Phase 1, First-in-Human, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of KO-2806 When Administered as Monotherapy and in Combination Therapy in Adult Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 68
- 主要终点
- Rate of dose-limiting toxicities (DLTs)
研究概览
简要总结
This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess KO-2806, a farnesyltransferase inhibitor (FTI), as a monotherapy and in combination, in adult patients with advanced solid tumors.
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
- •At least 18 years of age.
- •Histologically or cytologically confirmed advanced solid tumors
- •Arm #1 (KO-2806 monotherapy): Patients who have progressed on, or are refractory to, standard of care (SOC) treatments with advanced solid tumors, specifically: HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC
- •Arm #2 (Combination): Patients who have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype; non-clear cell RCC patients who are either treatment-naïve or have received any prior systemic treatment for locally advanced and metastatic RCC.
- •Arm #3 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC.
- •Arm #4 (Combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
- •Arm #5 (Cabozantinib monotherapy): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
- •Arm #6 (Cabozantinib rollover to combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
- •Arm #7 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC
- •Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.
- •Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.
- •Acceptable liver, renal, endocrine, and hematologic function.
- •Other protocol-defined inclusion criteria may apply.
排除标准
- •Any use of anticancer therapy within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day
- •Prior treatment with an FTI or HRAS inhibitor.
- •Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1, without complete recovery.
- •Spinal cord compression, leptomeningeal disease, or clinically active CNS metastases.
- •Toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent.
- •Active or prior documented autoimmune or inflammatory disorders within the past 5 years prior to Cycle 1 Day 1 (with exceptions).
- •Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
- •Inability to swallow, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs.
- •Inadequate cardiac and/or vascular function, including receipt of treatment for unstable angina, myocardial infarction, and/or cerebrovascular attack within the prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.
- •Other invasive malignancy within 2 years.
- •Other protocol-defined exclusion criteria may apply.
研究组 & 干预措施
Arm #1: RAS-altered advanced solid tumors, monotherapy (escalation phase)
Patients with advanced solid tumors and the following:
- HRAS-mutant and/or amplified tumors (any solid tumor type)
- HRAS overexpression (only for HNSCC tumors)
- KRAS and/or NRAS and/or HRAS-mutant and/or amplified for NSCLC or CRC
- KRAS-mutant and/or amplified PDAC
干预措施: Darlifarnib (Drug)
Arm #4: Advanced or metastatic ccRCC, combination therapy (expansion phase)
Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC
干预措施: Darlifarnib (Drug)
Arm #7: Advanced or metastatic NSCLC, combination therapy (expansion phase)
Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy including available approved standard of care treatments
干预措施: Darlifarnib (Drug)
Arm #2: Advanced or metastatic RCC, combination therapy (escalation phase)
Patients who have received at least 1 prior systemic therapy with immuno-oncology (IO)-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype; non-clear cell RCC patients who are either treatment naïve or have received any prior systemic treatment for locally advanced and metastatic RCC
干预措施: Darlifarnib (Drug)
Arm #3: Advanced or metastatic NSCLC, CRC, or PDAC, combination therapy (escalation phase)
Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC who have received at least 1 prior systemic therapy including available approved standard of care treatments
干预措施: Darlifarnib (Drug)
Arm #6: Advanced or metastatic ccRCC, cabozantinib rollover to combination therapy (expansion phase)
Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC
干预措施: Darlifarnib (Drug)
Arm #2: Advanced or metastatic RCC, combination therapy (escalation phase)
Patients who have received at least 1 prior systemic therapy with immuno-oncology (IO)-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype; non-clear cell RCC patients who are either treatment naïve or have received any prior systemic treatment for locally advanced and metastatic RCC
干预措施: Cabozantinib (Drug)
Arm #3: Advanced or metastatic NSCLC, CRC, or PDAC, combination therapy (escalation phase)
Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC who have received at least 1 prior systemic therapy including available approved standard of care treatments
干预措施: Adagrasib (Drug)
Arm #7: Advanced or metastatic NSCLC, combination therapy (expansion phase)
Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy including available approved standard of care treatments
干预措施: Adagrasib (Drug)
Arm #4: Advanced or metastatic ccRCC, combination therapy (expansion phase)
Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC
干预措施: Cabozantinib (Drug)
Arm #5: Advanced or metastatic ccRCC, monotherapy (expansion phase)
Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC
干预措施: Cabozantinib (Drug)
Arm #6: Advanced or metastatic ccRCC, cabozantinib rollover to combination therapy (expansion phase)
Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC
干预措施: Cabozantinib (Drug)
结局指标
主要结局
Rate of dose-limiting toxicities (DLTs)
时间窗: DLTs will be evaluated during the first 28 days of KO-2806 treatment (dose escalation)
Rate of dose-limiting toxicities (DLTs)
时间窗: DLTs will be evaluated during the first 28 days of KO-2806 treatment (dose escalation)
Descriptive statistics of adverse events (AEs)
时间窗: First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose escalation)
NCI-CTCAE v5.0
Incidence of dose interruptions, reductions, and discontinuations due to AE
时间窗: First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose escalation)
Objective Response Rate (ORR)
时间窗: Up to an estimated period of 24 months (dose expansion)
Assessed per RECIST v1.1
次要结局
- Objective Response Rate (ORR)(Up to an estimated period of 24 months (dose escalation))
- Disease control rate (DCR)(Up to an estimated period of 24 months (dose escalation and expansion))
- Duration of response (DoR)(Up to an estimated period of 24 months (dose escalation and expansion))
- Progression-Free Survival (PFS)(Up to an estimated period of 24 months (dose escalation and expansion))
- Disease control rate (DCR)(Up to an estimated period of 24 months (dose escalation and expansion))
- Incidence of dose interruptions, reductions, and discontinuations due to AE(First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose expansion))
- Descriptive statistics of AEs(First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose expansion))
- Duration of response (DoR)(Up to an estimated period of 24 months (dose escalation and expansion))
- Objective Response Rate (ORR)(Up to an estimated period of 24 months (dose escalation))
- Progression-Free Survival (PFS)(Up to an estimated period of 24 months (dose escalation and expansion))
- AUClast(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- AUC0-inf(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- t1/2(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- QTcF(Up to 28 days following last dose of KO-2806, cabozantinib, or adagrasib. (Dose escalation and dose expansion))
- Time to response (TTR)(Up to an estimated period of 24 months (dose escalation and expansion))
- Overall Survival (OS)(First dose of KO-2806 until death, or up to an estimated period of 37 months (dose escalation and expansion))
- Cmin(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- CL/F(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- Cmax(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- Tmax(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- Estimated terminal elimination rate constant (λz)(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- Vd/F(Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion))
- KO-2806 plasma concentration measurements(Up to day 28 following first dose of KO-2806 and adagrasib. (Dose escalation and dose expansion))
- Amount of KO-2806 excretion in urine(Up to 24 hours following first dose of KO-2806. (Dose escalation))
- CLr of KO-2806 excretion in urine(Up to 24 hours following first dose of KO-2806. (Dose escalation))