ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced publication of results from the Phase 1 study of ponatinib, its investigational, tyrosine kinase inhibitor in heavily pretreated patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The paper was published today in the New England Journal of Medicine (Vol. 367, No. 22, Pages 2075-88). The article is accompanied by an editorial by John M. Goldman, D.M., F.R.C.P. of the Department of Haematology, Imperial College London (Pages 2148-49).
The Phase 1 dose-escalation study of ponatinib enrolled 81 patients with resistant hematologic cancers, including 60 patients with CML and five patients with Ph+ ALL. With median follow-up at 73 weeks, 72 percent of patients (31 of 43) with chronic-phase CML enrolled in the study had a major cytogenetic response (MCyR), including 92 percent (11 of 12) who had the T315I gatekeeper mutation, which is the most common mutation among resistant patients. It was estimated that 89 percent of patients with chronic-phase CML who had a MCyR would remain in response at 1 year (95% confidence interval, 69% to 96% by Kaplan–Meier analysis). Of 22 patients with accelerated-phase or blast-phase CML or Ph+ ALL, 36 percent (8 of 22) had a major hematologic response, and 32% (7 of 22) had a MCyR.
Dose-limiting toxicities reported in the study included elevated lipase or amylase levels and pancreatitis. The most common treatment-related adverse events included rash (32%), thrombocytopenia (27%), arthralgia (17%), increased lipase (15%), fatigue (14%), acneiform dermatitis (14%), dry skin (14%), and nausea (14%). Neutropenia, headache, hypertriglyceridemia and myalgia occurred less frequently. The incidence of pancreatitis was 14% across all dose levels in the trial. The onset of pancreatitis, elevated amylase, and elevated lipase was dose-related with regard to both incidence and timing.
“These findings demonstrate that ponatinib is a highly active agent in patients with CML who had become resistant to one or more tyrosine kinase inhibitors,” stated Jorge Cortes, M.D., professor and deputy chair, department of leukemia, The University of Texas M.D. Anderson Cancer Center. “The response rates observed in this study confirm substantial and durable clinical activity and suggest that ponatinib may overcome BCR-ABL mutation-based resistance, as well as resistance when no mutations are detectable.”