PTK 787 is a selective inhibitor of all three types of the VEGF receptors. It has been shown to reduce the number of tumor microvessels with resultant dilation of the remaining vessels. It has also been shown to inhibit VEGF receptors and has been effective in animal tumor models. In addition, dynamic contrast-enhanced MRI (DCE-MRI) and PET imaging have shown a reduction in blood flow to tumors after the administration of PTK 787.
A phase 1 study of the VEGF-receptor tyrosine kinase inhibitor vatalanib (PTK787/Z 222584) and gemcitabine in patients with advanced pancreatic cancer was conducted at Stanford University. All patients received vatalanib 1250 mg daily; gemcitabine was escalated from 700 mg/m2 to 850 mg/m2 to a maximum of 1000 mg/m2. To date, 32 cycles have been given to 8 patients with pancreatic cancer, with a median of 4 cycles per patient. Only 1 patient, in the first cohort, experienced dose-limiting toxicity (DLT), with grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The remaining patients in this and the next cohort (850 mg/m2) have not experienced DLT. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (2), thromobocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Two of 8 patients had stable disease as the best response by RECIST. The remaining patients had stable disease as the best response from 2 to 6 months. No disease progression was seen at or before the first evaluation with computed tomography. No unexpected toxicities have been observed. Accrual to higher-dose gemcitabine cohorts continues. A phse II study of PTJ787alone is also ongoing.
Kuo T, Fitzgerald A, Kaiser H, Sikic BI, Fisher GA. A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer. Program and abstracts of the 2006 Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, California. Abstract 127.