Details

Details

Title A Phase II Simon Two-Stage Study of the Addition of Pracinostat to a Hypomethylating Agent (HMA) in Patients with Myelodysplastic Syndrome (MDS) Who Have Failed to Respond or Maintain a Response to the HMA Alone

IRB MEI1914

CC 14-334

Hospital Main Campus

Phase Phase 2

Disease Myelodisplastic Syndrome (MDS)

Drug Pracinostat

Description

Description

Primary Objective
  • Estimate Clinical Improvement rate including Complete Responses (CR), Marrow CR, Partial Responses (PR), Hematologic Improvement (HI) (CR+Marrow CR+PR+HI)
Secondary Objectives
  • Estimate Overall Response Rate (ORR), including all Complete Responses, Partial Responses, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses (CR+PR+Marrow CR+HI+SD+transfusion independence +cytogenetic responses)
  • Estimate Complete Response (CR) rate
  • Estimate Marrow CR rate
  • Assess transfusion independence
  • Estimate Hematologic Improvement (HI) rate
  • Estimate Stable Disease (SD) rate
  • Estimate Cytogenetic response rate
  • Estimate Duration of Response (DoR)
  • Estimate Progression Free Survival (PFS)
  • Estimate Event Free Survival (EFS)
  • Estimate Overall Survival (OS)
  • Assess the safety profile of pracinostat when combined with azacitidine or decitabine
Inclusion Criteria

Inclusion Criteria

  1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care
  2. Histologically or cytologically documented diagnosis of MDS (any French-American-British classification [FAB] subtype; see Appendix B)
  3. Bone marrow >5% and <30% bone marrow blasts, and a peripheral white blood cell (WBC) count of <20,000 /μL
  4. Bone marrow biopsy, aspirates, and peripheral blood smears within 28 days of first study treatment
  5. Group 1:

    Primary failures: Progression after their most recent HMA therapy according to 2006 International Working Group (IWG) criteria after receiving single agent azacitidine and/or single agent decitabine, or has worsening cytopenias (evidenced by increased frequency of transfusions), increased BM blasts, progression to a higher FAB type, or development of additional clinically significant cytogenetic abnormalities

    Secondary failures: Relapse after any CR, PR, HI or development of clinically significant cytogenetic abnormalities after receiving the most recent HMA therapy (single agent azacitidine and/or single agent decitabine)

    Group 2:

    Failure to achieve a response (any CR, PR or HI) according to IWG criteria definition of stable disease after the most recent HMA therapy (at least 6 cycles of single agent azacitidine and/or at least 4 cycles of single agent decitabine).

  6. Must have demonstrated tolerability to single agent HMA without dose reductions due to non-hematologic toxicity for at least one cycle prior to first study treatment
  7. Able to start combination therapy within 3 months of the last single agent HMA dose with no other therapy for disease under study received during this interval
  8. Not a candidate for hematopoietic stem cell transplant within 4 months of screening
  9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see Appendix E)
  10. 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 >60 mL/min
    • QTcF interval ≤470 msec
  11. Female or male patients ≥18 years-of-age
  12. 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 breastfeeding or planning to breast feed and must have a negative pregnancy test ≤7 days before first study treatment.
  13. Willingness and ability to understand the nature of this trial and to comply with the trial and follow-up procedures.
Exclusion Criteria

Exclusion Criteria

  1. Received any of the following within the specified time frame after the last single agent HMA dose until the first administration of study medication:
    • Any therapy for malignancy between the time of single agent HMA and first on-study treatment, including any investigational agent, chemotherapy, immunotherapy, biological or hormonal therapy
    • Hydroxyurea within 48 hours prior to first study treatment
    • Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists within 7 days (14 days for Aranesp) prior to first study treatment
    • Major surgery within 28 days prior to first study treatment
  2. Patients who are candidates for aggressive chemotherapy (e.g. typical AML induction therapy)
  3. 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
  4. Concomitant treatment with agents which have significant activity against histone deacetylase (HDAC) inhibitors is not permitted such as Istodax (romidepsin/depsipetide), or valproic acid
  5. Clinical evidence of central nervous system involvement
  6. 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)
  7. Active infection with human immunodeficiency virus or chronic hepatitis B or C
  8. 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
  9. 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 and other concurrent malignancies will be considered on a case by case basis
  10. Inability or unwillingness (including psychological, familial, sociological, or geographical conditions) to comply with trial and/or follow-up procedures as outlined in the protocol.