Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies

Rastislav Bahleda, Jackie Baker, Christophe Massard, Sirish M. Gadgeel, Jane E. Rogers, Hassan Izzedine, Eric Deutsch, Jeana L. Garris, Akbar Khan, Emmanuelle Boelle, Sylvie Assadourian, Jean Charles Soria, Jaffer A. Ajani

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    Abstract

    Purpose: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. Patients and Methods: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. Results: Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. Conclusion: Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5-fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.

    Original languageEnglish
    Pages (from-to)10-20
    Number of pages11
    JournalOncology (Switzerland)
    Volume90
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2016

    Keywords

    • Aflibercept
    • DCF chemotherapy
    • Solid tumors
    • VEGF Trap

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