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Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA (MEI-005)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01993641
Recruitment Status : Completed
First Posted : November 25, 2013
Last Update Posted : February 23, 2017
Sponsor:
Information provided by (Responsible Party):
Helsinn Healthcare SA

Tracking Information
First Submitted Date  ICMJE November 14, 2013
First Posted Date  ICMJE November 25, 2013
Last Update Posted Date February 23, 2017
Study Start Date  ICMJE December 2013
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
Estimate clinical improvement [ Time Frame: 6 months ]
Clinical Improvement Rate defined as the proportion of patients with CR, Marrow CR, PR, and HI.
Original Primary Outcome Measures  ICMJE
 (submitted: November 19, 2013)
Estimate clinical improvement [ Time Frame: 6 months ]
Clinical Improvement Rate defined as the proportion of patients with CR, PR, and HI.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
  • Estimate Overall Response Rate (ORR), including all Complete and Partial Responses, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses [ Time Frame: 6 months ]
    Overall Response Rate (ORR), defined as the proportion of patients with CR, PR, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses according to the IWG criteria
  • Estimate Complete Response (CR) rate [ Time Frame: 6 months ]
    Complete response (CR) rate, defined as the proportion of patients with a confirmed CR (i.e., confirmed by a CBC at least 4 weeks after CR) according to the IWG criteria
  • Estimate Hematologic Improvement (HI) rate [ Time Frame: 6 months ]
    Hematologic improvement (HI) rate, defined as the proportion of patients who demonstrate major hematologic improvement as defined by the IWG criteria. Only patients with pre-treatment abnormal values will be considered for this endpoint at 8 weeks.
  • Estimate Duration of Response (DoR) [ Time Frame: 6 months ]
    Duration of Response (for patients who have achieved CR, PR, or HI), defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first. For patients who are alive and have not experienced disease progression on study (prior to receiving subsequent/new treatment or stem cell transplant), duration of response will be censored at the day of the last adequate disease assessment.
  • Estimate Progression Free Survival (PFS) [ Time Frame: 6-12 months ]
    Progression-Free survival (PFS), defined as the time from first day of study drug administration (Day 1) to either disease progression or death. Patients who have not progressed or are alive will be censored at the date of last adequate disease assessment
  • Estimate Event Free Survival (EFS) [ Time Frame: 12 months ]
    Event Free Survival (EFS) defined as the time from first day of study drug administration (Day 1) to failure or death from any cause according to the IWG response criteria. Patients who have not progressed, are alive or died without progression will be censored at the date of last adequate disease assessment
  • Estimate Overall Survival (OS) [ Time Frame: 6-24 months ]
    Overall Survival (OS), defined as the time from the first day of study drug administration (Day 1) to death on study. Patients who are alive will be censored at the date last known alive.
  • Assess the safety profile of the combination [ Time Frame: 12 months ]
    Assess the adverse event (AE) profile of pracinostat combined with either azacitidine or decitabine by clinical review of safety events by grade, relationship and event outcomes.
  • Estimate Marrow CR rate [ Time Frame: 6 months ]
    Marrow CR rate, defined as bone marrow <5% myeloblasts and decrease by > 50% over pretreatment according to IWG criteria.
  • Assess transfusion independence [ Time Frame: 6 months ]
    Transfusion independence, defined as during the treatment period the patient had no RBC transfusions during any 56 consecutive days or more.
  • Estimate Stable Disease (SD) rate [ Time Frame: 6 months ]
    Stable disease rate defined as failure to achieve at least a PR, but no evidence of progression for > 8 weeks according to IWG criteria.
  • Estimate Cytogenetic Response rate [ Time Frame: 6 months ]
    Cytogenetic response rate, defined as complete disappearance of the chromosomal abnormality without appearance of new abnormalities, or partial response of at least 50% reduction of the chromosomal abnormality according to IWG criteria.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2013)
  • Estimate Overall Response Rate (ORR), including all Complete and Partial [ Time Frame: 6 months ]
    Overall Response Rate (ORR), defined as the proportion of patients with CR or PR, according to the IWG criteria
  • Estimate Complete Response (CR) rate [ Time Frame: 6 months ]
    Complete response (CR) rate, defined as the proportion of patients with a confirmed CR (i.e., confirmed by a CBC at least 4 weeks after CR) according to the IWG criteria
  • Estimate Hematologic Improvement (HI) rate [ Time Frame: 6 months ]
    Hematologic improvement (HI) rate, defined as the proportion of patients who demonstrate major hematologic improvement as defined by the IWG criteria. Only patients with pre-treatment abnormal values will be considered for this endpoint at 8 weeks.
  • Estimate Duration of Response (DoR) [ Time Frame: 6 months ]
    Duration of Response (for patients who have achieved CR, PR, or HI), defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first. For patients who are alive and have not experienced disease progression on study (prior to receiving subsequent/new treatment or stem cell transplant), duration of response will be censored at the day of the last adequate disease assessment.
  • Estimate Progression Free Survival (PFS) [ Time Frame: 6-12 months ]
    Progression-Free survival (PFS), defined as the time from first day of study drug administration (Day 1) to either disease progression or death. Patients who have not progressed or are alive will be censored at the date of last adequate disease assessment
  • Estimate Time to Progression (TTP) [ Time Frame: 12 months ]
    Time to Progression (TTP), defined as the time from first day of study drug administration (Day 1) to progression according to the IWG response criteria. Patients who have not progressed, are alive or died without progression will be censored at the date of last adequate disease assessment
  • Estimate Overall Survival (OS) [ Time Frame: 6-24 months ]
    Overall Survival (OS), defined as the time from the first day of study drug administration (Day 1) to death on study. Patients who are alive will be censored at the date last known alive.
  • Assess the safety profile of the combination [ Time Frame: 12 months ]
    Assess the adverse event (AE) profile of pracinostat combined with either azacitidine or decitabine by clinical review of safety events by grade, relationship and event outcomes.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA
Official Title  ICMJE 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
Brief Summary The purpose of this open label study is to determine whether combining pracinostat (study drug) with Vidaza (azacitidine) or Dacogen (decitabine) will improve clinical responses in Myelodysplastic Syndrome (MDS) patients who have failed an initial single agent hypomethylating agent (HMA), and to provide additional safety and efficacy data.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome
  • MDS
Intervention  ICMJE
  • Drug: pracinostat
    Histone deacetylase inhibitor (HDACi) Pracinostat is to be taken before HMA administration 3 times/week (e.g., Monday, Wednesday, and Friday) for 3 weeks, followed by 1 week of rest as a 28-day cycle. Pracinostat administration will be at the clinic on Day 1 of Cycles 1 and 2 and subject will self-administer at home on all other days
    Other Name: SB939
  • Drug: Azacitidine
    All patients will receive the dose and schedule of azacitadine to which they previously failed to respond. (e.g. 75 mg/m2 via subcutaneous (SC) injection or intravenous infusion if SC injections are intolerable; 7 days of each 28 day cycle, either Days 1-7, or Days 1-5, rest on Days 6-7, and azacitadine dosing on Days 8-9)
    Other Name: Vidaza
  • Drug: Decitabine

    All patients will receive the dose and schedule of decitabine to which they previously failed to respond. Common 28 day treatment regimens include: 20 mg/m2 IV for either 5 or 10 days of each 28-day cycle, 10 mg/m2 given intravenously daily for first 10 days of each 28 day cycle, or 20 mg/m2 given subcutaneously daily for the first 5 days of each 28 day cycle.

    The 6-week regimen utilizes a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days repeated every 6 weeks.

    Other Name: Dacogen
Study Arms  ICMJE Experimental: Pracinostat added to HMA
Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient
Interventions:
  • Drug: pracinostat
  • Drug: Azacitidine
  • Drug: Decitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 14, 2016)
45
Original Estimated Enrollment  ICMJE
 (submitted: November 19, 2013)
76
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Voluntary written informed consent
  2. Histologically or cytologically documented diagnosis of MDS (any French-American-British classification [FAB] subtype)
  3. Bone marrow blasts >5% and <30% 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 IWG criteria after receiving single agent azacitidine and/or single agent decitabine, or has worsening cytopenias (increased transfusion requirement), increased BM blasts, progression to a higher FAB type, or develops additional clinically significant cytogenetic abnormalities; Secondary failures: Relapse after any initial CR, PR, HI, or development of clinically significant cytogenetic abnormalities at any time according to IWG criteria after receiving single agent azacitidine or 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 azacitidine or 4 cycles of decitabine)

  6. Must have demonstrated tolerability to single agent HMA
  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. ECOG performance status of 0, 1, or 2
  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 are required to use two forms of acceptable contraception; Female patients of childbearing potential 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

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
    • Hydroxyurea within 48 hours prior to first study treatment
    • Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), 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 of study day 1
  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 Class III or IV)
    • History of myocardial infarction within 6 months of enrollment
    • Current unstable angina
  4. Concomitant treatment with agents that have activity against HDAC inhibitors is not permitted
  5. Clinical evidence of CNS involvement
  6. Patients with gastrointestinal (GI) tract disease, 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01993641
Other Study ID Numbers  ICMJE MEI-005
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Helsinn Healthcare SA
Study Sponsor  ICMJE Helsinn Healthcare SA
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Guillermo Garcia-Manero, MD M.D. Anderson Cancer Center
PRS Account Helsinn Healthcare SA
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP