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

Sponsor

Helsinn Healthcare SA (Industry)

Overall Status

Completed

CT.gov ID

NCT01993641

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

2.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome MDS	Drug: pracinostat Drug: Azacitidine Drug: Decitabine	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

45 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2013

Actual Primary Completion Date :

May 1, 2015

Actual Study Completion Date :

Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pracinostat added to HMA Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient	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 Names: 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 Names: 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 Names: Dacogen

Arm

Intervention/Treatment

Experimental: Pracinostat added to HMA

Pracinostat in combination with HMA treatment (either azacitidine or decitabine) used in initial single agent treatment for that patient

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 Names:

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 Names:

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 Names:

Dacogen

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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 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
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.
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.
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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Voluntary written informed consent
Histologically or cytologically documented diagnosis of MDS (any French-American-British classification [FAB] subtype)
Bone marrow blasts >5% and <30% and a peripheral white blood cell (WBC) count of <20,000 /µL
Bone marrow biopsy, aspirates, and peripheral blood smears within 28 days of first study treatment
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)

Must have demonstrated tolerability to single agent HMA
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
Not a candidate for hematopoietic stem cell transplant within 4 months of screening
ECOG performance status of 0, 1, or 2
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

Female or male patients ≥18 years-of-age
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.
Willingness and ability to understand the nature of this trial and to comply

Exclusion Criteria:

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

Patients who are candidates for aggressive chemotherapy (e.g. typical AML induction therapy)
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

Concomitant treatment with agents that have activity against HDAC inhibitors is not permitted
Clinical evidence of CNS involvement
Patients with gastrointestinal (GI) tract disease, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
Active infection with human immunodeficiency virus or chronic hepatitis B or C
Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could 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 and other concurrent malignancies will be considered on a case by case basis
Inability or unwillingness (including psychological, familial, sociological, or geographical conditions) to comply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Cancer Center	Mobile	Alabama	United States	36608
2	City of Hope	Duarte	California	United States	91010
3	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	Sutter Medical Group	Sacramento	California	United States	95816
5	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
6	Yale School of Medicine	New Haven	Connecticut	United States	06520
7	Florida Cancer Specialist South	Fort Myers	Florida	United States	33916
8	Florida Cancer Specialist North	St Petersburg	Florida	United States	33705
9	Northwestern University	Chicago	Illinois	United States	60601
10	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
11	University of Kentucky	Lexington	Kentucky	United States	40536
12	John Theurer Cancer Center	Hackensak	New Jersey	United States	07601
13	Oncology Hematology Care	Cincinati	Ohio	United States	45242
14	Cleveland Clinic	Cleveland	Ohio	United States	44195
15	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma	United States	73104
16	Tennessee Oncology-Chattanooga	Chattanooga	Tennessee	United States	37404
17	Tennessee Oncology	Nashville	Tennessee	United States	37203
18	Baylor University Medical Center	Dallas	Texas	United States	75246
19	University of Texas Southwestern	Dallas	Texas	United States	75390
20	MD Anderson Cancer Center	Houston	Texas	United States	77030
21	Cancer Care Centers of South Texas	San Antonio	Texas	United States	78229