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

Phase 2

Completed

• Conditions: Myelodysplastic Syndrome; MDS
• Interventions: Drug: pracinostat; Drug: Azacitidine; Drug: Decitabine

• Registration Number: NCT01993641
• Lead Sponsor: Helsinn Healthcare SA

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 available

Study Timeline

• Study First Submitted: 2013-11-14
• Study First Submitted QC: 2013-11-19
• Study First Posted: 2013-11-25
• Study Start: 2013-12
• Primary Completion: 2015-05
• Study Completion: 2016-06
• Disposition First Submitted: 2016-09-12
• Status Verified: 2017-02
• Disposition First Submitted QC: 2017-02-22
• Last Update Submitted: 2017-02-22
• Disposition First Posted: 2017-02-23
• Last Update Posted: 2017-02-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pracinostat added to HMA	pracinostat	Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient
Pracinostat added to HMA	Azacitidine	Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient
Pracinostat added to HMA	Decitabine	Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient

Primary Outcome Measures

Name	Time	Method
Estimate clinical improvement	6 months	Clinical Improvement Rate defined as the proportion of patients with CR, Marrow CR, PR, and HI.

Secondary Outcome Measures

Name	Time	Method
Estimate Overall Response Rate (ORR), including all Complete and Partial Responses, Marrow CR, HI, SD, transfusion independence, and cytogenetic responses	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	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 Event Free Survival (EFS)	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)	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.
Estimate Marrow CR rate	6 months	Marrow CR rate, defined as bone marrow \<5% myeloblasts and decrease by \> 50% over pretreatment according to IWG criteria.
Estimate Stable Disease (SD) rate	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	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.
Estimate Hematologic Improvement (HI) rate	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)	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)	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
Assess the safety profile of the combination	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.
Assess transfusion independence	6 months	Transfusion independence, defined as during the treatment period the patient had no RBC transfusions during any 56 consecutive days or more.

Trial Locations

Locations (21)

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of Kansas Cancer Center; 🇺🇸 Westwood, Kansas, United States

University of Oklahoma Health Science Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

Cancer Care Centers of South Texas; 🇺🇸 San Antonio, Texas, United States

Southern Cancer Center; 🇺🇸 Mobile, Alabama, United States

Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

City of Hope; 🇺🇸 Duarte, California, United States

Florida Cancer Specialist South; 🇺🇸 Fort Myers, Florida, United States

Sutter Medical Group; 🇺🇸 Sacramento, California, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Florida Cancer Specialist North; 🇺🇸 St Petersburg, Florida, United States

John Theurer Cancer Center; 🇺🇸 Hackensak, New Jersey, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

Oncology Hematology Care; 🇺🇸 Cincinati, Ohio, United States

Baylor University Medical Center; 🇺🇸 Dallas, Texas, United States

Tennessee Oncology-Chattanooga; 🇺🇸 Chattanooga, Tennessee, United States

University of Texas Southwestern; 🇺🇸 Dallas, Texas, United States

Yale School of Medicine; 🇺🇸 New Haven, Connecticut, United States