A Phase 2 Study of PRT3789 in Combination with Pembrolizumab in Patients with Advanced or Metastatic Solid Tumors with a SMARCA4 Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prelude Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 May 2025 → 23 Jan 2026

Decision date (initial)

2025-04-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516889-11-00

ClinicalTrials.gov

NCT06682806

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

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

Secondary objectives 3

1. To evaluate the efficacy of PRT3789 in combination with pembrolizumab
2. To evaluate the safety and tolerability of PRT3789 in combination with pembrolizumab
3. To evaluate the PK profile of PRT3789 in combination with pembrolizumab

Conditions and MedDRA coding

non-small cell lung cancer (NSCLC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patients age ≥ 18 at the time of informed consent
2. 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.
3. 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)
4. 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
5. 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.
6. 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
7. Eastern Cooperative Oncology Group performance status of 0 or 1.
8. Willingness and ability to provide tumor tissue (i.e., archived or fresh if archived tumor tissue is unavailable).
9. 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.
10. Adequate organ function (hematology, renal, hepatic, coagulation)

Exclusion criteria 11

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.
2. Other acute or chronic medical or psychiatric conditions that would make the patient inappropriate for entry into this study.
3. 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).
4. Uncontrolled or symptomatic (e.g., clinical symptoms, cerebral edema) central nervous system metastases or leptomeningeal disease and/or carcinomatous meningitis).
5. 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.
6. 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.
7. 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.
8. Pregnant or breastfeeding or plan to become pregnant during the study.
9. Severe hypersensitivity (≥ Grade 3) to pembrolizumab or contraindication to any excipients of study treatment (PRT3789 or pembrolizumab)
10. 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.
11. Currently participating in an interventional study of an investigational agent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Incidence of dose-limiting toxicities
2. Incidence and severity of adverse events according to the NCI CTCAE v5.0
3. 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
4. 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 endpoints 9

1. 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)
2. 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)
3. 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
4. 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
5. Overall survival defined as the time from the date of first dose of study treatment to death due to any cause
6. Incidence and severity of adverse events according to the NCI CTCAE v5.0
7. Changes in clinical laboratory parameters
8. Incidence of dose interruptions, dose modifications, and discontinuations due to adverse events
9. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prelude Therapeutics Inc.

Sponsor organisation

Prelude Therapeutics Inc.

Address

175 Innovation Boulevard

City

Wilmington

Postcode

19805

Country

United States

Scientific contact point

Organisation

Prelude Therapeutics Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Prelude Therapeutics Inc.

Contact name

General Contact

Third parties 10

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications