PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation
- Conditions
- Advanced Solid TumorMetastatic Solid TumorNon-small Cell Lung CancersSMARCA4 Gene Mutation
- Interventions
- Registration Number
- NCT05639751
- Lead Sponsor
- Prelude Therapeutics
- 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 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.
- 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 186 participants will be enrolled in monotherapy, dose escalation, backfill, and combination cohorts.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 226
- 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)
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PRT3789 Monotherapy PRT3789 PRT3789 will be administered by intravenous infusion PRT3789/Docetaxel Combination PRT3789 PRT3789 and Docetaxel will be administered by intravenous infusions PRT3789/Docetaxel Combination Docetaxel PRT3789 and Docetaxel will be administered by intravenous infusions
- Primary Outcome Measures
Name Time Method Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: 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)
Dose limiting toxicity (DLT) of PRT3789 monotherapy and in combination with docetaxel Baseline through Day 21 Dose limiting toxicities will be evaluated over the 21-day observation period
Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 monotherapy and in combination with docetaxel Baseline through approximately 3 years The MTD/RP2D will be established for further investigation in participants with advanced solid tumors
- Secondary Outcome Measures
Name Time Method Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel: Target engagement Baseline through approximately 3 years 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
Efficacy of PRT3789 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: 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
Efficacy of PRT3789 monotherapy and in combination with docetaxel: 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 monotherapy and in combination with docetaxel: 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
Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Maximum observed plasma concentration Baseline through approximately 3 years Pharmacokinetics will be calculated including the maximum observed plasma concentration
Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Area under the curve Baseline through approximately 3 years Pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC)
Trial Locations
- Locations (32)
University of California, Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
UCLA Hematology/Oncology - Santa Monica
🇺🇸Santa Monica, California, United States
Smilow Cancer Hospital Phase 1 Unit
🇺🇸New Haven, Connecticut, United States
AdventHealth Medical Group Oncology Research at Celebration
🇺🇸Celebration, Florida, United States
Mayo Clinic, Jacksonville
🇺🇸Jacksonville, Florida, United States
Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Mayo Clinic, Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine - Siteman Cancer Center
🇺🇸Saint Louis, Missouri, United States
Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
🇺🇸New York, New York, United States
New York Presbyterian Hospital - Columbia University Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Providence Cancer Institute Franz Clinic
🇺🇸Portland, Oregon, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
NEXT Virginia
🇺🇸Fairfax, Virginia, United States
lnstitut Bergonie Centre Regionale de Lutte Contre le cancer, Service Oncologie-Medicale
🇫🇷Bordeaux, France
Centre Leon Berard
🇫🇷Lyon Cedex 08, France
lnstitut Paoli Calmettes
🇫🇷Marseille, France
Oncopole Claudius Regaud IUCT ONCOPOLE
🇫🇷Toulouse, France
Institut Gustave Roussy
🇫🇷Villejuif Cedex, France
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
National University Hospital
🇸🇬Singapore, Singapore
National Cancer Centre Singapore
🇸🇬Singapore, Singapore
START Barcelona - HM Nou Delfos
🇪🇸Barcelona, Spain
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
START MADRID - FJD Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, Spain