A phase I dose escalation and pharmacokinetic (PK) study of intravenous aflibercept (VEGF trap) plus docetaxel (D) in patients (pts) with advanced solid tumors: Preliminary results

Abstract

3599 Background: Aflibercept (AF), a potent angiogenesis inhibitor fusion protein, is comprised of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG1. AF binds and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to assess the safety, dose limiting toxicities (DLTs)/ recommended dose (RD) and PK of AF + D. Methods: This phase I study explored escalating doses of AF followed by D (fixed dose 75 mg/m2) every 3 weeks (q3w). A standard 3+3 escalation scheme was utilized. Results: 54 heavily pretreated pts were enrolled (34 in the dose escalation cohort and 20 in the feasibility): 25 male/29 female, median age 57 [37-73], ECOG-PS 0/1: 24/30, with a variety of advanced solid tumors including breast (n=13) and colorectal (n=9). A total of 241 cycles (cy) (median 4, [1-12]) of AF plus D have been administered across 6 AF dose levels (DL) ranging from 2.0 to 9.0 mg/kg. DLTs at cy 1 included: neutropenic infection at 2.0, grade (Gr) 3 dysphonia at 7.0, and uncontrolled hypertension (HTN) at 9.0 mg/kg. The main Gr3-4 AF-related toxicity (% pts) was HTN (15%). Moderate (Gr2) proteinuria (12%) epistaxis (8%) and dysphonia (2%) were observed. Free and bound AF concentrations are comparable to those observed with AF in monotherapy. PK analysis did not reveal any drug-drug interactions. AF 6.0 mg/kg fulfills the criteria for RD: having an excess of free AF at the end of the q3w dosing interval, no DLT and manageable HTN versus highest DLs. Five partial responses (3 breasts, thymoma, thyroid) and 32 stable diseases were noted. Conclusions: AF was safely combined with D with no evidence of exacerbation of D-related toxicities. AF at 6.0 mg/kg + D q3w is the RD.