Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 24, No 18S (June 20 Supplement), 2006: 5075
© 2006 American Society of Clinical Oncology

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Abstract

A phase IB, open label, safety and pharmacokinetic (PK) study of escalating doses of PTK787/ZK 222584 (PTK/ZK) in combination with paclitaxel and carboplatin in patients (Pts) with stage IC to IV epithelial ovarian cancer (EOC)

Kinikum Bremen-Mitte gGmbH, Bremen, Germany; Centre René Gauducheau, St. Herblain, France; Centre Paul Papin, Angers, France; UMC Utrecht, Utrecht, The Netherlands; Institute Paoli Calmettes, Marseille, France; Schering OY, Helsinki, Finland; Novartis Pharmaceuticals, East Hanover, NJ; Schering AG, Berlin, Germany; HSK Dr. Horst Schmidt Hospital, Wiesbaden, Germany

5075

Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis and their expression is associated with poor prognosis in EOC. PTK/ZK is a novel, oral, angiogenesis and lymphangiogenesis inhibitor that blocks tyrosine kinase signaling from all known VEGFRs. Methods: An open label, multicenter, phase IB dose escalation study evaluating PTK/ZK with chemotherapy as first line therapy in Pts with stage IC to IV EOC. Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of PTK/ZK were assessed; PK of PTK/ZK, carboplatin and paclitaxel was characterized. Paclitaxel was administered as a 3-hour infusion on day 1 of each 21-day cycle at a dose of 175 mg/m². Carboplatin was given immediately after paclitaxel as a 30-min IV infusion to AUC of 5 mg min/mL. PTK/ZK was given once daily from day 3 to day 21 of each chemotherapy cycle. Cohorts of 3 to 6 Pts received doses of PTK/ZK at 250, 500, 750, 1000 or 1250 mg/day. Dose expansion in 21 additional Pts was conducted with 1250 mg/day without reaching MTD. After completion of chemotherapy, PTK/ZK was given continuously until disease progression. PK samples were collected in cycle 1 (without PTK/ZK) and cycle 2 (after PTK/ZK pre-treatment). Results: 42 Pts were enrolled. To date 39 Pts are evaluated for safety, 19 Pts for DLT, 35 Pts for PK and 21 Pts with residual disease for tumor response. No DLTs were reported. The most frequently observed grade 3/4 toxicity was neutropenia (31%), leucopenia (18%) and hypertension (10%). PTK/ZK did not aggravate chemotherapy related side effects. To date 67% of Pts had achieved CR/PR, 9% SD, 5% PD and 19% UNK. PTK/ZK exposure at steady state was similar in cycle 1 and 2. PTK/ZK had no impact on the systemic exposure of carboplatin. Paclitaxel exposure was decreased by an average of 18% in cycle 2 compared to cycle 1 for Pts treated with PTK/ZK 1250 mg/day. Conclusion: Combination of PTK/ZK with paclitaxel and carboplatin is feasible and shows favorable safety profile. The combination is active in EOC and deserves further evaluation.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Schering AG Schering SA Schering AG Bristol-Myers Squibb Bristol-Myers Squibb, Schering

Abstract presentation from the 2006 ASCO Annual Meeting