Clinical trial NCT05639751: PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Metastatic Solid Tumor
Non-small Cell Lung Cancers
SMARCA4 Gene Mutation
Keywords: Advanced Solid Tumors
BRG1
BRM
Metastatic Solid Tumors
Non-Small Cell Lung Cancers
NSCLC
PRT3789
SMARCA2 Degrader
SMARCA4
Docetaxel
Lead sponsor: Prelude Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-12-06
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose limiting toxicity (DLT) of PRT3789 monotherapy and in combination with docetaxel
timeFrame: Baseline through Day 21
measure: Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: AEs, CTCAE Assessments
timeFrame: Baseline through approximately 3 years
measure: Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 monotherapy and in combination with docetaxel
timeFrame: Baseline through approximately 3 years
Secondary outcomes:
measure: Efficacy of PRT3789 monotherapy and in combination with docetaxel: Objective response rate (ORR)
timeFrame: Baseline through approximately 3 years
measure: Efficacy of PRT3789 monotherapy and in combination with docetaxel: Progression-free survival (PFS)
timeFrame: Baseline through approximately 3 years
measure: Efficacy of PRT3789 monotherapy and in combination with docetaxel: Clinical benefit rate (CBR)
timeFrame: Baseline through approximately 3 years
measure: Efficacy of PRT3789 monotherapy and in combination with docetaxel: Duration of response (DOR)
timeFrame: Baseline through approximately 3 years
measure: Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Maximum observed plasma concentration
timeFrame: Baseline through approximately 3 years
measure: Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Area under the curve
timeFrame: Baseline through approximately 3 years
measure: Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel: Target engagement
timeFrame: Baseline through approximately 3 years
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology - Santa Monica
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital Phase 1 Unit
state: Connecticut
city: Celebration
country: United States
facility: AdventHealth Medical Group Oncology Research at Celebration
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Siteman Cancer Center
state: Missouri
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital - Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Cancer Institute Franz Clinic
state: Oregon
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Bordeaux
country: France
facility: lnstitut Bergonie Centre Regionale de Lutte Contre le cancer, Service Oncologie-Medicale
city: Lyon Cedex 08
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: lnstitut Paoli Calmettes
city: Toulouse
country: France
facility: Oncopole Claudius Regaud IUCT ONCOPOLE
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: START Barcelona - HM Nou Delfos
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: START MADRID - FJD Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
Study officials:
References: