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

Study Overview
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Brief Summary
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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
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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: Experimental arm: APR-246 + azacitidine; or Control arm: Azacitidine

Official Title
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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

Conditions
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MDS

Intervention / Treatment
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* Drug: APR-246 + azacitidine
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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: Creatinine clearance > 30 mL/min (by Cockcroft-Gault method) 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 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): Myocardial infarct within six months prior to registration, 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 A history of familial long QT syndrome, Clinically significant pericardial disease Electrocardiographic evidence of acute ischemia Symptomatic atrial or ventricular arrhythmias not controlled by medications QTc ≥ 470 msec (QT cardiac interval) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

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

What is the study measuring?
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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 |