A Phase 1b Study Evaluating the Safety and Pharmacokinetics of Venetoclax as a Single-Agent and in Combination With Azacitidine in Subjects With Relapsed/Refractory Myelodysplastic Syndromes
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 70
- 试验地点
- 23
- 主要终点
- AUCt for azacitidine
研究概览
简要总结
This is a Phase 1b, open-label, multicenter study designed to evaluate the safety and pharmacokinetics of venetoclax as a single-agent and in combination with azacitidine in participants with relapsed/refractory Myelodysplastic Syndromes (MDS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Subjects who have relapsed or refractory MDS.
- •Subject enrolled in venetoclax monotherapy must have documented failure of prior therapy with a hypomethylating agent (HMA). HMA-failure is defined as:
- •Relapse after initial complete or partial response or hematological improvement after at least 4 cycles of azacitidine or at least 4 cycles of decitabine within the last 5 years, OR
- •Failure to achieve complete or partial response or hematological improvement after at least 4 cycles of azacitidine or at least 4 cycles of decitabine within the last 5 years
- •Subjects must have presence of < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening.
- •Subject is not a candidate to undergo allogenic hematopoietic stem cell transplantation (HSCT).
- •Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤
- •Subject must have adequate hematologic, renal, and hepatic function.
排除标准
- •Subject has received prior therapy with a BH3 mimetic.
- •Subject has MDS evolving from a pre-existing myeloproliferative neoplasm (MPN).
- •Subject has MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
- •Subject has received allogeneic HSCT or solid organ transplantation.
- •Subject has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug.
- •Subject is pregnant or breastfeeding.
研究组 & 干预措施
Venetoclax monotherapy (Cohort 1)
干预措施: venetoclax (Drug)
Venetoclax + azacitidine (Cohort 2)
干预措施: venetoclax (Drug)
Venetoclax + azacitidine (Cohort 2)
干预措施: azacitidine (Drug)
Safety Expansion (Cohort 3)
干预措施: venetoclax (Drug)
Safety Expansion (Cohort 3)
干预措施: azacitidine (Drug)
结局指标
主要结局
AUCt for azacitidine
时间窗: Up to 32 days
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine
Clearance (CL) for azacitidine
时间窗: Up to 32 days
Cmax for azacitidine
时间窗: Up to 32 days
Maximum plasma concentration (Cmax) of azacitidine
Tmax for venetoclax
时间窗: Up to 32 days
Time to Cmax (peak time, Tmax) for venetoclax
Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine
时间窗: Measured from Day 1 until day 28 per dose level.
AUC[0 to infinity] for azacitidine
时间窗: Up to 32 days
Area under the plasma concentration-time curve from Time 0 to infinite time.
Tmax for azacitidine
时间窗: Up to 32 days
Time to Cmax (peak time, Tmax) for azacitidine
AUC [0-24] for venetoclax
时间窗: Up to 32 days
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax
AUCt for venetoclax
时间窗: Up to 32 days
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax
Cmax of venetoclax
时间窗: Up to 32 days
Maximum plasma concentration (Cmax) of venetoclax
Half-life (t[1/2]) for azacitidine
时间窗: Up to 32 days
Terminal elimination half-life (t\[1/2\]) for azacitidine
Number of Participants With Adverse Events (AEs)
时间窗: Up to Maximum of 24 months
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
次要结局
- Event-Free Survival (EFS)(Measured from the date of the first dose of study drug to date of earliest disease progression, death, or initiation of new non-protocol-specified anti-MDS therapy without documented progression, and for up to 5 years after the last subject is enrolled.)
- Overall Survival (OS)(Measured from the date of first dose of study drug to the date of death, and for up to 5 years after the last subject is enrolled.)
- Rate of Modified Overall Response (mORR)(Measured from Cycle 1 Day 1 (C1D1) as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Time to next treatment (TTNT)(Measured from first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last subject is enrolled.)
- Duration of mORR(Measured from the date of first response (CR, mCR or PR) to the earliest documentation of progressive disease (PD), and for an anticipated maximum duration of 24 months.)
- Rate of platelet (PLT) transfusion independence(Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Time to Transformation acute myeloid leukemia (AML)(Measured from the date of first dose of study drug to the date of documented AML transformation for an anticipated maximum duration of 24 months.)
- Progression-Free Survival (PFS)(Measured from the date of the first dose of study drug to the date of earliest disease progression or death, and for an anticipated maximum duration of 24 months.)
- Overall Response Rate (ORR)(Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Complete Remission (CR) Rate(Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Rate of red blood cell (RBC) transfusion independence(Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Duration of Complete Response (CR)(Measured from date of first response (CR) to the to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.)
- Rate of Hematologic Improvement (HI)(Measured from Cycle 1 Day 1 as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Rate of marrow complete remission (mCR)(Measured from Cycle 1 Day 1 (C1D1) as long as the subject continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.)
- Duration of ORR(Measured from the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.)