First-in-Human Study of STX-478, a Mutant-Selective PI3Kα Inhibitor as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 880
- 试验地点
- 113
- 主要终点
- Number of participants who experience at least 1 Dose Limiting Toxicity (DLT)
研究概览
简要总结
Study STX-478-101 (LY4064809) is a multipart, open-label, phase 1/2 study evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of STX-478 (LY4064809) in participants with advanced solid tumors with P13Ka mutations.
Part 1 will evaluate STX-478 as monotherapy in participants with advanced solid tumors. Part 2 will evaluate STX-478 therapy as combination therapy with fulvestrant in participants with hormone receptor positive (HR+) breast cancer. Part 3 will evaluate STX-478 as combination therapy with endocrine therapy (aromatase inhibitors, fulvestrant, tamoxifen, or imlunestrant) and a CDK4/6 Inhibitor (either Ribociclib, Palbociclib or Abemaciclib) in participants with HR+ breast cancer.
Each study part will include a 28-day screening period, followed by treatment with STX-478 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
盲法说明
In Part 1, Part 2 B0, B2, and B3, and Part 3 C0, D0, E0, F and A8, participants are assigned to intervention. In Part 2 B1 and Part 3 C1, D1, and E1, participants are randomized to doses
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
- •Has an advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable (as specified by Cohort)
- •Has a new or recent tumor biopsy (collected at screening, if feasible) or will provide an adequate tissue sample prior to screening
- •Has a tumor that harbors a documented PI3Kα mutation (cohort specific criterion for cohort-specific mutation types)
- •Is ≥18 years of age at the time of signing the ICF
- •Has an ECOG performance status score of 0 or 1 at screening
- •Has adequate organ function as defined per protocol
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
- •Has an established diagnosis of uncontrolled diabetes mellitus (defined as HbA1c ≥8% and/or FBG ≥140 mg/dL [7.7 mmol/L] and/or requiring or required insulin).
- •Has had prior treatment with PI3K/AKT/mTOR inhibitor(s), except in certain circumstances
- •Has had treatment with any local or systemic antineoplastic therapy or investigational anticancer agent within 14 days or 4 half-lives, whichever is longer, prior to the initiation of study treatment up to a maximum washout period of 28 days. Endocrine therapy does not require a washout period if the patient is enrolling in a cohort with the same combination endocrine therapy.
- •Has toxicities from previous anticancer therapies that have not resolved to baseline levels or CTCAE grade ≤1, with the exception of alopecia and peripheral neuropathy.
- •Has had radiotherapy within 14 days before the initiation of study treatment
研究组 & 干预措施
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Palbociclib (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Letrozole (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Anastrozole (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Exemestane (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Tamoxifen (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Abemaciclib (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Imlunestrant (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: STX-478 (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Fulvestrant (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Ribociclib (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Palbociclib (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Letrozole (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Anastrozole (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Exemestane (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Abemaciclib (Drug)
Experimental: Drug to Drug Interaction (DDI) Metformin STX-478 +/- ET ([AIs or fulvestrant]
CDK4/6 inhibitor therapy in Cohort A8: all solid tumors Cohort B2 and Cohort F: HR+/HER2- or HR+/HER2 low breast cancer expressing PI3Kα mutations
干预措施: Metformin (Drug)
Dose Escalation (Advanced Solid Tumors)
- Cohort A0: Advanced Solid tumors expressing PI3Kα mutations
- Cohort A1: HR+ breast cancer expressing PI3Kα mutations
干预措施: STX-478 (Drug)
Dose Expansion
- Cohort A2: Gynecologic cancers
- Cohort A3: Head and Neck Squamous Cell Carcinoma
- Cohorts A4/A5: Other solid tumors not included in Cohorts A1, A2, A3 expressing PI3Kα mutations
- Cohort A6: Endometrial cancer
- Cohort A7: Non-gastrointestinal solid tumors
干预措施: STX-478 (Drug)
Dose Selection/Expansion: Combination STX-478 + fulvestrant
Cohort B: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Kα mutations
干预措施: STX-478 (Drug)
Dose Selection/Expansion: Combination STX-478 + fulvestrant
Cohort B: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Kα mutations
干预措施: Fulvestrant (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: STX-478 (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Fulvestrant (Drug)
Dose Selection/Expansion Combination
STX-478 + Endocrine therapy + CDK4/6 inhibitor Cohort C/D/E: HR+/HER2- or HR+/HER2low breast cancer expressing PI3Ka mutations
干预措施: Ribociclib (Drug)
结局指标
主要结局
Number of participants who experience at least 1 Dose Limiting Toxicity (DLT)
时间窗: First 28 days of treatment
Proportion of participants who experience at least 1 DLT during the first 28 days of treatment
时间窗: First 28 days of treatment
Cmax of STX-478
时间窗: 12 months
AUC(0-inf) of STX-478
时间窗: 12 months
AUC(0-t) of STX-478
时间窗: 12 months
AUC(0-τ) of STX-478
时间窗: 12 months
Change from baseline in ctDNA levels
时间窗: 12 months
Changes in circulating markers of glucose metabolism as assessed by changes in circulating glycosylated hemoglobin (HbA1c)
时间窗: 12 months
Changes in circulating markers of glucose metabolism as assessed by circulating fasting plasma glucose
时间窗: 12 months
Changes in circulating markers of glucose metabolism as assessed by circulating C-peptide
时间窗: 12 months
Objective response rate (ORR) defined as the percentage of participants with partial response or complete response based on RECIST 1.1
时间窗: 12 months
Incidence of TEAEs/SAEs ≥ grade 2
时间窗: 12 months
Frequency of TEAEs according to CTCAE v5.0 criteria
时间窗: 12 months
Change in ECOG performance status
时间窗: 12 months
次要结局
- Cmax of STX-478(12 months)
- AUC(0-inf) of STX-478(12 months)
- AUC(0-t) of STX-478(12 months)
- AUC(0-τ) of STX-478(12 months)
- Change from baseline in ctDNA levels(12 months)
- Changes in circulating markers of glucose metabolism as assessed by changes in circulating glycosylated hemoglobin (HbA1c)(12 months)
- Changes in circulating markers of glucose metabolism as assessed by circulating fasting plasma glucose(12 months)
- Changes in circulating markers of glucose metabolism as assessed by circulating C-peptide(12 months)
- Change in ECOG performance status(12 months)
- Disease Control Rate (DCR) per RECIST v1.1, measured as percentage of participants with Complete Response(12 months)