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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04214860
Recruitment Status : Completed
First Posted : January 2, 2020
Last Update Posted : January 19, 2022
Sponsor:
Information provided by (Responsible Party):
Aprea Therapeutics

Study Description
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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
Myeloid Malignancy Drug: APR-246 Drug: Venetoclax Drug: Azacitidine 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
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
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
Official Title: Phase I Study of APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
Actual Study Start Date : December 13, 2019
Actual Primary Completion Date : January 14, 2022
Actual Study Completion Date : January 14, 2022

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Arms and Interventions
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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
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Primary Outcome Measures :
  1. 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).

  2. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04214860


Locations
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United States, Connecticut
Yale Cancer Center
New Haven, Connecticut, United States, 06511
United States, Florida
H. Lee Moffitt CC
Tampa, Florida, United States, 33612
United States, Illinois
Northwestern Medicine
Chicago, Illinois, United States, 60611
University of Chicago Medicine
Chicago, Illinois, United States, 60637
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Weill Cornell Cancer Center
New York, New York, United States, 10021
Memorial Sloan Kettering CC
New York, New York, United States, 10065
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Aprea Therapeutics
More Information
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Responsible Party: Aprea Therapeutics
ClinicalTrials.gov Identifier: NCT04214860    
Other Study ID Numbers: A19-11184
First Posted: January 2, 2020    Key Record Dates
Last Update Posted: January 19, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
 Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors