A First-in-Human Study of PI3Kα Inhibitor, RLY-5836, in Combination With Targeted and Endocrine Therapies in Participants With Advanced Breast Cancer and as a Single Agent in Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 7
- 主要终点
- Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of RLY-5836
研究概览
简要总结
This is a Phase 1, first-in-human, open-label study designed to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RLY-5836 in advanced solid tumors in participants harboring a PIK3CA mutation in blood and/or tumor per local assessment. The study consists of 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
- •Patient has ECOG performance status of 0-1
- •One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per local assessment
- •RLY-5836 single agent arm key inclusion criteria
- •Disease that is refractory to standard therapy, intolerant to standard therapy, or participant has declined standard therapy.
- •A histologically or cytologically confirmed diagnosis of unresectable or metastatic solid tumor
- •Combination arms key inclusion criteria
- •Males, postmenopausal females, or pre-/perimenopausal females previously treated with gonadotropin-releasing GnRH agonist at least 4 weeks prior to start of study drug with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy.
- •Had previous treatment for advanced or metastatic breast cancer with antiestrogen therapy including, but not limited to, selective estrogen receptor degraders (e.g., fulvestrant), selective estrogen receptor modulators (e.g., tamoxifen), and aromatase inhibitors (AI) (letrozole, anastrozole, exemestane)
- •Part 1: Prior PI3Kα inhibitor treatment is allowed if taken for < 14 days and not discontinued due to disease progression, hypersensitivity, or ≥ Grade 3 TEAEs.
排除标准
- •Part 2: Prior treatment with PI3Kα inhibitors.
- •Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.
研究组 & 干预措施
RLY-5836 Single Agent Arm
RLY-5836 single agent arm for participants with unresectable or metastatic solid tumors
干预措施: RLY-5836 (Drug)
RLY-5836 + Fulvestrant Arm
RLY-5836 + fulvestrant combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: RLY-5836 (Drug)
RLY-5836 + Fulvestrant Arm
RLY-5836 + fulvestrant combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Fulvestrant (Drug)
RLY-5836 + Palbociclib + Fulvestrant Arm
RLY-5836 + palbociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: RLY-5836 (Drug)
RLY-5836 + Palbociclib + Fulvestrant Arm
RLY-5836 + palbociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Fulvestrant (Drug)
RLY-5836 + Palbociclib + Fulvestrant Arm
RLY-5836 + palbociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Palbociclib (Drug)
RLY-5836 + Ribociclib + Fulvestrant Arm
RLY-5836 + ribociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: RLY-5836 (Drug)
RLY-5836 + Ribociclib + Fulvestrant Arm
RLY-5836 + ribociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Fulvestrant (Drug)
RLY-5836 + Ribociclib + Fulvestrant Arm
RLY-5836 + ribociclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Ribociclib (Drug)
RLY-5836 + Abemaciclib + Fulvestrant Arm
RLY-5836 + abemaciclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: RLY-5836 (Drug)
RLY-5836 + Abemaciclib + Fulvestrant Arm
RLY-5836 + abemaciclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Fulvestrant (Drug)
RLY-5836 + Abemaciclib + Fulvestrant Arm
RLY-5836 + abemaciclib + fulvestrant triple combination arm for participants with HR+, HER2- locally advanced or metastatic breast cancer
干预措施: Abemaciclib (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of RLY-5836
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 participants with any dose-limiting toxicity (DLT)
时间窗: Cycle 1, up to 28 days.
Number of participants with adverse events (AEs)
时间窗: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
Number of participants with serious adverse events (SAEs)
时间窗: Every cycle (4-week cycles) until study discontinuation, approximately 24 months
次要结局
- PK of RLY-5836: maximum plasma concentration (Cmax)(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months)
- PK of RLY-5836: half-life (t½)(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Changes in circulating markers of glucose metabolism: changes in circulating glucose(Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Changes in circulating markers of glucose metabolism: changes in circulating C-peptide(Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Preliminary antitumor activity of RLY-5836: duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)(Approximately every 8 weeks until progressive disease, approximately 36 months)
- Preliminary antitumor activity of RLY-5836: objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)(Approximately every 8 weeks until progressive disease, approximately 36 months)
- PIK3CA genotype in blood and tumor tissue by next generation nucleic acid sequencing(Every cycle (4-week cycles) through Cycle 3 and every other cycle thereafter until study discontinuation, approximately 24 months)
- PK of RLY-5836: area under the concentration-time curve (AUC)(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months)
- PK of RLY-5836: time to maximum concentration (tmax)(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months)
- PK of RLY-5836: clearance following oral dose (CL/F)(Approximately every 2 weeks in Cycle 1 (4-week cycle) and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Changes in circulating markers of glucose metabolism: changes in circulating insulin(Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Changes in circulating markers of glucose metabolism: changes in circulating glycosylated hemoglobin [HbA1c](Approximately every week in Cycle 1 (4-week cycle), every 2 weeks in Cycle 2 (4-week cycle), and every cycle through end of treatment (4-week cycles), approximately 24 months)
- Preliminary antitumor activity of RLY-5836: disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)(Approximately every 8 weeks until progressive disease, approximately 36 months)