Safety and Efficacy Study of Pracinostat With Azacitadine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and effectiveness of pracinostat when combined with azacitadine for patients who are 65 years of age or older and have Acute Myelogenous Leukemia (AML)

Official Title
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A Phase II Open-Label, Single-arm, Two-Stage, Multicenter Trial of Pracinostat in Combination With Azacitidine in Elderly (Age 65 Years or Older) Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Pracinostat
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged ≥65 years. Voluntary written informed consent before performance of any study related procedure not part of normal medical care. Newly diagnosed de novo, secondary, or treatment-related AML with intermediate or unfavorable-risk cytogenetics based on the Southwest Oncology Group (SWOG) classifications (Slovak et al, 2000). One prior cycle of therapy with an approved hypomethylating agent (HMA) such as azacitidine or decitabine is allowed for either an antecedent hematologic disorder (AHD) or AML. Patients are also eligible if they have received lenolidamide, immunosuppressive therapy or low dose chemotherapy for their AHD. Prior hydroxyurea is allowed. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. ≥20% blasts in bone marrow. Peripheral WBC <30,000/uL. Adequate organ function as evidenced by: Total bilirubin 2x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)2.5x ULN Serum creatinine 2x ULN QT interval corrected according to Fridericia's formula (QTcF) ≤450 milliseconds (ms) for male subjects or ≤470 ms for female subjects on ECG at Screening. Male subjects who are surgically sterile or willing to use adequate contraceptive measures or abstain from heterosexual intercourse during the entire study treatment period. Female subjects who are not of childbearing potential. Willingness and ability to understand the nature of this study and to comply with the study and follow up procedures Exclusion Criteria: Acute promyelocytic leukemia (French-American-British [FAB] M3 classification). Known AML-associated t(15;17), t(8;21), t(16;16), del(16q), or inv(16) karyotype abnormalities. 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. Other malignancies will be considered on a case-by-case basis. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator's opinion, could compromise the subject's safety, or put the study outcomes at risk. Uncontrolled or symptomatic arrhythmias, unstable angina, or any Class 3 or 4 cardiac diseases as defined by the New York Heart Association (NYHA) Functional Classification. Clinical evidence of central nervous system (CNS) involvement. Are candidates for intensive chemotherapy (induction chemotherapy, bone marrow, or stem cell transplant) within the next 4 months. Received more than one prior cycle of HMA, previous bone marrow transplant or other intensive chemotherapy regimens for either an AHD or AML. Received prior radiation therapy for extramedullary disease within 2 weeks of study enrollment. Received prior histone deacetylase (HDAC) inhibitor or deacetylase (DAC) inhibitor is not permitted such as Istodax (romidepsin/depsipetide) or valproic acid. Received 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 study enrollment. Have been treated with any chemotherapeutic agent within 2 weeks or 5 half-lives of the first dose of study drug, whichever is longer. Are being treated with systemic corticosteroids. Inhaled and topical steroids as well as intermittent dexamethasone for nausea or vomiting are permitted. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Uncontrolled active systemic infections. Gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, 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 study drugs, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the subject inappropriate for this study.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pracinostat with azacitadine<br>60 mg of pracinostat by mouth 3 times a week for 3 weeks followed by 1 week of rest repeated every 28 days 75 mg/m2 azacitadine for the first 7 days of each 28 day cycle, via subcutaneous (SC) injection or intravenous (IV) infusion if SC injections are intolerable | Drug: Pracinostat<br>* Elderly newly diagnosed patients will all receive pracinostat<br>* Other names: SB939;Drug: Azacitidine<br>* Elderly newly diagnosed patients will all receive azacitadine<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response Rate | Proportion of patients assessed as having achieved a disease response of either CR or CRi or MLFS according to the IWG criteria. CR (ie, complete remission defined as <5% blasts in the bone marrow, no blasts with Auer rods, no extramedullary disease, ANC ≥1000/μL, and platelets ≥100,000/μL must be independent of transfusions for at least 1 week before each assessment). CRi (ie, morphologic complete remission with incomplete blood count recovery, defined as morphologic CR with residual neutropenia (<1,000/μL) or residual thrombocytopenia (<100,000/μL), no extramedullary disease, does not require transfusion independence) MLFS (ie, morphologic leukemia free state, defined as <5% blasts in an aspirate sample with marrow spicules, no extramedullary disease, does not require transfusion independence) | through study completion up to a maximum of three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | proportion of patients with CR plus CRi plus MLFS plus PR plus PRi | through study completion up to a maximum of three years | 
| Complete Cytogenetic Response Plus Molecular Complete Remission | proportion of patients assessed as having complete cytogenetic response (CRc) + molecular complete remission (CRm) to pracinostat plus azacitidine | through study completion up to a maximum of three years | 
| Progression Free Survival | time from the first day of study administration to PD, relapse from CR/CRi/MLFS, lack of efficacy or death. | through study completion up to a maximum of three years | 
| Overall Survival | time from the first day of study drug administration to death | through study completion up to a maximum of three years | 
| Duration of Best Response | The duration of the best response to treatment with pracinostat plus azacitidine was determined by the Investigator for patients who achieved a CR, CRi, or MLFS. The duration was defined as the time from the initial determination of response to the time of relapse, PD, or death, whichever occurred first plus 1 day. | through study completion up to a maximum of 3 years | 
| Duration of Response | The duration of the response to treatment with pracinostat plus azacitidine was determined by the Investigator for patients who achieved a CR, CRi, PR, PRi, or MLFS. The duration was defined as the time from the initial determination of response to the time of relapse, PD, or death, whichever occurred first plus 1 day. | through study completion up to a maximum of three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, open label, nonrandomized, single arm, elderly patients, HMA, newly diagnosed