Acute Myeloid Leukemia
Conditions
Interventions
Clinical safety/efficacy, randomized, double-blinded, phase 3 trial of placebo versus pracinostat (PRA) in association to azacitidine (AZA). It will be included 500 patients of both sexes aged 18 year
Drug
E02.319.267.530.620
E02.319.267.082.750
Sponsors
Helsinn Healthcare SA
Clinipace Pesquisas Clínicas do Brasil Ltda. - CPWW
Eligibility
Inclusion criteria
Inclusion criteria: Male or female patients equal or older than 18 years of age with newly diagnosed, histologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics; patients unable to receive intensive chemotherapy regimens at enrollment, based on one of the following: a. age equal older than 75 years, or b. age less than 75 years with at least 1 of the following co-morbidities: b1. an ECOG performance status of 2, b2. clinically significant cardiovascular disease defined as: left ventricular ejection fraction (LVEF) equal or less than 50% measured within 3 months prior to Day 1, confirmed by ECHO/MUGA, congestive heart failure requiring medical therapy, chronic stable angina requiring medical therapy, prior cerebrovascular accident with sequelea, b3. clinically significant pulmonary disease defined as: forced expiratory volume in 1 second (FEV1) equal or less than 65% of expected, lung diffusing capacity for carbon monoxide (DLCO) equal or less than 65% of expected confirmed by pulmonary tests, b4. diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, nephropathy, neuropathy, vasculopathy), b5. autoimmune inflammatory conditions (e.g., rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel disease, or similar) requiring chronic disease modifying therapy (e.g., etanercept, adalimumab, infliximab, rituximab, methotrexate, or similar), b6. class III obesity defined as a Body Mass Index (BMI) more than 40 kg/m2, b7. renal impairment defined as serum creatinine greater than 1.3 mg/dL (greater than 115 ?mol/L) or creatinine clearance less than 70 mL/min, b8. clinically significant cognitive impairment defined as requiring medical therapy and/or assistance with activities of daily living; presence of at least 20% blasts in bone marrow; peripheral white blood cell (WBC) count less than 30,000/?L, for cyto-reduction, hydroxyurea is allowed during screening and up to Cycle 1, Days 1-14, to reduce WBC count to less than 30,000 ?L prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited; ECOG performance status less or equal to 2; adequate organ function as evidenced by the following laboratory findings: total bilirubin less than 2 × upper limit of normal (ULN) or less than 3 × ULN for patients with Gilbert-Meulengracht Syndrome, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less or equal to 2.5 × ULN; serum creatinine less or equal to 1.5 × ULN or creatinine clearance equal or greater than 50 mL/min according to institutional standards; QT-interval corrected according to Fridericia’s formula (QTcF) equal or less than 450 ms on electrocardiogram (ECG) at screening; male patient who is surgically sterile, or male patient who is willing to agree to remain completely abstinent (refrain from heterosexual intercourse) or who use barrier contraceptive measures and agree to refrain from donating sperm during the entire study treatment period; female patient who is of childbearing potential willing to use adequate contraceptive measures while participating on study, or willing to completely abstain from heterosexual intercourse during the entire study treatment period; female patient who is of childbearing potential must have a negative serum pregnancy test result within 3 weeks prior to starting study drugs; willing to provide voluntary written informed consent before performance of any study related
Exclusion criteria
Exclusion criteria: Able to receive intensive induction chemotherapy; AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e. promyelocytic leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or complex karyotypes; resence of an active malignant disease within the last 12 months, with the exception of adequately treated cervical cancer in-situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]). Other malignancies may be considered after consultation with the Medical Monitor; life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator’s opinion, could compromise the patient’s safety or put the study outcomes at risk; uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classification; evidence of central nervous system (CNS) involvement; previous chemotherapy for AML except for the following, which are allowed: hydroxyurea for cytoreduction, one course of hypomethylating agent therapy (i.e.; up to 7 doses of azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment (Day1); use of experimental drugs within 30 days prior to screening; received prior HDAC inhibitor therapy; received prior treatment with a hypomethylating agent, except as allowed in Exclusion Criterion 7.b; known hypersensitivity to any components of pracinostat, AZA, or mannitol; history of human immunodeficiency virus (HIV) or an active and uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus (HBV); gastrointestinal (GI) tract disease that causes an inability to take oral medication, malabsorption syndrome, or a requirement for IV alimentation; prior surgical procedures affecting absorption; or uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis); any disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of pracinostat and/or AZA, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics endpoint 1: to characterize the pharmacokinetics (PK) of pracinostat and its metabolite SB991 in AML patients by a population pharmacokinetic approach;Pharmacokinetics endpoint 2: to characterize demographic, physiopathological and therapeutic covariates that may influence pracinostat PK parameters and their interindividual variability;Pharmacokinetics endpoint 3: to characterize the pracinostat exposure-response relationship for safety and efficacy endpoints (PK/PD) ;Pharmacokinetics endpoint 4: to assess the possible drug interaction of Pracinostat on the PK of AZA in AML patients by comparing the descriptive statistics of PK parameters of azacitidine in the two groups;Primary efficacy endpoint: the primary efficacy endpoint is the overall survival measured as the time from randomization until death from any cause | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary efficacy endpoint 1: morphologic complete remission rate;Secondary efficacy endpoint 2: cytogenetic complete remission rate;Secondary efficacy endpoint 3: transfusion independence;Secondary efficacy endpoint 4: complete remission rate with no minimal residual disease (CRMRD-);Exploratory endpoint 1: composite complete remission rate;Exploratory endpoint 2: relapse free survival;Exploratory endpoint 3: duration of complete remission;Exploratory endpoint 4: duration of composite complete remission;Exploratory endpoint 5: quality of life | — |
Countries
Argentina, Australia, Austria, Brazil, Czech Republic, France, Germany, Hungary, Italy, Poland, Republic of Korea, Romania, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactDaniela Garcia
Clinipace Pesquisas Clínicas do Brasil Ltda. - CPWW
Outcome results
None listed