A Phase 1/1b Open-Label, Dose Escalation, First-in- Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-leukemic Activity of the Orally Available CDC-Like Kinase (CLK) Inhibitor, BH-30236, in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML) or Higher-Risk Myelodysplastic Syndrome (HR-MDS)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 170
- 试验地点
- 13
- 主要终点
- Dose Expansion: Composite Complete Remission (CR) Rate
研究概览
简要总结
Study BH-30236-01 is a first-in-human (FIH), Phase 1/1b, open-label, dose escalation and expansion study in participants with relapsed/refractory acute myelogenous leukemia (R/R AML) or higher-risk myelodysplastic syndrome (HR-MDS).
Phase 1, Part 1 Dose Escalation - Monotherapy will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BH-30236 administered orally. Approximately 50 participants may be enrolled in Phase 1, Part 1 Dose Escalation - Monotherapy.
Phase 1, Part 2 Dose Escalation - Combination with Venetoclax will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BH-30236 administered as a combination therapy with venetoclax. Approximately 48 participants may be enrolled in Phase 1, Part 2 Dose Escalation - Combination with Venetoclax.
Phase 1b (Dose Expansion) will follow Phase 1 to further understand the relationships among dose, exposure, toxicity, tolerability, and clinical activity. Up to 72 participants may be enrolled in Phase 1b of the study as a monotherapy or in combination with venetoclax.
详细描述
This is a Phase 1/1b, multi-center, open-label, dose escalation, first-in-human study to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of the CLK inhibitor, BH-30236 as a monotherapy or in combination with venetoclax, in adult participants with R/R AML or HR-MDS.
The study consists of three parts: Phase 1, Part 1 Dose Escalation - Monotherapy, Phase 1, Part 2 Dose Escalation - Combination with Venetoclax, and Phase 1b Dose Expansion.
Phase 1, Part 1 Dose Escalation - Monotherapy is anticipated to enroll approximately 50 participants to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of BH-30236, as well as determine the MTD and/or the preliminary recommended dose(s) for expansion (RDEs).
Phase 1, Part 2 Dose Escalation - Combination with Venetoclax is anticipated to enroll approximately 48 participants to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of BH-30236, as well as determine the MTD and/or the preliminary recommended dose(s) for expansion (RDEs).
Phase 1 will follow a Bayesian optimal interval (BOIN) design dose escalation, where participants will receive ascending doses of BH-30236 to determine the recommended RDEs.
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
- 未提供
排除标准
- •Diagnosis of acute promyelocytic leukemia or chronic myeloid leukemia with blast crisis.
- •Prior allogeneic HSCT within 3 months or donor lymphocyte infusion within 30 days of start of therapy;
- •Active and uncontrolled infections.
- •Unresolved AEs greater than Grade from prior therapies.
- •History of other active malignancy (with certain exceptions)
- •Prior treatment with a CLK inhibitor.
- •Any acute or chronic graft versus host disease requiring systemic therapy within 4 weeks prior to study drug administration with the exception of topical steroids or the equivalent of 20 mg of prednisone or less.
- •The above is a summary, other exclusion criteria details may apply.
研究组 & 干预措施
Dose Escalation Cohort - Monotherapy
BH-30236 Monotherapy for Dose Escalation
干预措施: BH-30236 (Drug)
Dose Escalation Cohort - Combination with Venetoclax
BH-30236 in Combination with Venetoclax for Dose Escalation.
干预措施: BH-30236 (Drug)
Dose Escalation Cohort - Combination with Venetoclax
BH-30236 in Combination with Venetoclax for Dose Escalation.
干预措施: Venetoclax (Drug)
Dose Expansion Cohort - Monotherapy
BH-30236 based on Monotherapy dose escalation data.
干预措施: BH-30236 (Drug)
Dose Expansion Cohort - Combination with Venetoclax
BH-30236 in Combination with Venetoclax based on Dose Escalation data
干预措施: BH-30236 (Drug)
Dose Expansion Cohort - Combination with Venetoclax
BH-30236 in Combination with Venetoclax based on Dose Escalation data
干预措施: Venetoclax (Drug)
结局指标
主要结局
Dose Expansion: Composite Complete Remission (CR) Rate
时间窗: From first dose of BH-30236 until disease progression (up to approximately 1 year)
Composite CR rate disease assessment in accordance with the following guidelines: European Leukemia Network (ELN) 2022 for acute myelogenous leukemia (AML) and International Working Group (IWG) 2023 for myelodysplastic syndrome (MDS).
Dose Escalation and Expansion: Safety evaluation of BH-30236: Number of participants with treatment-related adverse events as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
时间窗: From first dose until 28 days after last dose of BH-30236
Frequency, severity and relationship to study drug of AEs and SAEs
Dose Escalation: Frequency of dose limiting toxicities (DLTs)
时间窗: Dose-limiting toxicities are collected during the first treatment cycle (28 days)
DLTs are dose-limiting toxicities as defined in the study protocol.
次要结局
- Dose Escalation: Area under the blood concentration time curve (AUC) of BH-30236.(Evaluation performed in Cycle 1 (cycle duration is 28 days).)
- Dose Escalation and Expansion: Relapse-free Survival (RFS)(From first dose of BH-30236 until disease progression, death, or initiation of a new anti-leukemic therapy (approximately 1 year).)
- Dose Escalation and Expansion: Measurable Residual Disease (MRD)(From time of first dose until discontinuation of BH-30236 (approximately 1 year).)
- Dose Escalation and Expansion: Measurement of the change in RNA alternative splicing markers on BH-30236 treatment(From time of first dose until discontinuation of BH-30236 (approximately 1 year).)
- Dose Escalation and Expansion: Time to remission (TTR)(From first dose of BH-30236 until complete remission, disease progression or death (approximately 1 year).)
- Dose Escalation and Expansion: Complete remission (CR) / complete remission with partial hematologic recovery (CRh) rate for AML and complete remission/partial remission (CR/PR) rate for HR-MDS(Time from first documented response until disease progression or death (approximately 1 year))
- Dose Escalation and Expansion: Duration of Response (DoR)(Time from first documented response until disease progression or death (approximately 1 year).)
- Dose Escalation and Expansion: Objective Response Rate (ORR)(From first dose of BH-30236 until disease progression (up to approximately 1 year))
- Dose Escalation and Expansion: Maximum observed blood concentration (Cmax) of BH-30236.(Evaluation performed in Cycle 1 (cycle duration is 28 days).)
- Dose Escalation and Expansion: Concentration before dose at steady state (Ctrough).(Evaluation performed in all treatment cycles up to one year (cycle duration is 28 days).)