Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome

A Phase 2 Randomized Double-Blind 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)

The purpose of this randomized, double-blind, placebo-controlled study is to determine the safety and efficacy of pracinostat compared to placebo when combined with azacitidine, and FDA approved treatment for Myelodysplastic Syndrome (MDS).

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: pracinostat; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center
  • California
    • La Jolla, California, United States, 92037
      • Scripps Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists South
    • Pensacola, Florida, United States, 32503
      • Woodlands Medical Specialists
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists NORTH
    • Tallahassee, Florida, United States, 32308
      • Florida Cancer Specialist and Research Institute
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Fort Wayne Medical Oncology and Hematology
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Ctr
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer at Johns Hopkins
    • Bethesda, Maryland, United States, 20817
      • Center For Cancer And Blood Disorders
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Lansing, Michigan, United States, 48910
      • Michigan State University
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology - Chattanooga
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center, Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Cancer Care Centers of South Texas
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Voluntary written informed consent
• Histologically or cytologically documented diagnosis of MDS (any French-American-British [FAB] classification subtype; 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 risk category, with >5% and <30% blasts, and a peripheral blast count of <20,000
• Bone marrow aspirate smears and bone marrow biopsies 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 performance status of 0, 1, or 2

• Adequate organ function as evidenced by:

  1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x the upper limit of normal (ULN) (≤5 x ULN for patients with hepatic metastases
  2. Total bilirubin ≤1.5 x ULN or total bilirubin of 2, whichever is higher
  3. Serum creatinine <2 mg/dL, or creatinine clearance ≤1.5 x ULN
  4. QTcF interval ≤470 msec
• Female or male patients ≥18 years-of-age
• Male patients who are surgically sterile or willing to use adequate contraceptive measures or abstain from heterosexual intercourse during the entire study treatment period
• Female patients who are surgically sterile or post menopausal or female patients who are not of child-bearing potential and female patients of child-bearing potential who agree to use adequate contraceptive measures or abstain from intercourse during the study treatment period, who are not breastfeeding, and who have had a negative serum pregnancy test ≤7 days prior to first study treatment.
• Willingness and ability to comply with the trial and follow-up procedures

Exclusion Criteria:

• Received any of the following within the specified time frame prior to administration of study medication:

  1. Any investigational agent within 14 days or 5 half-lives prior to first study treatment, whichever is longer
  2. 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)
  3. Hydroxyurea within 48 hours prior to first study treatment
  4. 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
  5. Major surgery within 4 weeks prior to first study treatment
• Patients that have not recovered from side effects of previous therapy

• Cardiopulmonary function exclusion:

  1. Current unstable arrhythmia requiring treatment
  2. History of symptomatic congestive heart failure (New York Heart Association Classes III or IV)
  3. History of myocardial infarction within 6 months of enrollment
  4. Current unstable angina
• Concomitant treatment with histone deacetylase (HDAC) inhibitors or drugs with significant action as HDAC inhibitors, such as valproic acid, 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 HIV 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 (including psychological, familial, sociological, or geographical conditions) to comply with trial and/or follow-up procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: pracinostat plus azacitadine; 60 mg of pracinostat by mouth 3 times a week for 3 weeks followed by 1 week of rest repeated every 28 days. 75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable	Drug: pracinostat; Histone deacetylase inhibitor (HDACi); Other Names: SB939; Drug: Azacitidine; Active comparator 75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable; Other Names: Vidaza
PLACEBO_COMPARATOR: Placebo with Azacitadine; Placebo by mouth 3 times a week for 3 weeks followed by 1 week of rest repeated every 28 days. 75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable	Drug: Placebo; Placebo; Drug: Azacitidine; Active comparator 75 mg/m2 Azacitidine for 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimate efficacy	Estimate the relative efficacy, measured by complete remission rate of treatment wiht pracinostat plus azacitidine versus placebo plus azacitidine	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Estimate the overall response rate [ORR = CR + complete remission + partial response (PR)]	6 months
Hematologic Improvement	Estimate the overall hematologic improvement (HI) response rate by review of hematologic lab values each cycle including bone marrow blast counts, platelets and erythrocytes.	6 months
Duration of response	Estimate the duration of response	6 months
Progression free survival	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	12 months
Rate of leukemic transformation	Estimate the rate of leukemic transformation at landmark time points (6 months, 12 months, 18 months, and 24 months) using clinical review of hematologic lab counts each cycle	6 - 24 months
Overall survival	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	6-24 months
AE profile	Assess the adverse event (AE) profile of pracinostat and placebo when combined with azacitidine by clinical review of safety events by grade, relationship and event outcomes.	12 months

Collaborators and Investigators

• Sponsor: Helsinn Healthcare SA

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2016

Study Registration Dates

• First Submitted: May 22, 2013
• First Submitted That Met QC Criteria: June 7, 2013
• First Posted (ESTIMATE): June 10, 2013

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2018
• Last Update Submitted That Met QC Criteria: September 11, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: MDS; Untreated; High risk myelodysplastic syndrome; Intermediate-2 Myelodysplastic syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: MEI-003