Phase I study of combination treatment with PTK 787/ZK 222584 (PTK/ZK) and cetuximab for patients with advanced solid tumors: Safety, pharmacokinetics, pharmacodynamics, and toxicity analysis

2575 Background: Based on the current knowledge of tumor biology there is a rationale to combine targeted therapies that block different growth factor pathways. Here we combined PTK/ZK, a small molecule inhibitor of all three vascular endothelial growth factor receptors, PDGFR and c-kit, with cetuximab, a monoclonal antibody against the epidermal growth factor receptor.

METHODS: In this phase I study patients were treated with PTK/ZK daily (cohort 1; 750 mg od, cohort 2; 1250 mg od, cohort 3; 250 mg [morning] and 500 mg [evening], cohort 4; 500 mg [morning] and 750 mg [evening]) combined with cetuximab 250mg/m(2) weekly in cycles of 28 days in cohorts of 3 patients. Toxicity was evaluated conform CTCAE classification version 3.0. Pharmacokinetics and circulating endothelial (progenitor) (CE(P)) cell analysis by flow cytometry were performed. Response was assessed using RECIST criteria.

RESULTS: Safety and tolerability were evaluated in 16 out of 18 treated patients (median age 61, range 43-78) with advanced tumors of the colon (8), lung (1), chordoma (2), biliary tract (1), cervix (1), ovarian (1), breast (1) and pancreatic cancer (1). The most frequently reported adverse events (all CTCAE grades) were acne (87%), dry skin (81%), fatigue (69%), nausea (63%), ataxia/dizziness (50%), vomiting (50%), headache (38%) and diarrhea (31%). One dose limiting toxicity (DLT) occurred in cohort 3 (grade 3 transaminitis (AST)). The study was terminated after cohort 4 because the predefined maximum doses for vatalanib and cetuximab were attained. Preliminary PK analysis revealed no significant changes in PTK/ZK exposure upon coadministration with cetuximab. Biomarker analysis showed stabilized CE(P)Cs levels during treatment. 7 out of 14 patients evaluable for efficacy analysis (50%) showed SD for at least 2 months and 1 patient (colon cancer) a PR for 11.5 months.

CONCLUSIONS: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has anti tumor activity. No MTD was defined; the recommended phase II dose is the predefined maximum combination dose: weekly cetuximab 250 mg/m2 combined with twice daily PTK/ZK 500/750 mg. No significant financial relationships to disclose.