A Phase 1b Dose Escalation Study Evaluating the Safety and Pharmacokinetics of Venetoclax in Combination With Azacitidine in Subjects With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 134
- 试验地点
- 68
- 主要终点
- Cmax for azacitidine
研究概览
简要总结
This is a Phase 1b, open-label, non-randomized, multicenter, dose-finding study evaluating venetoclax in combination with azacitidine in participants with treatment-naïve higher-risk MDS comprising a dose-escalation portion and a safety expansion portion.
研究设计
- 研究类型
- 干预性
- 分配方式
- 非随机
- 干预模型
- 单组
- 主要目的
- 治疗
- 盲法
- 开放（无盲法）
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
- Participant must have documented diagnosis of untreated de novo MDS with:
- International Prognostic Scoring System (IPSS) risk categories Int-2 or High (minimum IPSS overall score of 1.5) OR Revised IPSS (IPSS-R) categories intermediate, high or very high (score of > 3) and
- Presence of less than 20% bone marrow blasts per bone marrow biopsy/aspirate.
- Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.
排除标准
- Participant has received prior therapy for MDS. (Prior supportive care in form of transfusions or growth factors, etc., is not considered prior therapy).
- Participant has received prior therapy with a BCL-2 Homology 3 (BH3) mimetic.
- Participant has a diagnosis other than previously untreated de novo MDS (as defined in the protocol) including:
- MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5)
- Therapy-related MDS (t-MDS).
- MDS evolving from a pre-existing myeloproliferative neoplasm (MPN).
- MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
- Participant has received allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or solid organ transplantation.
- Participant has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug.
研究组 & 干预措施
Venetoclax + Azacitidine
干预措施: Azacitidine (Drug)
Venetoclax + Azacitidine
干预措施: Venetoclax (Drug)
结局指标
主要结局
Cmax for azacitidine
时间窗: Up to 32 days
Maximum plasma concentration (Cmax) of azacitidine.
Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine
时间窗: Measured from Day 1 until Day 28 per dose level.
The RPTD of venetoclax \[co-administered venetoclax and azacitidine\] will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data \[upon completion of the dose escalation phase\].
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.
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.
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.
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.
Tmax of venetoclax
时间窗: Up to 32 days
Time to Cmax (peak time, Tmax) of venetoclax.
AUC[0-24] for venetoclax
时间窗: Up to 32 days
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax.
Clearance (CL) for azacitidine
时间窗: Up to 32 days
Clearance is defined as the volume of plasma cleared of the drug per unit time.
Tmax for azacitidine
时间窗: Up to 32 days
Time to Cmax (peak time, Tmax) of azacitidine.
Complete Remission (CR) Rate
时间窗: Measured from Cycle 1 Day 1 as long as the participant 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 rate will be defined as the proportion of participants who achieved a complete response per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes (MDS).
次要结局
- Hematologic Improvement (HI) rate(Measured from Cycle 1 Day 1 as long as the participant 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.)
- Overall Response Rate (OR)(Measured from Cycle 1 Day 1 as long as the participant 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.)
- Marrow Complete Remission (mCR) Rate(Measured from Cycle 1 Day 1 as long as the participant 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 AML transformation(Measured from the date of first dose of study drug to date of documented AML transformation, defined as the presence of blast count greater than or equal to 20% in either peripheral blood or bone marrow for an anticipated maximum duration of 24 months.)
- Rate of platelet (PLT) transfusion independence(Measured from Cycle 1 Day 1 as long as the participant 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.)
- Modified Overall Response Rate (mOR)(Measured from Cycle 1 Day 1 as long as the participant 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 CR(Measured from Cycle 1 Day 1 as long as the participant 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 participant 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.)
- Progression-Free Survival (PFS)(Measured from the date of first dose of study drug to the date of earliest disease progression or death due to disease progression or febrile neutropenia, and for an anticipated maximum duration of 24 months.)
- 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 participant is enrolled.)
- Event-Free Survival (EFS)(Measured from the date of the first dose of study drug to the date of earliest disease progression, death of any cause and for up to 5 yrs after the last participant is enrolled)
- Time to next treatment (TTNT)(Measured from the first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last participant is enrolled.)
- Time to transformation to acute myeloid leukemia (AML)(Measured from the date of first dose of study drug to date of documented AML transformation, defined as the presence of blast count greater than or equal to 20% in either peripheral blood or bone marrow for an anticipated maximum duration of 24 months.)
- Duration of mOR(Measured from Cycle 1 Day 1 as long as the participant 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 OR(Measured from Cycle 1 Day 1 as long as the participant 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 First Response (mOR)(Measured from Cycle 1 Day 1 as long as the participant 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 First Response (OR)(Measured from Cycle 1 Day 1 as long as the participant 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 First Response (CR)(Measured from Cycle 1 Day 1 as long as the participant 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.)
研究者
研究点 (68)
标识符
- NCT 编号
- NCT02942290
- 其他研究编号
- M15-531, 2016-001657-41, 2023-507154-32-00
日期
- 首次提交
- (9年前)
- 首次发布
- (9年前)
- 主要完成日期
- (5个月前)
- 研究完成日期
- (5个月前)
- 最近核实
- (去年)
- 最近更新
- (上个月)
监管与共享
- FDA 监管药物
- 是
- FDA 监管器械
- 否
- 个体参与者数据共享计划
- 否
- 是否有结果
- 否