An Open-label, Multicenter Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 127
- 试验地点
- 48
- 主要终点
- Number of Participants with Dose-limiting Toxicities (DLTs)
研究概览
简要总结
A Phase 1, an Open-label, Multicenter Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 (RVT-2001) for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia
详细描述
This study is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of H3B-8800 (RVT-2001) in subset of participants with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). The study consists of three parts, the dose escalation part (Part 1) exploring multiple once daily (QD) schedules and MDS Expansion part (Part 2) and Dose Optimization part (Part 3) exploring dosing schedules in lower-risk 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
- •Confirmed diagnosis of MDS, CMML, or AML.
- •For the MDS Expansion cohort, participants must be lower-risk MDS, defined as low or intermediate-1 risk categorization per International Prognostic Scoring System (IPSS) criteria that carries a missense SF3B1 mutation.
- •For the Dose Optimization cohort, participants must be transfusion-dependent, lower-risk MDS, defined as very-low to intermediate risk categorization per IPSS-R criteria that carries a missense SF3B1 mutation.
- •Participants must meet the following criteria relevant to their specific diagnosis:
- •A. Participants with higher-risk MDS/CMML must be intolerant of hypomethylating agents (HMAs) or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of an HMA.
- •B. For the Dose Escalation portion, participants with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets.
- •For the MDS expansion cohort, lower risk MDS participants must be RBC transfusion dependent according to IWG 2006 criteria and must also have failed erythropoiesis stimulating agents (ESA) or have serum erythropoietin (EPO) levels greater than (>) 500 units per liter (U/L).
- •C. For the Dose Optimization cohort, lower-risk MDS participants must be RBC transfusion-dependent at baseline defined as ≥3 RBC units (concentrates) in 16-weeks in at least 2 transfusion episodes prior to the first dose of H3B-8800 (RVT-2001) and must also have failed ESA or have serum EPO levels > 500 U/L. Any ESA use should be discontinued ≥6 weeks prior to enrollment.
- •D. Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such participants.
- •E. Participants with CMML must have been treated with at least one prior therapy (hydroxyurea or a hypomethylating agent [HMA]).
- •Eastern Cooperative Oncology Group (ECOG) performance score of 0-
- •For MDS expansion and Dose optimization cohorts - absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).
- •For expansion and Dose optimization cohorts- platelet count >50,000/mcL (50*10^9/L).
- •For Dose-optimization cohort: No prior HMA or lenalidomide in participants with lower-risk MDS.
- •Adequate baseline organ function.
排除标准
- •Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)). Diagnosis of acute promyelocytic leukemia (t(15;17))
- •Participants are deemed candidate for hematopoietic stem cell transplants at the time of enrollment (for AML participants only).
- •Known prior or current retinal or optic nerve disease (example, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) not stable for at least 6 months.
- •History of clinically significant, uncorrected vitamin B12 or folate deficiency.
研究组 & 干预措施
H3B-8800 (RVT-2001) Dose Escalation
H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.
干预措施: H3B-8800 (RVT-2001) (Drug)
H3B-8800 (RVT-2001) MDS Expansion
Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1.
干预措施: H3B-8800 (RVT-2001) (Drug)
H3B-8800 (RVT-2001) Dose Optimization
Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1, and who have not been exposed to HMA's or lenalidomide in a prior line of therapy.
干预措施: H3B-8800 (RVT-2001) (Drug)
结局指标
主要结局
Number of Participants with Dose-limiting Toxicities (DLTs)
时间窗: Escalation Cycle 1 (28 days)
Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From the first dose of study drug until 30 days after final dose of study drug (up to approximately 50 months)
The type and frequency of AEs and SAEs using CTCAE v4.03, as well as changes in clinical laboratory values, ECG parameters, ophthalmologic examinations, and vital sign measurements.
次要结局
- Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t)(Up to Cycle 6 Day 15 (each cycle length=28 days))
- Maximum Observed Plasma Concentration (Cmax)(Up to Cycle 6 Day 15 (each cycle length=28 days))
- Time of Maximum Observed Plasma Concentration (Tmax)(Up to Cycle 6 Day 15 (each cycle length=28 days))
- Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence(Up to approximately 50 months)
- Number of Participants with Hematologic Improvement(Up to approximately 50 months)
- Objective Response Rate (ORR)(Up to approximately 50 months)
- Duration of Response (DOR)(Up to approximately 50 months)
- Time to Progression(Up to approximately 50 months)
- Overall Survival (OS)(Up to approximately 50 months)
- Mortality Rate at 3 and 6 Months(Months 3 and 6)