APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: APR-246 APR-246 4.5 g/day |
Drug: APR-246
APR-246 4.5 g/day
Drug: Venetoclax
Venetoclax 400 mg once daily
Drug: Azacitidine
Subcutaneous injection, or intravenous infusion
|
Outcome Measures
Primary Outcome Measures
- 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]
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).
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Signed informed consent and ability to comply with protocol requirements.
-
Documented diagnosis of AML according to World Health Organization WHO) classification
-
Adequate organ function as defined by the following laboratory values:
-
Creatinine clearance > 30 mL/min
-
Total serum bilirubin < 1.5 × ULN
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN
-
Age ≥18 years
-
At least one TP53 mutation
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
-
Projected life expectancy of ≥ 12 weeks.
-
Negative serum or urine pregnancy test
-
Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception
Exclusion Criteria:
-
Prior treatment for TP53-mutant AML (*dependent upon treatment arm assigned).
-
Known history of HIV or active hepatitis B or active hepatitis C infection.
-
Any of the following cardiac abnormalities:
-
Myocardial infarction within six months prior to registration;
-
New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
-
A history of familial long QT syndrome;
-
Symptomatic atrial or ventricular arrhythmias
-
QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.
-
Concomitant malignancies for which patients are receiving active therapy
-
Known active CNS involvement from AML.
-
Malabsorption syndrome
-
Pregnancy or lactation.
-
Active uncontrolled systemic infection (viral, bacterial or fungal).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Yale Cancer Center | New Haven | Connecticut | United States | 06511 |
| 2 | H. Lee Moffitt CC | Tampa | Florida | United States | 33612 |
| 3 | Northwestern Medicine | Chicago | Illinois | United States | 60611 |
| 4 | University of Chicago Medicine | Chicago | Illinois | United States | 60637 |
| 5 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
| 6 | Weill Cornell Cancer Center | New York | New York | United States | 10021 |
| 7 | Memorial Sloan Kettering CC | New York | New York | United States | 10065 |
| 8 | MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Aprea Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- A19-11184