PTK787/ZK 222584 (PTK/ZK), an Oral Tyrosine Kinase Inhibitor, Has Activity in Patients with Agnogenic Myeloid Metaplasia (AMM).

Increased angiogenesis and vascular endothelial growth factor (VEGF) levels are prognostic in AMM. Agents with anti-VEGF activity including thalidomide (Thomas. Cancer 2006) and lenalidomide (Tefferi. Blood 2006) have activity in AMM. PTK/ZK, a novel oral aminophthalazine, is a small molecule inhibitor of VEGFR-2, PDGFR, c-kit and c-fms. Twenty-nine patients with angogenic myeloid metaplasia (AMM) were enrolled between June 2002 and November 2003 on a phase I/II study of PTK/ZK, administered orally on a continuous twice daily (BID) dosing schedule as follows: two (7%) patients received 750 mg BID and 27 (93%) patients received 500 mg BID. The age range was 42 to 78 (median 62), seventeen (59%) patients were male, and Karnofsky performance status was ≥ 70% in all (100%) patients. In twelve (41%) previously treated patients, the median number of prior regimens was 2.5 (range 1–6). Nine (31%) of the 29 patients had abnormal cytogenetics at the time of enrollment. The most commonly reported potentially PTK/ZK-related adverse events (AEs) were nausea, vomiting, dizziness, fatigue, thrombocytopenia and anorexia. One or more of these AEs occurred in > 15% of patients. Five (17 %) patients achieved clinical improvement (CI), as determined by the International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia. Four CIs had improvement in splenomegaly and the fifth had improvement in hemoglobin. As had similarily been seen in patients with AML treated with PTK/ZK monotherapy, PTK/ZK exposure, both AUC and Cmin, showed decreases after multiple doses (Roboz.Leukemia.2006). PTK/ZK is an active, well tolerated agent in the treatment of AMM and warrants further investigation within combination regimens.