A Phase 1/2, Open-label, First-in-human Study of the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of ETX-636, a Pan-mutant-selective PI3Kα Inhibitor, as Monotherapy and in Combination With Other Anticancer Therapies in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 233
- 试验地点
- 20
- 主要终点
- Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
研究概览
简要总结
Phase 1/2, open-label study of ETX-636 in participants with advanced solid tumors
详细描述
Brief Summary: This is a Phase 1/2, open-label, multicenter, 3-part study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ETX-636 in participants with advanced solid tumors harboring a PIK3CA mutation.
Part A will evaluate escalating doses of ETX-636 as monotherapy in participants with advanced solid tumors. Part B will evaluate escalating doses of ETX-636 as combination therapy with fixed dose fulvestrant in participants with hormone receptor positive (HR+), HER2 negative (HER2-) locally advanced or metastatic breast cancer. Part C will be a combination therapy expansion in participants with HR+, HER2- locally advanced or metastatic breast cancer.
Each study part will include a 28-day screening period, followed by treatment with ETX-636 monotherapy or combination therapy.
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
- •Metastatic or locally advanced and unresectable solid tumor that has progressed on or after at least one available therapy.
- •Tumor harboring an activating PIK3CA mutation detected in either tumor tissue or ctDNA.
- •At least 1 measurable lesion or evaluable disease per RECIST v1.
- •An ECOG performance status score of 0 or
- •Adequate organ function.
- •Additional key inclusion criterion for Parts B and C:
- •- Confirmed metastatic or locally advanced HR+/HER2- breast cancer not amenable to surgical resection with curative intent and must have received at least 1 prior CDK4/6 inhibitor and at least 1 prior anti-estrogen therapy.
排除标准
- •Has history (within ≤2 years before screening) of a solid tumor or hematological malignancy that is histologically distinct from the cancers being studied.
- •Has symptomatic brain or spinal metastases or a known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement.
- •Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type
- •Has received treatment with any local or systemic anticancer therapy or investigational anticancer agent within 14 days prior to start of treatment.
- •Has toxicities from previous anticancer therapies that have not resolved to baseline levels with the exception of alopecia and peripheral neuropathy.
- •Has had radiotherapy outside the target tumor lesions within 14 days prior to start of treatment.
研究组 & 干预措施
Part B Dose Escalation Combination Therapy (HR+/HER2- locally advanced or metastatic breast cancer)
Part B is a dose escalation combination therapy in HR+/HER2- locally advanced or metastatic breast cancer. The study treatment will be ETX-636, a pan-mutant-selective PI3Kα inhibitor, in combination with fulvestrant (Faslodex) at a fixed dose of 500 mg IM.
干预措施: ETX-636 dose escalation in combination with fulvestrant (Drug)
Part C Dose Expansion Combination Therapy (HR+/HER2- locally advanced or metastatic breast cancer)
Part B is a dose expansion combination therapy in HR+/HER2- locally advanced or metastatic breast cancer. The study treatment will be ETX-636, a pan-mutant-selective PI3Kα inhibitor, in combination with fulvestrant (Faslodex) at a fixed dose of 500 mg IM.
干预措施: ETX-636 dose expansion in combination with fulvestrant (Drug)
Part A Dose Escalation Monotherapy (Advanced Solid Tumors with PIK3CA mutation)
Part A is a dose escalation monotherapy of ETX-636 in advanced solid tumors with PIK3CA mutation
干预措施: ETX-636 dose escalation (Drug)
结局指标
主要结局
Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
时间窗: First 28 days of treatment
Proportion of participants who experience at least 1 Dose Limiting Toxicity (DLT)
Evaluate Safety and Tolerability of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B
时间窗: Average of 6 months
Incidence of AEs, treatment discontinuations due to AEs, changes from baseline in laboratory assessments, ECGs and vital signs.
Select the Recommended Phase 2 Dose(s) (RP2D) in Part B to be further explored in Part C (combination therapy expansion)
时间窗: Average of 6 months
Safety Parameters as described for primary outcomes
Evaluate efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C
时间窗: Average of 6 months
ORR and CBR according to RECIST v1.1
次要结局
- Evaluate additional measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C(Average of 6 months)
- Characterize the Cmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B(First 2 treatment cycles (each cycle is 28 days))
- Characterize the Tmax (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B(First 2 treatment cycles (each cycle is 28 days))
- Characterize the AUC (PK) of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B(First 2 treatment cycles (each cycle is 28 days))
- Measure PD effects of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B and ETX-636 plus fulvestrant at the RP2D(s) in Part C(First 3 cycles (each cycle is 28 days))
- Changes in fasting blood glucose (All Parts)(Average of 6 months)
- Changes in longitudinal glucose metabolism (All Parts)(Average of 6 months)
- Assess preliminary efficacy of ETX-636 monotherapy in Part A and ETX-636 plus fulvestrant combination therapy in Part B(Average of 6 months)
- Evaluate measures of efficacy of ETX-636 plus fulvestrant combination therapy at the RP2D(s) in Part C(Average of 6 months)
- Evaluate Safety of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C(Average of 6 months)
- Evaluate tolerability of ETX-636 plus fulvestrant combination therapy at the RP2Ds in Part C(Average of 6 months)
- Characterize the PK of ETX-636 plus fulvestrant using population PK modeling (Part C, to be reported separately)(First 2 treatment cycles (each cycle is 28 days))