Clinical trial NCT01650805: Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) (EPIC)
Official title: A Phase 3 Randomized,Open-Label Study of Ponatinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia
Keywords: Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Lead sponsor: Ariad Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2012-07-26
Enrollment: 307
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: The purpose of this study is to compare the efficacy of ponatinib and imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase.

Detailed description: This multicenter, international, phase 3 trial will test the hypothesis that ponatinib is an effective treatment for newly diagnosed CP-CML patients when compared with standard imatinib.

Patients will be randomized in a 1:1 fashion, stratified by Sokal risk score at diagnosis (low, intermediate, high), to receive once daily oral administration of either ponatinib or imatinib. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various timepoints; time to, duration of, and durability of responses; and survival follow-up. Safety measures include clinical laboratory testing, adverse event monitoring, vital signs, physical exams, ECGs, and ECHOs. Other measures include two patient-reported health outcomes questionnaires (FACT-Leu and EQ-5D-5L), determination of mutation status, and, for ponatinib only, measurement of steady-state plasma concentration. Accrual is expected to take approximately 2 years, and patients will be followed for survival for up to 8 years after the last patient's first dose; therefore, patient participation may last up to 10 years.

Eligibility criteria: Inclusion Criteria:

1. CP CML within 6 months of diagnosis

   * CP-CML will be defined by (i) \<15% blasts in bone marrow; (ii) \<30% blasts plus promyelocytes in bone marrow; (iii) \<20% basophils in peripheral blood; (iv) ≥100 × 10\^9/L platelets (≥100,000/mm\^3); (v) No evidence of extramedullary disease except hepatosplenomegaly; AND (vi) No prior diagnosis of AP-CML or BP-CML
2. Cytogenetic assessment must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome

   * (a)Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques; (b) Conventional chromosome banding must be performed; AND (c) A minimum of 20 metaphases must be assessable at entry
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
4. Adequate hepatic function as defined by the following criteria:

   (a) Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome; (b) Alanine aminotransferase (ALT) ≤2.5 × ULN; AND (c) Aspartate aminotransferase (AST) ≤2.5 × ULN
5. Adequate renal function as defined as defined by serum creatinine \<1.5 x ULN
6. Adequate pancreatic function as defined by serum lipase and amylase ≤1.5 × ULN

Exclusion Criteria:

1. Received prior imatinib therapy
2. Received prior dasatinib therapy
3. Received prior nilotinib therapy
4. Received, for CML, any other systemic anticancer therapy, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea
5. Major surgery within 28 days prior to initiating therapy
6. History of bleeding disorder unrelated to CML
7. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
8. History of alcohol abuse
9. Have uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL)
10. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

    1. Myocardial infarction, within 6 months prior to randomization
    2. Unstable angina within 6 months prior to randomization
    3. Congestive heart failure within 6 months prior to randomization
    4. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia
    5. Any history of ventricular arrhythmia
    6. Cerebrovascular accident or transient ischemic attack within 6 months prior to randomization
    7. Any history of peripheral arterial occlusive disease requiring revascularization
    8. Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism
11. Uncontrolled hypertension (diastolic blood pressure \>90 mm Hg; systolic \>140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control
12. Taking medications that are known to be associated with Torsades de Pointes
13. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection
14. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history
15. Pregnant or breastfeeding
16. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs
17. Diagnosed with or received anticancer therapy for another primary malignancy within 3 years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ)
18. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug

Primary outcomes:
measure: Major Molecular Response (MMR) Rate at 12 Months
timeFrame: 12 months after first dose
Secondary outcomes:
measure: MMR Rate
timeFrame: 5 years after first dose
measure: <10% BCR-ABL^IS Rate
timeFrame: 3 months after first dose
measure: Complete Cytogenetic Response (CCyR) Rate
timeFrame: 12 months after first dose
measure: Progression-free Survival
timeFrame: Up to 8 years after the last patient's first dose
measure: Overall Survival
timeFrame: Up to 8 years after the last patient's first dose
Other outcomes:
Locations:
city: Burbank
country: United States
facility: US Oncology - Providence Health System, Site #167
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Medicine, Site #027
state: California
city: Pleasant Hill
country: United States
facility: Bay Area Cancer Research Group, Site #156
state: California
city: Pleasant Hill
country: United States
facility: Bay Area Cancer Research Group, Site #157
state: California
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers, Site #191
state: Colorado
city: Southington
country: United States
facility: Cancer Center of Central Connecticut, Site #147
state: Connecticut
city: Newark
country: United States
facility: Christiana Care Health Services, Site #155
state: Delaware
city: Boynton Beach
country: United States
facility: University Cancer Institute, Site #149
state: Florida
city: Fort Meyers
country: United States
facility: Florida Cancer Specialists, Site #180
state: Florida
city: St. Petersburg
country: United States
facility: Florida Cancer Specialists, Site #179
state: Florida
city: Atlanta
country: United States
facility: Emory University, Site #058
state: Georgia
city: Chicago
country: United States
facility: John H. Stroger, Jr. Hospital of Cook County, Site #192
state: Illinois
city: Chicago
country: United States
facility: University of Chicago, Site #001
state: Illinois
city: Maywood
country: United States
facility: Loyola University Chicago, Site #054
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan St. Francis Health, Site #138
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics, Site #050
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology Associates, Site #198
state: Iowa
city: Wichita
country: United States
facility: US Oncology - Cancer Center of Kansas, Site #168
state: Kansas
city: Shreveport
country: United States
facility: Willis-Knighton Cancer Center, Site #196
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland, Greenebaum Cancer Center, Site #040
state: Maryland
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center, Site #140
state: Maryland
city: Baltimore
country: United States
facility: St. Agnes Healthcare, Site #185
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital, Site #047
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute, Site #008
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Worcester, Site #152
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center, Site #011
state: Michigan
city: Southfield
country: United States
facility: Providence Cancer Institute, Site #197
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Site #044
state: Minnesota
city: St. Louis Park
country: United States
facility: Oncology Research Park Nicollet Institute, Site #195
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital, Site #162
state: Missouri
city: Springfield
country: United States
facility: Mercy Clinic - Cancer & Hematology, Site #151
state: Missouri
city: Lincoln
country: United States
facility: Nebraska Hematology-Oncology, P.C., Site # 133
state: Nebraska
city: Las Vegas
country: United States
facility: US Oncology - Comprehensive Cancer Center of Nevada, Site #169
state: Nevada
city: Hackensack
country: United States
facility: John Theurer Cancer Center, Site #128
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center, Site #166
state: New Mexico
city: Brooklyn
country: United States
facility: Maimonides Cancer Center, Site #177
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital, Site #153
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center, Site #145
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine, Site #189
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center, Site #078
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College, Site #006
state: New York
city: Valhalla
country: United States
facility: New York Medical College, Site #146
state: New York
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology Center, Site #188
state: North Carolina
city: Middletown
country: United States
facility: Signal Point Clinical Research Center, Site #139
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma, Site #028
state: Oklahoma
city: Portland
country: United States
facility: Providence Cancer Center Oncology and Hematology Care Eastside, Site #194
state: Oregon
city: Portland
country: United States
facility: Kaiser Permanente Northwest, Site #200
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University, Site #048
state: Oregon
city: Gettysburg
country: United States
facility: Gettysburg Cancer Center, Site #160
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital, Site #159
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina, Site #148
state: South Carolina
city: Sumter
country: United States
facility: Carolina Hematology Oncology, Site #143
state: South Carolina
city: Chattanooga
country: United States
facility: Associates in Oncology & Hematology, Site #186
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute, Site #076
state: Tennessee
city: Austin
country: United States
facility: US Oncology - Texas Oncology Austin, Site #172
state: Texas
city: Dallas
country: United States
facility: US Oncology - Texas Oncology Dallas, Site #171
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center, Site #178
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine, Site #063
state: Texas
city: Midland
country: United States
facility: US Oncology - Texas Oncology Midland, Site #173
state: Texas
city: San Antonio
country: United States
facility: US Oncology - Cancer Care Center of South Texas, Site #170
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, Site #043
state: Utah
city: Richmond
country: United States
facility: VCU Massey Cancer Center, Dalton Oncology Clinic, Site #069
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance, Site #100
state: Washington
city: Vancouver
country: United States
facility: US Oncology - Northwest Cancer Specialists, Site #174
state: Washington
city: Morgantown
country: United States
facility: West Virginia University, Site #154
state: West Virginia
city: Green Bay
country: United States
facility: Green Bay Oncology, Ltd. / St. Mary's Hospital Medical Center, Site #193
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin, Site #030
state: Wisconsin
city: Garran
country: Australia
facility: Canberra Hospital, Site #971
state: Australian Capital Territory
city: Sydney
country: Australia
facility: Royal North Shore Hospital, Site #941
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital, Site #951
state: South Australia
city: East Melbourne
country: Australia
facility: The Peter MacCallum Cancer Center, Site #950
state: Victoria
city: Melbourne
country: Australia
facility: Box Hill Hospital, Site #940
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital, Site #972
state: Western Australia
city: Wien
country: Austria
facility: Medizinische Universitat Wien / AKH, Universitatsklinik fur Inniere Medizin I, Site #561
city: Brussel
country: Belgium
facility: UZ Brussel - Department Hematology, Site #544
city: Bruxelles
country: Belgium
facility: Clinique Universitaire de Saint-Luc, Department of Haematology, Site #508
city: Gent
country: Belgium
facility: UZ Gent - Department Hematology, Site #756
city: Leuven
country: Belgium
facility: UZ Gasthuisberg - Department of Hematology, Site #700
city: Toronto
country: Canada
facility: University Health Network, Princess Margaret Hospital, Site #083
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital, Site #129
state: Quebec
city: Brno
country: Czech Republic
facility: Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika, Site #514
city: Hradec Kralove
country: Czech Republic
facility: FN Hradec Kralove, Site #517
city: Olomouc
country: Czech Republic
facility: Fakultni nemocnice Olomouc, Hematoonkologicka klinika, Site #515
city: Praha
country: Czech Republic
facility: Ustav hematologie a krevni transfuse, Site #516
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital, Site #542
city: Bordeaux
country: France
facility: Institut Bergonie, Site #772
city: Brest
country: France
facility: CHRU de Brest, Hopital Morvan, Site #523
city: Creteil Cedex
country: France
facility: CHU Henri Mondor, Site #520
city: Le Chesnay Cedex
country: France
facility: Centre Hospitalier de Versailles, Site #958
city: Lille Cedex
country: France
facility: Hospital Claude Huriez, Site #952
city: Marseille
country: France
facility: Institut Paoli Calmette, Site #519
city: Nancy Cedex
country: France
facility: CHU de Brabois, Site #953
city: Nantes Cedex
country: France
facility: CHU de Nantes, Site #521
city: Nice Cedex
country: France
facility: Service Hematologie - Hospital Archet I, Site #509
city: Paris
country: France
facility: Hopital Saint-Louis, Site #957
city: Paris
country: France
facility: Hospital Saint Antoine, Site #518
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud, Site #956
city: Poitiers
country: France
facility: CHU de Poitiers, Site #954
city: Toulouse Cedex
country: France
facility: CHU Purpan, Site #955
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, AÖR, Site #513
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin, Site #701
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus an der TU Dresden, Site #526
city: Freiburg
country: Germany
facility: Universitatsklinikum Freiburg, Site #527
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf, Site #524
city: Jena
country: Germany
facility: Universitatsklinikum Jena, Site #946
city: Koln
country: Germany
facility: Universitatsklinikum Koln-AOR, Site #525
city: Mannheim
country: Germany
facility: Universitat Heidelberg, CML - Studienzentrale III. Medizinische Klinik, Site #947
city: Munchen
country: Germany
facility: Klinikum rechts der Isar, Site #949
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital, Site #974
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital, Site #973
city: Bari
country: Italy
facility: Unita Operativa di Ematologia con Trapianto, Site #529
city: Bologna
country: Italy
facility: Istituto di Ematologia "L. & A. Seragnoli", Site #959
city: Catania
country: Italy
facility: A.O. Universitaria Policlinico Vittorio Emanuele di Catania, Site #530
city: Genova
country: Italy
facility: Clinica Ematologica, Site #528
city: Milan
country: Italy
facility: Ospedale Niguarda Ca' Granda di Milano, Site #531
city: Modena
country: Italy
facility: S.C. Ematologia, Site #960
city: Monza
country: Italy
facility: San Gerardo Hospital, Site #961
city: Napoli
country: Italy
facility: U.O.C Ematologia con trapianto di midollo osseo, Site #560
city: Napoli
country: Italy
facility: Universita Federico II, Site #510
city: Orbassano
country: Italy
facility: SCDU Medicina Interna II - Indirizzo Ematologico, Site #785
city: Rome
country: Italy
facility: Dipartimento di Biotecnologie Cellulari ed Ematologia Universita La Sapienza - Policlinico Umberto I, Site #511
city: Rome
country: Italy
facility: U.O. di Ematologia - Ospedale S. Eugenio, Site #962
city: Seocho-gu
country: Korea, Republic of
facility: The Catholic University of Korea, Site #938
state: Seoul
city: Amsterdam
country: Netherlands
facility: VU Medical Centre - Department Haematology, Site #948
city: Grafton
country: New Zealand
facility: Auckland City Hospital, Site #921
state: Auckland
city: Christchurch
country: New Zealand
facility: Christchurch Hospital, Site #922
city: Hamilton
country: New Zealand
facility: Waikato Hospital, Site #977
city: Takapuna
country: New Zealand
facility: North Shore Hospital, Site #976
city: Gdansk
country: Poland
facility: Klinika Hematologii i Transplantologii, Uniwersyteckie Centrum Medyczne, Site #548
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne, Site #546
city: Lodz
country: Poland
facility: Klinika Hematologii Wojewodzkiego Szpitala Specjalistycznego, Site #550
city: Rzeszow
country: Poland
facility: Oddzial Hematologii, Site #551
city: Wroclaw
country: Poland
facility: Katedra i Klinika Hematologii, Site #547
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia, Site #545
city: San Juan
country: Puerto Rico
facility: Fundacion de Investigacion de Diego, Site #199
city: Singapore
country: Singapore
facility: Singapore General Hospital, Site #939
city: Bratislava
country: Slovakia
facility: Narodny onkologicky ustav, Site #532
city: Martin
country: Slovakia
facility: Univerzitna nemocnica Martin, Site #533
city: A Coruna
country: Spain
facility: Complejo Hospitalario Universitario A Coruna, Hospital "Teresa Herrera," Site #554
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol, Site #512
city: Barcelona
country: Spain
facility: Hospital Clinic, Site #963
city: Girona
country: Spain
facility: Institut Catala d' Oncologia de Girona, S. de Hematologia Clinica, Site #734
city: Islas Baleares
country: Spain
facility: Hospital Universitari Son Espases, Site #553
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa, Site #555
city: Madrid
country: Spain
facility: Hospital Gregorio Maranon, Site #536
city: Madrid
country: Spain
facility: H.U. Ramon y Cajal, Site #538
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre, Site #537
city: Madrid
country: Spain
facility: Hospital La Paz, Site #966
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias, Site #535
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca, Site #965
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia, Site #964
city: Lund
country: Sweden
facility: Skane University Hospital, Site #944
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge, Site #534
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Solna, Site #763
city: Uppsala
country: Sweden
facility: Uppsala University Hospital, Site #945
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau, Site #541
city: St Gallen
country: Switzerland
facility: Kantonsspital St. Gallen, Site #707
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital, Site #980
city: Taiching
country: Taiwan
facility: China Medical University Hospital, Site #978
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital, Site #979
city: Edinburgh
country: United Kingdom
facility: Western General Hospital, Site #556
city: Gillingham
country: United Kingdom
facility: Kent and Medway Cancer Research Network, Site #558
city: Glasgow
country: United Kingdom
facility: University of Glasgow, Site #797
city: Leeds
country: United Kingdom
facility: St. James University Hospital, Site #540
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital, Site #969
city: London
country: United Kingdom
facility: Hammersmith Hospital, Site #967
city: Newcastle
country: United Kingdom
facility: Newcastle University, Site #970
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital Foundation Trust, Site #557
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust, Site #968
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust, Site #543
Study officials:
References:
citation: Hanley MJ, Diderichsen PM, Narasimhan N, Srivastava S, Gupta N, Venkatakrishnan K. Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development. J Clin Pharmacol. 2022 Apr;62(4):555-567. doi: 10.1002/jcph.1990. Epub 2021 Dec 16.
citation: Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW; EPIC investigators. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016 May;17(5):612-21. doi: 10.1016/S1470-2045(16)00080-2. Epub 2016 Apr 12.