Geburtshilfe Frauenheilkd 2006; 66 - PO_O_04_33
DOI: 10.1055/s-2006-952829

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)

W Schröder 1, M Campone 2, S Abadie 3, PO Witteveen 4, P Viens 5, A Du Bois 6
  • 1Klinikum Bremen-Mitte gGmbH, Bremen
  • 2Centre Rene Gauducheau, Nantes, Frankreich
  • 3Centre Paul Papin, Angers, Frankreich
  • 4UMC Utrecht, Utrecht, Niederlande
  • 5Institut Paoli Calmettes, Marseille, Frankreich
  • 6Dr. Horst-Schmidt Klinikum Wiesbaden, Wiesbaden

Aims: 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 175mg/m2. Carboplatin was given immediately after paclitaxel as a 30-min IV infusion to AUC of 5mg 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 1250mg/day. Dose expansion in 21 additional Pts was conducted with 1250mg/day without reaching MTD. After completion of chemotherapy, PTK/ZK was given continuously until disease progression.

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 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 1250mg/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.