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

Syros Pharmaceuticals

Status and phase: Terminated; Phase 2

Conditions: Acute Myeloid Leukemia

Treatments: Drug: Azacitidine; Drug: Venetoclax; Drug: Tamibarotene

Study type: Interventional

Funder types: Industry

Identifiers

NCT04905407

SY-1425-202

Details and patient eligibility

About

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.

Full 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.

Enrollment: 66 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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66 participants in 4 patient groups

Part 1: Tamibarotene/Venetoclax/Azacitidine

Experimental group

Description:

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.

Treatment:

Drug: Tamibarotene

Drug: Venetoclax

Drug: Azacitidine

Part 2: Tamibarotene/Venetoclax/Azacitidine

Experimental group

Description:

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

Treatment:

Drug: Tamibarotene

Drug: Venetoclax

Drug: Azacitidine

Part 2: Venetoclax/Azacitidine

Active Comparator group

Description:

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

Treatment:

Drug: Venetoclax

Drug: Azacitidine

Part 3: Tamibarotene/Venetoclax/Azacitidine

Experimental group

Description:

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.

Treatment:

Drug: Tamibarotene

Drug: Venetoclax

Drug: Azacitidine