A Phase II Randomized, Double-Blinded, 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)
This is a Phase II randomized, placebo-controlled trial of pracinostat/placebo in combination with azacitidine. Patients will be randomized (1:1) to one of two groups: Group 1 (experimental group) pracinostat plus azacitidine will be compared to Group 2 (control group) placebo plus azacitidine. Trial therapies should be continued until disease progression or intolerable toxicity. It is important to note that the median time to achieving a response with azacitidine is 4 to 5 months. Therefore, early ( less than 6 months) discontinuation of trial therapy for no response should be avoided. Primary Objective The primary objective of this study is to: ï¿½ Estimate the relative efficacy, as measured by complete remission (CR) within 180 days following randomization, of pracinostat plus azacitidine versus placebo plus azacitidine. Secondary Objectives The secondary objectives of this study are to: ï¿½ Estimate the overall response rate [ORR equal to CR complete remission with incomplete blood count recovery (CRi)plus partial response (PR)] ï¿½ Estimate the overall hematologic improvement (HI) response rate ï¿½ Estimate the clinical benefit rate, which will be calculated by: ORR HI. ï¿½ Estimate the duration of response (DoR) ï¿½ 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 ï¿½ Estimate the rate of leukemic transformation at landmark time points (6 months, 12 months, 18 months, and 24 months) ï¿½ 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 ï¿½ Assess the tolerability and adverse event (AE) profile of pracinostat and placebo when combined with azacitidine.
Inclusion criteria: 1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care 2. Histologically or cytologically documented diagnosis of MDS (any French- American-British classification [FAB] subtype; that is classified as intermediate 2 (1.5 to 2.0 points) or high risk (greater than 2.5 points) according to the International Prognostic Scoring System (IPSS) risk category, with greater than 5% and less than 30% blasts and a peripheral blast count of less than 20,000. 3. Bone marrow aspirate smears and bone marrow biopsies within 28 days of first study treatment must be provided (at least 2 unstained slides each). If recent smears and biopsies are not available, this testing must be done at screening. The local laboratory will be used for enrollment assessment. 4. There must be a clinical indication for treatment with azacitidine. 5. Previously untreated with hypomethylating agents (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed) 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 7. Adequate organ function as evidenced by: ï¿½ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ï¿½ less than or equal to 2.5 x the upper limit of normal (ULN) ï¿½ Total bilirubin less than or equal to 1.5 x ULN or total bilirubin of 2 mg/dL, whichever is higher ï¿½ Serum creatinine less than 2 mg/dL, or creatinine clearance less than or equal to 1.5 x ULN ï¿½ QTcF interval less than or equal to 470 msec 8. Female or male patients greater than or equal to 18 years-of-age 9. Male patients who are surgically sterile or willing to use adequate contraceptive measures or abstain from heterosexual intercourse during the entire study treatment period 10. Female patients who are surgically sterile or post menopausal or female patients of childbearing potential who agree to use adequate contraceptive measures or abstain from heterosexual intercourse during the entire study treatment period, who are not breastfeeding, and who have had a negative serum pregnancy test less than or equal to 7 days prior to first study treatment 11. Willingness and ability to understand the nature of this trial and to comply with the trial and follow-up procedures. Exclusion criteria: 1. Received any of the following within the specified time frame prior to administration of study medication: ï¿½ Any investigational agent within 14 days or 5 half-lives prior to first study treatment, whichever is longer ï¿½ 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) ï¿½ Hydroxyurea within 48 hours prior to first study treatment ï¿½ 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. ï¿½ Major surgery within 4 weeks prior to first study treatment 2. Patients that have not recovered from side effects of previous therapy 3. Cardiopulmonary function criteria: ï¿½ Current unstable arrhythmia requiring treatment ï¿½ History of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV) ï¿½ History of myocardial infarction within 6 months of enrollment ï¿½ Current unstable angina 4. Concomitant treatment with histone deacetylase (HDAC) inhibitors or drugs with significant action as HDAC inhibitors, such as valproic acid, is not permitted 5. Clinical evidence of central nervous system involvement 6. Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). 7. Active infection with human immunodeficiency virus, chronic hepatitis B or C 8. 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 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, of nonmelanomatous skin cancer 10. Inability or unwillingness (including psychological, familial, sociological,
One-hundred patients will be enrolled in this trial and they will be randomized (1:1) to one of two groups: ï?· Group 1 (experimental group) pracinostat plus azacitidine ï?· Group 2 (control group) placebo plus azacitidine Pracinostat or placebo will be administered orally 3 days a week (e.g., Monday, Wednesday, and Friday) for the first 3 weeks of each 28-day cycle. Each 28-day cycle will include one week of rest from pracinostat/placebo dosing. All patients will receive a standard regimen of azacitidine at 75 mg/m2 for 7 days of each 28-day cycle. Delivery via subcutaneous (SC) injection is preferred, but intravenous (IV) infusion is allowed if SC injections are intolerable. Administration may be as one of two schedules. Schedule 1: continuous therapy on Days 1 through 7; or Schedule 2: a 5-2-2 schedule wherein patients receive azacitidine for 5 consecutive weekdays (Days 1 through 5) and resume azacitidine dosing the first two weekdays of the next week (Days 8 and 9) of each 28-day cycle. Each site will declare preference as to which schedule is preferred and use that preference throughout the trial for all enrolled patients.
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