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

NCT04905407 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: SY-1425-202
• Study Type: interventional
• Target: 66
• Locations: 2 countries
• Sites: 28

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• Part 1: Overall Response Rate (ORR)

  Up to 3 years

• 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 2: Number of Participants With Treatment Emergent Adverse Events

  Up to 3 years

• Part 2: Complete Remission (CR) Rate

  Up to 3 years

• Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate

  Up to 3 years

Study Arms (4)

Part 1: Tamibarotene/Venetoclax/Azacitidine

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Azacitidine

Part 2: Tamibarotene/Venetoclax/Azacitidine

EXPERIMENTAL

Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.

Drug: Tamibarotene; Drug: Venetoclax; Drug: Azacitidine

Part 2: Venetoclax/Azacitidine

ACTIVE COMPARATOR

Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.

Drug: Venetoclax; Drug: Azacitidine

Part 3: Tamibarotene/Venetoclax/Azacitidine

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Azacitidine

Interventions

Tamibarotene DRUG

Tamibarotene tablets will be administered per dose and schedule specified in the arm.

Part 1: Tamibarotene/Venetoclax/Azacitidine; Part 2: Tamibarotene/Venetoclax/Azacitidine; Part 3: Tamibarotene/Venetoclax/Azacitidine

Venetoclax DRUG

Venetoclax tablets will be administered per dose and schedule specified in the arm.

Also known as: Venclexta

Part 1: Tamibarotene/Venetoclax/Azacitidine; Part 2: Tamibarotene/Venetoclax/Azacitidine; Part 2: Venetoclax/Azacitidine; Part 3: Tamibarotene/Venetoclax/Azacitidine

Azacitidine DRUG

Azacitidine injection will be administered per dose and schedule specified in the arm.

Also known as: Vidaza

Part 1: Tamibarotene/Venetoclax/Azacitidine; Part 2: Tamibarotene/Venetoclax/Azacitidine; Part 2: Venetoclax/Azacitidine; Part 3: Tamibarotene/Venetoclax/Azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Syros Pharmaceuticals: lead

Study Sites (28)

City of Hope

Duarte, California, 91010, United States

Location

UCLA Medical Center Division of Hematology/Oncology

Los Angeles, California, 90095, United States

Location

University of Colorado

Denver, Colorado, 80204, United States

Location

Sarah Cannon Research Institute at Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

Hartford HealthCare

Hartford, Connecticut, 06102, United States

Location

Northside

Atlanta, Georgia, 30342, United States

Location

University of Mississippi

Jackson, Mississippi, 39213, United States

Location

HCA Midwest Research Medical Center

Kansas City, Missouri, 64132, United States

Location

Atlantic Health

Morristown, New Jersey, 07960, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Novant Health

Charlotte, North Carolina, 28204, United States

Location

The Ohio State University James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

CHU Lyon Sud

Pierre-Bénite, Pierre Benite, 69495, France

Location

CHU Angers

Angers, 49000, France

Location

CH de la Côte Basque

Bayonne, 64100, France

Location

Hôpital Avicenne Hématologie Clinique

Bobigny, 93000, France

Location

CHU de Caen Normandie

Caen, 14033, France

Location

CHU Limoges

Limoges, France

Location

CHU de Nantes - Hôtel Dieu

Nantes, France

Location

Hôpital l'Archet- CHU de Nice

Nice, 06202, France

Location

CHU de Bordeaux - Hôpital Haut-Lévèque

Pessac, 33604, France

Location

CHU de Poitiers

Poitiers, 86021, France

Location

Hôpital Saint-Louis

Vellefaux, 75475, France

Location

Centre Hospitalier de Versailles

Versailles, 78150, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

tamibarotene; venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Tiffany Crowell
• Organization: Syros Pharmaceuticals

info@syros.com

617-674-9069

Study Officials

• Michael Kelly Executive Medical Director, MD

  Syros Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2021
• First Posted: May 27, 2021
• Study Start: August 26, 2021
• Primary Completion: August 12, 2024
• Study Completion: August 12, 2024
• Last Updated: February 24, 2025
• Results First Posted: February 24, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (15); FR (13)