A Study of LY4050784 in Participants With Advanced or Metastatic Solid Tumors

Official title

An Open-label, Multicenter Study of LY4050784, a Selective SMARCA2/BRM Inhibitor, in Advanced Solid Tumor Malignancies With SMARCA4/BRG1 Alterations

Overview

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.

Interventions

• Drug LY4050784
  Oral
• Drug Pembrolizumab
  Administered IV.
• Drug Cisplatin
  Administered IV.
• Drug Carboplatin
  Administered IV.
• Drug Pemetrexed
  Administered IV.
• Drug Paclitaxel
  Administered IV.
• Drug Nab paclitaxel
  Administered IV.

Primary outcome measures

• Phase Ia: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs), Serious Adverse Event(s) (SAEs), and Adverse Event(s) (AEs) [Time frame: Up to Approximately 48 Months or 4 Years]
• Phase 1a: To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of LY4050784 [Time frame: Up to Approximately 48 Months or 4 Years]
• Phase 1b: To assess the antitumor activity of LY4050784 Monotherapy: Overall response rate (ORR) [Time frame: Up to Approximately 48 Months or 4 Years]
• Phase 1b (Dose optimization only): To confirm the RP2D/optimal dose based on safety and efficacy of LY4050784 [Time frame: Up to Approximately 48 Months or 4 Years]
• Phase 1b (Combination cohorts/Part C): To assess the safety and tolerability of LY4050784 when administered in combination with other anticancer agents [Time frame: Up to Approximately 48 Months or 4 Years]

Secondary outcome measures (11)

• To characterize the pharmacokinetics (PK) properties of LY4050784: Maximum Concentration (Cmax) [Time frame: Cycle 1 (Day 8)]
• To characterize the PK properties of LY4050784: Time to Maximum Concentration (Tmax) [Time frame: Cycle 1 (Day 8)]
• To characterize the PK properties of LY4050784: Area under the concentration versus time curve (AUC) [Time frame: Cycle 1 (Day 8)]
• Phase Ia: To evaluate the preliminary antitumor activity of LY4050784: Overall response rate (ORR) [Time frame: Up to Approximately 48 Months or 4 Years]
• To evaluate the preliminary antitumor activity of LY4050784: Duration of response (DOR) [Time frame: Up to Approximately 48 Months or 4 Years]
• To evaluate the preliminary antitumor activity of LY4050784: Time to response (TTR) [Time frame: Up to Approximately 48 Months or 4 Years]
• To evaluate the preliminary antitumor activity of LY4050784: Disease control rate (DCR) [Time frame: Up to Approximately 48 Months or 4 Years]
• To evaluate the preliminary antitumor activity of LY4050784: Progression free survival (PFS) [Time frame: Up to Approximately 48 Months or 4 Years]
• To evaluate the PK properties of LY4050784 in combination cohorts: Maximum Concentration (Cmax) PK: Cmax of LY4050784 [Time frame: Cycle 1 (Day 8)]
• To evaluate the PK properties of LY4050784 in combination cohorts: Time to Maximum Concentration (Tmax) PK: Tmax of LY4050784 [Time frame: Cycle 1 (Day 8)]
• To evaluate the PK properties of LY4050784 in combination cohorts: Area under the concentration versus time curve (AUC) [Time frame: Cycle 1 (Day 8)]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 17 centers

• UCLA — Santa Monica
• University of Colorado Health Hospital — Aurora
• Sarah Cannon Research Institute at HealthOne — Denver
• Florida Cancer Specialists ORLANDO/DDU — Lake Mary
• University of Miami — Miami
• University of Chicago — New Lenox
• Massachusetts General Hospital — Boston
• Dana-Farber Cancer Institute — Boston
• … and 9 more centers

Japan · 5 centers

• National Cancer Center Hospital — Chūōku
• National Cancer Center Hospital East — Kashiwa
• The Cancer Institute Hospital of JFCR — Kōtō City
• Shizuoka Cancer Center — Nagaizumi-cho,Sunto-gun
• Aichi Cancer Center Hospital — Nagoya

France · 3 centers

• Institut Bergonie — Bordeaux
• Institut Curie — Paris
• Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP — Villejuif

Germany · 3 centers

• Charite-Universitatsmedizin Berlin — Berlin
• Universitaetsklinikum Essen — Essen
• Krankenhaus Nordwest — Frankfurt am Main

South Korea · 3 centers

• National Cancer Center — Ilsandong-gu
• Severance Hospital, Yonsei University Health System — Seoul
• The Catholic University of Korea, St. Vincent's Hospital — Suwon

Spain · 2 centers

• Hospital Universitari Vall d'Hebron — Barcelona
• South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jimenez — Madrid

Identifiers

NCT: NCT06561685 · 27191 · J5M-OX-JOXA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗