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.
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.
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
Parallel
LY4050784
DrugOral
Pembrolizumab
DrugAdministered IV.
Cisplatin
DrugAdministered IV.
Carboplatin
DrugAdministered IV.
Pemetrexed
DrugAdministered IV.
Paclitaxel
DrugAdministered IV.
Nab paclitaxel
DrugAdministered IV.
6
Treatment groupsSee each treatment group below.
Phase Ia: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs), Serious Adverse Event(s) (SAEs), and Adverse Event(s) (AEs)
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
Number of participants with dose-limiting toxicities (DLTs)
Phase 1b: To assess the antitumor activity of LY4050784 Monotherapy: Overall response rate (ORR)
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
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
To characterize the pharmacokinetics (PK) properties of LY4050784: Maximum Concentration (Cmax)
PK: Cmax of LY4050784
To characterize the PK properties of LY4050784: Time to Maximum Concentration (Tmax)
PK: Tmax of LY4050784
To characterize the PK properties of LY4050784: Area under the concentration versus time curve (AUC)
PK: AUC of LY4050784
Phase Ia: To evaluate the preliminary antitumor activity of LY4050784: Overall response rate (ORR)
ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)
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