Phase I Dose-Escalation Study of Intravenous Aflibercept in Combination With Docetaxel in Patients With Advanced Solid Tumors

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors. Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept 2, 4, 5, 6, 7 or 9 mg/kg with docetaxel 75 mg/m2 on day 1 every-3-weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability and antitumor activity were also investigated. Results: Fifty-four patients (mean age, 56 years) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n=34), there were 3 DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg) and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses ≥5 mg/kg. The pharmacokinetics of aflibercept and docetaxel were not modified by co-administration. Aflibercept 6 mg/kg was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AEs) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with VEGF blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses and 32 patients stable disease (>3 months in 18 patients). Conclusion: Based on findings from this study, aflibercept 6 mg/kg was the dose recommended for further clinical development.

Clinical Cancer Research

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