First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 930
- 试验地点
- 37
- 主要终点
- Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent
研究概览
简要总结
This is an open-label, FIH study designed to evaluate the maximum tolerated dose, recommended Phase 2 dose, safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of RLY-2608, in advanced solid tumor patients with a Phosphatidylinositol-4,5-bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutation in blood and/or tumor per local assessment. The study will evaluate RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors. It will also evaluate RLY-2608 in combination RLY-2608 + fulvestrant and in triple combination RLY-2608 + fulvestrant + CDK4/6 inhibitor (palbociclib or ribociclib) or CDK4 inhibitor (PF-07220060) for patients with HR+ HER2- locally advanced or metastatic breast cancer. The RLY-2608 single agent arm, RLY-2608 + fulvestrant combination arm, and triple combination arms will have 2 parts: a dose escalation (Part 1) and a dose expansion (Part 2).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
RLY-2608 for patients with unresectable or metastatic solid tumors
Multiple doses of RLY-2608 for oral administration.
干预措施: RLY-2608 (Drug)
RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.
干预措施: RLY-2608 (Drug)
RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
干预措施: RLY-2608 (Drug)
RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+palbo125mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.
干预措施: Palbociclib 125mg (Drug)
RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
干预措施: RLY-2608 (Drug)
RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+ribo400mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.
干预措施: Ribociclib 400mg (Drug)
RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
干预措施: RLY-2608 (Drug)
RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+ribo600mg for HR+HER2- locally advanced metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.
干预措施: Ribociclib 600mg (Drug)
RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation
干预措施: RLY-2608 (Drug)
RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation
干预措施: PF-07220060 100mg (Drug)
RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation
干预措施: RLY-2608 (Drug)
RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation
干预措施: Fulvestrant (Drug)
RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer
Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation
干预措施: PF-07220060 300 mg (Drug)
结局指标
主要结局
Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 as a single agent
时间窗: Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months
Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant
时间窗: Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months
Determination of maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
时间窗: Cycle 1 (4-week cycle) of treatment for MTD and at the end of every cycle (4-week cycles) for RP2D until study discontinuation, approximately 24 months
Number of patients with adverse events and serious adverse events of RLY-2608 as a single agent
时间窗: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant
时间窗: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Number of patients with adverse events and serious adverse events of RLY-2608 in combination with fulvestrant and a CDK 4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant
时间窗: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
次要结局
- PIK3CA gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue(Day 1 of Cycle 1 (each cycle is 28 days))
- Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) as single agent(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including area under the plasma concentration versus time curve during a dose interval (AUC0-tau) of RLY-2608 (and its metabolites, as appropriate) as single agent(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) as single agent(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including area under the plasma concentration versus time curve during a dose interval (AUC0-tau) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- PK parameters including maximum plasma drug concentration (Cmax) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant + palbociclib or ribociclib, and in combination (PF-07220060) +fulvestrant(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- PK parameters including area under the plasma concentration vs time curve during a dose interval (AUC0-tau) of RLY-2608 (and its metabolites, as appropriate) administered with fulvestrant + palbociclib, or ribociclib, or PF-07220060(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Pharmacokinetic parameters including half-life (t1/2) of RLY-2608 (and its metabolites, as appropriate) when RLY-2608 is administered in combination with fulvestrant + palbociclib or ribociclib, and in combination with PF-07220060 +fulvestrant(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment, approximately 24 months)
- Changes in circulating blood of fasting glucose in RLY-2608 as a single agent(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of insulin in RLY-2608 as a single agent(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of C-peptide in RLY-2608 as a single agent(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of HbA1c in RLY-2608 as a single agent(Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months)
- Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant(Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months)
- Changes in circulating blood of fasting glucose in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib) and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of insulin in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of C-peptide in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant(Approximately every week in Cycle 1 (4-week cycle), every two weeks in Cycle 2 (4-week cycle), and every cycle starting with Cycle 3 through end of treatment, approx 24 months)
- Changes in circulating blood of HbA1c in RLY-2608 in combination with fulvestrant and a CDK4/6 inhibitor (palbociclib, ribociclib), and in combination with CDK4 inhibitor (PF-07220060) and fulvestrant(Once in Cycle 2 (4-week cycle) and then once every 3rd cycle beginning with Cycle 5 through end of treatment, approximately 24 months)
- Objective response rate (ORR) as assessed by RECIST v1.1(Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months)
- Duration of Response (DOR) as assessed by RECIST v1.1(Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months)
- Disease Control Rate (DCR) as assessed by RECIST v1.1(Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months)
- Clinical benefit rate (CBR) as assessed by RECIST v1.1([Time Frame: Approximately every 8 weeks during treatment and every 12 weeks after the last dose in the absence of progressive disease, approximately 36 months])