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An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia

Phase 3
Terminated
Conditions
Acute Myeloid Leukemia
Interventions
Registration Number
NCT03151408
Lead Sponsor
Helsinn Healthcare SA
Brief Summary

This is a Phase III, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (AZA) as background therapy in patients ≥ 18 years of age with newly diagnosed acute myeloid leukemia (AML), excluding acute promyelocytic leukemia and cytogenetic low-risk AML, who are unfit to receive intensive remission induction chemotherapy due to age ≥ 75 years or comorbidities. Patients will be randomized in a 1:1 ratio to one of two groups: Group A (experimental group) to receive pracinostat plus AZA and Group B (control group) to receive placebo plus AZA. Randomization will be stratified by cytogenetic risk category (intermediate vs. unfavorable-risk, according to SWOG Cytogenetic Risk Category Definitions) and ECOG performance status (0-1 vs. 2). Treatments will be administered based on 28-day cycles, with pracinostat/placebo administered orally once every other day, 3 times a week for 3 weeks, followed by one week of no treatment and AZA administered for 7 days of each cycle. Study treatment should continue until there is documented disease progression, relapse from complete remission (CR), or non-manageable toxicity. A minimum of 6 cycles may be required to achieve a complete remission. Once permanently discontinued from study treatment, patients will enter the Long-term Follow-up phase of the study and will be followed for assessment of disease progression, if applicable, and survival every 3 months (±1 month) until death. The end of this study is defined when 390 events (deaths) have occurred and the study is unblinded for final overall survival analysis. Patients who are receiving study treatment at the end of the study may have the opportunity to continue to receive the study drugs to which they were randomized to (Post- Study Observation Period), until the Sponsor informs the Investigators of the appropriate course of action based on the study results. The Post-Study Observation Period is defined as the period starting from the end of the study for a maximum of 12 months.

Detailed Description

Not available

Recruitment & Eligibility

Status
TERMINATED
Sex
All
Target Recruitment
406
Inclusion Criteria
  1. Male or female patient ≥ 18 years of age with newly diagnosed, histologically or cytologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics

  2. Unable to receive intensive chemotherapy regimens at enrollment, based on one of the following:

    I. Age ≥ 75 years, or

    II. Age < 75 years with at least 1 of the following co-morbidities:

    1. An ECOG performance status of 2
    2. Clinically significant cardiovascular disease defined as:

    i. Left ventricular ejection fraction (LVEF) ≤ 50%, measured within 3 months prior to Day 1 confirmed by ECHO/MUGA ii. Congestive heart failure requiring medical therapy iii. Chronic stable angina requiring medical therapy iv. Prior cerebrovascular accident with sequelae c. Clinically significant pulmonary disease defined as: i. Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected ii. Lung diffusing capacity for carbon monoxide (DLCO) ≤ 65% of expected Confirmed by pulmonary tests. d. Diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, nephropathy, neuropathy, vasculopathy) e. 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) f. Class III obesity defined as a Body Mass Index (BMI) > 40 kg/m2 g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 115 µmol/L) or creatinine clearance <70 ml/min h. Clinically significant cognitive impairment defined as requiring medical therapy and/or assistance with activities of daily living

  3. 20% blasts in bone marrow

  4. Peripheral white blood cell (WBC) count 30,000/µL For cyto-reduction, hydroxyurea is allowed during screening and up to Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.

  5. ECOG performance status ≤ 2

  6. Adequate organ function as evidenced by the following laboratory findings:

    1. Total bilirubin ≤ 2 × upper limit of normal (ULN) or < 3 x ULN for patients with Gilbert-Meulengracht Syndrome
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
  7. Serum creatinine ≤ 1.5 × ULN according to institutional standards or creatinine clearance ≥ 50 mL/min

  8. QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 ms on electrocardiogram (ECG) at Screening

  9. 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 and for 3 months after the last administration of study drug

  10. 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

  11. Female patient who is of childbearing potential must have a negative serum pregnancy test result within 3 weeks prior to starting study drugs.

  12. Willing to provide voluntary written informed consent before performance of any study related procedure not part of normal medical care

  13. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria
  1. Able to receive intensive induction chemotherapy

  2. 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

  3. Presence 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

  4. 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

  5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classification

  6. Evidence of AML central nervous system (CNS) involvement

  7. Previous chemotherapy for AML except for the following, which are allowed:

    1. Hydroxyurea for cytoreduction
    2. 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 (Day 1)
  8. Use of experimental drugs ≤ 30 days prior to screening

  9. Received prior HDAC inhibitor therapy

  10. Received prior treatment with a hypomethylating agent, except as allowed in Exclusion Criterion 7.b

  11. Known hypersensitivity to any components of pracinostat, azacitidine, or mannitol

  12. History of human immunodeficiency virus (HIV) or an active and uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

  13. 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)

  14. 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

  15. Breast-feeding woman

  16. current smokers(use of patches, chewing gums and vaping nicotine conaining fluids is permitted). Patients who stopped smoking at least 8 day prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study

  17. prohibited concomitant medications

  18. uncontrolled infections

  19. receive more than 1 prior cycle of HMA or bone marrow transplant for any prior hematological disorder antecedent to AML

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Pracinostat plus AZAPracinostat60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.
Placebo plus AZAPlacebos1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.
Pracinostat plus AZAAzacitidine60 mg capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.
Placebo plus AZAAzacitidine1 capsule orally, once a day, 3 times a week for 3 weeks, followed by 1 week of rest of each 28-day cycle. As a background therapy azacitidine (AZA) will be administered at a dose of 75 mg/m2 by SC or IV injection daily for 7 days of each 28-day cycle.
Primary Outcome Measures
NameTimeMethod
Overall Survival826 days

OS measures the time from randomization to death due to any cause.

Secondary Outcome Measures
NameTimeMethod
Morphologic Complete Remission (CR) Rate744 days

The CR rate is the proportion of patients who achieve a morphologic CR according to the response criteria

* \<5% blasts in a bone marrow aspirate sample with spicules

* There should be no blasts with Auer rods

* No EMD

* Absolute Neutrophil Count (ANC) ≥1,000/μL

* Platelet count of ≥100,000/μL

* Patient must be independent of transfusions (for at least 1week before each assessment)

Complete Remission Without Minimal Residual Disease (CRmrd) Rate826 days

proportion of patients who achieve a CR without minimal residual disease by multicolor flow cytometry according to the following criteria

* Morphologic CR

* Minimal Residual Disease (MRD) by MFC negative

Cytogenetic Complete Remission (CRc) Rate826 days

The CRc rate is the proportion of patients who achieve a reversion to a normal karyotype at CR within the study period. This endpoint applies only to patients with abnormal cytogenetic at enrollment according to the following criterion

Morphologic CR plus reversion to a normal karyotype (defined as no clonal abnormalities detected in a minimum of 20 mitotic cells)

Transfusion Independence (TI)826 days

Transfusion independence rate is defined as the proportion of patients who show eight weeks or over without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion during study period

Trial Locations

Locations (138)

Mayo clinic hospital

🇺🇸

Phoenix, Arizona, United States

Arizona Oncology Associates, East Valley Cancer Center

🇺🇸

Tempe, Arizona, United States

University of Arizona cancer center-north campus

🇺🇸

Tucson, Arizona, United States

10666 N.Torrey Pines-Scripps Cancer Center

🇺🇸

La Jolla, California, United States

UC San Diego Moores Cancer Center

🇺🇸

La Jolla, California, United States

Georgetown University Medical Center

🇺🇸

Washington, District of Columbia, United States

Saint alphonsus Regional medical center-cancer care center

🇺🇸

Boise, Idaho, United States

Loyola University Chicago

🇺🇸

Maywood, Illinois, United States

Universitz of Kansas Cancer Center

🇺🇸

Westwood, Kansas, United States

Norton Cancer Institute, St. Matthews Campus

🇺🇸

Louisville, Kentucky, United States

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Mayo clinic hospital
🇺🇸Phoenix, Arizona, United States
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