A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes

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 myelodysplastic syndrome (MDS) who are previously untreated with hypomethylating agents (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 1a 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 1b.

A discontinuation rate of approximately ≤10% in Stage 1a, a rate comparable to that observed with azacitidine alone in study MEI-003 (NCT01873703), supports expansion into Stage 1b.

Stage 1b will be conducted as expansion of stage 1a. Approximately 20 additional subjects will be enrolled. 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 Complete Response (CR) in study MEI-003 (NCT01873703) 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.


Eligibility 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.
   * chronic myelomonocytic leukemia CMML-1 and CMML-2 subtypes
3. Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category. CMML-1 and CMML-2 subtypes will be considered high-risk MDS and will not require IPSS-r scoring
4. Bone marrow biopsy (BMBx) and/or aspirate 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).

   a. subjects who require the start of an HMA (e.g., azacitidine) due to progressing MDS may receive up to 1 cycle of azacitidine within 30 days prior to planned first dose (Cycle 1 Day 1)
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. Total bilirubin \< 3 x ULN for patients with Gilbert-Meulengracht Syndrome
   * Serum creatinine \<1.5 mg/dL, or creatinine clearance\>40 mL/min.
   * 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 who 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, pulmonary embolism or cerebrovascular accident within 6 months of enrollment.
   * Current unstable angina.
5. Prior treatment for MDS with 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. Other malignancies may be considered after consultation with the Medical Monitor
11. An unwillingness or inability (including breastfeeding women, prohibited concomitant medications, uncontrolled infections, psychological, familial, sociological, or geographical conditions) to comply with study and/or follow-up procedures as outlined in the protocol
12. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol
13. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, chewing tobacco, or nicotine gum is permitted). Subjects who stopped smoking at least 8 days prior to first pracinostat dosing can be, provided they refrain from smoking during the whole study.