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.
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.
Brief Title
Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Acute Myeloid Leukemia
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.
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.
Inclusion Criteria
inclusion/ 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.
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.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04905407
Org Class
Industry
Org Full Name
Syros Pharmaceuticals
Org Study Id
SY-1425-202
Overall Status
Terminated
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
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'.
Outcome Measure
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Outcome Time Frame
Up to 3 years
Outcome Description
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.
Outcome Measure
Part 2: Complete Remission/Complete Remission With Incomplete Hematologic Recovery (CR/CRi) Rate
Outcome Time Frame
Up to 3 years
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 1: Overall Response Rate (ORR)
Outcome Time Frame
Day 8 and 22 of Cycle 1, Day 15 of Cycles 2 and 3 (cycle length = 28 days)
Outcome Measure
Part 1: Plasma Concentration of Tamibarotene
Outcome Description
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'.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Number of Participants With Treatment Emergent Adverse Events
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Complete Remission (CR) Rate
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Duration of Complete Remission
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Duration of CR/CRi
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Duration of CR/CRh
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Time to Complete Response
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Time to CR/CRi
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Time to CR/CRh
Outcome Description
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.
Outcome Time Frame
Up to 3 years
Outcome Measure
Part 2: Overall Response Rate
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Ioannis Mantzaris
Investigator Email
IMANTZAR@montefiore.org
Categories Mesh Debug
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID, ACUTE
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID
Cancer --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA
Cancer --- NEOPLASMS
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
MeSH Terms
LEUKEMIA, MYELOID, ACUTE
LEUKEMIA, MYELOID
LEUKEMIA
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
TAMIBAROTENE
VENETOCLAX
AZACITIDINE
AZA COMPOUNDS
ORGANIC CHEMICALS
CYTIDINE
PYRIMIDINE NUCLEOSIDES
PYRIMIDINES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS
NUCLEOSIDES
NUCLEIC ACIDS, NUCLEOTIDES, AND NUCLEOSIDES
RIBONUCLEOSIDES