Clinical trial NCT01993641: Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndrome
MDS
Keywords: Myelodysplastic Syndrome
MDS
pracinostat
Hypomethylating Agent
HMA
azacitadine
Vidaza
decitabine
dacogen
Lead sponsor: Helsinn Healthcare SA
Sponsor class: INDUSTRY
First posted: 2013-11-25
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Estimate clinical improvement
timeFrame: 6 months
Secondary outcomes:
measure: Estimate Overall Response Rate (ORR), including all Complete and Partial Responses, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses
timeFrame: 6 months
measure: Estimate Complete Response (CR) rate
timeFrame: 6 months
measure: Estimate Hematologic Improvement (HI) rate
timeFrame: 6 months
measure: Estimate Duration of Response (DoR)
timeFrame: 6 months
measure: Estimate Progression Free Survival (PFS)
timeFrame: 6-12 months
measure: Estimate Event Free Survival (EFS)
timeFrame: 12 months
measure: Estimate Overall Survival (OS)
timeFrame: 6-24 months
measure: Assess the safety profile of the combination
timeFrame: 12 months
measure: Estimate Marrow CR rate
timeFrame: 6 months
measure: Assess transfusion independence
timeFrame: 6 months
measure: Estimate Stable Disease (SD) rate
timeFrame: 6 months
measure: Estimate Cytogenetic Response rate
timeFrame: 6 months
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Southern Cancer Center
state: Alabama
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: Sutter Medical Group
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialist South
state: Florida
city: St Petersburg
country: United States
facility: Florida Cancer Specialist North
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Hackensak
country: United States
facility: John Theurer Cancer Center
state: New Jersey
city: Cincinati
country: United States
facility: Oncology Hematology Care
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Science Center
state: Oklahoma
city: Chattanooga
country: United States
facility: Tennessee Oncology-Chattanooga
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Guillermo Garcia-Manero, MD
role: PRINCIPAL_INVESTIGATOR
References: