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

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

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.

Study Overview

• Status: Completed
• Conditions: MDS
• Intervention / Treatment: Drug: APR-246 + azacitidine; Drug: Azacitidine

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

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Nantes, France, 44093
    • CHU Nantes
  • Nice, France, 06000
    • CHU Nice
  • Paris, France, 75010
    • Hôpital Saint-Louis
  • Toulouse, France, 31100
    • IUCT Oncopole
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Palo Alto, California, United States, 94304
      • Stanford University Cancer Research Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Health Care System South Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Tampa, Florida, United States, 12902
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
    • Chicago, Illinois, United States, 60611
      • Robert H Lurie Comprehensive Cancer Center, Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics, Holden Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University St. Louis
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Cornell Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Abramson Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center, Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 19023
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm: APR-246 + azacitidine; Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):	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
Experimental: Control arm: Azacitidine; Patients will be randomized (1:1) to one of two arms: stratified by age (< 65 years versus ≥ 65):	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Aprea Therapeutics
• Investigators: Principal Investigator: David Sallman, MD, PhD, Moffitt Cancer Center, Tampa, US

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2019
• Primary Completion (Actual): November 27, 2020
• Study Completion (Actual): January 14, 2022

Study Registration Dates

• First Submitted: November 14, 2018
• First Submitted That Met QC Criteria: November 16, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: A18-15331

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No