Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) (EPIC)

Chronic Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01650805
• Other study ID #: AP24534-12-301
• Status: Terminated
• Phase: Phase 3
• First received: July 18, 2012
• Last updated: November 5, 2014
• Start date: June 2012
• Est. completion date: October 2013

Study information

• Verified date: October 2014
• Source: Ariad Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEuropean Union: European Medicines AgencyCanada: Health CanadaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationNew Zealand: Medicines and Medical Devices Safety AuthorityTaiwan: National Laboratories of Foods and DrugsIsrael: Israeli Health Ministry Pharmaceutical AdministrationHong Kong: Department of HealthJapan: Pharmaceuticals and Medical Devices AgencyKorea: Food and Drug AdministrationSingapore: Health Sciences AuthoritySouth Africa: Medicines Control CouncilSwitzerland: Swissmedic
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 307
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• ponatinib
45 mg tablet, taken orally once daily
• imatinib (Gleevec/ Glivec)
400 mg tablet, taken orally once daily

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ariad Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czech Republic,  Finland,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Poland,  Portugal,  Puerto Rico,  Singapore,  Slovakia,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major Molecular Response (MMR) Rate at 12 Months	A ratio of reverse transcribed transcript of BCR-ABL to ABL = 0.1% on the international scale, measured by real-time quantitative polymerase chain reaction.	12 months after first dose	No
Secondary	MMR Rate	To compare the efficacy of ponatinib with imatinib, as measured by MMR rate, at 5 years	5 years after first dose	No
Secondary	<10% BCR-ABL^IS Rate	To compare the proportion of patients achieving a ratio of <10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (<10% BCR-ABL^IS), in patients administered ponatinib versus those administered imatinib	3 months after first dose	No
Secondary	Complete Cytogenetic Response (CCyR) Rate	The percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. Responses are defined as follows: Complete (CCyR): 0% Ph+ metaphases.	12 months after first dose	No
Secondary	Progression-free Survival	To compare, according to treatment with ponatinib versus imatinib, progression-free survival	Up to 8 years after the last patient's first dose	No
Secondary	Overall Survival	To compare, according to treatment with ponatinib versus imatinib, overall survival	Up to 8 years after the last patient's first dose	No