Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-positive AML Who Are Ineligible for Standard Induction Therapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 66
- 试验地点
- 28
- 主要终点
- Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All participants must have obtained a blood sample for RARA biomarker investigational assay testing prior to starting treatment on Cycle 1 Day
- •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.
排除标准
- •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.
研究组 & 干预措施
Part 3: Tamibarotene/Venetoclax/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.
干预措施: Tamibarotene (Drug)
Part 1: Tamibarotene/Venetoclax/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.
干预措施: Tamibarotene (Drug)
Part 1: Tamibarotene/Venetoclax/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.
干预措施: Venetoclax (Drug)
Part 1: Tamibarotene/Venetoclax/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.
干预措施: Azacitidine (Drug)
Part 2: Tamibarotene/Venetoclax/Azacitidine
Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.
干预措施: Tamibarotene (Drug)
Part 2: Tamibarotene/Venetoclax/Azacitidine
Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.
干预措施: Venetoclax (Drug)
Part 2: Tamibarotene/Venetoclax/Azacitidine
Participants will receive the tamibarotene/venetoclax/azacitidine triplet combination at the dose and regimen selected in Part 1.
干预措施: Azacitidine (Drug)
Part 2: Venetoclax/Azacitidine
Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.
干预措施: Venetoclax (Drug)
Part 2: Venetoclax/Azacitidine
Participants will receive the venetoclax/azacitidine combination at the dose and regimen selected in Part 1.
干预措施: Azacitidine (Drug)
Part 3: Tamibarotene/Venetoclax/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.
干预措施: Venetoclax (Drug)
Part 3: Tamibarotene/Venetoclax/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.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
时间窗: 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
时间窗: 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.
次要结局
- Part 1: Overall Response Rate (ORR)(Up to 3 years)
- 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)
- Part 2: Complete Remission (CR) Rate(Up to 3 years)
- Part 2: Duration of Complete Remission(Up to 3 years)
- Part 2: Complete Remission/ Complete Remission With Partial Hematologic Recovery (CR/CRh) Rate(Up to 3 years)
- Part 2: Duration of CR/CRi(Up to 3 years)
- Part 2: Duration of CR/CRh(Up to 3 years)
- Part 2: Time to Complete Response(Up to 3 years)
- Part 2: Time to CR/CRi(Up to 3 years)
- Part 2: Time to CR/CRh(Up to 3 years)
- Part 2: Overall Response Rate(Up to 3 years)