Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)

Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard Induction Therapy

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

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

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Tamibarotene; Drug: Venetoclax; Drug: Azacitidine

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49000
    • Chu Angers
  • Bayonne, France, 64100
    • CH de la Côte Basque
  • Bobigny, France, 93000
    • Hôpital Avicenne Hématologie Clinique
  • Caen, France, 14033
    • CHU de Caen Normandie
  • Limoges, France
    • CHU Limoges
  • Nantes, France
    • CHU de Nantes - Hotel Dieu
  • Nice, France, 06202
    • Hôpital l'Archet- CHU de Nice
  • Pessac, France, 33604
    • Chu de Bordeaux - Hopital Haut-Leveque
  • Poitiers, France, 86021
    • CHU De Poitiers
  • Vellefaux, France, 75475
    • Hôpital Saint-Louis
  • Versailles, France, 78150
    • Centre Hospitalier de Versailles
  • Villejuif, France, 94800
    • Institut Gustave Roussy
  • Pierre Benite
    • Pierre-Bénite, Pierre Benite, France, 69495
      • CHU Lyon Sud
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center Division of Hematology/Oncology
  • Colorado
    • Denver, Colorado, United States, 80204
      • University of Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute at Colorado Blood Cancer Institute
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Healthcare
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside
  • Mississippi
    • Jackson, Mississippi, United States, 39213
      • University of Mississippi
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • HCA Midwest Research Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Atlantic Health
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University James Cancer Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

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

Description

Note: all inclusion/exclusion criteria should be met prior to the first dose of venetoclax/azacitidine on Cycle 1 Day 1 with the exception of the RARA-biomarker test result referenced in inclusion criterion 2, which should be positive by Cycle 1 Day 8 to continue treatment on study.

Inclusion Criteria:

• All participants must have obtained a blood sample for RARA biomarker investigational assay testing prior to starting treatment on Cycle 1 Day 1. The results of the investigational biomarker assay for all participants must be confirmed as RARA-positive by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study.

• Participants must have newly diagnosed, previously untreated non-acute promyelocytic leukemia (APL) AML with a bone marrow or peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or comorbidities based on at least one of the following criteria:

  • age ≥75 years old, or

  • age <75 years old, with at least one of the following:

    • Eastern Cooperative Oncology Group (ECOG) performance status of 3
    • cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤50%
    • pulmonary disease with diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in one second (FEV1) ≤65%
    • creatinine clearance ≥30 milliliters (mL)/minute (min) to <45 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation
    • hepatic impairment with total bilirubin >1.5 to ≤3.0 * upper limit of normal (ULN)
    • any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the sponsor.

Exclusion Criteria:

• Participants have APL.
• Participants have known active central nervous system involvement with AML.
• Prior treatment (before Cycle 1 Day 1) for the diagnosis of AML, myelodysplastic syndromes (MDS), or antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation (HSCT), with the exception of prior treatment with hydroxyurea.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Tamibarotene/Venetoclax/Azacitidine; Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination as follows: Azacitidine (intravenously or subcutaneously) at 75 milligrams (mg)/square meter (m^2) once daily, on Days 1 through 7 of each 28-day therapy cycle (per VIDAZA USPI). Alternative dosing of azacitidine (Days 1 through 5, 8, and 9) will be permitted throughout the study. Venetoclax (orally) daily on Days 1 through 28 per standard of care. Standard of care daily dosing is 100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and beyond. Tamibarotene 6 mg twice daily (BID) orally, on Days 8 through 28 of each 28-day therapy cycle. Tamibarotene will only be administered to participants who have been confirmed as RARA-positive.	Drug: Tamibarotene; Tamibarotene tablets will be administered per dose and schedule specified in the arm.; Drug: Venetoclax; Venetoclax tablets will be administered per dose and schedule specified in the arm.; Other Names: Venclexta; Drug: Azacitidine; Azacitidine injection will be administered per dose and schedule specified in the arm.; Other Names: Vidaza
Experimental: Part 2: Tamibarotene/Venetoclax/Azacitidine; Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.	Drug: Tamibarotene; Tamibarotene tablets will be administered per dose and schedule specified in the arm.; Drug: Venetoclax; Venetoclax tablets will be administered per dose and schedule specified in the arm.; Other Names: Venclexta; Drug: Azacitidine; Azacitidine injection will be administered per dose and schedule specified in the arm.; Other Names: Vidaza
Active Comparator: Part 2: Venetoclax/Azacitidine; Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.	Drug: Venetoclax; Venetoclax tablets will be administered per dose and schedule specified in the arm.; Other Names: Venclexta; Drug: Azacitidine; Azacitidine injection will be administered per dose and schedule specified in the arm.; Other Names: Vidaza
Experimental: Part 3: Tamibarotene/Venetoclax/Azacitidine; Part 2 participants treated with venetoclax/azacitidine who experience progressive disease, relapse after initial CR or CRi response, or treatment failure may begin subsequent treatment in Part 3, where tamibarotene will be added to their regimen.	Drug: Tamibarotene; Tamibarotene tablets will be administered per dose and schedule specified in the arm.; Drug: Venetoclax; Venetoclax tablets will be administered per dose and schedule specified in the arm.; Other Names: Venclexta; Drug: Azacitidine; Azacitidine injection will be administered per dose and schedule specified in the arm.; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event (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. A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. TEAEs were defined as those adverse events AEs with onset after the first dose of study treatment or existing events that worsened after the first dose during the study up until the last dose of study treatment plus 30 days. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.	Up to 3 years
Part 2: Complete Remission/Complete Remission With Incomplete Hematologic Recovery (CR/CRi) Rate	CR/CRi rate was estimated by the percentage of participants who achieved complete Remission (CR) and/or CR with incomplete hematologic recovery (CRi),CR/CRi (as determined by the investigator). CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.CRi was defined as absolute neutrophil count <1,000/µL, platelets count <100,000/µL, bone marrow blasts <5% and all CR criteria met except either neutrophils or platelets not recovered.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Plasma Concentration of Tamibarotene		Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days)
Part 1: Overall Response Rate (ORR)	ORR: percentage of participants who achieved a overall response as comprised of CR(ANC ≥1,000/µL, platelets count (PC) ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods;absence of extramedullary disease),CRi (ANC <1,000/µL, PC <100,000/µL, bone marrow blasts <5% and all CR criteria met except either neutrophils or platelets not recovered), CRh (ANC >500/µL, PC >500,000/µL, bone marrow blasts <5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts), morphologically leukemia-free state (bone marrow blasts <5%, absence of blasts with auer rods and <5% blasts in marrow sample with a count of at least 200 nucleated cells or cellularity ≥10%. Absence of EMD. No hematologic criteria required.), or PR was defined as ANC <1,000/µL, PC <100,000/µL, ≥50% decrease from baseline, with decrease to 5-25. ORR was calculated as ORR (%)=number of overall responders/number of participants in the Safety Population×100.	Up to 3 years
Part 2: Number of Participants With Treatment Emergent Adverse Events	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. A TEAE was any untoward medical occurrence associated with use of a study drug/study participation, whether or not considered related to study drug after first dose. TEAEs were defined as those adverse events AEs with onset after the first dose of study treatment or existing events that worsened after the first dose during the study up until the last dose of study treatment plus 30 days. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.	Up to 3 years
Part 2: Complete Remission (CR) Rate	CR rate was estimated by the percentage of participants who achieved complete remission (as determined by the investigator). CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.	Up to 3 years
Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate	CR/CRh rate was estimated by the percentage of participants who achieved complete Remission (CR) and/or CR with partial hematologic recovery (CRh),CR/CRh (as determined by the investigator). CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.CRh was defined as absolute neutrophil count >500/µL, platelets count >500,000/µL, bone marrow blasts <5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.	Up to 3 years
Part 2: Duration of Complete Remission	Duration of CR was defined as duration from the date of first documented evidence of CR to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurred first. CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.	Up to 3 years
Part 2: Duration of CR/CRi	Duration of CR/CRi was defined as duration from the date of first documented evidence of CR/CRi to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occured first.CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.CRi was defined as absolute neutrophil count <1,000/µL, platelets count <100,000/µL, bone marrow blasts <5% and all CR criteria met except either neutrophils or platelets not recovered.	Up to 3 years
Part 2: Duration of CR/CRh	Duration of CR/CRh was defined as duration from the date of first documented evidence of CR/CRh to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occured first. CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease. CRh was defined as absolute neutrophil count >500/µL, platelets count >500,000/µL, bone marrow blasts <5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.	Up to 3 years
Part 2: Time to Complete Response	Time to CR was defined as the duration from the date of Cycle 1 Day 1 visit to the date of the first documented evidence of CR as determined by the investigator. CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.	Up to 3 years
Part 2: Time to CR/CRi	Time to CR/CRi was defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRi as determined by the investigator. CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease.CRi was defined as absolute neutrophil count <1,000/µL, platelets count <100,000/µL, bone marrow blasts <5% and all CR criteria met except either neutrophils or platelets not recovered.	Up to 3 years
Part 2: Time to CR/CRh	Time to CR/CRh was defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRh as determined by the investigator. CR was defined as absolute neutrophil count ≥1,000/µL, platelets count ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods; absence of extramedullary disease. CRh was defined as absolute neutrophil count >500/µL, platelets count >500,000/µL, bone marrow blasts <5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.	Up to 3 years
Part 2: Overall Response Rate	ORR: percentage of participants who achieved a overall response as comprised of CR(ANC ≥1,000/µL, platelets count (PC) ≥100,000/µL, bone marrow blasts <5% and absence of circulating blasts and blasts with auer rods;absence of extramedullary disease),CRi (ANC <1,000/µL, PC <100,000/µL, bone marrow blasts <5% and all CR criteria met except either neutrophils or platelets not recovered), CRh (ANC >500/µL, PC >500,000/µL, bone marrow blasts <5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts), morphologically leukemia-free state (bone marrow blasts <5%, absence of blasts with auer rods and <5% blasts in marrow sample with a count of at least 200 nucleated cells or cellularity ≥10%. Absence of EMD. No hematologic criteria required.), or PR was defined as ANC <1,000/µL, PC <100,000/µL, ≥50% decrease from baseline, with decrease to 5-25. ORR was calculated as ORR (%)=number of overall responders/number of participants in the Safety Population×100.	Up to 3 years

Collaborators and Investigators

• Sponsor: Syros Pharmaceuticals
• Investigators: Study Director: Michael Kelly Executive Medical Director, MD, Syros Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2021
• Primary Completion (Actual): August 12, 2024
• Study Completion (Actual): August 12, 2024

Study Registration Dates

• First Submitted: May 24, 2021
• First Submitted That Met QC Criteria: May 24, 2021
• First Posted (Actual): May 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Venetoclax; Azacitidine
• Other Study ID Numbers: SY-1425-202

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
• product manufactured in and exported from the U.S.: No