APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS)

NCT ID: NCT03745716

Last Updated: 2025-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 154 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-11
• Study Completion Date: 2022-01-14

Brief Summary

A Phase III, multicenter, randomized study to compare the rate of complete response (CR) and duration of CR, in patients with TP53-mutated MDS who will receive APR-246 and azacitidine or azacitidine alone.

Detailed Description

A Phase III, multicenter, randomized study to compare the rate of CR and duration of CR, in patients with TP53-mutated MDS who will receive APR-246 and azacitidine or azacitidine alone.

Treatment will be administered on an outpatient basis. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's disease.

Patients will be randomized (1:1) to one of two arms:

1. Experimental arm: APR-246 + azacitidine; or

2. Control arm: Azacitidine

Conditions

MDS

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental arm: APR-246 + azacitidine

Patients will be randomized (1:1) to one of two arms: stratified by age (\< 65 years versus ≥ 65):

Group Type: EXPERIMENTAL

APR-246 + azacitidine

Intervention Type: DRUG

Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):

Experimental arm: APR-246 + azacitidine; or Control arm: Azacitidine

Control arm: Azacitidine

Patients will be randomized (1:1) to one of two arms: stratified by age (\< 65 years versus ≥ 65):

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):

Experimental arm: APR-246 + azacitidine; or Control arm: Azacitidine

Interventions

APR-246 + azacitidine

Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):

Experimental arm: APR-246 + azacitidine; or Control arm: Azacitidine

Intervention Type: DRUG

Azacitidine

Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):

Experimental arm: APR-246 + azacitidine; or Control arm: Azacitidine

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Signed Informed Consent (ICF) and is able to comply with protocol requirements
• Documented diagnosis of MDS, according to World Health Organization (WHO) classification
• Patient has adequate organ function as defined by the following laboratory values:

1. Creatinine clearance > 30 mL/min (by Cockcroft-Gault method)

2. Total serum bilirubin < 1.5 x Upper Limit of Normal (ULN) or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome or hemolysis or who required regular blood transfusions

3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN

• Age ≥18 years at the time of signing the informed consent form (ICF)
• Having at least one TP53 mutation which is not benign or likely benign
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• If of childbearing potential, negative pre-treatment urine or serum pregnancy test
• If of childbearing potential (males and females), willing to use an effective form of contraception such as latex condom, hormonal birth control, intrauterine device or double barrier method during chemotherapy treatment and for at least six months thereafter

Exclusion Criteria

• Patient has a known history of human immunodeficiency virus (HIV) or active hepatitis B or active hepatitis C infection (testing not mandatory)
• Patient has any of the following cardiac abnormalities (as determined by treating MD):

1. Myocardial infarct within six months prior to registration,

2. New York Heart Association Class II or worse heart failure (Appendix II) or known left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by echocardiogram

3. A history of familial long QT syndrome,

4. Clinically significant pericardial disease

5. Electrocardiographic evidence of acute ischemia

6. Symptomatic atrial or ventricular arrhythmias not controlled by medications

7. QTc ≥ 470 msec (QT cardiac interval)

8. Bradycardia (<40 bpm)

• Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of signing consent. Patients with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis
• Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
• Prior exposure to intensive chemotherapy
• Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS within 14 days of the first day of study drug treatment
• No concurrent use of erythroid stimulating agents
• Patients with history of allogeneic stem cell transplantation
• Pregnant women are excluded from this study because APR-246 has not been studied in pregnant patients. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with APR 246, breastfeeding should be discontinued if the mother is treated with APR-246.
• Patients with active uncontrolled infections

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aprea Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Sallman, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Moffitt Cancer Center, Tampa, US

Locations

City of Hope

Duarte, California, United States

Stanford University Cancer Research Center

Palo Alto, California, United States

Yale Cancer Center

New Haven, Connecticut, United States

Memorial Health Care System South Florida

Hollywood, Florida, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Robert H Lurie Comprehensive Cancer Center, Northwestern University

Chicago, Illinois, United States

University Of Chicago Medicine

Chicago, Illinois, United States

University of Iowa Hospitals and Clinics, Holden Cancer Center

Iowa City, Iowa, United States

Ochsner Cancer Institute

New Orleans, Louisiana, United States

Johns Hopkins Medical Center

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University St. Louis

St Louis, Missouri, United States

Cornell Medical Center

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center, Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

CHU Nantes

Nantes, , France

CHU Nice

Nice, , France

Hôpital Saint-Louis

Paris, , France

IUCT Oncopole

Toulouse, , France

Countries

United States; France

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

A18-15331

Identifier Type: -

Identifier Source: org_study_id