Open-label, non-randomized, multicenter phase II study evaluating the angiogenesis inhibitor PTK787/ ZK222584 (PTK/ZK) in patients with advanced neuroendocrine carcinomas (NEC)

Abstract

14684 Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis. Since NEC of the gastroenteropancreatic system are highly vascularized and strongly express VEGF and its receptors, anti-VEGF receptor therapy should be a promising approach. PTK/ZK (Bayer Schering Pharma and Novartis Pharma) is an oral angiogenesis inhibitor which selectively blocks VEGF receptor tyrosine kinase signaling from all known VEGFRs. Methods: Patients (pts) with histologically confirmed NEC (proliferation index Ki67< 15%) non-surgically curable and progressive within 6 months according to RECIST criteria were included in an open label, non-randomized multicenter phase II study. All pts were treated daily with an oral dose of 1250 mg of PTK/ZK. In case of drug related adverse events (AE) the dose could be reduced. The primary endpoint was the overall response rate according to RECIST. Secondary endpoints were time to progression (TTP), survival time, WHO performance status, quality of life, toxicity and safety. Results: A total of 20 pts (10 male, 10 female) with a median age of 61 years (range 37 to 72) were enrolled between 8/2005 and 11/2007. 3 pts stopped treatment early for side effects. 17 pts were evaluable for tumor response. Primary tumors were located in the pancreas in 4, midgut in 7, hindgut in 3, in the lung in 1 and were unknown in 2 patients); 4 pts were treated simultaneously with somatostatin analogues. Best response was stable disease in 8/16 pts at 6 months (50%) and 4/15 pts at 12 months (27%). 2 pts have not yet reached the 12 months time line. Median TTP was 7 months (3–23 months), with 3 pts have not yet reached TTP (after 18, 12 and 6 months). Altogether 7 pts stopped PTK/ZK for treatment related AEs (dizziness, nausea, emesis, hypertension, proteinuria). Conclusions: PTK/ZK has some antiproliferative activity in pts with advanced NEC with a relatively high rate of disease stabilisation. The compound was well tolerated in the majority of the pts. Antiangiogenic therapies should be further evaluated in neuroendocrine tumor pts, preferably in combination with cytotoxic treatment modalities. No significant financial relationships to disclose.