Clinical trial NCT04214860: APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
Official title: Phase I Study of APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myeloid Malignancy
Lead sponsor: Aprea Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-01-02
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: The study will include a safety lead-in dose-finding portion followed by the expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: 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.
timeFrame: From baseline until event occures, i.e. through study completion, an average of 1 year
measure: 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.
timeFrame: From baseline until event occures, i.e. through study completion, an average of 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Tampa
country: United States
facility: H. Lee Moffitt CC
state: Florida
city: Chicago
country: United States
facility: Northwestern Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Weill Cornell Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering CC
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
References: