Clinical trial NCT04383938: Phase 1/2 Study of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumor Malignancies
Official title: Study of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumor Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Bladder Cancer
Gastric Cancer
Non Small Cell Lung Cancer
NSCLC
Urothelial Carcinoma
Advanced Solid Tumor
Keywords: Pembrolizumab
APR-246
Aprea
eprenetapopt
Lead sponsor: Aprea Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-05-12
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: To Evaluate the Safety of APR-246 in Combination With Pembrolizumab in Subjects With Solid Tumors.
timeFrame: Through study completion, approximately 1 year
measure: To Confirm the Recommended Phase 2 Dose (RP2D) for APR-246 in Combination With Pembrolizumab
timeFrame: Through safety lead in period, during cycle 1 (approximately 21 days)
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Theradex Oncology
name: Joachim Gullbo, MD
role: STUDY_DIRECTOR
References:
citation: 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.