A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With Relapsed/Refractory Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 42
- 主要终点
- Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: AEs, CTCAE Assessments
研究概览
简要总结
This is a Phase 1 dose-escalation study of PRT2527, a potent and highly selective cyclin-dependent kinase (CDK) 9 inhibitor, in participants with select relapsed or refractory (R/R) hematologic malignancies. The purpose of this study is to evaluate the safety, tolerability, recommended phase 2 dose (PR2D), and preliminary efficacy of PRT2527 as a monotherapy and in combination with zanubrutinib or venetoclax.
详细描述
This is an open-label, multi-center, dose-escalation, Phase 1 study of PRT2527, a CDK9 inhibitor, as monotherapy for participants with relapsed and refractory lymphoid and myeloid malignancies, in combination with zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi) for participants with lymphoid malignancies, or in combination with venetoclax, a B-cell lymphoma 2 inhibitor (BCL-2i) in participants with myeloid malignancies. The study will be conducted in two parts, the dose escalation phase and the dose confirmation phase for both monotherapy and combination therapy. The dose escalation phase will evaluate escalating doses of PRT2527 as a monotherapy and in combination with zanubrutinib or venetoclax until MTD is identified or when the RP2D is determined. The dose confirmation phase will evaluate indication-specific cohorts at the RP2D to confirm the dose.
Approximately 274 participants will be enrolled in the dose escalation and indication-specific, dose confirmation cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures
- •Histologically or cytologically confirmed diagnosis of aggressive B-cell lymphoma subtypes, MCL, MZL, or CLL/SLL (including Richter's syndrome) based on local testing, or TCL (monotherapy only), AML, CMML, MDS, or MDS/MPN overlap syndrome that have relapsed or become refractory to or be ineligible for standard-of-care therapy
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of <
- •Adequate organ function (hematology, renal, and hepatic)
- •Echocardiogram (or multigated acquisition [MUGA] scan) indicating a left ventricular ejection fraction of ≥ 50%
排除标准
- •Have active central nervous system involvement by malignancy, uncontrolled intercurrent illnesses, and active infections requiring systemic therapy
- •Have undergone HSCT within the last 90 days or have graft versus host disease (GvHD) Grade > 1 at study entry
- •Have severe pulmonary disease with hypoxemia
- •History of another malignancy except for adequately treated non-melanoma skin cancer or lentigo maligna, superficial bladder cancer, and carcinoma in situ of the cervix without evidence of disease, and asymptomatic prostate cancer without known metastatic disease and no requirement for therapy
- •Concurrent treatment or within 15 days of starting study treatment with strong CYP3A4 inhibitors
- •Prior exposure to a CDK9 inhibitor
- •Wait at least 5 half-lives of the agent or 14 days after their investigational or approved therapies before start of study treatment, whichever is shorter
- •Mean corrected QT interval of > 470 msec following triplicate ECG measurement or history of long QT syndrome
- •T-Cell leukemias
研究组 & 干预措施
PRT2527 Monotherapy in Lymphoid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.
干预措施: PRT2527 (Drug)
PRT2527/Zanubrutinib Combination in Lymphoid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase.
Zanubrutinib will be administered orally as combination therapy once or twice daily.
干预措施: PRT2527 (Drug)
PRT2527/Zanubrutinib Combination in Lymphoid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase.
Zanubrutinib will be administered orally as combination therapy once or twice daily.
干预措施: Zanubrutinib (Drug)
PRT2527 Monotherapy in Myeloid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.
干预措施: PRT2527 (Drug)
PRT2527/Venetoclax Combination in Myeloid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase.
Venetoclax will be administered orally as a combination therapy once daily.
干预措施: PRT2527 (Drug)
PRT2527/Venetoclax Combination in Myeloid Malignancies
PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase.
Venetoclax will be administered orally as a combination therapy once daily.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: AEs, CTCAE Assessments
时间窗: Baseline through approximately 2 years
Safety and tolerability will be evaluated by incidence of DLTs, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
Dose limiting toxicity (DLT) of PRT2527
时间窗: Baseline through Day 21, 28, or 35 days.
Dose limiting toxicities will be evaluated during Cycle 1 depending on the treatment arm and intrapatient ramp-up.
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax
时间窗: Baseline through approximately 2 years
The MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignancies
次要结局
- Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Maximum observed plasma concentration(Baseline through approximately 2 years)
- Anti-tumor activity of PRT2527 as monotherapy and in combination with zanubrutinib or venetoclax: Objective response rate (ORR)(Baseline through approximately 2 years)
- Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Duration of response/Complete Response (DOR/DoCR)(Baseline through approximately 2 years)
- Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Area under the curve(Baseline through approximately 2 years)
- Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Time of maximum concentration(Baseline through approximately 2 years)