Clinical trial NCT03151408: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: AML
Lead sponsor: Helsinn Healthcare SA
Sponsor class: INDUSTRY
Collaborators: name: Clinipace Worldwide
First posted: 2017-05-12
Enrollment: 406
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival
timeFrame: 826 days
Secondary outcomes:
measure: Morphologic Complete Remission (CR) Rate
timeFrame: 744 days
measure: Complete Remission Without Minimal Residual Disease (CRmrd) Rate
timeFrame: 826 days
measure: Cytogenetic Complete Remission (CRc) Rate
timeFrame: 826 days
measure: Transfusion Independence (TI)
timeFrame: 826 days
Other outcomes:
measure: Composite Complete Remission (cCR) Rate
timeFrame: 744 days
measure: Duration of Composite Complete Remission
timeFrame: 744 days
measure: Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30)
timeFrame: from baseline up to 660 days
measure: Relapse Free Survival
timeFrame: 744 days
measure: Progressive Free Survival Rate (PFS)
timeFrame: 800 days
measure: Duration of Morphologic CR
timeFrame: 744 days
measure: Time to CR
timeFrame: 616 days
measure: Morphologic CR Within 6 Cycles Rate
timeFrame: within 6 cycles
Locations:
city: Phoenix
country: United States
facility: Mayo clinic hospital
state: Arizona
city: Tempe
country: United States
facility: Arizona Oncology Associates, East Valley Cancer Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona cancer center-north campus
state: Arizona
city: La Jolla
country: United States
facility: 10666 N.Torrey Pines-Scripps Cancer Center
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boise
country: United States
facility: Saint alphonsus Regional medical center-cancer care center
state: Idaho
city: Maywood
country: United States
facility: Loyola University Chicago
state: Illinois
city: Westwood
country: United States
facility: Universitz of Kansas Cancer Center
state: Kansas
city: Louisville
country: United States
facility: Norton Cancer Institute, St. Matthews Campus
state: Kentucky
city: Covington
country: United States
facility: Pontchartrain Cancer Center (Research Location)
state: Louisiana
city: Bethesda
country: United States
facility: Rcca Md Llc
state: Maryland
city: Worcester
country: United States
facility: UMass Memorial medical center-university campus
state: Massachusetts
city: Farmington Hills
country: United States
facility: Michigan Center of Medical Research
state: Michigan
city: Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Rochester
country: United States
facility: Mayo clinic
state: Minnesota
city: Springfield
country: United States
facility: Mercy Research
state: Missouri
city: Joplin
country: United States
facility: 100 Mercy Way
state: Montana
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center-2400 Pratt Street
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Cleveland Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Mercy Clinic Oncology & Hematology
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma cancer specialist and research institute
state: Oklahoma
city: Greenville
country: United States
facility: GHS Cancer Institute
state: South Carolina
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
city: Dallas
country: United States
facility: VA North texas Health Care sytem,Dallas VA Medical Center div. Hematology Oncology
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: Emily Couric Clinical cancer center
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: Thomas Reeve Chauncey
state: Washington
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Hospital italiano de Buenos Aires
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Instituto Medico Especializado Alexander Fleming
state: Buenos Aires
city: La Plata
country: Argentina
facility: hospital Italiano la Plata
state: Buenos Aires
city: Rosario
country: Argentina
facility: Sanatorio Britanico SA Paraguay 40, 3P
state: Santa Fe
city: Córdoba
country: Argentina
facility: sanatorio Allende
city: Córdoba
country: Argentina
facility: H ospi tal Privado de Cordoba
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine coast university hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Epping
country: Australia
facility: The Northern hospital Pharmacy Department, Ground Floor
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health, University Hospital Geelong
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital, Clinical Trial Pharmacy
state: Victoria
city: Liverpool
country: Australia
facility: Liverpool hospital
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Randwick
country: Australia
facility: Prince of Wales Hospital
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz GmbH
city: Salzburg
country: Austria
facility: Müllner Hauptstrabe 48
city: Vienna
country: Austria
facility: General Hospital Hietzing
city: Curitiba
country: Brazil
facility: Liga Paranaense de Com bate ao Cancer - Hospital Erasto Gaertner
state: Paranà
city: Jau
country: Brazil
facility: Ce ntro de Pesquisas Hospital Amara l Ca rvalh o
state: SP
city: São Paulo
country: Brazil
facility: Centro de Pesquisa Clinica do Hospital Santa Marcelina
state: SP
city: Barretos
country: Brazil
facility: Hospital de Cancer de Barretos
city: Belo Horizonte
country: Brazil
facility: Hospital Santa Casa de Belo Horizonte -Serviyo de Oncologia Clinica
city: Florianópolis
country: Brazil
facility: Centro de Pesquisas Oncologicas - CEPON
city: Porto Alegre
country: Brazil
facility: Hospital de ClÃ-nicas de Porto Alegre
city: Rio De Janeiro
country: Brazil
facility: Institute Nacional de Cancer Jose de Alencar Gomes da Silva-INCA
city: Santo André
country: Brazil
facility: Faculdade de Medicina do ABC - Centro de Estudos e Pesquisas de Hematologia e Oncologia
city: São José Do Rio Preto
country: Brazil
facility: Hospital de Base de Sao Jose do Rio Preto
city: Hradec Králové
country: Czechia
facility: "Fakultni nemocnice Hradec Kralove,
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomuc
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice
city: Praha
country: Czechia
facility: "Fakultni nemocnice Kralovske Vinohrady,
city: Praha
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady,
city: Amiens
country: France
facility: CHU Amiens Picardie-Site Sud-Service d'Hematologie
city: Nantes
country: France
facility: L'Hopital privé du Confluent SAS
city: Nice
country: France
facility: CHU de Nice, Archet 1 Hospital-Hematology department
city: Paris
country: France
facility: Hospital saints Louis
city: Pessac
country: France
facility: Haut-Leveque-Service d'hématologie clinique et de thérapie cellular
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rouen Cedex 1
country: France
facility: Centre Henri Becquerel
city: Erlangen
country: Germany
facility: Universitatsklinikum Erlangen
state: Bavaria
city: Amberg
country: Germany
facility: Klinikum St. Marien Amberg
state: Bayern
city: Herne
country: Germany
facility: Marien Hospital Herne-Universitätsklinikum der Ruhr-Universität Bochum
state: North Rhine-westphalia
city: Berlin
country: Germany
facility: Charité-Universitätsmedizin - 1. Campus Mitte
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera GmbH
city: Kiel
country: Germany
facility: Staedtisches krankenhaus kiel
city: Mainz
country: Germany
facility: Universitaet Mainz
city: Pécs
country: Hungary
facility: university of Pécs
state: Baranya
city: Pécs
country: Hungary
facility: Pecsi Egyetem I. Belgy6gyaszati Klinika
state: Baranya
city: Budapest
country: Hungary
facility: St. Istvan & St. Laszlo Hospital, Deapartment of Hematology and Stem Cell Transplantation
city: Debrecen
country: Hungary
facility: University of Debrecen Clinical Center
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz, Dep. Of Haematology
city: Nyiregyhaza
country: Hungary
facility: Szabolcs-Szatmar-Bereg megyei Korhazak es Egyetemi Oktatokorhaz â€" Josa Andras Oktatokorhaz, Hematologiai Osztaly
city: Milano
country: Italy
facility: Ospedale San Raffaele-U.O. Ematologia e TMO
state: Lombardia
city: Palermo
country: Italy
facility: Ospedale la Maddalena, UO Oncoematologia e TMO
state: PA
city: Bari
country: Italy
facility: AOU Policlinico Consorziale di Bari
city: Bologna
country: Italy
facility: AOU Policlinico Sant'Orsola-Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliera-Università Careggi
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino
city: Lecce
country: Italy
facility: ospedale Vito Fazzi
city: Naples
country: Italy
facility: Azienda Ospedaliere Antonio Cardarelli,
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
city: Pavia
country: Italy
facility: Fondazione IRCCS policlinico San Matteo Pavia
city: Roma
country: Italy
facility: Fondazione PTV-Policlinico Tor Vergata
city: Roma
country: Italy
facility: Policlinico Universitario Gemelli
city: Torino
country: Italy
facility: Azienda Ospedaliera Ordine Mauriziano
city: Busan
country: Korea, Republic of
facility: Inje university Busan Paik Hospital
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil medical center, div hematology
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital, Div.Hematology/Oncology
city: Seoul
country: Korea, Republic of
facility: Sumsung medical center
city: Seoul
country: Korea, Republic of
facility: Seoul St.Mary Hospital, div hemato-oncology
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Poznań
country: Poland
facility: Examen Sp. Z o.o.,
city: Wałbrzych
country: Poland
facility: Specjalistyc:my Szpi tal im. dra Alfreda Sokolowskiego
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny
city: Łódź
country: Poland
facility: Wojewodzkie Wielospecjalistyczne Centrum onkologii I traumatologii
city: Craiova
country: Romania
facility: Spitalul Clinic Filantropia
state: Jud.dolj
city: Bucuresti
country: Romania
facility: Spitalul Clinic Colentina
city: Bucuresti
country: Romania
facility: clinical hospital Coltea Bld
city: Bucuresti
country: Romania
facility: Spitalul Universitar de Urgenta Bucuresti
city: Cluj-Napoca
country: Romania
facility: Oncological Institute "Ion Chiricuta"
city: Iaşi
country: Romania
facility: institutu Regional de Oncologie Iasi
city: Badalona
country: Spain
facility: Institut Català D'Oncologia (ICO)
state: Barcelona
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
state: Extremadura
city: A Coruña
country: Spain
facility: Hosp.Universitario A Coruña-Hospital Teresa Herrera
state: Galicia
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Isla Baleares
city: Barcelona
country: Spain
facility: "Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario la Paz
city: Madrid
country: Spain
facility: Hospital Univers itario HM Sanchinarro
city: Salamanca
country: Spain
facility: Hospital Uni vcrsitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico de La Fe
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Changhua
country: Taiwan
facility: Hematology and Oncology, Changhwa Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospita
city: Taipei
country: Taiwan
facility: Division of Hematology, National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: koo-Foundation Sun Yat-Sen Cancer Center
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital (Wonford site)
state: Devon
city: Blackpool
country: United Kingdom
facility: Blackpool Teaching Hospitals NHS Foundation Trust
state: Lancashire
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals NHS Foundation trust
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire NHS Trust
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
Study officials:
affiliation: MD Anderson
name: Guillermo Garcia-Manero, MD
role: STUDY_CHAIR
References: