APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS)
Condition: MDS
MeSH terms: Preleukemia; Myelodysplastic Syndromes
Intervention: APR-246 + azacitidine; Azacitidine
Intervention description: 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; 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 MeSH terms: Azacitidine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be 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: stratified by age (< 65 years versus ≥ 65):
Experimental arm: APR-246 + azacitidine; or
Control arm: Azacitidine
Masking: None (Open Label)
Enrollment: 154.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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