Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed AML

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04905407
• Other study ID #: SY-1425-202
• Status: Recruiting
• Phase: Phase 2
• Start date: August 26, 2021
• Est. completion date: April 2028

Study information

• Verified date: February 2024
• Source: Syros Pharmaceuticals
• Contact: Galina Craig
• Phone: 857-321-8698
• Email: gcraig[@]syros.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 95
• Est. completion date: April 2028
• Est. primary completion date: April 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia

Intervention

Drug:
• Tamibarotene
Tamibarotene tablets will be administered per dose and schedule specified in the arm.
• Venetoclax
Venetoclax tablets will be administered per dose and schedule specified in the arm.
• Azacitidine
Azacitidine injection will be administered per dose and schedule specified in the arm.

Locations

Country	Name	City	State
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 Lyon Sud	Pierre-Bénite	Pierre Benite
France	Hôpital Saint-Louis	Vellefaux
France	Centre Hospitalier de Versailles	Versailles
France	Institut Gustave Roussy	Villejuif
United States	Northside	Atlanta	Georgia
United States	Saint Alphonsus Regional Medical Center	Boise	Idaho
United States	Montefiore Medical Center	Bronx	New York
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Novant Health	Charlotte	North Carolina
United States	The Ohio State University James Cancer Hospital	Columbus	Ohio
United States	Sarah Cannon Research Institute at Colorado Blood Cancer Institute	Denver	Colorado
United States	University of Colorado	Denver	Colorado
United States	City of Hope	Duarte	California
United States	Hartford HealthCare	Hartford	Connecticut
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Mississippi	Jackson	Mississippi
United States	HCA Midwest Research Medical Center	Kansas City	Missouri
United States	UCLA Medical Center Division of Hematology/Oncology	Los Angeles	California
United States	Atlantic Health	Morristown	New Jersey
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	Oregon Health & Science University	Portland	Oregon
United States	New York Medical College	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Syros Pharmaceuticals

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of Participants With Adverse Events		up to 3 years
Primary	Part 2: CR/CRi Rate	CR/CRi rate is estimated by the proportion of participants who achieve CR/CRi (as determined by the investigator).	up to 3 years
Secondary	Part 1: Overall Response Rate (ORR)	Overall response assessment is comprised of CR, CRi, CR with partial hematologic recovery (CRh), morphologically leukemia-free state (MLFS), or partial remission (PR) (as determined by the investigator). ORR is estimated by the proportion of participants who achieve overall response.	up to 3 years
Secondary	Part 1: Plasma Concentration of Tamibarotene		Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days)
Secondary	Part 2: Number of Participants With Adverse Events		up to 3 years
Secondary	Part 2: CR Rate	CR rate is estimated by the proportion of participants who achieve CR (as determined by the investigator).	up to 3 years
Secondary	Part 2: CR/CRh Rate	CR/CRh rate is estimated by the proportion of participants who achieve CR/CRh (as determined by the investigator).	up to 3 years
Secondary	Part 2: Duration of CR	Duration of CR is 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 occurs first.	up to 3 years
Secondary	Part 2: Duration of CR/CRi	Duration of CR/CRi is 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 occurs first.	up to 3 years
Secondary	Part 2: Duration of CR/CRh	Duration of CR/CRh is 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 occurs first.	up to 3 years
Secondary	Part 2: Time to CR	Time to CR is 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.	up to 3 years
Secondary	Part 2: Time to CR/CRi	Time to CR/CRi is 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.	up to 3 years
Secondary	Part 2: Time to CR/CRh	Time to CR/CRh is 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.	up to 3 years
Secondary	Part 2: ORR	Overall response assessment is comprised of CR, CRi, CRh, MLFS, or PR (as determined by the investigator). ORR is estimated by the proportion of participants who achieve overall response.	up to 3 years