Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT04905407
- Lead Sponsor
- Syros Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 66
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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.
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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
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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.
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- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 2: Tamibarotene/Venetoclax/Azacitidine Tamibarotene Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1. Part 2: Tamibarotene/Venetoclax/Azacitidine Azacitidine Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1. Part 2: Venetoclax/Azacitidine Venetoclax Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1. Part 2: Venetoclax/Azacitidine Azacitidine Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1. Part 3: Tamibarotene/Venetoclax/Azacitidine Tamibarotene 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. Part 1: Tamibarotene/Venetoclax/Azacitidine Tamibarotene 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. Part 1: Tamibarotene/Venetoclax/Azacitidine Venetoclax 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. Part 1: Tamibarotene/Venetoclax/Azacitidine 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. Part 2: Tamibarotene/Venetoclax/Azacitidine Venetoclax Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1. Part 3: Tamibarotene/Venetoclax/Azacitidine Venetoclax 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. Part 3: Tamibarotene/Venetoclax/Azacitidine 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.
- Primary Outcome Measures
Name Time Method Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Up to 3 years 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'.
Part 2: Complete Remission/Complete Remission With Incomplete Hematologic Recovery (CR/CRi) Rate Up to 3 years 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.
- Secondary Outcome Measures
Name Time Method Part 1: Overall Response Rate (ORR) Up to 3 years ORR: percentage of participants who achieved a overall response as comprised of CR(ANC ≥1,000/µL, platelets count (PC) ≥100,000/µL, bone marrow blasts \<5% and absence of circulating blasts and blasts with auer rods;absence of extramedullary disease),CRi (ANC \<1,000/µL, PC \<100,000/µL, bone marrow blasts \<5% and all CR criteria met except either neutrophils or platelets not recovered), CRh (ANC \>500/µL, PC \>500,000/µL, bone marrow blasts \<5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts), morphologically leukemia-free state (bone marrow blasts \<5%, absence of blasts with auer rods and \<5% blasts in marrow sample with a count of at least 200 nucleated cells or cellularity ≥10%. Absence of EMD. No hematologic criteria required.), or PR was defined as ANC \<1,000/µL, PC \<100,000/µL, ≥50% decrease from baseline, with decrease to 5-25. ORR was calculated as ORR (%)=number of overall responders/number of participants in the Safety Population×100.
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 An 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'.
Part 2: Complete Remission (CR) Rate Up to 3 years CR rate was estimated by the percentage of participants who achieved complete remission (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.
Part 2: Duration of Complete Remission Up to 3 years Duration of CR was 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 occurred first. 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.
Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate Up to 3 years CR/CRh rate was estimated by the percentage of participants who achieved complete Remission (CR) and/or CR with partial hematologic recovery (CRh),CR/CRh (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.CRh was defined as absolute neutrophil count \>500/µL, platelets count \>500,000/µL, bone marrow blasts \<5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.
Part 2: Duration of CR/CRi Up to 3 years Duration of CR/CRi was 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 occured first.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.
Part 2: Duration of CR/CRh Up to 3 years Duration of CR/CRh was 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 occured first. 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. CRh was defined as absolute neutrophil count \>500/µL, platelets count \>500,000/µL, bone marrow blasts \<5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.
Part 2: Time to Complete Response Up to 3 years Time to CR was 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. 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.
Part 2: Time to CR/CRi Up to 3 years Time to CR/CRi was 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. 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.
Part 2: Time to CR/CRh Up to 3 years Time to CR/CRh was 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. 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. CRh was defined as absolute neutrophil count \>500/µL, platelets count \>500,000/µL, bone marrow blasts \<5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts.
Part 2: Overall Response Rate Up to 3 years ORR: percentage of participants who achieved a overall response as comprised of CR(ANC ≥1,000/µL, platelets count (PC) ≥100,000/µL, bone marrow blasts \<5% and absence of circulating blasts and blasts with auer rods;absence of extramedullary disease),CRi (ANC \<1,000/µL, PC \<100,000/µL, bone marrow blasts \<5% and all CR criteria met except either neutrophils or platelets not recovered), CRh (ANC \>500/µL, PC \>500,000/µL, bone marrow blasts \<5% and all CR criteria met except ANC and platelets with partial recovery of peripheral counts), morphologically leukemia-free state (bone marrow blasts \<5%, absence of blasts with auer rods and \<5% blasts in marrow sample with a count of at least 200 nucleated cells or cellularity ≥10%. Absence of EMD. No hematologic criteria required.), or PR was defined as ANC \<1,000/µL, PC \<100,000/µL, ≥50% decrease from baseline, with decrease to 5-25. ORR was calculated as ORR (%)=number of overall responders/number of participants in the Safety Population×100.
Trial Locations
- Locations (28)
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Hôpital l'Archet- CHU de Nice
🇫🇷Nice, France
City of Hope
🇺🇸Duarte, California, United States
The Ohio State University James Cancer Hospital
🇺🇸Columbus, Ohio, United States
University of Mississippi
🇺🇸Jackson, Mississippi, United States
UCLA Medical Center Division of Hematology/Oncology
🇺🇸Los Angeles, California, United States
Northside
🇺🇸Atlanta, Georgia, United States
Hartford HealthCare
🇺🇸Hartford, Connecticut, United States
Atlantic Health
🇺🇸Morristown, New Jersey, United States
CHU Angers
🇫🇷Angers, France
CHU de Nantes - Hôtel Dieu
🇫🇷Nantes, France
CHU Lyon Sud
🇫🇷Pierre-Bénite, Pierre Benite, France
CH de la Côte Basque
🇫🇷Bayonne, France
Hôpital Avicenne Hématologie Clinique
🇫🇷Bobigny, France
CHU de Bordeaux - Hôpital Haut-Lévèque
🇫🇷Pessac, France
Centre Hospitalier de Versailles
🇫🇷Versailles, France
Hôpital Saint-Louis
🇫🇷Vellefaux, France
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
CHU de Caen Normandie
🇫🇷Caen, France
CHU de Poitiers
🇫🇷Poitiers, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
Novant Health
🇺🇸Charlotte, North Carolina, United States
CHU Limoges
🇫🇷Limoges, France
HCA Midwest Research Medical Center
🇺🇸Kansas City, Missouri, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Sarah Cannon Research Institute at Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
University of Colorado
🇺🇸Denver, Colorado, United States