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



Status:Recruiting
Conditions:Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology
Healthy:No
Age Range:18 - Any
Updated:2/22/2019
Start Date:June 23, 2017
End Date:May 2021
Contact:Silvia Mappa, MD
Email:silvia.mappa@helsinn.com
Phone:+41 91 985 18 78

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A Phase III, Double-Blind, Placebo-Controlled, Multicenter, Randomized Study Of Pracinostat In Combination With Azacitidine In Patients ≥18 Years With Newly Diagnosed Acute Myeloid Leukemia Unfit For Standard Induction Chemotherapy

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.


Inclusion Criteria:

1. Male or female patient ≥ 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

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

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
We found this trial at
28
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Stony Brook, New York 11794
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Bethesda, Maryland 20817
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1055 North Curtis Road
Boise, Idaho 83706
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Charlottesville, Virginia 22903
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4190 Teniente General Juan Domingo Perón
Ciudad Autonoma De Buenos Aire, Buenos Aires C1199
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Ciudad Autonoma De Buenos Aire,
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11100 Euclid Avenue
Cleveland, Ohio 44106
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120 Lakeview Circle
Covington, Louisiana 70433
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30160 Orchard Lake Road
Farmington Hills, Michigan 48334
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Greenville, South Carolina 29615
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Houston, Texas 77030
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Joplin, Montana 64804
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Knoxville, Tennessee 37920
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10666 North Torrey Pines Road
La Jolla, California 92037
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409 West Circle Drive
Lansing, Michigan 48910
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3991 Dutchmans Lane
Louisville, Kentucky 40202
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Oklahoma City, Oklahoma 73120
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Seattle, Washington 98108
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Seattle, Washington 98104
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Springfield, Missouri 65806
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12697 East 51st Street South
Tulsa, Oklahoma 74146
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Westwood, Kansas 66205
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Worcester, Massachusetts 01655
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