Advanced Solid Tumor, Esophageal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Gastric Adenocarcinoma, Gastric Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma, Gastroesophageal Junction Squamous Cell Carcinoma, Metastatic Solid Tumor, Non-small Cell Lung Carcinoma, SMARCA4 Mutation
Conditions
Keywords
Advanced Solid Tumors, BRG1, BRM, Degrader, Metastatic Solid Tumors, Non-Small Cell Lung Cancers, NSCLC, PRT7732, SMARCA2, SMARCA4, Esophageal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Gastric Adenocarcinoma, Gastric Squamous Cell Carcinoma, Gastroesophageal Junction Adenocarcinoma, Gastroesophageal Junction Squamous Cell Carcinoma
Brief summary
This is a Phase 1 study to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PRT7732 in patients with select advanced or metastatic solid tumors with a SMARCA4 mutation.
Detailed description
This is an open-label, multi-center, first-in-human, Phase 1 study to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PRT7732 an oral SMARCA degrader in patients with select advanced or metastatic solid tumors with a SMARCA4 mutation. Approximately 104 participants will be enrolled.
Interventions
DRUGPRT7732
PRT7732 capsules will be self-administered once daily at the dose-level assigned
Sponsors
Prelude Therapeutics
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures * Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy with any mutation of SMARCA4 by local testing that has either progressed on or is ineligible for standard of care therapy * Must have measurable or non-measurable (but evaluable) disease per RECIST v1.1 * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Willing to provide either archival or fresh tumor tissue sample * Adequate organ function (hematology, renal, and hepatic)
Exclusion criteria
* Participants with solid tumors with known concomitant SMARCA2 mutation or loss of protein expression * Clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, uncontrolled or symptomatic central nervous system (CNS) metastases or leptomeningeal disease * History of other malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, prostate adenocarcinoma with Gleason score of 3+3 or less, carcinoma in situ of the cervix, or other non-invasive or indolent malignancies, or malignancies previously treated with curative intent and not on active therapy or expected to require treatment or recurrence during the study * Receipt of any targeted therapy directed against BRM/BRG1 (SMARCA2/SMARCA4).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting toxicity (DLT) of PRT7732 | Baseline through Day 21 | Incidence of dose limiting toxicities for patients in the dose escalation phase |
| Safety and tolerability of PRT7732 as measured by incidence of DLTs | Baseline through completion of study, an average of 2 years | Safety and tolerability will be evaluated by incidence of DLTs |
| Safety and tolerability of PRT7732 as measured by incidence of laboratory deviations | Baseline through study completion, an average of 2 years | Safety and tolerability will be evaluated by laboratory measurements |
| Safety and tolerability as measured by rates of dose modification due to AEs according to NCI CTCAE | Baseline through study completion, an average of 2 years | Safety and tolerability will be evaluated by dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) |
| Maximum tolerated dose (MTD) of PRT7732 | Baseline through study completion, an average of 2 years | Maximum tolerated dose will be determined by the sponsor based on the Safety Review Committee's recommendation considering the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data |
| Recommended dose for expansion (RDE) of PRT7732 | Baseline through study completion, an average of 2 years | The RDE will be determined by the sponsor based on the Safety Review Committee's recommendation considering the totality of the available clinical safety, clinical efficacy, pharmacokinetics (PK), and pharmacodynamic data |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of PRT7732 | Baseline through study completion, an average of 2 years | Best overall response of either complete response (CR) or partial response (PR), as assessed by the investigator per RECIST v1.1 |
| Pharmacokinetic profile of PRT7732 as a single agent: Maximum observed plasma concentration | Baseline through study completion, an average of 2 years | Pharmacokinetics will be calculated including the maximum observed plasma concentration |
| Pharmacokinetic profile of PRT7732 as a single agent: Area under the curve | Baseline through study completion, an average of 2 years | Pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC) |
| Pharmacokinetic profile of PRT7732 as a single agent: Time of maximum concentration (Tmax) and half-life (T1/2) | Baseline through study completion, an average of 2 years | Pharmacokinetic parameters will be calculated using standard non-compartmental techniques |
| Pharmacodynamic effects of PRT7732 as a single agent | Baseline through study completion, an average of 2 years | The pharmacodynamic effect of PRT7732 demonstrating target engagement by assessment of SMARCA2 protein in peripheral blood mononuclear cells and tumor tissue as assessed by reduction in protein levels of SMARCA2 in peripheral blood mononuclear cells and/or tumor tissue |
Countries
Australia, Germany, Japan, South Korea, Spain, United States
Outcome results
None listed