Abstract
13092 Background: Axitinib (AG-013736) is a novel small molecule inhibitor of the receptor tyrosine kinases with picomolar potency against VEGFR 1, 2 & 3 and nanomolar potency against PDGFR-beta and KIT. A phase I study in solid tumors identified 5 mg BID as the therapeutic dose; a phase II study in renal cell cancer demonstrated significant efficacy with a response rate (RR) of 46% (Rini et al, ASCO 2005). This study examined the safety, PK and preliminary efficacy of AG-013736 (AG) in combination with gemcitabine (GEM) as first-line therapy for advanced pancreatic cancer. Methods: A randomized phase II study was preceded by a phase I component. All patients (pts) in the phase I portion received 1000 mg/m2 GEM by 30-minute infusion on days 1, 8, and 15 followed by one week of rest from treatment. AG 5 mg p.o. BID was given beginning Cycle 1, Day 3 (C1D3). Eligible pts had no prior chemotherapy for advanced disease, ECOG 0–2, and no previous treatment with VEGF/VEGFR inhibitors, or anti-angiogenesis treatment. Full PK profiles were collected on C1D1 (GEM alone), C1D14 (steady state, AG alone), and C1D15 (GEM + AG). In the phase II trial, pts are randomized to AG or AG plus GEM beginning C1D1. Results: 8 pts were treated on the phase I portion of this trial. Toxicity: The primary Gr. 3/4 toxicity was hematologic: Gr. 4 anemia and Gr.3 thrombocytopenia in 1 pt and Gr. 3 neutropenia in 1 pt requiring a dose reduction for GEM in Cycle 3. Gr. 2 non-hematologic adverse events include pruritus (1 pt), abdominal pain (2 pts), epigastric pain (1 pt), melena (1 pt), and asthenia (2 pts). Gr. 2 hypertension was observed in 3 pts. Efficacy: Radiological assessment suggests 2 pts with partial response and 4 pts with stable disease: response assessments are ongoing. The median number of cycles is 3 [1,6]. Treatment for 4 pts is still ongoing: Cycle 6 (2 pts) and Cycle 2 (2 pts). Conclusions: This combination is safe and appears to be an effective treatment for advanced pancreatic cancer with significant tumor regression observed in 2 pts. Therapy was well tolerated with manageable toxicity. Additional investigation of AG-013736 in combination with GEM in the phase II setting for advanced pancreatic cancer is warranted. [Table: see text]
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