Abstract
3557 Background: Aflibercept (AF), a recombinant fusion molecule of the human VEGF receptor extracellular domains and the Fc portion of human IgG1, is a potent inhibitor of vascular endothelial growth factor. This study assessed the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and PK of AF+I-LV5FU2. Methods: DE of AF followed by I-LV5FU2 (fixed standard dose) every 2 weeks (q2w) were explored. Results: 38 pts were enrolled (M/F: 18/20, median age 53 [19–77], ECOG PS 0/1: 24/13) including colorectal (23) and ovarian (5) cancers. Thirty six pts received prior chemotherapy (CT): median 3 [1–5]. A total of 404 cycles (median 10 [1–26]) of AF+I- LV5FU2 were administered across 4 AF dose levels (DL) ranging from 2.0 to 6.0 mg/kg. DLTs were: 2/12 pts at 4.0 (Grade (Gr) 3 proteinuria (PrU)>2wks including 1 pt with thrombotic microangiopathy), 2/10 pts at 5.0 (Gr 3 stomatitis and esophageal reflux) and 2/12 pts at 6.0 mg/kg (febrile neutropenia, Gr 3 stomatitis). The main AF-related Gr3–4 toxicities (% pts) were hypertension (32%) and PrU (11%). Moderate (Gr2) epistaxis (18%) and dysphonia (24%) were observed. Free and bound AF concentrations in combination with I-LV5FU2 are comparable to those observed with AF in monotherapy. AF had no influence on the PK of I-LV5FU2. Seven partial responses (synovial sarcoma, ovarian, pancreas and 4 colon cancers), 19 stable diseases were reported. AF 4.0 mg/kg was selected as the RD for feasibility based on PK analysis (excess of free AF at the end of the q2w dosing interval) and the absence of relationship between DE and clinical parameters (toxicity and activity). Conclusions: AF was safely combined with I-LV5FU2 with no evidence of exacerbation of CT-related toxicities. Class-effect toxicities related to AF were reported. Clear signs of activity were observed. Updated results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis
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