An Open-label, Multicenter Study of LY4050784, a Selective SMARCA2/BRM Inhibitor, in Advanced Solid Tumor Malignancies With SMARCA4/BRG1 Alterations
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 340
- 试验地点
- 55
- 主要终点
- Phase Ia: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs), Serious Adverse Event(s) (SAEs), and Adverse Event(s) (AEs)
研究概览
简要总结
The main purpose of this study is to find out whether the study drug, LY4050784, is safe, tolerable and effective in participants alone or in combination with other anticancer agents. In addition, with locally advanced or metastatic solid tumors with a BRG1 (Brahma-related gene 1, also known as SMARCA4) alteration who have previously received, do not qualify for, or are refusing standard of care treatments, or there is no standard therapy available for the disease. The study is conducted in two parts - phase Ia (dose-escalation) and phase Ib (dose-optimization, dose-expansion). The study will last up to approximately 4 years.
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
- •Have one of the following locally advanced or metastatic solid tumor malignancy with SMARCA4 (BRG1) alteration:
- •Phase 1a dose escalation: Presence of any alteration in SMARCA4 (BRG1)
- •Phase 1b expansion: Part A: Non-small Cell Lung Cancer (NSCLC) that is locally advanced and not suitable for definitive locoregional therapy, or metastatic with presence of a known or likely loss of function alteration in SMARCA4 (BRG1) or loss of protein expression.
- •Phase 1b expansion: Part B: Any tumor type (other than NSCLC) that has the presence of a known or likely loss of function alteration in SMARCA4 (BRG1) or loss of protein expression.
- •Phase 1b expansion: Part C: Non-small Cell Lung Cancer (NSCLC) that is locally advanced and not suitable for definitive locoregional therapy, or metastatic with presence of a known or likely loss of function alteration in SMARCA4 (BRG1) or loss of protein expression.
- •Prior Systemic Therapy Criteria:
- •Phase 1a dose escalation and Phase 1b (Part B): Participants who received all standard therapies for which the individual was deemed to be an appropriate candidate by the treating Investigator; or the individual is refusing the remaining most appropriate standard of care treatment; or there is no standard therapy available for the disease.
- •Phase 1b expansion (Part A): Participants must have received at least one line of therapy for advanced or metastatic disease.
- •Phase 1b expansion (Part C): Participants may be treatment naïve or have received therapy for advanced or metastatic disease
- •Measurability of disease
- •Phase 1a dose escalation (excluding backfill): measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
- •Phase 1a backfill and Phase 1b expansion: Measurable disease required as defined by RECIST v1.1
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
排除标准
- •Participants with known or likely loss of function alteration of SMARCA2 (BRM) or malignancy with known association with SMARCA2 (BRM) alterations
- •Prior exposure to SMARCA2 (BRM) inhibitor(s) and/or degrader(s) (prior exposure may be permitted for dose escalation)
- •Participants with known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement
- •Participants with history of increased risk of prolonged QT or significant arrythmia
- •Significant cardiovascular disease
- •Participants with active and/or treated for an additional primary malignancy within 2 years prior to enrolment
- •Participants who are pregnant, breastfeeding or plan to breastfeed or expecting to conceive or father children during study or within 6 months after the last dose of study intervention
- •Participants with history of active autoimmune diseases, history of allogenic stem cell/organ transplant or compromised immune system within past 2 years (Part C only)
研究组 & 干预措施
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2a
LY4050784 administered orally in combination in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1a - Dose Escalation)
Escalating doses of LY4050784 administered orally.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2b
LY4050784 administered orally in combination in combination with pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2a
LY4050784 administered orally in combination in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Pembrolizumab (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2b
LY4050784 administered orally in combination in combination with pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Nab paclitaxel (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2b
LY4050784 administered orally in combination in combination with pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Pembrolizumab (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2a
LY4050784 administered orally in combination in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Carboplatin (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2b
LY4050784 administered orally in combination in combination with pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Paclitaxel (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C1
LY4050784 administered orally in combination in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C1
LY4050784 administered orally in combination in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Pembrolizumab (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2a
LY4050784 administered orally in combination in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Cisplatin (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2b
LY4050784 administered orally in combination in combination with pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Carboplatin (Drug)
LY4050784 (Phase 1b - Dose Optimization/Part A)
Comparing 2 or more doses (evaluated during dose escalation) of LY4050784 administered orally.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part B)
LY4050784 administered orally.
干预措施: LY4050784 (Drug)
LY4050784 (Phase 1b - Dose Expansion/Part C) Cohort C2a
LY4050784 administered orally in combination in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
干预措施: Pemetrexed (Drug)
结局指标
主要结局
Phase Ia: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs), Serious Adverse Event(s) (SAEs), and Adverse Event(s) (AEs)
时间窗: Up to Approximately 48 Months or 4 Years
A summary of TEAEs, SAEs, and AEs regardless of causality, will be reported in the Reported Adverse Events module
Phase 1a: To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of LY4050784
时间窗: Up to Approximately 48 Months or 4 Years
Number of participants with dose-limiting toxicities (DLTs)
Phase 1b: To assess the antitumor activity of LY4050784 Monotherapy: Overall response rate (ORR)
时间窗: Up to Approximately 48 Months or 4 Years
ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)
Phase 1b (Dose optimization only): To confirm the RP2D/optimal dose based on safety and efficacy of LY4050784
时间窗: Up to Approximately 48 Months or 4 Years
A summary of TEAEs, SAEs, and AEs regardless of causality, will be reported in the Reported Adverse Events module, ORR and Duration of Response (DOR) per Investigator
Phase 1b (Combination cohorts/Part C): To assess the safety and tolerability of LY4050784 when administered in combination with other anticancer agents
时间窗: Up to Approximately 48 Months or 4 Years
A summary of TEAEs, SAEs, and AEs regardless of causality, will be reported in the Reported Adverse Events module
次要结局
- To evaluate the PK properties of LY4050784 in combination cohorts: Area under the concentration versus time curve (AUC)(Cycle 1 (Day 8))
- To evaluate the PK properties of LY4050784 in combination cohorts: Maximum Concentration (Cmax) PK: Cmax of LY4050784(Cycle 1 (Day 8))
- To evaluate the PK properties of LY4050784 in combination cohorts: Time to Maximum Concentration (Tmax) PK: Tmax of LY4050784(Cycle 1 (Day 8))
- To evaluate the preliminary antitumor activity of LY4050784: Time to response (TTR)(Up to Approximately 48 Months or 4 Years)
- To evaluate the preliminary antitumor activity of LY4050784: Disease control rate (DCR)(Up to Approximately 48 Months or 4 Years)
- To evaluate the preliminary antitumor activity of LY4050784: Progression free survival (PFS)(Up to Approximately 48 Months or 4 Years)
- To characterize the pharmacokinetics (PK) properties of LY4050784: Maximum Concentration (Cmax)(Cycle 1 (Day 8))
- To characterize the PK properties of LY4050784: Time to Maximum Concentration (Tmax)(Cycle 1 (Day 8))
- To characterize the PK properties of LY4050784: Area under the concentration versus time curve (AUC)(Cycle 1 (Day 8))
- Phase Ia: To evaluate the preliminary antitumor activity of LY4050784: Overall response rate (ORR)(Up to Approximately 48 Months or 4 Years)
- To evaluate the preliminary antitumor activity of LY4050784: Duration of response (DOR)(Up to Approximately 48 Months or 4 Years)