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

• ClinicalTrials.gov Identifier: NCT04214860
• Recruitment Status: Completed
• First Posted: January 2, 2020
• Last Update Posted: January 19, 2022
• Sponsor: Aprea Therapeutics
• Information provided by (Responsible Party): Aprea Therapeutics

Tracking Information

• First Submitted Date: December 12, 2019
• First Posted Date: January 2, 2020
• Last Update Posted Date: January 19, 2022
• Actual Study Start Date: December 13, 2019
• Actual Primary Completion Date: January 14, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 30, 2019)

• 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. [ Time Frame: 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. [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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 Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Myeloid Malignancy

Intervention

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

Study Arms

Experimental: APR-246

APR-246 4.5 g/day

Interventions:

• Drug: APR-246
• Drug: Venetoclax
• Drug: Azacitidine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 28, 2021): 51
• Original Estimated Enrollment (submitted: December 30, 2019): 50
• Actual Study Completion Date: January 14, 2022
• Actual Primary Completion Date: January 14, 2022 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04214860
• Other Study ID Numbers: A19-11184
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Aprea Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Aprea Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Aprea Therapeutics
• Verification Date: January 2022