Abstract
3550 Background: EGFR and VEGFR are important targets in a number of human cancers with common downstream signalling pathways. Combined blockade of EGFR-VEGFR with E and OSI-930 has shown additional antitumor activity compared to either agent alone with long-term remissions in multiple xenograft models. Methods: Sequential cohorts of pts with advanced refractory solid tumors were treated with OSI-930 BID with addition of E QD from Day 8 and beyond to determine the maximum tolerated dose (MTD) and to evaluate safety, PK and efficacy of the combination. Escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. PK of OSI-930, E and its metabolite OSI-420 were determined. Levels of soluble VEGFR2 (sVEGFR2) in plasma were also measured. Results: 16 pts have been entered (13M/3F); median age 63 years (range 41–78), PS ≤2 and 38% pts with mCRC. OSI-930/E were administered at 3 levels [mg(pts entered/evaluable)]; 200 BID/100 QD (7/6), 200 BID/150 QD (4/3), and 300 BID/150 QD (5/5). Median duration of therapy was 8 weeks (range 1–22). DLT was seen in 1/6 pts at 200 BID/100 QD (>5 day interruption due to G4 neutropenia); and 1/5 at 300 BID/150 QD (G3 Asthenia/lethargy). Other common related toxicities (% all grades:% g3/4) were: skin-related (rash, HFS etc) (85:23), Asthenia/lethargy/fatigue (69:15), diarrhea (77:8), anorexia (92:0), and transaminitis (31:15). Reduction and/or interruptions of one or both study drugs during or beyond the initial 28 days were required in 8/14 pts. Six of 11 pts evaluable for response achieved SD ≥12 weeks. Median plasma Cmax (and AUCTau) of OSI -930 for Cohort 3 (300 BID/150 QD) were: 0.826 (6.08), 0.947 (5.57), and 1.66 (14.3) μg/mL (μg.hr/mL) on Days 7, 8 and 22, respectively. Exposure of OSI-930 increased approximately 2-fold upon co-administration with E at steady-state. OSI-930 appeared not to alter the PK properties of E or the ratio of OSI-420 to E. Decreases in plasma sVEGFR2 were observed, indicating a PD effect of OSI-930. Conclusions: Additional patients are being added to confirm the MTD of the combination. PK data indicate a drug-drug interaction with doubling of the OSI-930 exposure on co-administration with E. [Table: see text]
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