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

MDS Clinical Trial

Official title:

A Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination With Azacitidine Versus Azacitidine Alone for the Treatment of (Tumor Protein) TP53 Mutant Myelodysplastic Syndromes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03745716
• Other study ID #: A18-15331
• Status: Completed
• Phase: Phase 3
• Start date: January 11, 2019
• Est. completion date: January 14, 2022

Study information

• Verified date: February 2024
• Source: Aprea Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 154
• Est. completion date: January 14, 2022
• Est. primary completion date: November 27, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• MDS
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• 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
• 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

Locations

Country	Name	City	State
France	CHU Nantes	Nantes
France	CHU Nice	Nice
France	Hôpital Saint-Louis	Paris
France	IUCT Oncopole	Toulouse
United States	Johns Hopkins Medical Center	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Robert H Lurie Comprehensive Cancer Center, Northwestern University	Chicago	Illinois
United States	University Of Chicago Medicine	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	City of Hope	Duarte	California
United States	Memorial Health Care System South Florida	Hollywood	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics, Holden Cancer Center	Iowa City	Iowa
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Ochsner Cancer Institute	New Orleans	Louisiana
United States	Cornell Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Stanford University Cancer Research Center	Palo Alto	California
United States	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center, Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Washington University St. Louis	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Aprea Therapeutics

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response Rate (CR)	To compare the complete response rate, defined as the proportion of patients who achieve complete remission (CR) with APR 246 + azacitidine treatment vs. azacitidine only.	12 months