Clinical trial NCT04905407: Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)
Official title: Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard Induction Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Lead sponsor: Syros Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-05-27
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 3 years
measure: Part 2: Complete Remission/Complete Remission With Incomplete Hematologic Recovery (CR/CRi) Rate
timeFrame: Up to 3 years
Secondary outcomes:
measure: Part 1: Overall Response Rate (ORR)
timeFrame: Up to 3 years
measure: Part 1: Plasma Concentration of Tamibarotene
timeFrame: Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days)
measure: Part 2: Number of Participants With Treatment Emergent Adverse Events
timeFrame: Up to 3 years
measure: Part 2: Complete Remission (CR) Rate
timeFrame: Up to 3 years
measure: Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate
timeFrame: Up to 3 years
measure: Part 2: Duration of Complete Remission
timeFrame: Up to 3 years
measure: Part 2: Duration of CR/CRi
timeFrame: Up to 3 years
measure: Part 2: Duration of CR/CRh
timeFrame: Up to 3 years
measure: Part 2: Time to Complete Response
timeFrame: Up to 3 years
measure: Part 2: Time to CR/CRi
timeFrame: Up to 3 years
measure: Part 2: Time to CR/CRh
timeFrame: Up to 3 years
measure: Part 2: Overall Response Rate
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center Division of Hematology/Oncology
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: Sarah Cannon Research Institute at Colorado Blood Cancer Institute
state: Colorado
city: Hartford
country: United States
facility: Hartford HealthCare
state: Connecticut
city: Atlanta
country: United States
facility: Northside
state: Georgia
city: Jackson
country: United States
facility: University of Mississippi
state: Mississippi
city: Kansas City
country: United States
facility: HCA Midwest Research Medical Center
state: Missouri
city: Morristown
country: United States
facility: Atlantic Health
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Novant Health
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University James Cancer Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pierre-Bénite
country: France
facility: CHU Lyon Sud
state: Pierre Benite
city: Angers
country: France
facility: CHU Angers
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Bobigny
country: France
facility: Hôpital Avicenne Hématologie Clinique
city: Caen
country: France
facility: CHU de Caen Normandie
city: Limoges
country: France
facility: CHU Limoges
city: Nantes
country: France
facility: CHU de Nantes - Hôtel Dieu
city: Nice
country: France
facility: Hôpital l'Archet- CHU de Nice
city: Pessac
country: France
facility: CHU de Bordeaux - Hôpital Haut-Lévèque
city: Poitiers
country: France
facility: CHU de Poitiers
city: Vellefaux
country: France
facility: Hôpital Saint-Louis
city: Versailles
country: France
facility: Centre Hospitalier de Versailles
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Syros Pharmaceuticals
name: Michael Kelly Executive Medical Director, MD
role: STUDY_DIRECTOR
References: