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

• Pracinostat (Drug), also known as SB939: 60 mg capsule
• Placebos (Drug): capsule
• Azacitidine (Drug), also known as AZA: SC or IV injection

Primary outcomes

• Overall Survival [826 days]: OS measures the time from randomization to death due to any cause.

Secondary outcomes

• Morphologic Complete Remission (CR) Rate [744 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) Rate [826 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) Rate [826 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

Other outcomes

• Composite Complete Remission (cCR) Rate [744 days]: Composite complete remission (cCR) rate is the proportion of patients who achieve either a disease response of CR, CRi or MLFS (i.e., cCR = CR + CRi + MLFS) within the study period, according to the response criteria
• Duration of Composite Complete Remission [744 days]: Duration of cCR response is the time from first cCR until documented relapse (the definition of relapse from CR will be applied) or death. Duration of cCR is only defined for patients who achieve a cCR
• Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30) [from baseline up to 660 days]: QLQ-C30 is made of multi-item scales and single-item measures (functional and symptom scales, a global health status/QoL scale and single items). Item range is the difference between possible max and min response to individual items of the scale; most items take values from 1 to 4 (range=3). Global health status takes values from 1 to 7 (range = 6). For statistical analysis purpose, single-item and scale values were all standardized (according to linear transformation described in Scoring Manual) to obtain scores ranging 0-100. An high scale score represents an higher response level. Thus an high score for a functional scale represents an high/healthy level of functioning, an high score for the global health status/QoL represents a high QoL, an high score for a symptom scale/item represents an high level of symptomatology/problems.
• Relapse Free Survival [744 days]: the time from the date of achievement of CR or CRi until the date of relapse or death from any cause
• Progressive Free Survival Rate (PFS) [800 days]: PFS is defined as the time from the date of randomization until the date of relapse (progression), or death from any cause, whichever occurs first.
• Duration of Morphologic CR [744 days]: Duration of morphologic CR is defined as the time from the date of achievement of CR until the date of relapse (progression).
• Time to CR [616 days]: Time to CR is defined as the time from the date of randomization until the date of CR in the absence of interceding therapies. The analysis set was the ITT set.
• Morphologic CR Within 6 Cycles Rate [within 6 cycles]: Morphologic CR within 6 cycles rate is defined as the proportion of patients who achieved CR in the absence of interceding therapies within 6 treatment cycles (i.e., during treatment phase up to Day 1 of Cycle 7 included). Analysis was performed in the ITT set.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Overall Survival (Primary), Median, days: Pracinostat Plus AZA 303 (209 to 400); Placebo Plus AZA 303 (248 to 346) (p 0.8275)
• Morphologic Complete Remission (CR) Rate (Secondary), Count of participants, Participants: Pracinostat Plus AZA 24; Placebo Plus AZA 35 (p 0.1244)
• Complete Remission Without Minimal Residual Disease (CRmrd) Rate (Secondary), Count of participants, Participants: Pracinostat Plus AZA 12; Placebo Plus AZA 20 (p 0.1430)
• Cytogenetic Complete Remission (CRc) Rate (Secondary), Count of participants, Participants: Pracinostat Plus AZA 7; Placebo Plus AZA 8 (p 0.9977)
• Transfusion Independence (TI) (Secondary), Count of participants, Participants: Pracinostat Plus AZA 81; Placebo Plus AZA 81 (p 0.9959)
• Composite Complete Remission (cCR) Rate (Other pre specified), Count of participants, Participants: Pracinostat Plus AZA 73; Placebo Plus AZA 64 (p 0.3502)
• Duration of Composite Complete Remission (Other pre specified), Median, days: Pracinostat Plus AZA 576 (276 to NA); Placebo Plus AZA 319 (170 to 744) (p 0.0502)
• Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30) (Other pre specified), Mean, score on a scale: Pracinostat Plus AZA -7.040 +/- 31.4458; Placebo Plus AZA -2.303 +/- 28.6611
• Relapse Free Survival (Other pre specified), Median, days: Pracinostat Plus AZA 291 (217 to 429); Placebo Plus AZA 190 (155 to 319) (p 0.4656)
• Progressive Free Survival Rate (PFS) (Other pre specified), Median, days: Pracinostat Plus AZA 217 (126 to 257); Placebo Plus AZA 220 (182 to 271) (p 0.7063)
• Duration of Morphologic CR (Other pre specified), Median, days: Pracinostat Plus AZA NA (352 to NA); Placebo Plus AZA 319 (119 to 744) (p 0.0592)
• Time to CR (Other pre specified), Median, days: Pracinostat Plus AZA NA (NA to NA); Placebo Plus AZA 361 (311 to NA) (p 0.3835)
• Morphologic CR Within 6 Cycles Rate (Other pre specified), Number, number of patients: Pracinostat Plus AZA 14; Placebo Plus AZA 16 (p 0.7099)

Adverse events

Time frame: TEAEs are with onset date/time at or after start date/time of first intake of pracinostat /placebo, or AEs with onset date/time prior to start date/time of first intake of pracinostat/placebo that worsen in severity after start date/time of first intake of pracinostat /placebo, up to end of observation period. Observation period is defined as 30 days after last dose of pracinostat/placebo or start of new therapy for AML whichever occurs first up to 672 days. OS was collected up to 826 days.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Results of the interim analysis (OS curves crossing at about 300 days) demonstrated futility according to the planned threshold and concluded that it was unlikely to meet the primary endpoint compared to the control group at the final analysis. Based on this outcome, the decision taken was to discontinue the recruitment of patients and terminate the study.

38 more sites not listed.

• Study Protocol (PDF, 2019-12-16)
• Statistical Analysis Plan (PDF, 2020-11-11)

• Guillermo Garcia-Manero, MD, Study chair, MD Anderson