A phase I study of gemcitabine + dasatinib (gd) or gemcitabine + dasatinib + cetuximab (GDC) in refractory solid tumors

Purpose This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients. Methods This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m 2 weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m 2 weekly after a loading dose of cetuximab of 400 mg/m 2 . There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment. Results Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3–4 neutropenia ( n = 7), Gr 4 colitis ( n = 1), Gr 3 bilirubin ( n = 2), Gr 3 anemia ( n = 2), Gr 3 thrombocytopenia ( n = 2), Gr 3 edema/fluid retention ( n = 1), and Gr 3 vomiting ( n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1–7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels. Conclusions The MTD/RPTD of GD is gemcitabine 1000 mg/m 2 weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.