Phase 1/2 Study of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumor Malignancies

Study Overview
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Brief Summary
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A phase 1/2, open-label, study to determine the safety and preliminary efficacy of APR-246 in combination with pembrolizumab in subjects with solid tumor malignancies. The study will include a safety lead-in portion followed by a phase 2 expansion portion in specific disease groups.

Detailed Description
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This is a phase 1/2, open-label, study to determine the safety and preliminary efficacy of APR-246 (eprenetapopt) in combination with pembrolizumab in subjects with solid tumor malignancies. In the safety lead-in part of study (phase 1), the safety and the recommended phase 2 dose (RP2D) of APR-246 will be investigated. In the expansion part of the study (phase 2), both safety and efficacy for the combination therapy will be investigated in the 3 cohorts.

Official Title
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Study of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumor Malignancies

Conditions
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Advanced Solid Tumor, Bladder Cancer, Gastric Cancer, Non Small Cell Lung Cancer, NSCLC, Urothelial Carcinoma

Intervention / Treatment
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* Drug: APR-246 (eprenetapopt) + Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form (ICF) and ability to comply with protocol requirements. Known tumor TP53 mutation status from recent or archival sample. Histologically and/or cytologically confirmed solid tumor malignancy Safety lead in- Advanced non-central nervous system (CNS) primary tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment, and for whom pembrolizumab, or pembrolizumab-based therapy is considered appropriate Expansion 1- Patients with a confirmed diagnosis of advanced gastric or gastroesophageal junction (GEJ) tumors that have progressed after first line treatment, who are intolerant to first line treatment, or who are unable to receive first line treatment Expansion 2- Patients with a confirmed diagnosis of advanced bladder/urothelial tumors that have progressed after first line treatment, or who are intolerant to first line treatment, or who are unable to receive first line treatment with cisplatin-based chemotherapy. Expansion 3- Confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy. Adequate organ function Creatinine clearance > 30 mL/min Total serum bilirubin < 1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome, tumor involvement, hemolysis or considered an effect of regular blood transfusions Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN, unless due to involvement by the underlying malignancy. Projected life expectancy of ≥ 12 weeks. Age ≥ 18 years at the time of signing the ICF. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 In the expansion portion, measurable disease meeting the following criteria: At least 1 lesion of ≥10 mm in the longest diameter (LD) for a non-lymph node or ≥15 mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1. Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show subsequent evidence of substantial size increase (ex. 20% increase in LD) to be deemed a target lesion. Negative serum or urine pregnancy test prior to study treatment initiation in female subjects of childbearing potential. Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception Exclusion Criteria: Known history of untreated human immunodeficiency virus (HIV)/HIV with a detectable viral load or active hepatitis B or active hepatitis C infection. Cardiac abnormalities Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent. Pregnancy or lactation. Active uncontrolled systemic infection. An autoimmune condition requiring ≥ 10 mg (or equivalent corticosteroid) prednisone daily, or any other systemic immunosuppressive treatment within 28 days of first dose of study therapy. Known history of active tuberculosis. Current (non-infectious) pneumonitis, or a history of pneumonitis that required steroids. A live vaccine administered within 30 days of the first dose of study treatment. Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest. Prior intolerance to pembrolizumab or other anti-PD-1/PD-L1 agents.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead In<br>Patients with advanced solid tumors. Up to 3 dose levels evaluated. | Drug: APR-246 (eprenetapopt) + Pembrolizumab<br>* APR-246 D1-4 + Pembrolizumab D3<br>|
| Experimental: Expansion 1<br>Patients with advanced gastric cancer. | Drug: APR-246 (eprenetapopt) + Pembrolizumab<br>* APR-246 D1-4 + Pembrolizumab D3<br>|
| Experimental: Expansion 2<br>Patients with advanced urothelial/bladder cancer. | Drug: APR-246 (eprenetapopt) + Pembrolizumab<br>* APR-246 D1-4 + Pembrolizumab D3<br>|
| Experimental: Expansion 3<br>Patients with advanced NSCLC. | Drug: APR-246 (eprenetapopt) + Pembrolizumab<br>* APR-246 D1-4 + Pembrolizumab D3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of APR-246 in combination with pembrolizumab in subjects with solid tumors. | To determine the occurrence of dose limiting toxicities (DLTs), classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with pembrolizumab. | Through study completion, approximately 1 year | 
| To confirm the maximum tolerated dose (MTD) for APR-246 in combination with pembrolizumab | To determine the dose of APR-246 to be selected for the expansion phase based on the occurence of dose limiting toxicities (DLTs) experienced during the safety assessment period | Through safety lead in period, approximately 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pembrolizumab, APR-246, Aprea, eprenetapopt