A Phase 1, Open-Label, Multicenter, Dose Escalation Study of PRT1419 Injection as Monotherapy or in Combination With Azacitidine or Venetoclax in Patients With Relapsed/Refractory Myeloid or B-cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 21
- 试验地点
- 9
- 主要终点
- Dose limiting toxicities (DLT) of PRT1419
研究概览
简要总结
This is a Phase 1 dose-escalation study of PRT1419, a myeloid cell leukemia-1 (MCL-1) inhibitor, in participants with selected relapsed/refractory myeloid or B-cell malignancies. The purpose of this study is to evaluate the safety and tolerability of PRT1419 monotherapy and in combination with either azacitidine or venetoclax, describe any dose limiting toxicities (DLTs), define the dosing schedule, and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D).
详细描述
This is a multicenter, open-label, dose-escalation, Phase 1 study of PRT1419, a MCL-1 inhibitor, evaluating participants with acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm (MPN) overlap syndrome, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and B-cell non-hodgkin lymphoma (NHL) including marginal zone lymphoma, follicular lymphoma or mantle cell lymphoma. Participants in study will receive PRT1419 as monotherapy or in combination with either Azacitidine (AZA) or Venetoclax (VEN). The study includes multiple dose escalations and expansion cohorts for RP2D confirmation.
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 (including contraception requirements), and other study procedures
- •Refractory/relapsed disease, having progressed on prior treatment, and without access to further approved therapies or ineligible for approved therapies, in one of the following disease categories: AML, CMML, MDS, MDS/MPN Overlap Syndrome, CLL/SLL, and B-cell NHLs
- •Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 2
- •Adequate organ function (hematology, hepatic, renal, and coagulation)
排除标准
- •Active inflammatory disorders of the gastrointestinal tract, a history of bariatric surgery or other disorders with the potential for GI malabsorption
- •Cardiac function compromise, as assessed by echocardiogram or protocol-specified biochemical markers of cardiac damage, or protocol-defined clinically significant heart disease
- •History of cerebrovascular accident or transient ischemic attack, within 6 months of screening. Participants with a history of pulmonary embolism must not be symptomatic at enrollment
- •Undergone hematopoietic stem-cell transplantation (HSCT) within the last 90 days or have graft-versus-host disease (GVHD) Grade > 1 at study entry
- •Uncontrolled intercurrent illnesses, poorly controlled hypertension or dyslipidemias, Unstable central nervous system (CNS) metastases
- •Treatment with either OATP1B1, OATP1B3 substrates or strong inhibitors of CYP2C8, CYP3A4, and any medication contraindicated in combination with AZA or VEN
- •Prior exposure to an MCL-1 inhibitor
- •Within 5 half-lives or 14 days (whichever is longer) following the last systemic anti-cancer therapy
- •History of another malignancy except for:
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated cervical or breast carcinoma in situ without evidence of disease
- •Asymptomatic prostate cancer without known metastatic disease and no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for >1 year prior to enrollment
- •Other malignancy treated with curative intent with no known active disease for > 2 years prior to enrollment
研究组 & 干预措施
PRT1419 Monotherapy
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned.
干预措施: PRT1419 (Drug)
PRT1419/Azacitidine Combination
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Azacitidine will be administered by intravenous or subcutaneous on Days 1 through 7 (or alternatively on Days 1 through 5, 8 and 9) of each 28-day treatment cycle.
干预措施: PRT1419 (Drug)
PRT1419/Azacitidine Combination
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Azacitidine will be administered by intravenous or subcutaneous on Days 1 through 7 (or alternatively on Days 1 through 5, 8 and 9) of each 28-day treatment cycle.
干预措施: Azacitidine (Drug)
PRT1419/Venetoclax Combination
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Venetoclax will be administered orally after either a 3-day or 5-week ramp-up period to reach 400 mg daily administration, prior to commencing PRT1419 administration.
干预措施: PRT1419 (Drug)
PRT1419/Venetoclax Combination
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Venetoclax will be administered orally after either a 3-day or 5-week ramp-up period to reach 400 mg daily administration, prior to commencing PRT1419 administration.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Dose limiting toxicities (DLT) of PRT1419
时间窗: Baseline through Day 28
Dose limiting toxicities will be evaluated over the 28-day observation period
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) and schedule of PRT1419
时间窗: Baseline through approximately 2 years
The MTD/RP2D will be established for further investigation in participants with advanced hematologic malignancies
Safety and tolerability of PRT1419: AEs, SAEs, CTCAE assessments
时间窗: Baseline through approximately 3 years
Safety and tolerability will be assessed by recording adverse events (AEs), serious adverse events (SAEs), and DLTs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
次要结局
- Safety and tolerability of PRT1419 in combination with AZA and VEN: AEs, SAEs, CTCAE assessments(Baseline through approximately 3 years)
- Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Time to maximal plasma concentration(Baseline through approximately 3.5 years)
- Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Progression-free survival (PFS)/event free survival (EFS)(Baseline through approximately 3.5 years)
- Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Duration of response (DOR)(Baseline through approximately 3.5 years)
- Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: maximum observed plasma concentration(Baseline through approximately 3.5 years)
- Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Area under the curve(Baseline through approximately 3.5 years)
- Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall response rate (ORR)(Baseline through approximately 3.5 years)
- Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall survival (OS)(Baseline through approximately 3.5 years)