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

• ClinicalTrials.gov Identifier: NCT03151408
• Recruitment Status: Terminated
• First Posted: May 12, 2017
• Results First Posted: March 10, 2022
• Last Update Posted: March 10, 2022
• Sponsor: Helsinn Healthcare SA
• Collaborator: Clinipace Worldwide
• Information provided by (Responsible Party): Helsinn Healthcare SA

Tracking Information

• First Submitted Date: May 5, 2017
• First Posted Date: May 12, 2017
• Results First Submitted Date: August 20, 2021
• Results First Posted Date: March 10, 2022
• Last Update Posted Date: March 10, 2022
• Actual Study Start Date: June 23, 2017
• Actual Primary Completion Date: August 20, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 28, 2021)

Overall Survival [ Time Frame: 826 days ]

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

Original Primary Outcome Measures (submitted: May 11, 2017)

Estimate efficacy rate [ Time Frame: from randomization until death from any cause, assessed up to 60 months ]

To show superiority in terms of overall survival (OS) of treatment with pracinostat (Group A - experimental group) versus placebo (Group B - control group) in patients treated with AZA as background therapy

Current Secondary Outcome Measures (submitted: November 4, 2021)

• Morphologic Complete Remission (CR) Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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

Original Secondary Outcome Measures (submitted: May 11, 2017)

• Morphologic Complete Remission (CR) rate [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  The CR rate is the proportion of patients who achieve a morphologic CR according to the response criteria
• Event Free Survival (EFS) [ Time Frame: from randomization until death from any cause, assessed up to 60 months ]
  EFS is defined as the time from randomization to the first documented occurrence of disease progression or disease relapse after CR, or patient death from any cause, whichever occurs first
• Duration of Complete Remission [ Time Frame: from complete remission until relapse, assessed up to 60 months ]
  Duration of Complete Remission is the time from the first documented morphologic CR using the response criteria until documented relapse or death. Duration of CR is only defined for patients who achieve a morphologic CR.

Current Other Pre-specified Outcome Measures (submitted: March 9, 2022)

• Composite Complete Remission (cCR) Rate [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Original Other Pre-specified Outcome Measures (submitted: May 11, 2017)

• Composite Complete Remission (cCR) rate [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  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
• Cytogenetic Complete Remission (CRc) rate [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  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
• Molecular Complete Remission rate (CRm) [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  The CRm rate is the proportion of patients who achieve a CR with MRD negativity by multicolor flow cytometry. CRm will be evaluated at the first patient's CR and then after further 4 cycles of treatment
• Duration of Composite Complete Remission [ Time Frame: from cCR until relapse, assessed up to 60 months ]
  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
• Duration of Cytogenetic Complete Remission [ Time Frame: from cytogenetic complete remission until relapse, assessed up to 60 months ]
  Duration of cytogenetic complete remission is the time from first CRc until documented relapse (defined as reappearance of abnormal karyotype or relapse from CR) or death. Duration of CRc is only defined for patients who achieve a CRc
• Transfusion Independence (TI) [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  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
• Quality of Life [ Time Frame: from randomization until end of treatment, assessed up to 48 months ]
  Computation of the global health status and of selected functional scales and symptom scales from the EORTC QLQ-C30 questionnaire will be performed and their change from baseline over the study period will constitute the endpoints.

Descriptive Information

• Brief Title: An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia

Intervention

• Drug: Pracinostat
  60 mg capsule
  Other Name: SB939
• Drug: Placebos
  capsule
• Drug: Azacitidine
  SC or IV injection
  Other Name: AZA

Study Arms

• Experimental: Pracinostat plus AZA
  60 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.
  Interventions:

  • Drug: Pracinostat
  • Drug: Azacitidine
• Placebo Comparator: Placebo plus AZA
  1 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.
  Interventions:

  • Drug: Placebos
  • Drug: Azacitidine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 4, 2020): 406
• Original Estimated Enrollment (submitted: May 11, 2017): 500
• Actual Study Completion Date: August 20, 2020
• Actual Primary Completion Date: August 20, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Brazil, Czechia, France, Germany, Hungary, Italy, Korea, Republic of, Poland, Romania, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03151408
• Other Study ID Numbers: PRAN-16-52
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Helsinn Healthcare SA
• Original Responsible Party: Same as current
• Current Study Sponsor: Helsinn Healthcare SA
• Original Study Sponsor: Same as current
• Collaborators: Clinipace Worldwide

Investigators

• Study Chair: Guillermo Garcia-Manero, MD; MD Anderson

• PRS Account: Helsinn Healthcare SA
• Verification Date: February 2022