A phase I study of aflibercept, pemetrexed (P), and cisplatin (C) in patients with advanced solid tumors.

Abstract

2536 Background: Aflibercept (AF) (aka VEGF-trap) is a fully human recombinant protein inhibitor of vascular endothelial growth factor (VEGF) that also binds to placental growth factor. AF consists of the second immunoglobulin domain of VEGFR-1 and the third domain from VEGFR-2, the two most potent VEGF binding domains, attached to the Fc portion of IgG1. P plus C is a standard regimen for the treatment of NSCLC and mesothelioma. Methods: The objectives of this study were to assess dose-limiting toxicity (DLT), recommended phase II dose (RD), and pharmacokinetics (PK) of aflibercept administered intravenously (IV) every 3 weeks with P plus C in patients with advanced solid tumors. AF was administered over 1 hour at escalating doses of 2, 4, or 6 mg/kg in combination with fixed doses of P (500 mg/m2) plus C (75 mg/m2). Results: 18 patients (M/F 9/9), median age 64 yr. range (37-73), ECOG PS 0 (n=2); PS 1 (n=16) were enrolled at 2 (n=4), 4 (n=7), 6 (n=7) mg/kg cohorts. Primary tumors included: mesothelioma (5), NSCLC (4), GI (4), other (5). Prior therapy included: surgery (77%), chemotherapy (44%), and radiation (44%). Patients received a median number of 3 cycles (range 1-8). No DLT was observed in any cohort. Most common adverse events (AEs) of all grades included (#pts): fatigue (13), nausea (10), vomiting (8), constipation (8), dysphonia (6), stomatitis (5), and diarrhea (5). Grade ≥ 3 AEs commonly related to anti-VEGF therapy included: pulmonary embolism (2), deep vein thrombosis (1), and hypertension (1). Non-DLT grade 3 hypophosphatemia was observed in one patient at 4 mg/kg and one at 6 mg/kg. Fifteen patients are evaluable for efficacy: SD (13) and PD (2). Four patients remain on treatment at 6 mg/kg (3+, 6+, 7+, 7+ cycles). No drug–drug interaction was observed. Conclusions: Aflibercept in combination with P plus C was well tolerated. AF 6 mg/kg IV every 3 weeks was selected as the phase 2 RD in combination with P plus C and is consistent with AF dosing of 2 mg/kg/wk in all ongoing combination phase III studies. The phase II study in first-line NSCLC is ongoing. Updated phase I efficacy, safety, and PK data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Regeneron Merck, Millennium, Ozmosis Research Regeneron AstraZeneca, Bayer, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, Exelixis, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche Regeneron