A phase I study of gemcitabine plus dasatinib (GD) or gemcitabine plus dasatinib plus cetuximab (GDC) in refractory solid tumors.
e15506 Background: Dasatinib (D) is a small molecule tyrosine kinase inhibitor with activity against both bcr-abl and src. Cetuximab (C) is a monoclonal antibody that blocks EGFR. Preclinical models suggest D reverses resistance to G. In addition, src and EGFR pathways interact; synergism of dual blockade by D + C is possible. We evaluated two combination regimens, GD and GDC, in a Phase I dose escalation study. METHODS: Patients (pts) with advanced solid tumors were enrolled in cohorts of 3-6 to either GD or GDC. G was dosed in mg/m(2) weekly for 3 of 4 weeks, D was dosed in mg PO BID, and C was dosed at 250 mg/m(2) weekly after loading dose of C=400; cycle length was 28 days. Dose levels were as follows: 1) G 1000 + D 50 ± C; 2) G 1,000 + D 70 ± C; 3) G 1,000 + D 100 ± C. Standard cycle 1 DLT definitions were used. Eligible pts had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on treatment. RESULTS: 25 pts have been enrolled, including 21 with pancreatic adenocarcinoma, 3 of whom had received prior G. 21 pts were evaluable for toxicity and 18 for efficacy. Four DLT were observed: Gr 3 ANC with infection (GDC1, n=1), Gr 3 ALT (GD2, n=2), and Gr 5 pneumonitis (GDC2, n=1). Possible treatment-related adverse events in later cycles included: Gr3-4 ANC (n=4), Gr4 colitis (n=1), Gr3 bilirubin (n=2), Gr3 Hgb (n=2), Gr3 Plt (n=2), Gr3 edema/fluid retention syndrome (n=1), and Gr3 vomiting (n=2). One previously untreated pt had a partial response. Eight of 18 pts, 3 of whom had received prior G, had stable disease as best response, median duration = 5 months (range 1-7). Biomarker results are pending. CONCLUSIONS: The MTD of the GD arm is G1000/D50BID. Stable disease in previous G-refractory pts was noted. Hematologic toxicities were dose-limiting; later toxicities including hematologic, LFT changes, pneumonitis, and fluid retention were seen. To address these toxicities, once daily dosing of D will be explored, followed by an expanded cohort of G + daily D vs G + bid D in pts with treatment-naïve pancreatic cancer. [Table: see text].
Uronis, HE; Bullock, K; Blobe, G; Hsu, S; Morse, M; Nixon, A; Haley, S; O'Neill, M; Hurwitz, H; Bendell, J
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