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

Sponsor

Syros Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04797780

Collaborator

(none)

190

Enrollment

Locations

Arms

Anticipated Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 (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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Tamibarotene + Azacitidine Drug: Tamibarotene Matched Placebo + Azacitidine	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

190 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official 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 (SELECT MDS-1)

Actual Study Start Date :

Feb 8, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Feb 8, 2029

Arms and Interventions

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 + Azacitidine Tamibarotene will be administered at 6 mg twice per day (BID) (orally) each day on Days 8 through 28 of each 28-day treatment cycle (total daily dose of 12 mg). 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. Other Names: SY-1425
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: Tamibarotene Matched Placebo + Azacitidine Tamibarotene matched placebo will be administered at 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.

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 + Azacitidine

Tamibarotene will be administered at 6 mg twice per day (BID) (orally) each day on Days 8 through 28 of each 28-day treatment cycle (total daily dose of 12 mg). 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.

Other Names:

SY-1425

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: Tamibarotene Matched Placebo + Azacitidine

Tamibarotene matched placebo will be administered at 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.

Outcome Measures

Primary Outcome Measures

Proportion of Participants with Complete Remission [Up to 5 Years]

Secondary Outcome Measures

Proportion of Participants Who Achieve Objective Response [Up to 5 Years]
Duration of Event Free Survival [Up to 5 Years]
Duration of Overall Survival [Up to 5 Years]
Proportion of Participants Who Achieve Transfusion Independence [Up to 5 Years]
Duration of Complete Response [Up to 5 Years]
Duration of Overall Response [Up to 5 Years]
Time to Complete Remission [Up to 5 Years]
Time to Initial Response [Up to 5 Years]
Proportion of participants with Adverse Events and Serious Adverse Events [Up to 5 Years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Participants must be at least 18 years old at the time of signing of an informed consent.
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 (Arber 2016) 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 HSCT at the time of Screening.
Participants who received prior treatment for MDS with any hypomethylating agent, chemotherapy or allogeneic HSCT.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85719
2	UC Irvine	Irvine	California	United States	92697
3	University of Southern California	Los Angeles	California	United States	90033
4	University of California, Los Angelas	Los Angeles	California	United States	90095
5	Cancer specialists of North Florida	Jacksonville	Florida	United States	32256
6	BRCR Medical Center, Inc	Plantation	Florida	United States	33322
7	Comprehensive Hematology and Oncology	Saint Petersburg	Florida	United States	33709
8	University of Illinois Cancer Center	Chicago	Illinois	United States	60612
9	Orchard Healthcare Research Inc.	Skokie	Illinois	United States	60077
10	University of Iowa	Iowa City	Iowa	United States	52242
11	Johns Hopkins University	Baltimore	Maryland	United States	21287
12	American Oncology Partners of Maryland, PA	Bethesda	Maryland	United States	20817
13	SCL Health Research Institute, Inc. (St. Vincent Frontier Cancer Center)	Billings	Montana	United States	59102
14	Morristown Medical Center- Atlantic Hematology Oncology	Morristown	New Jersey	United States	02140
15	Montefiore Medical Center & Albert Einstein College of Medicine	Bronx	New York	United States	11102
16	Northwell Health	Lake Success	New York	United States	11042
17	New York Medical College	Valhalla	New York	United States	10595
18	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
19	Cleveland Clinic	Cleveland	Ohio	United States	44195
20	Oregon Health and Science University	Portland	Oregon	United States	97239
21	Texas Oncology - Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
22	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
23	Klinik Hietzing	Vienna		Austria
24	Institut Jules Bordet	Brussels		Belgium
25	Hospital De Jolimont	La Louvière		Belgium	7100
26	CHU de Liège	Liège		Belgium
27	AZ Delta	Roeselare		Belgium	8800
28	CHU-UCL Namur	Yvoir		Belgium	5530
29	Juravinski Cancer Centre	Hamilton	Ontario	Canada	ON L8V 1C3
30	CHU Amiens-Picardie	Amiens		France	80054
31	CHU d'Angers	Angers		France	49933
32	Centre Hospitalier de la Côte Basque Hématologie Clinique	Bayonne		France	64109
33	Hôpital Avicenne	Bobigny		France	93000
34	CHRU de BREST - Hôpital Morvan	Brest		France	29200
35	Hopital Mignot	Le Chesnay		France	78150
36	CHU Nantes - Hotel Dieu	Nantes		France	44093
37	CHU de Nice - Hopital L'Archet	Nice		France	06200
38	Hôpital Saint Louis	Paris		France	75475
39	Centre Hospitalier de Perpignan	Perpignan		France	66046
40	CHU Bordeaux	Pessac		France	33604
41	CHU Lyon Sud	Pierre-Bénite		France	69495
42	CHU Poiters	Poitiers		France	86021
43	ICANS Strasbourg	Strasbourg		France	67033
44	Institut Gustave Roussy	Villejuif		France	94805
45	IRCCS Azienda Ospedaliero-Universitaria di Bologna	Bologna		Italy	40138
46	Azienda Ospedaliero-Universitaria di Ferrara	Ferrara		Italy	44124
47	Ospedale Policlinico San Martino	Genova		Italy	16132
48	Romagnolo Institute to Study Tumors "Dino Amadori "/ Meldona	Meldola		Italy	47014
49	A.O.U. Maggiore della Carità	Novara		Italy	28100
50	Ospedale Infermi di Rimini	Rimini		Italy	47923
51	H. Santa Creu i Sant Pau	Barcelona		Spain	08025
52	Fundación Privada Instituto de Investigación Oncológica Vall d'Hebron	Barcelona		Spain	08035
53	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08041
54	MD Anderson Cancer Center	Madrid		Spain	28033
55	Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain	28040
56	H. Universitario La Paz	Madrid		Spain	28046
57	Hospital Universitario Central de Asturia	Oviedo		Spain	33011
58	Hospital Son Llatzer	Palma De Mallorca		Spain	07198
59	Clinica Universidad Navarra	Pamplona		Spain	31008
60	Hospital Universitario de Salamanca	Salamanca		Spain	37007
61	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008