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ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced twelve-month follow-up data from the pivotal PACE trial of
ponatinib, its investigational BCR-ABL inhibitor, in heavily pretreated patients with advanced forms of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The study now shows that 57 percent of accelerated-phase CML patients in the trial, including 50 percent of patients with the T315I mutation, achieved a major hematologic response (MaHR), the primary end-point for patients with advanced disease in the trial.
The data are being featured today at 8:00 a.m. (ET) in an oral presentation at the 54th Annual Meeting of the American Society of Hematology (ASH) being held in Atlanta, Georgia. ARIAD filed for regulatory approval of ponatinib in the third quarter of 2012 in the U.S. and in the E.U. based on clinical data from the pivotal PACE trial.
“Patients with advanced forms of Philadelphia chromosome-positive leukemia and those who have failed currently available therapy have limited treatment options available to them,” said Hagop M. Kantarjian, M.D., chairman and professor, Department of Leukemia, University of Texas M.D. Anderson Cancer Center. “The overall prognosis is poor for patients with advanced disease.”
“The pivotal PACE trial data show that ponatinib has robust activity in heavily pretreated patients with accelerated phase CML, more than doubling their reported best prior responses to available TKI therapy,” he added. “What is equally striking is that the median time to achieve a response to ponatinib among accelerated phase patients was only three weeks and that the median duration of major hematologic response in these patients is one year.”
Efficacy data were reported at ASH on 444 treated patients in six pre-specified cohorts at 45 mg of ponatinib administered orally once daily, including 177 treated patients with advanced disease ( i.e., accelerated and blast phase CML and Ph+ ALL).
Sixty percent of accelerated phase CML patients and 53 percent of blast-phase CML and Ph+ ALL patients in the trial had received three or more tyrosine kinase inhibitors (TKI) prior to enrollment.
Advanced disease patients had a blood test approximately every month for determination of hematologic response and a bone-marrow assessment approximately every two months for determination of cytogenetic response.
Advanced CML and Ph+ ALL patients evaluable for response (N=177)
Fifty-seven percent (47 of 83) of accelerated-phase patients achieved a MaHR, including 50 percent (9 of 18) of accelerated-phase patients with the T315I mutation. At study entry, the reported best prior response of MaHR or better to their most recent TKI among accelerated-phase patients was 21 percent.
Thirty-four percent (32 of 94) of blast-phase CML or Ph+ ALL patients achieved a MaHR, including 33 percent (15 of 46) of blast-phase CML or Ph+ ALL patients with the T315I mutation. At study entry, the reported best prior response of MaHR or better to their most recent treatment with a TKI among blast-phase CML or Ph+ ALL patients was 24 percent.
Thirty-nine percent (32 of 83) of accelerated-phase CML patients and 31 percent (29 of 94) of blast-phase CML or Ph+ ALL patients achieved a MCyR. Furthermore, 24 percent (20 of 83) of patients with accelerated-phase CML and 24 percent (23 of 94) of patients with blast-phase CML or Ph+ ALL achieved a complete cytogenetic response.
Median duration, progression-free survival and overall survival
In accelerated-phase CML patients, the median time to achieve a MaHR was 21 days, and the median duration of this response was 12 months. In blast-phase CML or Ph+ ALL patients, the median time to achieve a MaHR was 26 days, and the median duration of this response was 5 months.
Progression-free survival (PFS) in accelerated-phase CML patients was estimated to be 55 percent at 12 months (median, 18 months). Progression-free survival in blast-phase CML or Ph+ ALL patients was estimated to be 15 percent at 12 months (median, 3 months).
Overall survival at 12 months in accelerated-phase CML patients was estimated to be 84 percent (median not yet reached). Overall survival at 12 months in blast-phase CML or Ph+ ALL patients was estimated to be 33 percent, with a median overall survival of 7 months.
Safety profile (N=449)
The most common non-hematologic treatment-emergent adverse events across all patients in the PACE trial included rash (in 38% of patients), abdominal pain (38%), headache (35%), dry skin (35%), and constipation (34%), with the majority of these being grades 1 or 2 in severity.
The most common hematologic treatment-emergent adverse events were thrombocytopenia (42%), neutropenia (24%), and anemia (20%), which were primarily grades 3 or 4 in severity.
Pancreatitis and pneumonia were the most common non-hematologic treatment-emergent serious adverse events (5% each), followed by abdominal pain (4%), myocardial infarction (3%), congestive heart failure (3%), atrial fibrillation (3%), and pyrexia (3%). The most common hematologic serious adverse events were anemia, febrile neutropenia, and thrombocytopenia (3% each).
Internally discovered at ARIAD, ponatinib is an investigational BCR-ABL inhibitor that also selectively inhibits certain other tyrosine kinases in preclinical studies, including FLT3, RET, KIT, and the members of the FGFR, PDGFR and VEGFR families of kinases.