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

Sponsor

Prelude Therapeutics (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05639751

Collaborator

(none)

Enrollment

Arm

37.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor Metastatic Solid Tumor Non-small Cell Lung Cancers SMARCA4 Gene Mutation	Drug: PRT3789	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

86 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Mar 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PRT3789 PRT3789 will be administered by intravenous infusion	Drug: PRT3789 PRT3789 will be administered by intravenous infusion

Arm

Intervention/Treatment

Experimental: PRT3789

PRT3789 will be administered by intravenous infusion

Drug: PRT3789

PRT3789 will be administered by intravenous infusion

Outcome Measures

Primary Outcome Measures

Dose limiting toxicity (DLT) of PRT3789 [Baseline through Day 21]
Dose limiting toxicities will be evaluated over the 21-day observation period
Safety and tolerability of PRT3789: AEs, CTCAE Assessments [Baseline through approximately 3 years]
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)
Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 [Baseline through approximately 3 years]
The MTD/RP2D will be established for further investigation in participants with advanced solid tumors

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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