A Phase 1, First-in-Human, Open-Label Study to Evaluate the Safety, Tolerability, PK, and Preliminary Anti-tumor Activity of the Novel Oral Selective CDK2/CDK4 Dual Degrader NKT5097 in Adults With Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 361
- 试验地点
- 19
- 主要终点
- Incidence of dose-limiting toxicities as Assessed by CTCAE
研究概览
简要总结
The goal of this open-label dose escalation and expansion study is to evaluate the safety and tolerability of NKT5097 in adults with advanced/metastatic tumors (emphasis on breast cancer and solid tumors with CCNE1 amplification). Main questions to answer include:
- What is the recommended dose for expansion and/or Phase 2, for both monotherapy and in combination with ET
- What medical issues/symptoms do participants experience when taking NKT5097 as monotherapy as well as in combination with ET
详细描述
This First-in-Human, Open-Label Study to Evaluate the Safety, Tolerability, PK, and Preliminary Anti-tumor Activity of NKT5097, a novel dual protein degrader of CDK2 and CDK4, is split into 3 Parts:
Part 1: Monotherapy Dose Escalation in selected advanced/metastatic non-CNS primary solid tumors will be enrolled based on a projected total of 5 dose levels
Part 2: Food Effect Analysis: Subjects with solid tumors (as noted in Part 1) will be enrolled (by backfilling selected dose cohorts) to evaluate the effect of dosing with food on NKT5097.
Part 3: Monotherapy Tumor-specific Expansion: Subjects may be enrolled (by backfilling selected dose cohorts) into each selected tumor-specific cohort. One or more of these cohorts may be opened at the discretion of the Sponsor in consultation with the DEC
Part 4: Combination Dose Escalation with ET in selected HR+/HER2- breast cancer will be enrolled based on a projected 2 dose levels
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Able to provide written informed consent
- •Advanced unresectable or metastatic solid tumor (Part 1, 2 & 3 only)
- •Advanced unresectable or metastatic HR+/HER2- breast cancer (Part 4 & 5 only)
- •Refractory to or unable to tolerate existing therapies (Part 1, 2 & 4 only)
- •Measurable or evaluable disease (Part 1, 2, & 4 only).
- •Measurable disease (Part 3 & 5 only)
- •Eighteen years of age or older
- •ECOG status of 0 or 1
- •Adequate organ function
- •Patients with female reproductive organs must be surgically sterile, post- menopausal or willing to use effective contraception per protocol
- •Patients who are capable of insemination must be willing to use highly effective contraception and to refrain from sperm donation during treatment and for 28 days after the last dose
- •Able to swallow oral meds
- •Willing to provide tumor tissue
排除标准
- •Advanced solid tumor that is a candidate for curative treatment
- •History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage I or Stage II cancers currently in complete remission
- •Not recovered from the effects of prior anticancer therapy
- •Clinically significant cardiovascular event, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months
- •Known active CNS metastases and/or carcinomatous meningitis
- •Active interstitial lung disease requiring treatment
- •History of uveitis, retinopathy, or other clinically significant retinal disease
- •Major surgery within 30 days of administration of first dose
- •Active uncontrolled infectious disease
- •Significant liver disease (Child Pugh class B or C)
- •Should not have received any prior selective investigational inhibitors or degraders (Part 5 only)
研究组 & 干预措施
Part 1 Dose Escalation
Escalation of orally administered NKT5097
干预措施: NKT5097 CDK2/CDK4 dual degrader (Drug)
Part 2 Food Effect
Orally administered NKT5097 with and without meal
干预措施: NKT5097 CDK2/CDK4 dual degrader (Drug)
Part 3 Expansion
Expansion of dose levels based upon safety and PK following Part 1 escalation.
干预措施: NKT5097 CDK2/CDK4 dual degrader (Drug)
Part 4 Combination Dose Escalation
Escalation of orally administered NKT5097 in combination with Endocrine Therapy (ET)
干预措施: Fulvestrant (Drug)
Part 5 Combination Expansion
Expansion of dose levels based upon safety and PK following Part 4 escalation
干预措施: Letrozole (Drug)
Part 4 Combination Dose Escalation
Escalation of orally administered NKT5097 in combination with Endocrine Therapy (ET)
干预措施: Letrozole (Drug)
Part 5 Combination Expansion
Expansion of dose levels based upon safety and PK following Part 4 escalation
干预措施: Fulvestrant (Drug)
Part 4 Combination Dose Escalation
Escalation of orally administered NKT5097 in combination with Endocrine Therapy (ET)
干预措施: NKT5097 CDK2/CDK4 dual degrader (Drug)
Part 5 Combination Expansion
Expansion of dose levels based upon safety and PK following Part 4 escalation
干预措施: NKT5097 CDK2/CDK4 dual degrader (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities as Assessed by CTCAE
时间窗: From enrollment through end of safety monitoring period of 28 days from first dose
次要结局
- Incidence of adverse events (AEs) as defined by CTCAE Version 5(From enrollment through end of treatment up to 2 years)
- Maximum concentration Cmax after a single dose and multiple doses(Day 1 and Day 15 of Cycle 1 (Cycle 1 is 28 days))
- Area under the concentration-time curve (AUC last) after a single dose and multiple doses from first dose through the last timepoint with quantifiable concentration (Tlast)(Day 1 and Day 15 of Cycle 1 ((Cycle 1 is 28 days))
- Maximum concentration (Cmax) when dosed with and without food(Day 1 and Day 2 of Cycle 1 (Cycle 1 is 28 days))
- Area under the concentration-time curve (AUC last) when dosed with and without food from dosing through the last timepoint with quantifiable concentration (Tlast)(Day 1 through Day 3 of Cycle 1 (Cycle 1 is 28 days))
- Time to maximum plasma concentration (Tmax) after a single dose and multiple doses(Day 1 through Day 3 and Day 15 of Cycle 1 (Cycle 1 is 28 days))
- Investigator-assessed ORR by RECIST v1.1(From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months)
- Investigator-assessed PFS by RECIST v1.1(From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months)
- Duration of Response (DOR)(From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months)