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

Myeloid Malignancy Clinical Trial

Official title:

Phase I Study of APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04214860
• Other study ID #: A19-11184
• Status: Completed
• Phase: Phase 1
• Start date: December 13, 2019
• Est. completion date: January 14, 2022

Study information

• Verified date: January 2022
• Source: Aprea Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: January 14, 2022
• Est. primary completion date: January 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Myeloid Malignancy
• Neoplasms

Intervention

Drug:
• APR-246
APR-246 4.5 g/day
• Venetoclax
Venetoclax 400 mg once daily
• Azacitidine
Subcutaneous injection, or intravenous infusion

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Northwestern Medicine	Chicago	Illinois
United States	University of Chicago Medicine	Chicago	Illinois
United States	MD Anderson Cancer Center	Houston	Texas
United States	Yale Cancer Center	New Haven	Connecticut
United States	Memorial Sloan Kettering CC	New York	New York
United States	Weill Cornell Cancer Center	New York	New York
United States	H. Lee Moffitt CC	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Aprea Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	1. Dose-limiting toxicities (DLTs), classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).	From baseline until event occures, i.e. through study completion, an average of 1 year
Primary	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.	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.	From baseline until event occures, i.e. through study completion, an average of 1 year