A Phase 1 Study of KZR-261, a Small Molecule Sec61 Inhibitor, in Subjects With Advanced Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 61
- 试验地点
- 12
- 主要终点
- Number and Percentage of Participants Experiencing Adverse Events as Assessed by CTCAE v5.0 (Part 1 & 2)
研究概览
简要总结
A first-in-human, open-label, multicenter, Phase 1 study of KZR-261 designed to assess the safety and tolerability, preliminary anti-tumor activity, and pharmacokinetics (PK) of KZR-261, as well as identify the recommended Phase 2 dose (RP2D). The study comprised a Part 1 (Dose Escalation) and a Part 2 (2A Dose Expansion and 2B Dose Optimization) in solid organ tumors (melanoma/uveal melanoma, mesothelioma, colorectal cancer, castration-resistant prostate cancer, and "All-Tumors").
详细描述
The first-in-human, open-label, multicenter, Phase 1 study of KZR-261, Study KZR-261-101, was conducted in two parts (dose escalation and dose expansion) to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and evaluate the preliminary anti-tumor activity of KZR-261 in participants with locally advanced or metastatic solid malignancies for whom no therapeutics are available (or available therapeutics were refused) that can confer a reasonable likelihood of clinical benefit. The 5 tumor cohorts in the dose expansion part include advanced malignant:
- melanoma/uveal melanoma
- mesothelioma
- colorectal cancer
- castration-resistant prostate cancer
- "All-Tumors" (other advanced solid malignancies)
Part 1 (Dose Escalation) and Part 2 (2A Dose Expansion and 2B Dose Optimization) comprised a 4-week Screening Period, a Treatment Period lasting approximately 24 weeks, 4-6-week Safety Follow-up, and a 12-month Long-Term Follow-up Period (after last dose of study treatment), for a total study duration of approximately 20 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Histologic or cytologic evidence of malignant solid tumor with advanced disease (except primary central nervous system [CNS] neoplasms), defined as cancer that is either metastatic or locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered to result in reasonable clinical benefit).
- •Disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy in the Investigator's judgement likely to result in clinical benefit, or if such therapy has been refused by the subject. Documentation of the reason must be provided for subjects who have not received a standard therapy likely to result in clinical benefit.
- •Eastern Cooperative Oncology Group Performance Status score of 0 or
- •Adequate baseline hematologic and organ function.
- •Willing to use contraception.
- •Additional Inclusion for Part 2: Histologic or cytologic evidence of malignancy (melanoma/uveal melanoma, colorectal cancer, castration-resistant prostate cancer, mesothelioma).
排除标准
- •Subjects who have participated in Part 1 dose escalation are not eligible to enroll in Part 2 dose expansion.
- •Persistent clinically significant toxicities from previous anticancer therapy (excluding alopecia).
- •Treatment with cytotoxic, biologic, or targeted therapies for advanced cancer within 14 days before administration of the subject's first dose of KZR-
- •Treatment with an investigational drug within 28 days before administration of the subject's first dose of KZR-
- •Radiation therapy within 14 days of before administration of the subject's first dose of KZR-
- •Major surgical procedure within 28 days before administration of the subject's first dose of KZR-
- •History of risk factors for Torsades de pointes.
- •Active, symptomatic CNS metastases or primary CNS malignancy.
- •Any female who is breastfeeding or who plans to become pregnant during the study, or who are actively trying to conceive at the time of signing of the informed consent form (ICF).
- •Uncontrolled, clinically significant pulmonary disease.
研究组 & 干预措施
KZR-261 with standard therapy: open-label
Part 1 (Dose Escalation):
The initial dose cohort of the Dose Escalation received 1.8 mg/m2 of KZR-261. Participants received 3 doses in a 28-day cycle as an intravenous (IV) infusion for up to 6 cycles.
_________________
Part 2A (Dose Expansion):
Following safety review of all Dose Escalation cohorts and determination of the maximum tolerated dose (MTD) or maximum administered dose (MAD), KZR-261 was to be evaluated for safety and preliminary efficacy in 4 tumor-specific cohorts and 1 all-tumor cohort to determine the recommended phase 2 dose (RP2D). The 4 tumor-specific cohorts will include:
- melanoma (including uveal melanoma)
- colorectal cancer
- castration-resistant prostate cancer
- mesothelioma
Part 2B (Dose Optimization):
Dose optimization in tumor-specific cohorts could have been initiated based on the totality of data after the MTD/MAD had been determined. Participants were to receive KZR-261 at the MTD/MAD or a lower clinically active dose of KZR-261.
干预措施: KZR-261 (Drug)
结局指标
主要结局
Number and Percentage of Participants Experiencing Adverse Events as Assessed by CTCAE v5.0 (Part 1 & 2)
时间窗: 20 months
Incidence and percentage of adverse events and serious adverse events will be collected from start of enrollment
Number and Percentage of Participants Experiencing Dose-limiting Toxicities
时间窗: 28 days
Number and percentage of participants experiencing dose-limiting toxicities (DLT) collected from start of enrollment through the first 28 days of Cycle 1 as assessed by CTCAE v5.0 (Part 1).
Maximum Plasma Concentration of KZR-261 (Part 1)
时间窗: Cycle 1: Day 1, Cycle 1: Day 15, Cycle 2: Day 1, and Cycle 2: Day 15
This is the maximum observed plasma concentration (Cmax) observed after administration of KZR-261 in Cycle 1 (Days 1 and 15) and Cycle 2 (Days 1 and 15). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose, 15 minutes post start of infusion, end of infusion, and 5, 15, 30 minutes, 1, 2, 4, 6, 24, 48, and 96 hours post infusion.
The Plasma Concentration Time Curve of KZR-261 (Part 1)
时间窗: Cycle 1: Day 1, Cycle 1: Day 15, Cycle 2: Day 1, and Cycle 2: Day 15
This is the area under the curve (AUC) from predose through postdose observed after administration of KZR-261 in Cycle 1 (Days 1 and 15) and Cycle 2 (Days 1 and 15). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose, 15 minutes post start of infusion, end of infusion, and 5, 15, 30 minutes, 1, 2, 4, 6, and 24 hours post infusion.
次要结局
- Objective Response (ORR) Following KZR-261(20 months)
- Participants With Clinical Benefit of Stable Disease Following KZR-261(20 months)
- Progression-free Survival of Participants Treated With KZR-261(4 months and 6 months)
- Overall Survival of Participants Treated With KZR-261(20 months)