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

• Pracinostat (Drug), also known as SB939: 45 mg capsule
• Azacitidine (Drug): SC or IV injection

Primary outcomes

• Overall Response Rate (ORR) [36 months]: Percentage of subjects with confirmed complete remission (CR), partial remission (PR) and marrow CR, as per modified International Working Group (IWG) criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hemoglobin (Hb) ≥11 g/dL; Platelets ≥100 × 10\^9/L; Neutrophils ≥1.0 × 10\^9/L; Blasts 0%. PR: All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by ≥ 50% over pre-treatment but still >5%; Cellularity and morphology not relevant Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pre-treatment

Secondary outcomes

• Complete Response (CR) Rate [36 months]: Percentage of subjects with confirmed CR (i.e., 2 CRs at least 28 days apart) as per modified IWG criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hb ≥11 g/dL; Platelets ≥100 × 109/L; Neutrophils ≥1.0 × 109/L; Blasts 0%.
• Overall Hematologic Improvement (HI) Response Rate [36 months]: Percentage of subjects demonstrating major hematologic improvement according to modified IWG: Erythroid response (pre-treatment, <11 g/dL): Hb increase by ≥1.5 g/dL; Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pre-treatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of ≤9.0 g/dL pre-treatment will count in the RBC transfusion response evaluation. Platelet response (pre-treatment, <100 × 10\^9/L): Absolute increase of ≥30 × 10\^9/L for patients starting with >20 × 10\^9/L platelets; Increase from <20 × 10\^9/L to >20 × 10\^9/L and by at least 100%. Neutrophil response (pre-treatment, <1.0 × 10\^9/L): At least 100% increase and an absolute increase >0.5 × 10\^9/L. Progression or relapse after HI: at least 1 of the following: * At least 50% decrement from maximum response levels in granulocytes or platelets * Reduction in Hb by≥1.5 g/dL * Transfusion dependence
• Clinical Benefit Rate [36 months]: Percentage of subjects with confirmed CR, PR, Marrow CR, and HI with clinical benefit rate, defines as rate of CR + PR + HI + Marrow CR. All subjects who achieve hematologic CR, PR, marrow CR, or hematologic improvement on the erythrocytic lineage per modified IWG response criteria will be considered responders
• Rate of Cytogenetic CR [36 months]: Percentage of subjects with confirmed CR by cytogenetic assessment. Complete cytogenetic response is defined per modified IWG response criteria: Complete: Disappearance of the chromosomal abnormality without appearance of new ones Partial: At least 50% reduction of the chromosomal abnormality
• Duration of Response (DoR) [36 months]: For subjects who have achieved CR, PR, Marrow CR, or HI, DoR is defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first.
• Rate of Leukemic Transformation [6 months]: Percentage of subjects with leukemic transformation at landmark time point of 6 months
• Event-free Survival (EFS) [36 months]: time from the first day of study drug administration (Day 1) to failure or death from any cause
• Progression-free Survival (PFS) [36 months]: time from the first day of study drug administration (Day 1) to disease recurrence or progression as defined by the IWG criteria, or death on study: Disease progression for subjects with: Less than 5% blasts: ≥50% increase in blasts to >5% blasts 5%-10% blasts: ≥50% increase to >10% blasts 10%-20% blasts: ≥50% increase to >20% blasts 20%-30% blasts: ≥50% increase to >30% blasts Any of the following: At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hb by ≥2 g/dL Transfusion dependence
• Overall Survival (OS) [form day 1 to death on study, assessed up to 36 months]: time from the first day of study drug administration (Day 1) to death on study
• Rate of Leukemic Transformation [12 months]: Percentage of subjects with leukemic transformation at landmark time point of 12 months
• Rate of Leukemic Transformation [18 months]: Percentage of subjects with leukemic transformation at landmark time point of 18 months
• Rate of Leukemic Transformation [24 months]: Percentage of subjects with leukemic transformation at landmark time point of 24 months

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Overall Response Rate (ORR) (Primary), Number, percentage of subjects: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 35.9 (24.3 to 48.9)
• Complete Response (CR) Rate (Secondary), Number, percentage of subjects with CR: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 35.9 (24.3 to 48.9)
• Overall Hematologic Improvement (HI) Response Rate (Secondary), Number, percentage of subjects with HI: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 71.4 (58.7 to 82.1)
• Clinical Benefit Rate (Secondary), Number, percentage of subjects with benefit rate: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 78.1 (66.0 to 87.5)
• Rate of Cytogenetic CR (Secondary), Number, percentage of subjects with cCR: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 46.9 (34.3 to 59.8)
• Duration of Response (DoR) (Secondary), Median, months: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 15.67 (9.00 to 22.11)
• Rate of Leukemic Transformation (Secondary), Number, percentage of subjects: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 5.4 (1.8 to 15.8)
• Event-free Survival (EFS) (Secondary), Median, months: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 17.05 (11.50 to 21.95)
• Progression-free Survival (PFS) (Secondary), Median, months: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 16.43 (11.33 to 22.57)
• Overall Survival (OS) (Secondary), Median, months: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 23.56 (16.49 to 30.26)
• Rate of Leukemic Transformation (Secondary), Number, percentage of subjects: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 9.5 (3.3 to 25.4)
• Rate of Leukemic Transformation (Secondary), Number, percentage of subjects: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 13.8 (5.5 to 32.4)
• Rate of Leukemic Transformation (Secondary), Number, percentage of subjects: Stage 1a and 1b Open-label Pracinostat Plus Azacitidine 21.6 (8.8 to 47.3)

Adverse events

Time frame: All AEs regardless of seriousness or relationship to pracinostat or azacitidine, from the start of study drug treatment until 30 calendar days after discontinuation or completion of treatment as defined by the clinical study for that subject, have been recorded.

Serious adverse events by term

11 more terms not shown.

Other adverse events by term

27 more terms not shown.

• Study Protocol (PDF, 2018-06-25)
• Statistical Analysis Plan (PDF, 2020-08-28)

• Richard Ghalie, MD, Study director, MEI Pharma
• Ehab Atallah, MD, Study chair, Medical College of Wisconsin adn Froedtert Hospital