Tamibarotene Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome

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)

This study compares the efficacy of Tamibarotene in combination with azacitidine to azacitidine in combination with placebo in participants who are Retinoic Acid Receptor Alpha (RARA) positive, and newly diagnosed with higher-risk myelodysplastic syndrome (HR-MDS), and who have not received treatment for this diagnosis. The primary goal of the study is to compare the complete remission rate between the two treatment arms.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Placebo; Drug: Tamibarotene; Drug: Azacitidine

Detailed Description

A subset of participants have MDS characterized by an overexpression of the RARA gene. A blood test will be used to identify participants with RARA-positive MDS. Assessment of the RARA biomarker for study eligibility will be done by collection of blood samples from potential study participants at the pre-screening visit and testing at a central laboratory. Participants who meet eligibility requirements will be randomized 2:1 to receive either Tamibarotene plus azacitidine or placebo plus azacitidine.

• Study Type: Interventional
• Enrollment (Actual): 246
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medical University of Graz
  • Salzburg, Austria, 5020
    • Salzburg Cancer Research Institute (SCRI)
  • Vienna, Austria
    • Klinik Hietzing
• Belgium
  • Antwerp, Belgium
    • ZNA Middelheim
  • Brussels, Belgium
    • Institut Jules Bordet
  • Gent, Belgium
    • Ghent University Hospital
  • La Louvière, Belgium, 7100
    • Hospital de Jolimont
  • Liège, Belgium
    • CHU de Liege
  • Roeselare, Belgium, 8800
    • AZ Delta
  • Yvoir, Belgium, 5530
    • CHU-UCL Namur
• Canada
  • Calgary, Canada
    • Tom Baker Cancer Centre
  • London, Canada, ON
    • London Health Sciences Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • CancerCare Manitoba
  • Ontario
    • Hamilton, Ontario, Canada, ON L8V 1C3
      • Juravinski Cancer Centre
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center
    • Toronto, Ontario, Canada
      • Princess Margaret Cancer Centre - University Health Network
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre (MUHC)
• Czechia
  • Olomouc, Czechia
    • Fakultni nemocnice Olomouc (University Hospital Olomouc)
  • Ostrava, Czechia
    • University Hospital Ostrava
  • Prague, Czechia
    • General University Hospital Prague
• France
  • Amiens, France, 80054
    • CHU Amiens-Picardie
  • Angers, France, 49933
    • CHU d'Angers
  • Bayonne, France, 64109
    • Centre Hospitalier de la Côte Basque Hématologie Clinique
  • Bobigny, France, 93000
    • Hôpital Avicenne
  • Brest, France, 29200
    • CHRU de Brest - Hopital Morvan
  • Clermont-Ferrand, France
    • CHU Clermont Ferrand / CHU Estaing
  • La Tronche, France
    • CHU Grenoble Alpes Hopital Nord Michallon
  • Le Chesnay, France, 78150
    • Hopital Mignot
  • Limoges, France, 87000
    • CHU de Limoges
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France
    • CHU la Conception
  • Nantes, France, 44093
    • CHU Nantes - Hotel Dieu
  • Nice, France, 06200
    • CHU DE Nice - Hôpital l'Archet
  • Paris, France, 75475
    • Hopital Saint Louis
  • Pessac, France, 33604
    • CHU Bordeaux
  • Pierre-Bénite, France, 69495
    • CHU Lyon Sud
  • Poitiers, France, 86021
    • CHU Poiters
  • Saint-Priest-en-Jarez, France
    • CHU Saint Etienne
  • Strasbourg, France, 67033
    • ICANS Strasbourg
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Augsburg, Germany
    • Universitätsklinikum Augsburg
  • Berlin, Germany
    • HELIOS Klinikum Berlin Buch GmbH
  • Freiburg, Germany
    • Universitatsklinikum Freiburg
  • Göttingen, Germany
    • Universitatsmedizin Gottingen
  • Halle, Germany
    • Universitatsklinikum Halle (Saale)
  • Marburg, Germany
    • Universitätsklinikum Marburg
  • Münster, Germany
    • Universitätsklinikum Münster
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Debrecen, Hungary, H-4012
    • Debrecen University Medical and Health Science Centre
  • Eger, Hungary
    • Markhot Ferenc Oktatókórház és Rendelőintézet, Belgyógyászati- és Infektológiai Centrum
  • Győr, Hungary
    • Petz Aladár County Teaching Hospital
  • Nyíregyháza, Hungary, 4400
    • Josa Andras Teaching Hospital
• Israel
  • Ashkelon, Israel
    • Barzilai Medical Center of Ashkelon
  • Haifa, Israel, 31048
    • Bnai Zion Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Ramat Gan, Israel
    • Sheba Medical Center
  • Rehovot, Israel, 7661041
    • Kaplan Medical Center
  • Tel Aviv, Israel
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna
  • Brescia, Italy
    • ASST Spedali Civili di Brescia
  • Ferrara, Italy, 44124
    • Azienda Ospedaliero-Universitaria di Ferrara
  • Firenze, Italy
    • AOU Careggi
  • Genova, Italy, 16132
    • Ospedale Policlinico San Martino
  • Meldola, Italy, 47014
    • Romagnolo Institute to Study Tumors "Dino Amadori "/ Meldona
  • Novara, Italy, 28100
    • A.O.U. Maggiore della Carita
  • Pesaro, Italy, 61122
    • Ospedali Marche Nord Centro Ematologia e Trapianti
  • Ravenna, Italy
    • Ospedale S.Maria delle Croci
  • Roma, Italy
    • Ospedale S. Eugenio - ASL Roma 2
  • Rome, Italy, 00133
    • Fondazione Policlinico Tor Vergata
  • Verona, Italy
    • AOUI di Verona
• Poland
  • Gdańsk, Poland, 80-952
    • University Clinic Gdansk
  • Gdynia, Poland, 81-519
    • Pomeranian Hospital Gdynia
  • Legnica, Poland, 59-220
    • Wojewodzki Szpital Specjalistyczny w Legnicy
  • Warszawa, Poland
    • Instytut Hematologii i Transfuzjologii, Klinika Hematologii
  • Warszawa, Poland
    • University Clinic Warsaw
  • Wałbrzych, Poland
    • Alfred Sokołowski Hospital Wałbrzych
• Spain
  • Badalona, Spain
    • Institut Catala d'Oncologia - Hospital Duran i Reynals Location
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08025
    • H. Santa Creu i Sant Pau
  • Barcelona, Spain, 08035
    • Fundación Privada Instituto de Investigación Oncológica Vall d'Hebron
  • Barcelona, Spain
    • Hospital del Mar Secretaria d'Hematologia Clínica
  • Burgos, Spain, 09006
    • Hospital Universitario de Burgos
  • Cáceres, Spain
    • Hospital San Pedro De Alcantara
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain
    • Hospital Universitario de La Princesa
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center
  • Madrid, Spain, 28046
    • H. Universitario La Paz
  • Murcia, Spain
    • Hospital General Universitario J.M. Morales Meseguer
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturia
  • Palma De Mallorca, Spain, 07198
    • Hospital Son Llàtzer
  • Pamplona, Spain, 31008
    • Clinica Universidad Navarra
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • San Sebastián, Spain
    • Hospital Universitario Donostia
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe
  • Valencia, Spain
    • Hospital Clinico Universitario de Valencia
• United Kingdom
  • Cottingham, United Kingdom
    • Castle Hill Hospital, Cottingham
  • Dundee, United Kingdom
    • Ninewells Hospital
  • Edinburgh, United Kingdom
    • Western General Hospital in NHS Lothian Edinburgh Scotland
  • Liverpool, United Kingdom
    • Clatterbridge Cancer Centre NHS Foundation Trust
  • London, United Kingdom
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom
    • The Royal Marsden Foundation Trust
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust
  • West Bromwich, United Kingdom
    • Sandwell and West Birmingham Hospital NHS Trust
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angelas
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Florida
    • Saint Petersburg, Florida, United States, 33709
      • Comprehensive Hematology and Oncology
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Cancer Center
    • Skokie, Illinois, United States, 60077
      • Orchard Healthcare Research Inc.
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
  • New Jersey
    • Morristown, New Jersey, United States, 02140
      • Morristown Medical Center- Atlantic Hematology Oncology
  • New York
    • Lake Success, New York, United States, 11042
      • Northwell Health
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Inc
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
    • Winston-Salem, North Carolina, United States, 27103
      • Novant Health Cancer Institute - Forsyth
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • TriStar - Sarah Cannon BMT
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participants must be RARA-positive based on the investigational assay.

• Participants must be newly diagnosed with HR-MDS as follows:

  • Diagnosis of MDS according to the World Health Organization (WHO) classification and classified by the Revised International Prognostic Scoring System (IPSS R) risk category as very high, high, or intermediate risk.
• Participants must have Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.

Key Exclusion Criteria:

• Participants are suitable for and agree to undergo allogeneic hematopoietic stem cell transplant (HSCT) at the time of screening.

  • Participants who need treatment prior to stem cell transplant can receive treatment on this study and stop the study treatment when they are ready to proceed to transplant.
• Participants who received prior treatment for MDS with any hypomethylating agent, lenalidomide, chemotherapy or allogeneic HSCT.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tamibarotene + Azacitidine; Tamibarotene: 6 mg administered orally twice per day (BID) on Days 8 through 28 of each 28-day treatment cycle. Azacitidine: 75 mg/m^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.	Drug: Tamibarotene; Administered as specified in the treatment arm; Other Names: SY-1425; Drug: Azacitidine; Administered as specified in the treatment arm
Placebo Comparator: Tamibarotene Matched Placebo + Azacitidine; Placebo: Tamibarotene-matching tablets administered orally BID on Days 8 through 28 of each 28-day treatment cycle. Azacitidine: 75 mg/m^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.	Drug: Placebo; Administered as specified in the treatment arm; Drug: Azacitidine; Administered as specified in the treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Complete Remission (CR)	CR was determined by the investigator per the modified International Working Group Myelodysplastic Syndrome (IWG MDS). CR was defined as participants with hemoglobin ≥11 grams/deciliter (g/dL), neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia were noted.	Up to 45 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Overall Response (DOR)	DOR: duration from date of first documented evidence of CR, partial remission (PR), marrow CR (mCR), or hematologic improvement (HI) to date of documented disease progression or relapse of disease as determined by investigator per modified IWG MDS criteria or death due to any cause, whichever occurred first. CR: hemoglobin (Hb)≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs≤5% & normal maturation of all cell lines, persistent dysplasia. PR: Hb ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but >5%. mCR: Hb ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by≥50% from baseline, & ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of≥30*10^9/L if starting with >20*10^9/L platelets; increase from <20 to >20*10^9/L and by ≥100%),neutrophil response (≥100% increase & absolute increase >0.5*10^9/L).	Up to 45 months
Number of Participants Who Achieved Transfusion Independence (TI)	TI was defined as a period of at least 56 days with no red blood cell (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 occurred first.	Up to 45 months
Percentage of Participants Who Achieved Overall Response (OR)	OR: Participants who achieved CR, PR, mCR, or subcategories of HI, as determined by investigator per modified IWG MDS criteria. CR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia were noted. PR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but >5%. mCR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, and ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of ≥30*10^9 /L if starting with >20*10^9/L platelets increase from <20*10^9/L to >20*10^9/L and by at least 100%), neutrophil response (at least a 100% increase and an absolute increase >0.5*10^9 /L).	Up to 45 months
Duration of Complete Response (DOCR)	DOCR was defined as the duration from the date of first documented evidence of CR to the date of documented relapse of disease or disease progression, as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurred first. CR was defined as participants with hemoglobin ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs ≤5% and normal maturation of all cell lines, persistent dysplasia were noted. Among CR responders, DOCR was calculated as: DOCR (months) = (first date of documented relapse of disease, disease progression, or death due to any cause - date of first documented evidence of CR + 1) / 30.4375.	Up to 45 months
Time to Complete Remission (TCR)	TCR was 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. Among CR responders, this outcome measure was calculated as: Time to CR= (date of the first documented evidence of CR - date of randomization + 1) / 30.4375. CR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, bone marrow blasts ≤5% and normal maturation of all cell lines, persistent dysplasia were noted.	Up to 45 months
Time to Initial Response (TIR)	TIR: duration from date of randomization to the date of first documented evidence of CR, PR, mCR, or HI as determined by investigator per modified IWG MDS criteria. CR: hemoglobin (Hb) ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia. PR: Hb ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but >5%. mCR: Hb ≥11 g/dL, neutrophils ≥1.0*10^9/L, platelets ≥100*10^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, and ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of ≥30*10^9/L if starting with >20*10^9/L platelets increase from <20 to >20*10^9/L and by at least 100%), neutrophil response (at least a 100% increase and absolute increase>0.5*10^9 /L).	Up to 45 months
Change in Health-Related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 Scale (EORTC QLQ-30)	HRQoL was evaluated by EORTC QLQ-C30 global health status/quality of life composite scale in all randomized participants. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicated better quality of life (QoL), while higher scores on the symptom scales indicated declining QoL.	Up to 45 months
Change in HRQOL as Assessed by the European Quality of Life 5 Dimensions Scale (EuroQoL-5D)	The EQ-5D-3L essentially consisted of- the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 3 levels: no problems, some problems, extreme problems. Total scale range for each dimension reported was 1 to 3. The EQ VAS recorded the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Total scale range for VAS dimension reported was 0 to 100.	Up to 45 months
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An AE was defined as any untoward medical occurrence that developed or worsened in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. TEAEs are defined as those AEs with onset after the first dose of study drug or existing events that worsened after the first dose during the study up until the last dose of study drug + 30 days. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.	Up to 45 months

Collaborators and Investigators

• Sponsor: Syros Pharmaceuticals
• Investigators: Study Director: Medical Director, Syros Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2021
• Primary Completion (Actual): November 13, 2024
• Study Completion (Actual): November 13, 2024

Study Registration Dates

• First Submitted: March 11, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 7, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndromes; Newly Diagnosed; Higher-Risk; Retinoic Acid Receptor Alpha (RARA) positive
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Syndrome; Preleukemia; Myelodysplastic Syndromes; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Azacitidine
• Other Study ID Numbers: SY-1425-301; 2020-004528-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No