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A Phase II Randomized, Double-Blinded, Placebo-Controlled Study of Pracinostat in Combination with Azacitidine in Patients with Previously Untreated International Prognostic Scoring System (IPSS) Intermediate Risk 2 or High-Risk Myelodysplastic Syndrome (MDS)
|Myelodysplastic Syndrome (MDS)
- Estimate the relative efficacy, as measured by CR at or before the Cycle 6 response assessment following randomization of pracinostat plus azacitidine versus placebo plus azacitidine.
- Estimate the overall response rate [ORR = CR + partial response (PR)]
- Estimate the overall hematologic improvement (HI) response rate
- Estimate the clinical benefit rate, which will be calculated by: ORR+HI+Marrow CR.
- Estimate the duration of response (DoR)
- Estimate the progression-free survival (PFS) duration of pracinostat plus azacitidine and the relative benefit of that combination versus placebo plus azacitidine as assessed by the PFS hazard ratio
- Estimate the rate of leukemic transformation at landmark time points (6 months, 12 months, 18 months, and 24 months)
- Estimate the overall survival (OS) duration of pracinostat plus azacitidine and the relative benefit of that combination versus placebo plus azacitidine as assessed by the OS hazard ratio
- Assess the tolerability and AE profile of pracinostat and placebo when combined with azacitidine.
- Voluntary written informed consent before performance of any study-related procedure not part of normal medical care
- Histologically or cytologically documented diagnosis of MDS (any French-American-British classification [FAB] subtype; see Appendix B) that is classified as intermediate 2 (1.5 to 2.0 points) or high risk (≥2.5 points) according to the International Prognostic Scoring System (IPSS) risk category (see Appendix C), with >5% and <30% (6% and 29%) bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000 /μL.
- Bone marrow biopsy within 28 days of first study treatment
- There must be a clinical indication for treatment with azacitidine.
- Previously untreated with hypomethylating agents (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see Appendix E)
- Adequate organ function as evidenced by:
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x the upper limit of normal (ULN)
- Total bilirubin ≤1.5 x ULN or total bilirubin of ≤2 mg/dL, whichever is higher
- Serum creatinine <2 mg/dL, or creatinine clearance ≤1.5 x ULN
- QTcF interval ≤470 msec
- Female or male patients ≥18 years-of-age
- Male patients with female partners of child-bearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 30 days following last dose. Male patients must also refrain from donating sperm during their participation in the study (see Appendix G). Female patients of childbearing potential must not be breast-feeding or planning to breast feed and must have a negative pregnancy test ≤7 days before first study drug administration.
- Willingness and ability to understand the nature of this trial and to comply with the trial and follow-up procedures.
- Received any of the following within the specified time frame prior to administration of study medication:
- Any investigational agent within 14 days or 5 half-lives prior to first study treatment, whichever is longer
- Previous therapy for malignancy within 21 days prior to first study treatment, including any chemotherapy, immunotherapy, biological or hormonal therapy (6 weeks for nitrosoureas or mitomycin C)
- Hydroxyurea within 48 hours prior to first study treatment
- Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to study enrollment.
- Major surgery within 28 days prior to first study treatment
- Patients that have not recovered from side effects of previous therapy
- Cardiopulmonary function criteria:
- Current unstable arrhythmia requiring treatment
- History of symptomatic congestive heart failure (New York Heart Association [NYHA] Classes III or IV) (see Appendix F)
- History of myocardial infarction within 6 months of enrollment
- Current unstable angina
- Concomitant treatment with the histone deacetylase (HDAC) inhibitors Zolinza (vorinostat) or Istodax (romidepsin/depsipetide), or valproic acid, which has significant action as a HDAC inhibitor, is not permitted.
- Clinical evidence of central nervous system involvement
- Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
- Active infection with human immunodeficiency virus or chronic hepatitis B or C
- Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study
- Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, or non-melanomatous skin cancer
- Inability or unwillingness (including psychological, familial, sociological, or geographical conditions) to comply with trial and/or follow-up procedures as outlined in the protocol.
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