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

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ClinicalTrials.gov Identifier: NCT01650805
Recruitment Status : Terminated (Study terminated based on evaluation of safety data.)
First Posted : July 26, 2012
Results First Posted : October 21, 2014
Last Update Posted : November 17, 2014
Sponsor:
Information provided by (Responsible Party):
Ariad Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE July 18, 2012
First Posted Date  ICMJE July 26, 2012
Results First Submitted Date  ICMJE October 15, 2014
Results First Posted Date  ICMJE October 21, 2014
Last Update Posted Date November 17, 2014
Study Start Date  ICMJE June 2012
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2014)
Major Molecular Response (MMR) Rate at 12 Months [ Time Frame: 12 months after first dose ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 24, 2012)
Major Molecular response (MMR) rate [ Time Frame: 12 months after first dose ]
To compare the efficacy of ponatinib with imatinib as measured by major molecular response (MMR) rate at 12 months (1 month or cycle = 28 days)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2014)
  • MMR Rate [ Time Frame: 5 years after first dose ]
    To compare the efficacy of ponatinib with imatinib, as measured by MMR rate, at 5 years
  • <10% BCR-ABL^IS Rate [ Time Frame: 3 months after first dose ]
    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
  • Complete Cytogenetic Response (CCyR) Rate [ Time Frame: 12 months after first dose ]
    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.
  • Progression-free Survival [ Time Frame: Up to 8 years after the last patient's first dose ]
    To compare, according to treatment with ponatinib versus imatinib, progression-free survival
  • Overall Survival [ Time Frame: Up to 8 years after the last patient's first dose ]
    To compare, according to treatment with ponatinib versus imatinib, overall survival
Original Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2012)
  • <10% BCR-ABL^IS Rate [ Time Frame: 3 months after dose ]
    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
  • MMR Rate [ Time Frame: 18 months after first dose ]
    To compare, according to treatment with ponatinib versus imatinib, MMR rate at 18 months
  • Durable MMR rate [ Time Frame: 24 months after first dose ]
    To compare, according to treatment with ponatinib versus imatinib, the durable MMR rate at 24 months
  • Complete Cytogenetic Response (CCyR) Rate [ Time Frame: 12 months after first dose ]
    To compare, according to treatment with ponatinib versus imatinib, the CCyR rate at 12 months
  • Progression-free Survival [ Time Frame: Up to 8 years after the last patient's first dose ]
    To compare, according to treatment with ponatinib versus imatinib, progression-free survival
  • Overall Survival [ Time Frame: Up to 8 years after the last patient's first dose ]
    To compare, according to treatment with ponatinib versus imatinib, overall survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) (EPIC)
Official Title  ICMJE A Phase 3 Randomized,Open-Label Study of Ponatinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Myeloid Leukemia
Intervention  ICMJE
  • Drug: ponatinib
    45 mg tablet, taken orally once daily
  • Drug: imatinib (Gleevec/ Glivec)
    400 mg tablet, taken orally once daily
Study Arms  ICMJE
  • Experimental: ponatinib
    Intervention: Drug: ponatinib
  • Active Comparator: imatinib
    Intervention: Drug: imatinib (Gleevec/ Glivec)
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 18, 2013)
307
Original Estimated Enrollment  ICMJE
 (submitted: July 24, 2012)
528
Actual Study Completion Date  ICMJE October 2013
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01650805
Other Study ID Numbers  ICMJE AP24534-12-301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ariad Pharmaceuticals
Study Sponsor  ICMJE Ariad Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Ariad Pharmaceuticals
Verification Date October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP