/placebo should also be recorded. Three PK blood samples should be obtained on C1D8 and on C1D22, and collection 
time/date recorded: 1) pre-dose; 2) 1 hour post-dose (±30 min); 3) 3 hours post-dose (±30 min). 
 
 

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25 
2 INTRODUCTION 
Tamibarotene is a potent and selective agonist of RARα, approved for the treatment of R/R APL 
in Japan. Tamibarotene is being developed in a subset of non-APL AML and HR-MDS patients 
who are RARA-positive, as identified by high levels of RARA expression in blasts. 
2.1 
Study Rationale 
Initial clinical data in RARA-positive R/R AML and R/R HR-MDS patients treated with 
single-agent tamibarotene demonstrated evidence of biological activity with myeloid 
differentiation and blast reductions (Jurcic 2017). In newly diagnosed, unfit AML patients, 
tamibarotene in combination with azacitidine showed high CR rates and a rapid onset of action 
in RARA-positive patients (de Botton 2022). The AE profile of the 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). Approximately 
30% of AML patients (Jurcic 2017, Vigil 2017, de Botton 2022) and approximately 50% of 
MDS patients (data on file as of 27 May 2022) are RARA-positive. HR-MDS and AML are 
closely related biologically, with common cytogenetic abnormalities and gene mutations present 
in the blast populations in each condition (Arber 2016). Historical precedent demonstrates that 
active agents in AML, specifically hypomethylating agents, are active in HR-MDS, supporting 
the rationale for further development of the combination of tamibarotene with azacitidine in the 
HR-MDS patient population. Azacitidine remains the standard of care for the treatment of 
HR-MDS (VIDAZA USPI, VIDAZA SmPC, NCCN Guidelines for MDS, Malcovati 2013), 
however there is opportunity to improve upon the clinical outcomes of single-agent azacitidine. 
In this study, newly diagnosed, RARA-positive HR-MDS patients will be randomized to therapy 
with tamibarotene plus azacitidine or placebo plus azacitidine. 
2.2 
Background 
2.2.1 
Disease Under Study 
HR-MDS is a rare orphan disease with a high unmet need for effective, tolerable therapies. The 
hypomethylating agent azacitidine is the standard of care for newly diagnosed HR-MDS patients. 
However, CR and PR rates are low (VIDAZA USPI, VIDAZA SmPC) and treatment is not 
curative. Thus, novel therapies that replace or augment the efficacy of azacitidine are needed to 
extend survival of patients with HR-MDS. Furthermore, no standard of care exists for patients 
who fail frontline therapy with hypomethylating agents. Thus, patients with HR-MDS have a 
poor prognosis and a need for more effective treatment options. 
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 the 
presence of the t(15;17) translocation resulting in the PML-RARA gene fusion. Tamibarotene was 
designed to be a more potent and selective RARα agonist with significantly improved in vivo 

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26 
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. 
2.2.3 
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 United States (US) and European Union (EU) for treatment of MDS. Azacitidine 
is also approved for use in AML in the EU and is widely accepted as the standard of care for 
treatment of AML in the US. 
Additional information is available in VIDAZA label (VIDAZA USPI, VIDAZA SmPC, or as 
applicable). 
2.3 
Benefit/Risk Assessment 
HR-MDS is an orphan disease with a high unmet need for effective, tolerable therapies. 
Allogeneic HSCT is the only potentially curative treatment for this condition. 
In the ongoing SY-1425-201 study, Syros has explored the safety, pharmacokinetic (PK), 
pharmacodynamic, and clinical activity of tamibarotene in non-APL AML in combination with 
azacitidine. Clinical activity data (see IB) support the rationale for further development of the 
combination of tamibarotene with azacitidine in a genomically defined subset of patients 
characterized by overexpression of RARA in blasts. HR-MDS is biologically closely related to 
AML, with common mutations found across these conditions (Arber 2016), supporting the 
hypothesis that the combination of tamibarotene plus azacitidine will have clinical activity in 
those with newly diagnosed HR-MDS. 
The AE profile of the 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). 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. The majority of nonhematologic AEs 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 safety profile of tamibarotene is 
considered to be acceptable, with the benefit to the patient primarily defined by the potential 
clinical utility of receiving tamibarotene plus azacitidine for the duration of the study (for 
patients randomized to the active combination). Both treatment arms of the randomized study 
contain azacitidine, which is the current standard of care for treating HR-MDS. 
The risks of the underlying conditions evaluated in this study are significant and represent areas 
of high unmet medical need. HR-MDS is associated with the risk of infection and complications 

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27 
due to persistent cytopenias. Patients undergoing treatment for HR-MDS undergo the procedural 
risk of repeated bone marrow aspirations, which are also required assessments in this study. The 
clinical activity of tamibarotene plus azacitidine, coupled with the emerging favorable safety 
profile of the tamibarotene plus azacitidine combination, suggests that this combination has the 
potential to provide a valuable treatment option for RARA-positive patients with AML, as well 
as those with HR-MDS. 
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 
Primary 
• 
Characterize and compare the CR rate of 
tamibarotene plus azacitidine vs. placebo plus 
azacitidine 
• 
CR, as determined by the investigator per the 
modified IWG MDS criteria (Cheson 2006) 
Key Secondary 
• 
Characterize and compare the OS of tamibarotene 
plus azacitidine vs. placebo plus azacitidine 
• 
OS, defined as the time from the date of 
randomization to the date of death due to any cause 
Secondary 
• 
Characterize and compare the TI rate of 
tamibarotene plus azacitidine vs. placebo plus 
azacitidine 
• 
TI, defined as a period of at least 56 days with no 
RBC or platelet transfusion since the date of 
randomization to the last dose of study drug 
+30 days, the initiation of post-treatment therapy, 
or death, whichever occurs first 
• 
Characterize and compare the ORR of 
tamibarotene plus azacitidine vs. placebo plus 
azacitidine 
• 
Overall response, defined as achieving CR, PR, 
mCR, or HI as determined by the investigator per 
the modified IWG MDS criteria (Cheson 2006) 
• 
Characterize the DOCR and duration of overall 
response of tamibarotene plus azacitidine or 
placebo plus azacitidine 
• 
DOCR, defined as the duration from the date of 
first documented evidence of CR to the date of 
documented relapse of disease, as determined by 
the investigator per the modified IWG MDS 
criteria (Cheson 2006), or death due to any cause, 
whichever occurs first 
• 
Duration of overall response defined as the 
duration from the date of first documented 
evidence of CR, PR, mCR, or HI, to the date of 
documented disease progression, relapse of disease 
as determined by the investigator per the modified 
IWG MDS criteria (Cheson 2006), or death due to 
any cause, whichever occurs first 
• 
Characterize the time to CR and time to initial 
response of tamibarotene plus azacitidine vs. 
placebo plus azacitidine 
• 
Time to CR, defined as the duration from the date 
of randomization to the date of the first 
documented evidence of CR as determined by the 
investigator per the modified IWG MDS criteria 
(Cheson 2006) 

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Objectives 
Endpoints 
• 
Time to initial response, defined as the duration 
from the date of randomization to the date of the 
first documented evidence of CR, PR, mCR, or HI 
as determined by the investigator per the modified 
IWG MDS criteria (Cheson 2006) 
• 
Characterize and compare the EFS of tamibarotene 
plus azacitidine vs. placebo plus azacitidine 
• 
EFS, defined as the time from the date of 
randomization to the date of transformation to 
AML or death due to any cause, whichever occurs 
first 
• 
Compare changes in HRQOL of tamibarotene plus 
azacitidine vs. placebo plus azacitidine 
• 
Change in HRQOL as measured by the EORTC 
QLQ-30 and EQ-5D-5L 
• 
Characterize the safety of tamibarotene plus 
azacitidine vs. placebo plus azacitidine  
• 
AEs and changes in clinical laboratory values, 
ECG results, and vital sign measurements 
Exploratory 
• 
Characterize and compare the cytogenetic CR rate 
of tamibarotene plus azacitidine vs. placebo plus 
azacitidine 
• 
Cytogenetic CR, defined as patients achieving 
cytogenetic CR (Cheson 2006), as determined by 
the investigator 
• 
Characterize and compare the molecular response 
rate of tamibarotene plus azacitidine vs. placebo 
plus azacitidine 
• 
Molecular response, defined as patients achieving 
a reduction in variant allele frequency by next 
generation sequencing 
• 
Characterize and compare the change in 
transfusion requirements of tamibarotene plus 
azacitidine vs. placebo plus azacitidine 
• 
Transfusion requirement, defined as the frequency 
and amount of blood products (RBC or platelet) 
received 
• 
Characterize and compare the rate of consolidation 
treatment with allogeneic HSCT following 
treatment with tamibarotene plus azacitidine vs. 
placebo plus azacitidine 
• 
The rate of consolidation with allogeneic HSCT 
defined as the proportion of patients who are 
treated with allogeneic HSCT 
• 
Characterize the PK of tamibarotene 
• 
Plasma concentrations of tamibarotene 
• 
Characterize MDS molecular features associated 
with response and with loss of response for 
tamibarotene plus azacitidine vs. placebo plus 
azacitidine 
• 
Clinical response and genetic mutations and/or 
gene expression markers at baseline, at the time of 
response, and loss of response 
Abbreviations: AE = adverse events; AML = acute myeloid leukemia; CR = complete remission; DOCR = duration 
of complete remission; ECG = electrocardiogram; EFS = event-free survival; EORTC QLQ-30 = European 
Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30; EQ-5D-5L = EuroQol 5 
dimensions; HI = hematologic improvement; HRQOL = health-related quality of life; HSCT = hematopoietic stem 
cell transplantation; IWG = International Working Group; mCR = marrow CR; MDS = myelodysplastic syndrome; 
ORR = overall response rate; OS = overall survival; PK = pharmacokinetic(s); PR = partial remission; RBC = red 
blood cell; TI = transfusion independence; vs. = versus. 
4 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study comparing 
the activity of tamibarotene plus azacitidine to placebo plus azacitidine as first line of therapy in 

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29 
RARA-positive patients with newly diagnosed HR-MDS. Enrollment in countries in North 
America and Europe and in Israel is planned. 
At the Pre-screening Visit, blood samples will be collected and sent to the Almac Diagnostics 
Laboratory for assessment of RARA biomarker to determine study eligibility. Pre-screening 
assessments for the RARA biomarker will be performed within 45 days of Cycle 1 Day 1 and 
screening assessments for all other eligibility criteria will be performed within 30 days of 
Cycle 1 Day 1. 
Patients will be randomized 2:1 to receive either tamibarotene plus azacitidine or placebo plus 
azacitidine. Randomization will be stratified by the IPSS-R risk group (Intermediate, High, and 
Very High Risk) and by geographical region (North America, Western Europe, and Israel versus 
Eastern Europe); block randomization with a block size of 6 will be used. 
Response will be assessed by the investigator per the modified IWG MDS criteria 
(Cheson 2006). Bone marrow aspirates will be collected to measure response on Day 1 of 
Cycles 2 and 4, followed by every third cycle (7, 10, 13, etc.), with bone marrow aspirates 
collected at other times as clinically determined based upon clinical findings or changes in 
peripheral blood counts. Following the response assessment on Day 1 of Cycle 7, those in CR 
may have the frequency of bone marrow aspirates for response assessment reduced to every 
6 cycles. 
Patients will undergo response and safety evaluations throughout their study participation as 
detailed in the Schedule of Activities (SoA; Section 1.3). Patients may continue to receive study 
drug until experiencing an unacceptable toxicity, disease progression (including transformation 
into AML), 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. 
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 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 if possible 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 5 years after discontinuation of study drug (irrespective of initiation of HSCT or other 
subsequent anticancer therapy) or until disease progression/relapse, death, or the occurrence of 
the expected number of OS events to support the final OS analysis, whichever occurs first. It is 
estimated that a final analysis of OS will occur approximately 70 months following the 
enrollment of the first patient. 
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, the date of 
transformation to AML, and OS status until the expected number of OS events to support the 
final OS analysis is observed. 

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An IDMC will be established and will review the data at the 2 planned interim futility analyses 
and the safety interims, as specified in the IDMC Charter. 
4.2 
Scientific Rationale for Study Design 
Randomized, double-blind, placebo-controlled design is a well-established best practice for a 
Phase 3 study. 
The proposed eligibility criteria are intended to ensure that only newly diagnosed, 
RARA-positive patients with HR-MDS are enrolled in the study. Allogeneic HSCT is the only 
potentially curative therapy for HR-MDS; therefore, patients who are transplant-eligible at the 
time of screening and agree to undergo this treatment will be excluded. Patients who received 
prior treatment with hypomethylating agents or chemotherapy (including lenalidomide) are 
excluded to avoid confounding of interpretation of the effect of study treatment. 
Azacitidine is included as therapy in both the investigational and the comparator group, as it is 
the accepted standard-of-care treatment for patients with HR-MDS who are not 
transplant-eligible (VIDAZA USPI, VIDAZA SmPC). Key eligibility criteria are consistent with 
the current labeling for azacitidine (VIDAZA USPI, VIDAZA SmPC). 
The proposed CR primary endpoint is a response-based endpoint that is a meaningful surrogate 
for clinical benefit in newly diagnosed HR-MDS. CR in MDS is associated with prolonged 
survival, transfusion independence (TI), and improved health-related quality of life in MDS 
(Fenaux 2009, Platzbecker 2012). Moreover, CR rate has previously been used as a primary 
endpoint for the approval of azacitidine and decitabine in MDS (VIDAZA USPI, 
VIDAZA SmPC, DACOGEN USPI). 
4.3 
Rationale for Dose and Regimen 
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. 
The dose and regimen of tamibarotene in combination with azacitidine is supported by the data 
from Study SY-1425-201. 
The data from Study TOS-80T-003 indicate that the co-administration of 
 
 has limited impact on the PK of tamibarotene. Consequently, such co-administration 
does not warrant dose adjustments. 
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Additional information is provided in the IB. 
4.4 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the 
SoA (Section 1.3) for the last patient in the study globally. 
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 
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. Patients must be RARA-positive based on the investigational assay (Section 8.6.1). 
3. Patients must be newly diagnosed with HR-MDS as follows: 
Diagnosis of MDS according to the WHO classification (Arber 2016) and classified by 
the IPSS-R risk category as: 
a. 
Very High (risk score >6), 
b. 
High (risk score >4.5 to 6), OR 
c. 
Intermediate (risk score >3 to 4.5). 
4. Patients must have measurable disease with bone marrow blasts >5% at the Screening 
Visit. 
5. Patients must have ECOG Performance Status of ≤2. 
6. Patients must have adequate organ function, as defined by: 
a. 
total bilirubin ≤3.0 × the ULN,  
b. 
ALT and AST ≤3 × ULN, and 
c. 
creatinine clearance ≥30 mL/min based on the Cockcroft-Gault Glomerular 
Filtration Rate estimation. 

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7. Patients must have a serum/high-sensitivity urine 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 document. 
5.2 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening. 
2. Patients received prior treatment for MDS with any hypomethylating agent, 
chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior 
treatment with growth factors or hydroxyurea. Growth factor treatment must be 
discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be 
discontinued prior to starting study drug. 
3. Patients with history of cancer are excluded if they are in active treatment (with radiation, 
chemotherapy, antibodies, immunotherapies, or molecularly targeted therapies) or unless 
they are disease free for at least 2 years prior to the Screening Visit, following completion 
of a prior treatment. Exceptions include: localized prostate cancer treated with hormone 
monotherapy; localized breast cancer treated with adjuvant hormone monotherapy; or 
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 
12 weeks before the Screening Visit and have a documented undetectable viral load at the 
Screening Visit are eligible for enrollment. 

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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 investigational product 
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. 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. 
12. Patients known to be refractory to platelet or packed red blood cell transfusions per 
Institutional Guidelines, or patients who refuse blood product support. 
13. Patients received 
 (see 
) within 2 weeks prior to 
the first tamibarotene/placebo administration. 
14. 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. 
15. Patients require concurrent treatment with any investigational or approved oncology 
agent, other than the agents described in exclusion criterion #3. 
16. Patients with ≥20% blasts in peripheral blood or bone marrow or evidence of myeloid 
sarcoma (extramedullary AML). 
17. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, 
version 5). 
18. 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 Fridericia formula (QTcF). 
19. 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). 
20. Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their 
excipients. 
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21. Patients for whom treatment with tamibarotene or azacitidine is contraindicated. 
22. Patients with clinically significant cardiovascular disease, including unstable angina, 
acute myocardial infarction within 3 months prior to the start of study drug 
administration, or New York Heart Association Class III or IV congestive heart failure, 
cerebral vascular accident within 3 months prior to the start of study drug administration, 
or cardiac arrhythmia associated with hemodynamic instability. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to study drug. 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. 
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 
Intervention 
Name 
Tamibarotene 
Tamibarotene-matched 
Placebo 
Azacitidine 
Type  
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tamibarotene-matched 
tablet 
Reconstituted as solution or 
suspension 
Unit Dose 
Strength(s) 
2-mg tablets 
Not applicable 
100-mg single-use vials 

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Intervention 
Name 
Tamibarotene 
Tamibarotene-matched 
Placebo 
Azacitidine 
Dosage Level and 
Regimen 
6 mg twice per day (BID); 
Days 8 through 28 of each 
28-day treatment cycle 
See Section 6.2.1 for details 
of dose administration. 
3 tablets that match 
tamibarotene BID;  
Days 8 through 28 of each 
28-day treatment cycle 
See Section 6.2.1 for details 
of dose administration. 
75 mg/m2 once per day; 
Days 1 through 7 of each 
28-day treatment 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. 
See Section 6.2.2 for details 
of dose administration. 
Route of 
Administration 
Oral 
Oral 
Intravenous or subcutaneous 
Use 
Experimental 
Placebo comparator 
Background intervention 
Investigational 
Medicinal 
Product (IMP) 
and Non-
Investigational 
Medicinal 
Product (NIMP) 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by the 
sponsor  
Provided centrally by the 
sponsor 
As regionally applicable  
Packaging and 
Labeling 
Study drug will be provided 
in bottles. Each bottle will 
be labeled as required per 
country requirement. 
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. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Tamibarotene/Placebo 
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 to 30°C) and 
should not be removed from the bottles until immediately before administration. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all tamibarotene/placebo received, and any discrepancies are 
reported and resolved before its use. 

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Only patients enrolled in the study may receive tamibarotene/placebo and only authorized site 
staff may supply or administer it. All tamibarotene/placebo must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for tamibarotene/placebo accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused tamibarotene/placebo are 
provided in the Pharmacy Manual. 
6.2.2 
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 should be stored at room temperature (15°C to 30°C). Refer to the 
azacitidine package insert approved by your National Regulatory Agency/Competent Authority 
for complete details, as applicable (e.g., VIDAZA USPI, VIDAZA SmPC). 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will be double-blinded and will be performed on Cycle 1 Day 1 using an 
interactive response system.1 
Approximately 
 patients with HR-MDS will be randomly assigned to study drug. Patients 
will be randomized 2:1 to receive either tamibarotene plus azacitidine or placebo plus 
azacitidine. Randomization will be stratified by the IPSS-R risk group (Intermediate, High, and 
Very High Risk). In addition, stratification of analyses by geographical region (North America, 
Western Europe, and Israel versus Eastern Europe) will be performed, as there may be 
differences in available supportive care treatments and in access to subspecialty consultants and 
specialized hospital care among these regions. Block randomization with a block size of 6 will be 
used. 
All patients, investigators, pharmacist(s) performing drug preparation, and site staff will be 
blinded to treatment assignment. 
Personnel responsible for the bioanalysis of the tamibarotene concentrations in plasma will be 
provided with the randomization code in order to identify samples for analysis. The results will 
not be shared with the sponsor until the study is unblinded. 
 
 
 
 
1 Patients can be randomized earlier than Cycle 1 Day 1, but within 72 hours of the first dose of study drug, to 
accommodate operational needs. 
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In addition, at the time of CR futility analysis, preliminary PK analysis will be performed by 
designated contract research organization (CRO), the limited personnel from the CRO will have 
access to the unblinded PK data to build the population PK model. 
The interactive response system will be programmed with blind-breaking instructions. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s intervention assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If necessary, for patient safety, the investigator 
may unblind the patient’s intervention assignment immediately, without prior discussion with the 
sponsor. The investigator may, at the investigator’s discretion, contact the sponsor to discuss the 
situation prior to unblinding a patient’s intervention assignment, unless this could delay 
emergency treatment for the patient. Maintaining the blinded treatment assignment will preserve 
integrity of the study data. If a patient’s intervention assignment is unblinded without discussion 
with the sponsor, the sponsor must be notified within 24 hours of this occurrence. The date and 
reason that the blind was broken will be recorded. 
Sponsor safety staff may unblind the study drug assignment for any patient with a SAE if 
necessary. If the SAE requires that an expedited regulatory report be sent to one or more 
regulatory agencies, a copy of the report, identifying the patient’s study drug assignment, may be 
sent to the investigators in accordance with local regulations and/or sponsor policy. Contact 
information for the Pharmacovigilance group is provided in Appendix 3. 
6.4 
Study Drug Compliance 
Tamibarotene/placebo 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). 
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/placebo 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 applicable study visit (Section 1.3). 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. 

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6.5 
Dose Modification and Management of Toxicities 
The instructions provided in Table 1 and Table 2 must be followed to adjust 
tamibarotene/placebo or azacitidine 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 azacitidine (see most current VIDAZA USPI/VIDAZA SmPC, or applicable locally 
approved labeling). 

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Table 1: 
Dose Modifications 
Adverse Events (AEs) 
Dosage Modification  
Hematologic toxicity 
The dose of azacitidine should be modified as described in the most current 
VIDAZA USPI/VIDAZA SmPC or applicable locally approved labeling. 
If Grade 4 hematologic toxicity does not resolve after azacitidine dose 
modifications have been attempted, the dose of tamibarotene may be 
 
. 
Retinoic acid syndrome 
(RAS)a 
Hold tamibarotene/placebo until RAS is considered controlled and Grade ≤2. 
See Section 6.8.9 for additional information on monitoring and treatment of RAS. 
Grade 4 
hypertriglyceridemia  
Hold tamibarotene/placebo until AE resolves to Grade ≤1 or baseline. 
Tamibarotene/placebo 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/placebo will be 
 Dosing 
may be 
 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 
 
. 
Grade ≥3 non-hematologic 
toxicity (excluding 
hypertriglyceridemia and 
serum electrolyte and renal 
toxicity) 
Hold tamibarotene/placebo, if AE is deemed related to tamibarotene and not 
resolved with supportive care, until AE resolves to Grade ≤1 or baseline. 
Tamibarotene/placebo 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 
. Dosing may be 
 if the AE remains Grade ≤1 or at baseline for 
14 days. 
If Grade ≥3 non-hematologic toxicity does not resolve after dose modification to 
tamibarotene/placebo has been attempted, azacitidine may be held until AE 
resolves to Grade ≤1 or baseline. 
If attribution is unclear, follow tamibarotene dose modification first. If AE does not 
resolve, azacitidine modifications may be attempted next. 
Abbreviations: SmPC = Summary of Product Characteristics; USPI = United States Prescribing Information. 
Note: Tamibarotene administration should not be resumed in the case of ≥28-day dose delay due to treatment-related 
AEs. 
a 
Also referred to as differentiation syndrome. 
Table 2: 
Dose Reductions of Tamibarotene/Placebo 
Dose Level 
Tamibarotene/Placebo Dose 
Initial Dose: Level 0 
6 mg twice per day (BID) 
 
 
 
 
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6.5.1 
Dose Delay and Toxicity-related Discontinuation Guidelines 
If criteria for tamibarotene/placebo dose hold are met (Table 1), azacitidine dosing may continue, 
unless criteria for azacitidine hold are also met. 
If criteria for azacitidine dose hold are met (Table 1), tamibarotene/placebo dosing may continue, 
unless criteria for tamibarotene/placebo hold are also met. Day 1 of the next treatment cycle is 
delayed until azacitidine dosing may resume. 
If implementation of dose modification guidelines described in Table 1 (including dose holds 
and reductions) was not sufficient to adequately manage toxicity, the relevant study drug(s) 
should be discontinued. Discontinuation of only tamibarotene/placebo or only azacitidine while 
continuing administration of the other study drug 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 1 are insufficient to adequately 
manage toxicity and discontinuation of both tamibarotene/placebo and azacitidine is required, the 
patient should have an EoT Visit. 
6.5.2 
Phototoxicity 
Tamibarotene did not demonstrate phototoxic potential in Neutral Red Uptake Phototoxicity 
Assay (see IB). Furthermore, phototoxicity has not been reported in clinical studies of 
tamibarotene to date. 
6.5.3 
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 
with a disposition of hypertriglyceridemia such as those with diabetes mellitus, obesity, 
alcoholism, or abnormal lipid metabolism. 
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 
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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One case of overdose with azacitidine was reported during clinical trials (VIDAZA USPI, 
VIDAZA SmPC). 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 blood count tests and 
should receive supportive treatment, as necessary. There is no known antidote for azacitidine 
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 or whether the dose should be reduced. 
• 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. 
6.8 
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 
Growth factor treatment must be discontinued at least 2 weeks prior to starting study drug. 
Short-term use of myeloid growth factor is allowable for treatment of life-threatening infections. 
6.8.3 
Thrombopoietin Receptor Agonists 
Thrombopoietin receptor agonists must be discontinued prior to starting study drug and are not 
allowed during the study. 
6.8.4 
Oral Hydroxyurea 
Hydroxyurea treatment must be discontinued prior to starting study drug and is not allowed 
during the study. 
6.8.5 
Platelet Transfusions 
Administration of platelet transfusions may be utilized throughout the study, as clinically 
determined. 

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6.8.6 
Red Blood Cell Transfusions 
Administration of RBC transfusions may be utilized throughout the study, as clinically 
determined. 
6.8.7 
 
 are not allowed to be administered during the study as they may 
reduce exposure of tamibarotene. 
Though the in vitro 
-mediated metabolism of tamibarotene appears to be primarily due to 
, a clinical drug-drug interaction study with itraconazole (a 
; 
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 plasma PK exposure. 
A list of 
 is included in 
 
6.8.8 
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. 
6.8.9 
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/placebo therapy should be temporarily discontinued 
until RAS is considered controlled and ≤Grade 2. 
6.8.10 
Multivitamin and Supplements 
Vitamin A supplements (>10,000 IU/day) are not allowed while on study drug. 
6.8.11 
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. 
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7 DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Drug Administration 
Patients will continue to receive study drug until they meet one of the following criteria: 
• An unacceptable toxicity, including AEs that would result in permanent discontinuation 
of study drug (Section 6.5) 
• An AE related to study drug that requires ≥28 days (1 cycle) of dose interruption of both 
tamibarotene/placebo and azacitidine 
• Failure to achieve a minimum response of HI in at least 1 cell lineage following the 
completion of the Cycle 7 Day 1 response assessment 
• Disease progression/relapse 
• Pregnancy 
• Decision to pursue post-remission therapy (such as HSCT) or an alternative anticancer 
therapy; consolidation treatment with HSCT following the receipt of study drug is 
permissible. 
• 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 if possible 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 SoA 
(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. 

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• The sponsor may retain and use any data collected before withdrawal of consent for study 
participation. 
• If a patient withdraws their 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 
medical records. 
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 SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the 
SoA (Section 1.3), is essential and required for study conduct. 
• All pre-screening and screening evaluations must be completed and results reviewed 
prior to dosing on Cycle 1 Day 1. Minimal details of all patients screened will be 
captured to confirm eligibility or record reasons for screening failure, as applicable. 

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• 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 
for screening purposes, provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA (Section 1.3). Screening 
hematology parameter evaluation must be performed at least 7 days following any blood 
product transfusion. 
• 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 randomized patients, any untoward medical occurrences that happen before the 
first dose of the study drug should be captured as a part of medical history. 
8.1 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (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 per the modified IWG MDS criteria (Cheson 2006). A copy of the 
criteria is provided in Appendix 8. Note that resolution of dysplasia is not required for 
achievement of an IWG response. Physical examinations (Section 8.2.3) are scheduled at the 
time of all response assessments and include an assessment for the presence of extramedullary 
AML. Additional unscheduled hematology evaluations may be performed up to 2 weeks after the 
bone marrow aspiration, for those patients in marrow CR without full peripheral blood count 
recovery at the time of the bone marrow aspirate, to assess whether they meet IWG criteria for 
CR based on the results of this additional hematology evaluation. The CR date is assigned as the 
date of marrow sampling or peripheral count recovery, whichever is later. 
In addition to on-treatment assessments, patients who have not progressed/relapsed will enter the 
Disease Follow-up period, during which response assessments will be performed every 3 months 
for response assessment until disease progression/relapse, death, or the occurrence of the 
expected number of OS events to support the final OS analysis, 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, the date of 
transformation to AML, and OS status until the expected number of OS events to support the 
final OS analysis is observed. 

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8.1.2 
Bone Marrow Sample Collection 
A screening bone marrow aspirate will be performed, with samples for local assessment of blast 
count, cytogenetics, MDS-associated gene mutations, and immunophenotype. A bone marrow 
biopsy may be performed at investigator’s discretion to supplement the interpretation of the bone 
marrow aspirate. In addition, it is mandatory that an aspirate smear will be sent to the Central 
Laboratory for central morphologic review. An additional aspirate sample should be collected if 
possible and sent to the Central Laboratory for exploratory analyses. 
Bone marrow aspirate smears collected within 30 days of Cycle 1 Day 1 as a part of standard of 
care (pre-consent) are acceptable to support both local assessments and central review. 
Response assessment bone marrow aspirates will be collected on Day 1 of Cycles 2 and 4, 
followed by every third cycle (7, 10, 13, etc.), and at EoT, with bone marrow aspirates collected 
at other times as clinically determined. Following the Cycle 7 Day 1 response assessment, those 
in CR may have the frequency of bone marrow aspirates for response assessment reduced to 
every 6 cycles. The samples for the local assessment of response (blast count and cytogenetics) 
are required. In addition, an aspirate smear will be collected and sent to the Central Laboratory 
for central review. At Cycle 4 Day 1, Cycle 7 Day 1, every 6 cycles thereafter, as well as at EoT, 
an additional aspirate sample will be collected and sent to the Central Laboratory for exploratory 
analyses (Section 8.6.3). A bone marrow biopsy may be performed at investigator’s discretion to 
supplement the interpretation of the bone marrow aspirate. 
During the Disease Follow-up period, the response assessment bone marrow aspirates will be 
collected every 3 months during the Disease Follow-up period, with bone marrow aspirates 
collected at other times as clinically determined. Patients in CR may have the frequency of bone 
marrow aspirates for response assessment reduced to every 6 months. The samples for the local 
assessment of response (blast count and cytogenetics) are required. In addition, an aspirate smear 
for central review will be collected and sent to the Central Laboratory. An additional aspirate 
sample should be collected if possible and sent to the Central Laboratory for exploratory 
analyses (Section 8.6.3). A bone marrow biopsy may be performed at investigator’s discretion to 
supplement the interpretation of the bone marrow aspirate. 
Instructions for the collection and handling of the bone marrow samples will be provided 
separately in the Laboratory Manual. 
8.1.3 
Hematologic Improvement 
Baseline hemoglobin and platelet values will be collected at the Screening Visit. The screening 
hematology parameter evaluation must be performed prior to or at least 7 days following any 
blood product transfusion (see Appendix 8). 
8.1.4 
Transformation to AML 
A diagnosis of AML (per WHO; Vardiman 2009, Arber 2016) is defined by either: 
• ≥20% blasts in the peripheral blood or bone marrow 

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OR 
• development of myeloid sarcoma 
8.1.5 
Blood Product Transfusions 
All RBC and platelet transfusions received by the patient from 16 weeks prior to randomization 
through the Disease Follow-up period will be recorded. 
8.1.6 
Overall Survival 
All patients will be followed for OS every 3 months until the expected number of OS events to 
support the final OS analysis is observed. 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 SoA (Section 1.3). 
8.2.1 
Prior, Concomitant, and Subsequent Medication Review 
Every medication (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements), vaccines, and blood products 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:  
• 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 and an 
assessment for the presence of extramedullary AML. The skin examination should 

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include monitoring for cancerous and pre-cancerous lesions and appropriate referral to 
dermatologic evaluation and care, as clinically indicated. 
• An abbreviated physical examination will include, at a minimum, assessments of the 
skin, lungs, Cardiovascular system, and abdomen (liver and spleen) and an assessment 
for the presence of extramedullary AML. The skin examination should include 
monitoring for cancerous and pre-cancerous lesions and appropriate referral to 
dermatologic evaluation and care, as clinically indicated. 
• 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. 
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 

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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 SoA (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). 
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. 
Emergency unblinding procedures are described in Section 6.3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be captured from the time of the first study drug administration through the 
Safety Follow-up Visit. 
All SAEs will be recorded and reported to the sponsor or designee immediately without undue 
delay and under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 

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investigator will submit any updated SAE data to the sponsor immediately without undue delay 
and 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. 
Germany only: AEs and SAEs will be captured from the time of the first study drug 
administration through the Safety Follow-up Visit. 
All SAEs will be recorded and reported to the sponsor or designee immediately without undue 
delay, as indicated in Appendix 3. The investigator will submit any updated SAE data to the 
sponsor immediately without undue delay. 
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 6 months after the last 
dose of study drug for female patients and 90 days after the last dose of study drug for 
male patients. 
• 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 
or Fax #: 
 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. 
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. 
PPD
PPD

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8.3.6.2 
New Cancers 
The development of a new primary cancer 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 in the study. They do not include 
metastases of the original cancer or diagnosis of AML in a patient previously diagnosed with 
MDS. 
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
If a new cancer is detected, patients should be referred to appropriate care and long-term 
follow-up. 
8.4 
Pharmacokinetics 
Samples will be collected from all patients. Placebo samples will not be analyzed. Samples from 
the patients receiving tamibarotene 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 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 at 
the Pre-screening Visit as “RARA-positive” based on an investigational assay, conducted at the 

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Almac Diagnostics Laboratory. The investigational assay will be repeated at the EoT Visit to 
explore potential changes in the RARA biomarker associated with treatment. 
8.6.2 
Companion Diagnostic Assay Development  
Blood samples collected at the Pre-screening Visit 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 MDS molecular features associated with response to drug treatment (Section 8.6.3). 
8.6.3 
Molecular Markers of Tumor Response and Resistance  
Blood samples and bone marrow aspirates will be collected for exploratory research to evaluate 
MDS molecular features associated with response to drug treatment and loss of response to drug 
treatment. Consent will be requested to retain residual samples for future research that may be 
conducted following the completion of this study. Consent for this future research is not required 
to participate in this study. 
8.7 
Health-related Quality of Life 
Patient-reported health-related quality of life will be evaluated to determine the impact of the 
addition of tamibarotene to the standard of care azacitidine treatment. The patients will be 
evaluated using the European Organization for Research and Treatment of Cancer Quality of 
Life Core Questionnaire 30 (Appendix 9) and EuroQol 5 dimensions (Appendix 11) tools. These 
questionnaires are to be self-administered by the patient and reviewed by the site for 
completeness. If any questions were incomplete, the site should encourage the patient to 
complete any missing information. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis 
Primary: CR 
Null hypothesis (H0): In RARA-positive patients with newly diagnosed HR-MDS, CR rate for 
patients in the tamibarotene plus azacitidine treatment group is the same as the CR rate for 
patients in the placebo plus azacitidine treatment group. 
Alternative hypothesis (H1): In RARA-positive patients with newly diagnosed HR-MDS, CR 
rate for patients in the tamibarotene plus azacitidine treatment group is higher than the CR rate 
for patients in the placebo plus azacitidine treatment group. 
Key Secondary: OS 
Null hypothesis (H0): In RARA-positive patients with newly diagnosed HR-MDS, OS for 
patients in the tamibarotene plus azacitidine treatment group is the same as the OS for patients in 
the placebo plus azacitidine treatment group. 

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Alternative hypothesis (H1): In RARA-positive patients with newly diagnosed HR-MDS, OS for 
patients in the tamibarotene plus azacitidine treatment group is superior to the OS for patients in 
the placebo plus azacitidine treatment group. 
Multiplicity Adjustment 
The study will be claimed positive when the primary endpoint (CR rate) is statistically 
significant. To maintain the overall type I error among the primary endpoint and the key 
secondary endpoint, the CR rate will be tested at 1-sided alpha of 
, and if it is significant, 
OS will be tested at 1-sided alpha of 
. 
9.2 
Sample Size Determination 
 patients will provide 
 power to detect the difference in CR rates 
between the tamibarotene plus azacitidine treatment group and the placebo plus azacitidine 
treatment group, with assumed CR rates of 
 versus 
 in the 2 treatment groups, 
respectively, a 2:1 randomization, and 1-sided alpha of 
. 
A total of 
 death events will provide 
 power to detect the difference in OS between 
tamibarotene plus azacitidine treatment group and the placebo plus azacitidine treatment group, 
with assumed median survival of 
 months versus 
 months (hazard ratio = 
) in the 
2 treatment groups, respectively, a 2:1 randomization, and 1-sided alpha of 
. 
A total of approximately 
 patients (
 in the tamibarotene plus azacitidine treatment group 
and 
 in the placebo plus azacitidine treatment group) are expected to be randomized in this 
study to obtain the 
 death events and final analysis time at approximately 70 months. 
9.3 
Analysis Sets 
For the purposes of the analyses, the following analysis sets are defined: 
Intent-to-treat Population 
All patients who are randomized. Treatment groups for this analysis set will 
be determined according to the treatment assignment at the time of 
randomization. 
Safety Population 
All patients who are randomized and have received any amount of study 
drug (tamibarotene/placebo or azacitidine). Treatment groups for this 
population will be determined according to the actual treatment the patients 
received. 
Per-protocol Population 
All patients who are randomized and are considered to be sufficiently 
compliant with the protocol. Specific criteria for this population will be 
defined in the statistical analysis plan, and the exclusion of patients from this 
population will be based on blinded review of the clinical data. 
Pharmacokinetic (PK) Evaluable 
Population 
All patients who are randomized and have received at least 1 dose of 
tamibarotene and have at least 1 quantifiable PK concentration. 
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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, key secondary, and secondary endpoints. 
9.4.1 
General Considerations 
When applicable, analyses will be stratified by IPSS-R risk group (Intermediate, High, and Very 
High Risk) and by geographical region (North America, Western Europe, and Israel versus 
Eastern Europe). 
Frequency distributions will be used for categorical variables and appropriate summary statistics 
(i.e., mean, median, and range) for quantitative/continuous variables. 
Additional details of the analyses will be provided in the SAP. 
9.4.2 
Primary Endpoint 
Complete Remission 
CR will be determined by the investigator per the modified IWG MDS criteria (Cheson 2006). 
Per the IWG MDS criteria responses must last at least 4 weeks. Instructions for the assessment of 
IWG response including the provision of a 2-week window for unscheduled hematology 
evaluations to meet the IWG criteria of CR are provided in Section 8.1.1. 
The CR will be evaluated in the Intent-to-Treat (ITT) population. CR rate and 95% exact 
binomial confidence intervals (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 stratified Cochran–Mantel–Haenszel (CMH) test will be 
applied to compare the CR rates between the 2 treatment groups, stratified by IPSS-R risk group 
(Intermediate, High, and Very High Risk) and by geographical region (North America, Western 
Europe, and Israel versus Eastern Europe). The final analysis of CR is planned for the time when 
all 190 patients have completed the Cycle 7 Day 1 response assessment or discontinued 
treatment, whichever comes first. Patients with missing response assessment data will be 
considered as a failure to achieve CR, including patients who have died, withdrew consent, or 
started a new treatment prior to achieving a CR. 
The point estimate of the difference of the proportions for CR rate between the 2 treatment 
groups will also be provided along with 95% CI. 
9.4.3 
Key Secondary Endpoint 
Overall Survival 
OS, defined as the time from the date of randomization to the date of death due to any cause, will 
be analyzed in the ITT population. Patients who do not die at the time of a data cutoff date 

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(interim and/or final) will be censored at the last date the patient is known to be alive or at the 
analysis cutoff date, whichever is earlier. 
The distribution of OS will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between 2 treatment groups using the log-rank test stratified by 
IPSS-R risk group (Intermediate, High, and Very High Risk) and by geographical region (North 
America, Western Europe, and Israel versus Eastern Europe). The hazard ratio and the 
corresponding 95% CI between the 2 treatment groups will be estimated using the stratified Cox 
proportional hazards model with the same stratification factors that are used for stratified 
log-rank test. OS will be displayed by Kaplan-Meier curves. The 25th percentile, median, and 
75th percentile OS and the 95% CI will be provided for each treatment group. The 12-month and 
24-month OS rates will be estimated using the Kaplan-Meier method.

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Table 3: 
Estimands (Primary and Key Secondary) 
Objectives 
Estimand Category 
Treatment 
Population 
Variable/Endpoint 
Intercurrent Event; 
Strategy 
Population Level 
Summary  
CR: To demonstrate 
the superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in CR in 
RARA-positive newly 
diagnosed HR-MDS 
patients 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-R 
risk category as 
intermediate, high, or 
very high risk 
CR, as determined by the 
investigator per the modified 
IWG MDS criteria 
(Cheson 2006) 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment before 
achieving a response; 
Composite strategy 
• CR rate by 
treatment arm 
• Difference in 
proportion of 
CR rate 
between two 
treatment arms 
OS: To demonstrate 
the superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in overall 
survival in RARA-
positive newly 
diagnosed HR-MDS 
patients 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-R 
risk category as 
intermediate, high, or 
very high risk 
OS, defined as the time from 
the date of randomization to 
date of death from any cause 
Treatment discontinuation; 
Treatment policy 
Initiation of HSCT or other 
subsequent anticancer 
therapy; 
Treatment policy 
Kaplan-Meier 
estimate of OS 
and hazard ratio 
Abbreviations: CR = complete remission; HR-MDS = higher-risk myelodysplastic syndrome; HSCT = hematopoietic stem cell transplantation; 
IPSS-R = Revised International Prognostic Scoring System; ITT = intent-to-treat; IWG = International Working Group; RARA = retinoic acid receptor alpha; 
OS = overall survival; WHO = World Health Organization. 

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9.4.4 
Secondary Endpoints 
Transfusion Independence 
TI, defined as a period of at least 56 days with no RBC or platelet transfusion since the date of 
randomization to the last dose of study drug +30 days, the initiation of post-treatment therapy, or 
death, whichever occurs first. 
TI rate (based on receiving neither RBC nor platelet transfusion for a period of at least 56 days) 
with respective 95% exact binomial CIs will be calculated by treatment group. The stratified 
CMH test will be applied to compare the TI rates between the 2 treatment groups. 
Overall Response 
Overall response, defined as achievement of CR, PR, marrow CR (mCR), or HI as determined by 
the investigator per the modified IWG MDS criteria (Cheson 2006). 
Overall response rate (ORR) and 95% exact binomial CIs will be calculated by treatment group. 
The stratified CMH test will be applied to compare the ORRs between the 2 treatment groups. 
The rates of CR or PR; rates of CR, PR, or marrow CR; and the rates of HI will also be 
summarized with 95% exact binomial CIs and compared between the treatment groups using the 
stratified CMH test. 
Overall response may also be analyzed in line with the updated IWG response criteria 
(Zeidan 2023). 
Duration of Complete Remission 
DOCR, defined as the duration from the date of first documented evidence of CR to the date of 
documented relapse of disease, as determined by the investigator per the modified IWG MDS 
criteria (Cheson 2006), or death due to any cause, whichever occurs first. 
Kaplan-Meier estimation of median DOCR and corresponding 95% CIs will be presented by 
treatment group. 
Duration of Overall Response 
Duration of overall response defined as the duration from the date of first documented evidence 
of CR, PR, mCR, or HI, to the date of documented disease progression, relapse of disease as 
determined by the investigator per the modified IWG MDS criteria (Cheson 2006), or death due 
to any cause, whichever occurs first. 
Kaplan-Meier estimation of median duration of overall response and corresponding 95% CIs will 
be presented by treatment group. 

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Time to CR 
Time to CR, defined as the duration from the date of randomization to the date of the first 
documented evidence of CR as determined by the investigator per the modified IWG MDS 
criteria (Cheson 2006). 
Time to CR will be summarized descriptively for the 2 treatment groups. 
Time to Initial Response 
Time to initial response, defined as the duration from the date of randomization to the date of the 
first documented evidence of CR, PR, mCR, or HI as determined by the investigator per the 
modified IWG MDS criteria (Cheson 2006). 
Time to initial response will be summarized descriptively for the 2 treatment groups. 
EFS 
EFS, defined as the time from the date of randomization to the date of transformation to AML or 
death due to any cause, whichever occurs first. 
Kaplan-Meier estimation of median EFS and 95% CI will be presented by treatment group. The 
stratified log rank test will be used to analyze the difference in EFS between treatment groups. 
Change in HRQOL 
EORTC QLQ-30 and EQ-5D-5L test results will be summarized separately by treatment group, 
parameter, and visit. For EORTC QLQ-30, results for global health status, each of the five 
functional scales (physical, role, emotional, cognitive, and social functioning), and each of the 
eight symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, 
constipation, and diarrhea) will be summarized. The scores for global health status, functional 
scales and symptom scales will be calculated and standardized using the methods described in 
The EORTC QLQ-C30 Scoring Manual (3rd Edition) (Fayers 2001). For EQ-5D-5L, results for 
overall health and each of the 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression) will be summarized. 
Descriptive statistics will be presented for observed values and changes from baseline by 
parameter at each visit where the questionnaires were scheduled to be collected per the clinical 
study protocol. Change from baseline in important parameters will be analyzed using MMRM. 
The model will include treatment, visit, and treatment-by-visit interaction as fixed effects and 
baseline as covariate. An unstructured covariance matrix will be used to model the between- and 
within-patient errors. 
The Kenward-Roger method will be used to estimate the degrees of freedom. Treatment least 
squares means (LSMs) will be estimated within the framework of the MMRM using type 3 sums 
of squares. Differences in LSM between treatment groups (and associated standard errors and 
95% CI) will be used for statistical inference. The LSM difference, standard error, and 95% CI 
and will be reported for each parameter and visit. 

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A by-patient listing of all EORTC QLQ-30 and EQ-5D-5L results will be provided. 
Safety Analyses 
Adverse Events 
The number and percentage of patients with AEs or 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 change in National Cancer Institute (NCI) CTCAE (version 5) 
grade from baseline to worst grade postbaseline. 
Laboratory Tests 
Changes from baseline will be analyzed for each scheduled post-baseline visit for chemistry and 
hematology parameters. Where applicable, chemistry and hematology laboratory determinations 
will be categorized according to NCI CTCAE (Version 5) grades, and shift from baseline NCI 
CTCAE grades to worst post-baseline grades will be assessed. 
Vital Signs 
A shift from baseline to the worst post-baseline blood pressure category (normal to stage 2 
hypertension) summary will be presented by treatment group and total according to each of the 
American College of Cardiology and American Heart Association 2017 guidelines. 
Changes from baseline in systolic and diastolic blood pressure results will also be presented as 
box plots by visit and for each treatment group. 
ECG 
A shift from baseline category to the worst post-baseline category (Normal, Abnormal NCS, 
Abnormal CS) summary will be presented by treatment group and total. Prolonged QTcF 
intervals (>450 msec, >480 msec, and >500 msec) will be summarized by each visit. Change 
from baseline categories will also be summarized for measurements that represent a change 
>30 msec or >60 msec relative to the baseline value. 
Change from baseline in QTcF interval results will also be presented as box plots by visit and for 
each treatment group. 
All AE data, vital sign data and ECG data will be listed. 
Additional details on the analyses will be provided in the SAP. 

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Table 4: 
Estimands (Secondary) 
Secondary Objectives 
Estimand Category 
Treatment 
Population 
Variable/Endpoint 
Intercurrent Event; 
Strategy 
Population Level 
Summary  
TI: To demonstrate the 
superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in TI  
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-
R risk category as 
intermediate, high, or 
very high risk 
TI, defined as a period of at 
least 56 days with no RBC or 
platelet transfusion since the 
date of randomization to the 
last dose of study drug 
+30 days, the initiation of 
post-treatment therapy, or 
death, whichever occurs first 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment before 
achieving a response; 
Composite strategy 
TI rate by 
treatment arm 
Overall Response: To 
demonstrate the 
superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in overall 
response 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-
R risk category as 
intermediate, high, or 
very high risk 
Overall response, defined as 
achieving CR, PR, mCR, or 
HI as determined by the 
investigator per the modified 
IWG MDS criteria 
(Cheson 2006) 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment before 
achieving a response; 
Composite strategy 
Overall response 
rate by treatment 
arm 

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Secondary Objectives 
Estimand Category 
Treatment 
Population 
Variable/Endpoint 
Intercurrent Event; 
Strategy 
Population Level 
Summary  
DOCR: To 
demonstrate the 
superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in duration 
of complete remission 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-
R risk category as 
intermediate, high, or 
very high risk 
DOCR, defined as the duration 
from the date of first 
documented evidence of CR to 
the date of documented 
relapse of disease, as 
determined by the investigator 
per the modified IWG MDS 
criteria (Cheson 2006), or 
death due to any cause, 
whichever occurs first 
Treatment discontinuation; 
Treatment policy 
Initiation of HSCT or other 
subsequent anticancer 
therapy; 
Treatment policy 
Kaplan-Meier 
estimate of 
DOCR 
Duration of Overall 
Response: To 
demonstrate the 
superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in duration 
of overall response 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the 
IPSS-R risk category as 
intermediate, high, or 
very high risk 
Duration of overall response 
defined as the duration from 
the date of first documented 
evidence of CR, PR, mCR, or 
HI, to the date of documented 
disease progression, relapse of 
disease as determined by the 
investigator per the modified 
IWG MDS criteria 
(Cheson 2006), or death due to 
any cause, whichever occurs 
first 
Treatment discontinuation; 
Treatment policy 
Initiation of HSCT or other 
subsequent anticancer 
therapy; 
Treatment policy 
Kaplan-Meier 
estimate of 
duration of 
overall response 

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Secondary Objectives 
Estimand Category 
Treatment 
Population 
Variable/Endpoint 
Intercurrent Event; 
Strategy 
Population Level 
Summary  
Time to CR:  
Characterize the time 
to CR and time to 
initial response of 
tamibarotene plus 
azacitidine vs. placebo 
plus azacitidine 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-
R risk category as 
intermediate, high, or 
very high risk 
Time to CR, defined as the 
duration from the date of 
randomization to the date of 
the first documented evidence 
of CR as determined by the 
investigator per the modified 
IWG MDS criteria 
(Cheson 2006) 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment before 
achieving a response;  
Composite strategy 
Summary 
statistics (n, 
mean, median, 
min, max) 
Time to Initial 
Response:  
Characterize the time 
to initial response of 
tamibarotene plus 
azacitidine vs. placebo 
plus azacitidine 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the IPSS-
R risk category as 
intermediate, high, or 
very high risk 
Time to initial response, 
defined as the duration from 
the date of randomization to 
the date of the first 
documented evidence of CR, 
PR, mCR, or HI as determined 
by the investigator per the 
modified IWG MDS criteria 
(Cheson 2006) 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment before 
achieving a response; 
Composite strategy 
Summary 
statistics (n, 
mean, median, 
min, max) 

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Secondary Objectives 
Estimand Category 
Treatment 
Population 
Variable/Endpoint 
Intercurrent Event; 
Strategy 
Population Level 
Summary  
EFS: To demonstrate 
the superiority of 
tamibarotene plus 
azacitidine compared 
to placebo plus 
azacitidine in event 
free survival 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the 
IPSS-R risk category as 
intermediate, high, or 
very high risk 
EFS, defined as the time from 
the date of randomization to 
the date of transformation to 
AML or death due to any 
cause, whichever occurs first. 
Treatment discontinuation; 
Treatment policy 
Initiation of HSCT or other 
subsequent anticancer 
therapy; 
Treatment policy 
Kaplan-Meier 
estimate of EFS 
Change in HRQOL: 
Compare changes in 
HRQOL of patients 
treated with 
tamibarotene plus 
azacitidine vs. placebo 
plus azacitidine 
Tamibarotene plus 
azacitidine versus 
placebo plus 
azacitidine 
RARA-positive patients 
with newly diagnosed 
HR-MDS according to 
the WHO classification, 
classified by the 
IPSS-R risk category as 
intermediate, high, or 
very high risk 
Observed and change from 
baseline for EORTC QLQ-30 
and EQ-5D-5L parameters 
Treatment discontinuation; 
Treatment policy 
Patients who die, withdraw 
consent, or start a new 
anticancer treatment; 
Composite strategy 
Summary of  
Estimate of 
change from 
baseline for 
EORTC QLQ-30 
and EQ-5D-5L 
parameters from 
Linear mixed 
model 
Abbreviations: AML = acute myeloid leukemia; CR = complete remission; DOCR = duration of complete remission; EFS = event-free survival; EORTC QLQ-
30 = European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30; EQ-5D-5L = EuroQol 5 dimensions; 
HI = hematologic improvement; HR-MDS = higher-risk myelodysplastic syndrome; HRQOL = health-related quality of life; = hematopoietic stem cell 
transplantation; HSCT = IPSS-R = Revised International Prognostic Scoring System; IWG = International Working Group; max = maximum; min = minimum; 
mCR = marrow CR; PR = partial remission; RARA = retinoic acid receptor alpha; RBC = red blood cell; TI = transfusion independence; vs. = versus; 
WHO = World Health Organization.

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9.4.5 
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. 
9.4.6 
Timing of Efficacy Analysis 
The primary analysis for CR will occur when all 
 randomized subjects have completed the 
Cycle 7 Day 1 assessment or discontinued treatment, whichever comes first. The analysis for OS 
for the Key Secondary endpoint will be performed when approximately 
 OS death events 
have been observed. 
9.5 
Interim Analyses 
There will be 2 planned interim futility analyses, one for the CR and one for OS, respectively; 
these will be non-binding and will be conducted by the IDMC. The IDMC may recommend 
terminating the study for unfavorable results at an interim analysis. 
Interim Futility Analysis for CR 
An interim futility analysis of the CR rate is planned when the 
 randomized patient has 
completed the Cycle 7 Day 1 assessment or discontinued treatment, whichever comes first. The 
study may be terminated at CR interim futility analysis, if the 1-sided p-value from the stratified 
CMH test comparing the CR rates (tamibarotene plus azacitidine treatment group versus placebo 
plus azacitidine treatment group) is 
. The non-binding futility bound is derived using a 
HSD spending function with gamma = -4 (Hwang 1990). 
Interim Futility Analysis for OS 
If the CR rate is statistically significant at the time of the primary efficacy analysis of the CR 
rates between the 2 treatment groups, an interim OS futility analysis will be conducted when 
approximately 
 information fraction (
 of the total 
 events) has been observed. The 
study may be terminated at OS interim futility analysis if the 1-sided p-value from the stratified 
log rank test comparing the distribution of OS (tamibarotene plus azacitidine treatment group 
versus placebo plus azacitidine treatment group) is 
. The non-binding futility bound is 
derived using Lan-DeMets spending function. 
The details about the futility and efficacy stopping boundaries at interim analysis and final 
analysis for CR rate and OS endpoints are specified in Table 5 and Table 6. 
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Table 5 
Planned Stopping Boundaries for CR Futility Analysis and FA 
Endpoint 
 
Look 
IF 
Number of 
Subjects 
Boundary 
 (1-sided p-value) 
Minimum Critical Difference of 
CR Rate at the Boundary 
CR rate  
Futility 
0.5 
 
 
0.0045 
FA 
1 
 
 
0.1349 
Abbreviations: CR = complete remission; FA = final analysis; IF = information fraction. 
Table 6 
Planned Stopping Boundaries for OS Futility Analysis and FA 
Endpoint 
Look 
IF 
Number 
of Events 
Boundaries (1-sided 
p-value) 
Approx. Observed Hazard 
Ratios at the Boundary 
OS 
Futility  
0.249 
 
 
1.261 
FA 
1 
 
 
0.78 
Abbreviations: FA = final analysis; IF = information fraction; OS = overall survival. 
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. 
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• 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 
regulations 
10.1.2 
Informed Consent Process 
• A Pre-screening ICF and a Main ICF will be used in this study, as shown in the SoA 
(Section 1.3). 
• 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. 
United Kingdom only:  
• A Pre-screening ICF and a Main ICF will be used in this study, as shown in the SoA 
(Section 1.3). 
• The investigator or his/her representative will explain the nature of the study to the 
patient and answer all questions regarding the study. 

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• Patients must be informed that their participation is voluntary. Patients 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. 
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, 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 and 
by inspectors from regulatory authorities. 
10.1.4 
Committees Structure 
10.1.4.1 
Independent Data Monitoring Committee 
An IDMC will be established and will review the data at the 2 planned interim futility analyses 
and the safety interims, as specified in the IDMC Charter. The IDMC will be comprised of 
3 clinicians, one of whom will be the Chair, and one statistician (see IDMC Charter for 
additional details). The IDMC will meet approximately every 4 months to review the safety data 
from the study and ad hoc if needed based on request from sponsor. 

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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 electronic case report 
forms (eCRFs) via EDC. The investigator is responsible for verifying that data entries are 
accurate and correct by electronically signing the CRF. 
• Guidance on completion of eCRFs will be provided in the eCRF Completion Guidelines. 
• The investigator must permit study-related monitoring, audits, 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 site desires to destroy any study 
documentation or such other documents, site shall notify sponsor of such desire and 
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 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. 
• The source records are typically the patient’s medical chart and other sources, such as 
tamibarotene/placebo 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 

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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 investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
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). 
 
 

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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 SoA (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. 
Protocol-required Safety Laboratory Tests 
Laboratory 
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 
Prothrombin time or international normalized ratio 
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 

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Laboratory 
Tests 
Parameters 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• Hepatitis panel testing may include the following tests, as needed, to rule out an active or 
chronic hepatitis B or active hepatitis C virus (HCV) infection: HCV antibody test, nucleic 
acid test for HCV RNA, hepatitis B surface antigen, hepatitis B surface antibody, 
hepatitis B core antibody (total), and hepatitis B core antibody (IgM) 
a 
Local high-sensitivity urine pregnancy testing will be standard for the protocol unless serum testing is 
required by local regulation or IRB/IEC. 
 
 

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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 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. 
• Progressive disease (PD), including death from PD, is considered an efficacy outcome 
parameter and should not be captured as an AE/SAE. Documentation of PD must be 
obtained and recorded in the eCRF. Until a diagnosis of PD is made, signs and 
symptoms that meet the AE criteria should be reported as specific AEs, regardless of 
whether PD is suspected. 

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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. 

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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. 
• 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 National Cancer Institute CTCAE, version 5. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
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 
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. 
• 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. 

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• 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 
post-mortem 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 
 or Fax #: 
 immediately without 
undue delay and within 24 hours of receipt of the information. The investigator may 
also be asked by the sponsor to provide clarification or additional information. 
Germany only: The investigator will submit any updated SAE data to the sponsor’s 
designee via email at 
 or Fax #: 
 
immediately without undue delay from receipt of the information. The investigator 
may also be asked by the sponsor to provide clarification or additional information. 
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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 
 or Fax #: 
 immediately without 
undue delay and 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. 
Germany only: An SAE Report form will be completed and submitted to the sponsor’s 
designee via email at 
 or Fax #: 
 
immediately without undue delay from 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 immediately without undue delay and 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. 
Germany only: 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 immediately without undue delay from 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. 
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. 
Patients must be willing and able to comply with the use of 2 methods of birth control (including 
a barrier method) for WOCBP and male patients. 
Male patients with a partner who is a WOCBP must agree to use a condom combined with an 
additional contraceptive method that together result in a failure rate of <1% per year (see 
Section 10.4.2). Contraception use must be continued for at least 90 days after the last dose of 
study drug. Men should not donate sperm during this timeframe. Tamibarotene has been reported 
to cause abnormalities in spermatogenesis in nonclinical studies in rats and dogs. In addition, 
adverse reactions with azacitidine use on male fertility have been documented in animals. 
Consequently, male patients should consider banking sperm before tamibarotene is administered. 
WOCBP patients are required to use highly effective contraceptive measures, as defined in 
Section 10.4.2. Contraception use must be continued for at least 6 months after the last dose of 
study drug. Women should not donate ova during this timeframe. 
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 postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− 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. 
− 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 study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
− Documented hysterectomy 

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− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
− 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. 
• 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: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
d. 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 
a. A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
i. 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. 
ii. Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 

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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: 
 
The table below is prepared to provide examples and is not intended to be exhaustive. 
CCI
CCI

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10.7 Appendix 7: Criteria for Determination of MDS IPSS-R Risk Category 
MDS Cytogenetic Scoring System (IPSS-R) 
Cytogenetic Prognostic 
Subgroups 
Cytogenetic Abnormalities 
Very Good 
-Y, del(11q) 
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
del(7q), +8, +19, i(17q), any other single or double independent clones 
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities 
Very Poor 
Complex: >3 abnormalities 
MDS Prognostic Score Values (IPSS-R) 
 
Score Value 
Prognostic Variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very 
Good 
- 
Good 
– 
Inter-
mediate 
Poor 
Very 
Poor 
Marrow Blasts (%) 
≤2 
- 
>2 - <5 
- 
5-10 
>10 
- 
Hemoglobin (g/dL) 
≥10 
- 
8 - <10 
<8 
- 
- 
- 
Platelet Count (× 109/L) 
≥100 
50 - <100 
<50 
- 
- 
- 
- 
Absolute Neutrophil Count 
(× 109/L) 
≥0.8 
<0.8 
- 
- 
- 
- 
- 
MDS IPSS-R Prognostic Risk Category and Risk Score (Sum of Prognostic Score 
Values) 
Risk Category 
Overall Risk Score 
Very Low  
≤1.5 
Low  
>1.5-3 
Intermediate 
>3-4.5 
High 
>4.5-6 
Very High 
>6 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised 
international prognostic scoring system for myelodysplastic syndromes. Blood. 
2012;120(12):2454-65. Epub 2012 Jun 27. 

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10.8 Appendix 8: IWG Response Criteria for MDS 
Hematologic Improvement  
The IWG criteria for HI define specific responses of cytopenias in the 3 hematopoietic lineages: 
erythroid (HI-E), platelet (HI-P), and neutrophil (HI-N). The HIs are measured in patients with 
pretreatment abnormal values: hemoglobin level less than 110 g/L (11 g/dL) or RBC-transfusion 
dependence, platelet count less than 100 × 109/L or platelet-transfusion dependence, and absolute 
neutrophil count less than 1.0 × 109/L. 
Response Criteria and Progression Definitions for Myelodysplasia 
Response 
Criteriaa 
Peripheral Blood 
Bone 
Marrow 
Blasts (BMB) 
(%) 
Other 
Hemoglobin  
(g/dL) 
Neutrophils 
per (L) 
Platelets 
per (L) 
Blasts 
(%) 
 
 
Complete 
Remission 
(CR) 
≥11 
≥1.0 × 109  
≥100 × 109 
0 
≤5 
Normal maturation of all cell 
lines, persistent dysplasia will be 
noted 
Partial 
Remission 
(PR) 
 
 
 
 
Decreased by 
≥50% from 
baseline, but 
>5% 
All CR criteria if abnormal 
before treatment except BMB 
Marrow CR 
(mCR) 
If hematologic improvement (HI) response, note in 
addition to marrow CR 
decreased by 
≥50% from 
baseline, and 
≤5% 
 
Stable Disease 
 
 
 
 
 
Failure to achieve PR & no 
evidence of progression for 
>8 weeks 
Failure 
 
 
 
 
 
Death during treatment, or 
disease progression: worsening 
cytopenia, increase in % BM 
blasts, progression to a more 
advanced MDS FAB subtype 
Relapse after 
CR or PR 
 
 
 
 
 
At least one of the following: 
Return to pretreatment BMB % 
Decrement of ≥50% from 
maximum remission/response 
levels in granulocytes or 
platelets 
Reduction in Hgb ≥1.5g/dL or 
transfusion dependence 
Cytogenetic Response 
Complete 
Partial 
Evaluation 
Disappearance of chromosomal abnormality with no appearance of new 
ones 
≥50% reduction of chromosomal abnormality 

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Disease Progression, patients with: 
<5% bone marrow blasts 
5%-<10% bone marrow blasts 
10%-<20% bone marrow blasts 
For all categories 
Evaluation Criteria: 
≥50% increase to >5% bone marrow blasts 
≥50% increase to >10% bone marrow blasts 
≥50% increase to ≥20% bone marrow blasts 
At least 50% decrease from maximum remission/response in granulocytes 
or platelets 
or reduction in Hgb by ≥2 g/dL or transfusion dependence 
a 
Response must last at least 4 weeks. 
Response Criteria for Hematologic Improvement for Myelodysplasia 
Hematologic Improvement 
Response Criteria (Response Lasting 8 Weeks) 
Erythroid response (pretreatment <11 g/dL) 
Hgb increase by ≥1.5 g/dL 
Relevant reduction of units of red blood cell (RBC) transfusions by an 
absolute number of at least 4 RBC transfusions/8 week compared with 
the pretreatment transfusion number in the previous 8 weeks. Only RBC 
transfusions given for a Hgb of ≤9.0 g/dL pretreatment will count in the 
RBC transfusion response evaluation. 
Platelet Response (pretreatment <100 × 109/L) 
Absolute increase of ≥30 × 109/L if starting with >20 × 109/L platelets 
Increase from <20 × 109/L to >20 × 109/L and by at least 100% 
Neutrophil Response (pretreatment <1 × 109/L) 
At least a 100% increase and an absolute increase >0.5 × 109/L 
Progression or relapse after HI in the absence of 
another explanation 
At least one of the following: 
At least 50% decrease from maximum response levels in granulocytes or 
platelets; 
Reduction in Hgb by ≥1.5 g/dL; 
Transfusion dependence. 
Adapted from: Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer 
SD, et al. Clinical application and proposal for modification of the International Working Group 
(IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425. Epub 2006 Apr 11. 
 
 
 

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10.9 Appendix 9: European Organization for Research and Treatment of Cancer 
Quality of Life Core Questionnaire 30 (Sample) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.10 Appendix 10: EuroQol 5 Dimensions (Sample) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.11 Appendix 11: Abbreviations and Definitions 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia  
APL 
Acute promyelocytic leukemia 
ART 
Anti-retroviral therapy 
AST 
Aspartate aminotransferase 
ATRA 
All-trans retinoic acid  
BID 
Twice per day 
CI 
Confidence interval 
CMH 
Cochran–Mantel–Haenszel 
CR 
Complete remission/complete response 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DOCR 
Duration of complete response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture (system) 
EFS 
Event-free survival 
EORTC QLQ-30 
European Organization for Research and Treatment of Cancer Quality of Life 
Core Questionnaire 30 
EoT 
End of treatment  
EQ-5D-5L 
EuroQol 5 dimensions 
EU 
European Union 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
HCV 
Hepatitis C virus 
HI 
Hematologic improvement 
HIV 
Human immunodeficiency virus  
HR-MDS 
Higher-risk myelodysplastic syndrome 
HRQOL 
Health-related quality of life 
HRT 
Hormonal replacement therapy 

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Abbreviation 
Definition 
HSD 
Hwang-Shih-DeCani 
HSCT 
Hematopoietic stem cell transplantation 
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 
IPSS-R 
Revised International Prognostic Scoring System 
ITT 
Intent-to-Treat 
IWG 
International Working Group 
LSM 
Least squares mean 
mCR 
Marrow CR 
MDS 
Myelodysplastic syndrome 
MMRM 
Mixed models for repeated measures  
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PK 
Pharmacokinetic(s) 
PR 
Partial remission/partial response 
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 
SoA 
Schedule of Activities 
SmPC 
Summary of Product Characteristics 
TI 
Transfusion independence 
ULN 
Upper limit of normal 

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Abbreviation 
Definition 
US 
United States 
USPI 
United States Prescribing Information 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
 
 

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