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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Myeloid Malignancy

Intervention / Treatment
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* Drug: APR-246
* Drug: Venetoclax
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APR-246<br>APR-246 4.5 g/day | Drug: APR-246<br>* APR-246 4.5 g/day<br>Drug: Venetoclax<br>* Venetoclax 400 mg once daily<br>Drug: Azacitidine<br>* Subcutaneous injection, or intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 |