APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies

Phase 1

Completed

• Conditions: Myeloid Malignancy
• Interventions: Drug: APR-246; Drug: Venetoclax; Drug: Azacitidine

• Registration Number: NCT04214860
• Lead Sponsor: Aprea Therapeutics

Brief Summary

This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to determine the safety and preliminary efficacy of APR-246 in combination with venetoclax and azacitidine in patients with myeloid malignancies.

Detailed Description

This study will enroll adult male and female patients of age ≥ 18 years with documented diagnosis of AML, according to WHO classification, and documented TP53 mutation which is not benign or likely benign, who also meet the eligibility requirements of this protocol.

The study will include a safety lead-in dose-finding portion followed by expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design. Each cohort will enroll up to 6 patients.

The expansion portion will begin once the recommended phase II dose (RP2D) of APR-246 in combination with venetoclax and in combination with venetoclax and azacitidine have been determined in order to assess the antitumor activity of these combinations.

Study Timeline

• Study First Submitted: 2019-12-12
• Study Start: 2019-12-13
• Study First Submitted QC: 2019-12-30
• Study First Posted: 2020-01-02
• Primary Completion: 2022-01-14
• Study Completion: 2022-01-14
• Results First Submitted: 2024-02-27
• Results First Submitted QC: 2025-01-31
• Results First Posted: 2025-02-21
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-06
• Last Update Posted: 2025-03-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 51

Inclusion Criteria

1. Signed informed consent and ability to comply with protocol requirements.

2. Documented diagnosis of AML according to World Health Organization WHO) classification

3. Adequate organ function as defined by the following laboratory values:

   1. Creatinine clearance > 30 mL/min
   2. Total serum bilirubin < 1.5 × ULN
   3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN

4. Age ≥18 years

5. At least one TP53 mutation

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

7. Projected life expectancy of ≥ 12 weeks.

8. Negative serum or urine pregnancy test

9. Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception

Exclusion Criteria

1. Prior treatment for TP53-mutant AML (*dependent upon treatment arm assigned).

2. Known history of HIV or active hepatitis B or active hepatitis C infection.

3. Any of the following cardiac abnormalities:

   1. Myocardial infarction within six months prior to registration;
   2. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
   3. A history of familial long QT syndrome;
   4. Symptomatic atrial or ventricular arrhythmias
   5. QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.

4. Concomitant malignancies for which patients are receiving active therapy

5. Known active CNS involvement from AML.

6. Malabsorption syndrome

7. Pregnancy or lactation.

8. Active uncontrolled systemic infection (viral, bacterial or fungal).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
APR-246	Venetoclax	APR-246 4.5 g/day
APR-246	APR-246	APR-246 4.5 g/day
APR-246	Azacitidine	APR-246 4.5 g/day

Primary Outcome Measures

Name	Time	Method
To Evaluate the Tolerabililty and the Incidence of Treatment-Emergent Adverse Events of Administration of APR 246 in Combination With Venetoclax and Azacitidine in Patients With TP53 Mutant Myeloid Malignancies.	From baseline until event occures, i.e. through study completion, an average of 1 year	2. Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with venetoclax and azacitidine during the trial.

Trial Locations

Locations (8)

Northwestern Medicine; 🇺🇸 Chicago, Illinois, United States

H. Lee Moffitt CC; 🇺🇸 Tampa, Florida, United States

Weill Cornell Cancer Center; 🇺🇸 New York, New York, United States

University of Chicago Medicine; 🇺🇸 Chicago, Illinois, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Memorial Sloan Kettering CC; 🇺🇸 New York, New York, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States