PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation

A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT3789 as Monotherapy and in Combination With Docetaxel in Participants With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation

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 monotherapy and in combination with docetaxel, 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.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor; Metastatic Solid Tumor; Non-small Cell Lung Cancers; SMARCA4 Gene Mutation
• Intervention / Treatment: Drug: PRT3789; Drug: Docetaxel

Detailed Description

This is an open-label, multi-center, dose-escalation, first in human, Phase 1 study of PRT3789 as monotherapy and in combination with docetaxel, a SMARCA2 degrader, evaluating participants with 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 118 participants will be enrolled in monotherapy, dose escalation, backfill, and combination cohorts.

• Study Type: Interventional
• Enrollment (Estimated): 118
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Study Contact (Please Do Not Disclose Personal Information); Phone Number: See Email; Email: clinicaltrials@preludetx.com

Study Locations

• France
  • Bordeaux, France, 33000
    • Recruiting
    • lnstitut Bergonie Centre Regionale de Lutte Contre le cancer, Service Oncologie-Medicale
  • Lyon Cedex 08, France, 69373
    • Recruiting
    • Centre LEON BERARD
  • Villejuif Cedex, France, 94805
    • Recruiting
    • Institut Gustave Roussy
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Recruiting
    • Leids Universitair Medisch Centrum
• Singapore
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital
  • Singapore, Singapore, 168583
    • Recruiting
    • National Cancer Centre Singapore
• Spain
  • Barcelona, Spain, 08023
    • Recruiting
    • START Barcelona - HM Nou Delfos
  • Madrid, Spain, 28050
    • Recruiting
    • Hospital Universitario HM Sanchinarro
  • Madrid, Spain, 28040
    • Recruiting
    • START MADRID - FJD Hospital Universitario Fundacion Jimenez Diaz
• United States
  • California
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California, Davis Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404
      • Recruiting
      • UCLA Hematology/Oncology - Santa Monica
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Smilow Cancer Hospital Phase 1 Unit
  • Florida
    • Celebration, Florida, United States, 34747
      • Recruiting
      • AdventHealth Medical Group Oncology Research at Celebration
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • Recruiting
      • Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
    • New York, New York, United States, 10032
      • Recruiting
      • New York Presbyterian Hospital - Columbia University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • The University of Texas Md Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Next Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (dose escalation and combination cohorts) and loss of function mutation of SMARCA4 (backfill cohorts) by local testing that have either progress on or ineligible for standard of care therapy
• Must have measurable or non-measureable (but evaluable) disease per RECIST v1.1 for dose escalation and combination cohorts
• Must have measureable diseases per RECIST v1.1 for backfill cohort
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PRT3789 Monotherapy; PRT3789 will be administered by intravenous infusion	Drug: PRT3789; PRT3789 will be administered by intravenous infusion
Experimental: PRT3789/Docetaxel Combination; PRT3789 and Docetaxel will be administered by intravenous infusions	Drug: PRT3789; PRT3789 will be administered by intravenous infusion; Drug: Docetaxel; Docetaxel will be administered by intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicity (DLT) of PRT3789 monotherapy and in combination with docetaxel	Dose limiting toxicities will be evaluated over the 21-day observation period	Baseline through Day 21
Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel	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 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: Maximum observed plasma concentration	Pharmacokinetics will be calculated including the maximum observed plasma concentration	Baseline through approximately 3 years
Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Area under the curve	Pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC)	Baseline through approximately 3 years
Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel: Target engagement	Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel demonstrating target engagement by assessment of SMARCA2 protein in peripheral blood mononuclear cells (PBMCs) and tumor tissue	Baseline through approximately 3 years

Collaborators and Investigators

• Sponsor: Prelude Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: November 11, 2022
• First Submitted That Met QC Criteria: November 28, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Docetaxel; NSCLC; Advanced Solid Tumors; BRG1; BRM; Metastatic Solid Tumors; Non-Small Cell Lung Cancers; PRT3789; SMARCA2 Degrader; SMARCA4
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel
• Other Study ID Numbers: PRT3789-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No