A Phase 2 Study of PRT3789 in Combination with Pembrolizumab in Patients with Advanced or Metastatic Solid Tumors with a SMARCA4 Mutation
- Conditions
- Esophageal CancerAdvanced or Metastatic Solid Tumors with a SMARCA4 Mutationnon-small cell lung cancer (NSCLC)
- Interventions
- Registration Number
- 2024-516889-11-00
- Lead Sponsor
- Prelude Therapeutics Inc.
- Brief Summary
To evaluate the safety and tolerability of PRT3789 in combination with pembrolizumab in patients with advanced or metastatic solid tumors and to evaluate the efficacy of PRT3789 in combination with pembrolizumab in patients with advanced or metastatic esophageal or NSCLC and deleterious SMARCA4 mutation
- Detailed Description
This is an open-label, multi-center Phase 2 study of PRT 3789, a first-in-class SMARCA2 targeted protein degrader, in combination with pembrolizumab, a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, evaluating patients with Advanced or Metastatic Solid Tumors with a SMARCA4 Mutation. This study consists of 2 parts. Part 1 is a safety run-in and will establish the dose of PRT3789 to be used in combination with pembrolizumab in the main study (Part 2). For Part 2 (Main study) primary endpoints are ORR (defined as the proportion of patients with a confirmed best overall response of either complete response or partial response) and duration of response per investigator assessment per RECIST v1.1.
Approximately 46 to 60 patients will be enrolled in Part 1 and Part 2 based on the dose of PRT3789 selected/cleared during the safety run-in.
Recruitment & Eligibility
- Status
- Authorised, recruiting
- Sex
- Not specified
- Target Recruitment
- 20
Patients age ≥ 18 at the time of informed consent
Adequate organ function (hematology, renal, hepatic, coagulation)
Patients who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures, including providing informed consent.
Part 1 Safety Run-In: Patients with advanced, recurrent, or metastatic histologically or cytologically confirmed solid tumor malignancy and any mutation of SMARCA4 detected by next-generation sequencing in tumor tissue or blood, or absence of SMARCA4 protein (BRG1)
Part 2 Main Study: Patients with advanced, recurrent, or metastatic histologically confirmed esophageal cancer or NSCLC and have a deleterious (loss of function) SMARCA4 mutation
Patients must have at least one of the following: a. Primary resistance to prior anti-PD-1/PD-L1, defined by disease that did not respond at all and instead progressed on anti-PD-L1 therapy (e.g., best response of progressive disease per RECIST 1.1). b. Acquired resistance to prior anti-PD-1/PD-L1, defined as: (i) patients who received anti-PD-1/PD-L1 therapy, (ii) had a partial or complete response, and (iii) progressed within 6 months of prior anti-PD-1/PD-L1 therapy. c. Received prior standard of care therapy but did not receive prior anti-PD-1/PD-L1 therapy because tumor PD-L1 expression was negative. d. Prior anti-PD-1/PD-L1 therapy discontinued for reasons other than disease progression, and subsequent progression > 6 months from prior anti-PD-1/PD-L1.
Part 1 Safety Run-In: Measurable or non-measurable (but evaluable) disease per RECIST v1.1 as assessed by the local site investigator/radiologist. Part 2 Main Study: Measurable disease per RECIST v1.1 as assessed by the local site investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions
Eastern Cooperative Oncology Group performance status of 0 or 1.
Willingness and ability to provide tumor tissue (i.e., archived or fresh if archived tumor tissue is unavailable).
Adequately controlled blood pressure with or without antihypertensive medications, defined as blood pressure < 160/100 mmHg at screening and no change in antihypertensive medications within 1 week before Cyle 1 Day 1.
Patients who have adverse events due to previous anticancer therapies and/or complications from prior surgical intervention must have recovered to ≤ Grade 1 or baseline before starting study treatment. Patients with endocrine-related AEs who are adequately treated with hormone replacement or patients who have ≤ Grade 2 neuropathy are eligible. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (e.g., neuropathy, myalgia, alopecia and prior therapy-related endocrinopathies) are exceptions.
Receipt of any of the following within the specified time intervals before first dose of study treatment, unless otherwise specified or with approval by the Sponsor medical monitor: o Live or live-attenuated vaccine within 30 days o Chemotherapy or chemoimmunotherapy within 21 days or 5 half-lives, whichever is shorter. o Radiotherapy within 14 days. o Radiation therapy to the lung that is > 30 Gy within 6 months o Major surgery within 14 days.
Currently participating in an interventional study of an investigational agent.
Other acute or chronic medical or psychiatric conditions that would make the patient inappropriate for entry into this study.
Patients with solid tumors with a known concomitant SMARCA2 mutation or loss of protein expression (e.g., small-cell carcinoma of the ovary hypercalcemic type or thoracic sarcomatoid tumors).
Uncontrolled or symptomatic (e.g., clinical symptoms, cerebral edema) central nervous system metastases or leptomeningeal disease and/or carcinomatous meningitis).
Currently taking a strong or moderate Cytochrome P450 (CYP)3A4 inhibitor or inducer and St. John’s Wort and are unable to discontinue use within 15 days of the first dose of study treatment.
Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, who have undergone potentially curative therapy are not excluded.
Patients with clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, patients with an active infection requiring hospitalization or systemic therapy, HIV patients with Kaposi Sarcoma or Multicentric Castleman Disease, known history of hepatitis B or active hepatitis C.
Pregnant or breastfeeding or plan to become pregnant during the study.
Severe hypersensitivity (≥ Grade 3) to pembrolizumab or contraindication to any excipients of study treatment (PRT3789 or pembrolizumab)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PRT3789/Pembrolizumab combination pembrolizumab PRT3789 is administered as an intravenous infusion once weekly for 3 weeks; Pembrolizumab is administered at 200 mg as an intravenous infusion over 30 min every 3 weeks PRT3789/Pembrolizumab combination PRT3789 PRT3789 is administered as an intravenous infusion once weekly for 3 weeks; Pembrolizumab is administered at 200 mg as an intravenous infusion over 30 min every 3 weeks
- Primary Outcome Measures
Name Time Method Incidence of dose-limiting toxicities Incidence of dose-limiting toxicities
Incidence and severity of adverse events according to the NCI CTCAE v5.0 Incidence and severity of adverse events according to the NCI CTCAE v5.0
Objective response rate defined as the proportion of patients with a confirmed best overall response of either complete response or partial response, as determined per investigator assessment by RECIST v1.1 Objective response rate defined as the proportion of patients with a confirmed best overall response of either complete response or partial response, as determined per investigator assessment by RECIST v1.1
Duration of response defined as the time from the date of the first documented response (complete response or partial response) to the earliest date of disease progression, as determined per investigator assessment by RECIST v1.1, or death due to any cause Duration of response defined as the time from the date of the first documented response (complete response or partial response) to the earliest date of disease progression, as determined per investigator assessment by RECIST v1.1, or death due to any cause
- Secondary Outcome Measures
Name Time Method Objective response rate defined as the proportion of patients with a best overall response of either complete response or partial response, as determined per investigator assessment by RECIST v1.1 (Part 1 only) Objective response rate defined as the proportion of patients with a best overall response of either complete response or partial response, as determined per investigator assessment by RECIST v1.1 (Part 1 only)
Duration of response defined as the time from the date of the first documented response (complete response or partial response) to the earliest date of disease progression, as determined per investigator assessment by RECIST v1.1, or death due to any cause (Part 1 only) Duration of response defined as the time from the date of the first documented response (complete response or partial response) to the earliest date of disease progression, as determined per investigator assessment by RECIST v1.1, or death due to any cause (Part 1 only)
Clinical benefit response defined as the proportion of patients with a best overall response of complete response, partial response, or durable stable disease (24 weeks or longer), as determined per investigator assessment by RECIST v1.1 Clinical benefit response defined as the proportion of patients with a best overall response of complete response, partial response, or durable stable disease (24 weeks or longer), as determined per investigator assessment by RECIST v1.1
PFS defined as the time from the date of first dose of study treatment to the date of first documented progressive disease, as determined per investigator assessment by RECIST v1.1, or death due to any cause PFS defined as the time from the date of first dose of study treatment to the date of first documented progressive disease, as determined per investigator assessment by RECIST v1.1, or death due to any cause
Overall survival defined as the time from the date of first dose of study treatment to death due to any cause Overall survival defined as the time from the date of first dose of study treatment to death due to any cause
Incidence and severity of adverse events according to the NCI CTCAE v5.0 Incidence and severity of adverse events according to the NCI CTCAE v5.0
Changes in clinical laboratory parameters Changes in clinical laboratory parameters
Incidence of dose interruptions, dose modifications, and discontinuations due to adverse events Incidence of dose interruptions, dose modifications, and discontinuations due to adverse events
The pharmacokinetics of PRT3789 in combination with pembrolizumab including the maximum observed plasma concentration, time of maximum concentration, AUC, steady state trough concentrations, clearance, accumulation, and half-life The pharmacokinetics of PRT3789 in combination with pembrolizumab including the maximum observed plasma concentration, time of maximum concentration, AUC, steady state trough concentrations, clearance, accumulation, and half-life
Trial Locations
- Locations (5)
Goethe University Frankfurt
🇩🇪Frankfurt Am Main, Germany
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hospital Quironsalud Barcelona
🇪🇸Barcelona, Spain
Hospital Hm Nou Delfos
🇪🇸Barcelona, Spain
Institut Gustave Roussy
🇫🇷Villejuif, France
Goethe University Frankfurt🇩🇪Frankfurt Am Main, GermanyFabian AckerSite contact496963016217acker@med.uni-frankfurt.de