A Study of PRT3789 in Participants With Select Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation

Study Overview
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Brief Summary
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This is a Phase 1 dose-escalation study of PRT3789, a SMARCA2 degrader, in participants with advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of PRT3789, describe any dose limiting toxicities (DLTs), define the dosing schedule, and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) to be used in subsequent development of PRT3789.

Detailed Description
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This is an open-label, multi-center, dose-escalation, first in human, Phase 1 study of PRT3789, a SMARCA2 degrader, evaluating participants with selected advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The study will evaluate escalating doses of PRT3789 until the MTD or RP2D is determined. Taking into account pharmacokinetic and pharmacodynamic data from the preceding dose levels, the dose may be escalated until a dose limiting toxicity is identified. Approximately 86 participants will be enrolled in dose escalation and backfill cohorts.

Official Title
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A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT3789 in Participants With Select Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation

Conditions
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Advanced Solid Tumor, Metastatic Solid Tumor, Non-small Cell Lung Cancers, SMARCA4 Gene Mutation

Intervention / Treatment
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* Drug: PRT3789


Participation Criteria
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Eligibility Criteria
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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 loss of SMARCA4 due to truncating mutation and/or deletion by local testing that have either progress on or ineligible for standard of care therapy Must have measurable or non-measureable (but evaluable) disease 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 another malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive 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 Concurrent treatment with strong or moderate CYP3A4 inhibitor or inducer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT3789<br>PRT3789 will be administered by intravenous infusion | Drug: PRT3789<br>* PRT3789 will be administered by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) of PRT3789 | Dose limiting toxicities will be evaluated over the 21-day observation period | Baseline through Day 21 | 
| Safety and tolerability of PRT3789: AEs, CTCAE Assessments | Safety and tolerability will be evaluated by incidence of DLTs, laboratory measurements, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) | Baseline through approximately 3 years | 
| Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 | The MTD/RP2D will be established for further investigation in participants with advanced solid tumors | Baseline through approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of PRT3789: Objective response rate (ORR) | Best overall response of either complete response (CR) or partial response (PR), as assessed by the investigator per RECIST v1.1 | Baseline through approximately 3 years | 
| Efficacy of PRT3789: Progression-free survival (PFS) | Duration from Day 1 to the earliest date of first disease progression, as assessed by the investigator per RECIST v1.1, discontinuation because of disease progression, or death due to any cause | Baseline through approximately 3 years | 
| Efficacy of PRT3789: Clinical benefit rate (CBR) | Best overall response of CR, PR, or durable stable disease (24 weeks or longer duration), as assessed by the investigator per RECIST v1.1 | Baseline through approximately 3 years | 
| Efficacy of PRT3789: Duration of response (DOR) | Duration from time of first observed response (CR or PR) to the earliest date of disease progression, as assessed by the investigator per RECIST v1.1, or death due to any cause | Baseline through approximately 3 years | 
| Pharmacokinetic profile of PRT3789: Maximum observed plasma concentration | PRT3789 pharmacokinetics will be calculated including the maximum observed plasma concentration | Baseline through approximately 3 years | 
| Pharmacokinetic profile of PRT3789: Area under the curve | PRT3789 pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC) | Baseline through approximately 3 years | 
| Pharmacodynamic effect of PRT3789: Target engagement | Pharmacodynamic effect of PRT3789 demonstrating target engagement by assessment of SMARCA2 protein in peripheral blood mononuclear cells (PBMCs) | Baseline through approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid Tumors, BRG1, BRM, Metastatic Solid Tumors, Non-Small Cell Lung Cancers, NSCLC, PRT3789, SMARCA2 Degrader, SMARCA4