APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
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|ClinicalTrials.gov Identifier: NCT04214860|
Recruitment Status : Completed
First Posted : January 2, 2020
Last Update Posted : January 19, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Myeloid Malignancy||Drug: APR-246 Drug: Venetoclax Drug: Azacitidine||Phase 1|
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 (Clinical Trial)|
|Actual Enrollment :||51 participants|
|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)|
|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|
APR-246 4.5 g/day
APR-246 4.5 g/day
Venetoclax 400 mg once daily
Subcutaneous injection, or intravenous infusion
- 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.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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).
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
|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|
|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|
|Responsible Party:||Aprea Therapeutics|
|Other Study ID Numbers:||
|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|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Molecular Mechanisms of Pharmacological Action