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

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

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.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer; NSCLC; Non Small Cell Lung Cancer; Bladder Cancer; Advanced Solid Tumor; Urothelial Carcinoma
• Intervention / Treatment: Drug: APR-246 (eprenetapopt) + Pembrolizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University
  • Tennessee
    • Nashville, Tennessee, United States, 37235
      • Vanderbilt University
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent form (ICF) and ability to comply with protocol requirements.
2. Known tumor TP53 mutation status from recent or archival sample.

3. Histologically and/or cytologically confirmed solid tumor malignancy

   1. 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
   2. 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
   3. 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.
   4. Expansion 3- Confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.

4. Adequate organ function

   1. Creatinine clearance > 30 mL/min
   2. 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
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN, unless due to involvement by the underlying malignancy.
5. Projected life expectancy of ≥ 12 weeks.
6. Age ≥ 18 years at the time of signing the ICF.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

8. In the expansion portion, measurable disease meeting the following criteria:

   1. 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.
   2. 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.
9. Negative serum or urine pregnancy test prior to study treatment initiation in female subjects of childbearing potential.
10. Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception

Exclusion Criteria:

1. Known history of untreated human immunodeficiency virus (HIV)/HIV with a detectable viral load or active hepatitis B or active hepatitis C infection.
2. Cardiac abnormalities
3. Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent.
4. Pregnancy or lactation.
5. Active uncontrolled systemic infection.
6. 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.
7. Known history of active tuberculosis.
8. Current (non-infectious) pneumonitis, or a history of pneumonitis that required steroids.
9. A live vaccine administered within 30 days of the first dose of study treatment.
10. Receipt of any investigational product within 14 days or 5 half-lives prior to study treatment initiation, whichever is shortest.
11. Prior intolerance to pembrolizumab or other anti-PD-1/PD-L1 agents.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Lead In-Phase 1 Dose Level 1; APR-246 4.5g/d with pembrolizumab 200 mg IV (day 3) every 21 days in patients with advanced non-CNS primary tumors	Drug: APR-246 (eprenetapopt) + Pembrolizumab; APR-246 D1-4 + Pembrolizumab D3
Experimental: Expansion 1- Gastric Cancer; APR-246 4.5 g/d (days 1-4) with pembrolizumab 200 mg IV (day 3) every 21 days in patients with advanced gastric or GEJ tumors	Drug: APR-246 (eprenetapopt) + Pembrolizumab; APR-246 D1-4 + Pembrolizumab D3
Experimental: Expansion 2- Bladder Cancer; APR-246 4.5 g/d (days 1-4) with pembrolizumab 200 mg IV (day 3) every 21 days in patients with advanced bladder or urothelial tumors	Drug: APR-246 (eprenetapopt) + Pembrolizumab; APR-246 D1-4 + Pembrolizumab D3
Experimental: Expansion 3 -NSCLC; APR-246 4.5 g/d (days 1-4) with pembrolizumab 200 mg IV (day 3) every 21 days in patients with advanced NSCLC.	Drug: APR-246 (eprenetapopt) + Pembrolizumab; APR-246 D1-4 + Pembrolizumab D3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors.	To determine the 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 Recommended Phase 2 Dose (RP2D) 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, during cycle 1 (approximately 21 days)

Collaborators and Investigators

• Sponsor: Aprea Therapeutics
• Investigators: Study Director: Joachim Gullbo, MD, Theradex Oncology

Publications and helpful links

General Publications

• Park H, Shapiro GI, Gao X, Mahipal A, Starr J, Furqan M, Singh P, Ahrorov A, Gandhi L, Ghosh A, Hickman D, Gallacher PD, Wennborg A, Attar EC, Awad MM, Das S, Dumbrava EE. Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors. ESMO Open. 2022 Oct;7(5):100573. doi: 10.1016/j.esmoop.2022.100573. Epub 2022 Sep 7.

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2020
• Primary Completion (Actual): April 30, 2022
• Study Completion (Actual): April 30, 2022

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: May 11, 2020
• First Posted (Actual): May 12, 2020

Study Record Updates

• Last Update Posted (Actual): May 13, 2025
• Last Update Submitted That Met QC Criteria: May 12, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Pembrolizumab; APR-246; Aprea; eprenetapopt
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Urologic Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Urinary Bladder Diseases; Carcinoma, Non-Small-Cell Lung; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: A20-11195

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No