The reported data are from a Phase I trial of XL019 in patients with advanced primary myelofibrosis, or with advanced myelofibrosis occurring post-polycythemia vera or post-essential thrombocythemia. This study included patients with evidence of leukemic transformation, which has been reported to be uniformly fatal after a median of 2.6 months.
The dose-escalation trial enrolled a total of 30 patients. The data focused on 21 patients who received XL019 at doses of 25mg and 50mg.Disease assessments included hematologic parameters, spleen size, and bone marrow and neurologic evaluation.
Evidence of clinical activity was seen in patients with JAK2 V617F or MPL W515L mutations, and included the following: 50% or greater reduction of spleen size in 50% of patients receiving 25 or 50mg XL019 daily, and in 25% of patients receiving 25mg XL019 qMWF; reduction in leukocytosis in seven of nine patients who presented with baseline leukocytosis of greater than 15,000/mm3; improvement in anemia in four patients; and relief of constitutional symptoms in six of eight patients with baseline pruritus or inappetence.
Approximately three of four patients with pre-leukemic transformation showed a reduction in the levels of circulating blasts after the first cycle of XL019, and duration on study of 2.5, 3+, and 7.5+ months. Approximately two of these patients also showed normalization of blast counts in the bone marrow. Of the three patients who showed a reduction in circulating blasts, two had the JAK2 V617F mutation and one had wild type JAK2. XL019 was generally well-tolerated.
XL019 is a potent small molecule inhibitor of JAK2, a protein kinase that is mutationally-activated in approximately 50% of patients in myelofibrosis.
Michael Morrissey, president of R&D at Exelixis, said: With these newest data, XL019 continues to show evidence of clinical activity in patients with myeloproliferative disorders at tolerable doses. We view these results with particular interest as they point to a potential sign of disease modification with a selective JAK2 inhibitor, and will factor them into our future development plans for the compound.