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

NCT ID: NCT04905407

Last Updated: 2025-02-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-26
• Study Completion Date: 2024-08-12

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.

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.

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

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

Venetoclax

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

Part 2: Tamibarotene/Venetoclax/Azacitidine

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

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

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

Venetoclax

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

Part 2: Venetoclax/Azacitidine

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

Group Type: ACTIVE_COMPARATOR

Venetoclax

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Tamibarotene

Intervention Type: DRUG

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

Venetoclax

Intervention Type: DRUG

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

Azacitidine

Intervention Type: DRUG

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

Interventions

Tamibarotene

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

Intervention Type: DRUG

Venetoclax

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

Intervention Type: DRUG

Azacitidine

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

Intervention Type: DRUG

Other Intervention Names

Venclexta; Vidaza

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Syros Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Kelly Executive Medical Director, MD

Role: STUDY_DIRECTOR

Syros Pharmaceuticals

Locations

City of Hope

Duarte, California, United States

UCLA Medical Center Division of Hematology/Oncology

Los Angeles, California, United States

University of Colorado

Denver, Colorado, United States

Sarah Cannon Research Institute at Colorado Blood Cancer Institute

Denver, Colorado, United States

Hartford HealthCare

Hartford, Connecticut, United States

Northside

Atlanta, Georgia, United States

University of Mississippi

Jackson, Mississippi, United States

HCA Midwest Research Medical Center

Kansas City, Missouri, United States

Atlantic Health

Morristown, New Jersey, United States

Roswell Park Comprehensive Cancer Center

Buffalo, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Novant Health

Charlotte, North Carolina, United States

The Ohio State University James Cancer Hospital

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

CHU Lyon Sud

Pierre-Bénite, Pierre Benite, France

CHU Angers

Angers, , France

CH de la Côte Basque

Bayonne, , France

Hôpital Avicenne Hématologie Clinique

Bobigny, , France

CHU de Caen Normandie

Caen, , France

CHU Limoges

Limoges, , France

CHU de Nantes - Hôtel Dieu

Nantes, , France

Hôpital l'Archet- CHU de Nice

Nice, , France

CHU de Bordeaux - Hôpital Haut-Lévèque

Pessac, , France

CHU de Poitiers

Poitiers, , France

Hôpital Saint-Louis

Vellefaux, , France

Centre Hospitalier de Versailles

Versailles, , France

Institut Gustave Roussy

Villejuif, , France

Countries

United States; France

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

SY-1425-202

Identifier Type: -

Identifier Source: org_study_id