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

Prior treatment

• 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.
• 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).
• 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.

Other illness

• Other acute or chronic medical or psychiatric conditions that would make the patient inappropriate for entry into this study.
• Uncontrolled or symptomatic (e.g., clinical symptoms, cerebral edema) central nervous system metastases or leptomeningeal disease and/or carcinomatous meningitis).
• 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.
• Severe hypersensitivity (≥ Grade 3) to pembrolizumab or contraindication to any excipients of study treatment (PRT3789 or pembrolizumab)

Other

• Pregnant or breastfeeding or plan to become pregnant during the study.

• 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.