A Two-Stage, Open-Label Followed by Placebo-Controlled Phase 2 Study of Pracinostat and Azacitidine in Patients With IPSS-R High and Very High Risk Myelodysplastic Syndromes Previously Untreated With Hypomethylating Agents

This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with azacitidine in patients with IPSS-R high and very high risk MDS who are previously untreated with HMAs. Enrollment in this study will be limited to high/very high risk MDS because this group represents the highest unmet need, with median survival of less than 18 months.

Stage 1 will be conducted as an open-label single arm in up to 40 subjects to assess if this regimen with a lower pracinostat dose results in a discontinuation rate that meets a predefined threshold and in efficacy that justifies expansion of enrollment into Stage 2.

A discontinuation rate of approximately ≤10% in Stage 1, a rate comparable to that observed with azacitidine alone in study MEI-003, is considered desirable and supports expansion into Stage 2.

Stage 2 will be conducted as a randomized, double-blind, placebo-controlled, two-arm design to confirm that the discontinuation rate observed in an open-label design can be reproduced in a placebo controlled design, and to provide unbiased information on efficacy and safety. Subjects will be randomized in a 1:1 ratio to one of the 2 treatment arms (Arm A, pracinostat + azacitidine and Arm B, placebo + azacitidine). Study drugs should be continued until disease progression or intolerable toxicity. It is important to note that the median time to achieving a response with azacitidine alone is 4 to 5 months. Furthermore, the median time to achieving a CR in study MEI-003 was 4 cycles. Therefore, early (<6 months) discontinuation of trial therapy for 'no response' should be avoided. The Medical Monitor should be contacted prior to discontinuing a subject from the study to discuss the rationale for discontinuation.


Cancer (Oncology), Cancer (Oncology) - Myelodysplastic Syndrome (MDS)
Raya Mawad, MD

Swedish Cancer Institute

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female or male subjects ≥18 years-of-age.
  2. Histologically or cytologically documented diagnosis of MDS according to the World Health Organization (WHO) classification (Vardiman 2009, Arber 2016) with >5% and <20% bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000/μL

    • If WBC ≥20,000/μL, cytoreduction with hydroxyurea is permitted prior to enrollment.
  3. Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category.
  4. Bone marrow biopsy (BMBx) within 28 days prior to first study treatment.
  5. Clinical indication for treatment with azacitidine.
  6. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed).
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  8. Adequate organ function as evidenced by:

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).
    • Total bilirubin ≤1.5 × ULN or total bilirubin of ≤2 mg/dL, whichever is higher.
    • Serum creatinine <2 mg/dL, or creatinine clearance ≤1.5 × ULN.
    • QTcF interval ≤450 msec using the mean of triplicate electrocardiograms (ECGs).
  9. Female subjects of childbearing potential and male subjects with female partners 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. Female subjects of childbearing potential must not be breastfeeding, or planning to breastfeed, and must have a negative pregnancy test ≤7 days before first study drug administration.

     

    Male subjects must also refrain from donating sperm during their participation in the study.

  10. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
  11. Have the willingness and ability to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria:

  1. Bone marrow blasts ≥20%, indicating a diagnosis of acute myeloid leukemia (AML).
  2. 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 enrollment, whichever is longer.
    • Hydroxyurea within 48 hours prior to first day of 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.
  3. Subjects that have not recovered from side effects of previous therapy.
  4. Cardiopulmonary function criteria:

    • Current unstable arrhythmia requiring treatment.
    • History of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV).
    • History of myocardial infarction within 6 months of enrollment.
    • Current unstable angina.
  5. Prior treatment for MDS with the histone deacetylase (HDAC) inhibitors Zolinza (vorinostat), Belenodaq (belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant action as an HDAC inhibitor.
  6. Clinical evidence of central nervous system involvement.
  7. Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
  8. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.
  9. 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.
  10. Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin cancer, or malignancies treated with curative intent and no evidence of active disease in prior 12 months and felt to be low risk for recurrence.
  11. An unwillingness or inability (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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