Phase I of fixed-dose-rate gemcitabine in combination with bortezomib in patients with advanced solid tumors
Authors: T. H. Luu, W. A. Chow, D. Lim, M. Koczywas, P. Frankle, M. Cristea, G. Somlo, R. J. Morgan
Journal: Journal of Clinical Oncology (2008)

2563 Background: Administration of gemcitabine via fixed-dose rate (FDR) infusion at 10 mg/m2/min has been shown to increase accumulation of the active phosphorylated metabolite of the drug. Additionally, phase II trials comparing FDR versus standard 30-minute bolus infusion of gemcitabine demonstrate superior median survival with the former in the setting of advanced pancreatic carcinoma. Bortezomib is a proteasome inhibitor with efficacy in refractory multiple myeloma, and our preclinical data suggests synergism of this drug in combination with FDR gemcitabine. This phase I trial was set out to determine the safety, toxicity, and MTD of FDR gemcitabine with bortezomib in advanced solid tumors refractory to standard therapy. Methods: 29 patients (16 male, 13 female) with a median age of 63 (range 36–84) have been enrolled, 25/29 patients (86%) with ECOG performance status of 0–2. A wide array of primary sites of malignancy has been represented in enrollment (11 lung, 4 breast, 3 gastrointestinal, 2 genitourinary, 2 skin, 2 unknown primary, 2 salivary gland, 1 trachea, 1 sarcoma, 1 nasopharynx). Patients were titrated with bortezomib (1 and 1.3 mg/m2) and FDR gemcitabine (750, 1,000, 1,250 mg/m2). FDR gemcitabine was given on days 1 and 8, bortezomib was given on days 1,4,8 and 11 of each 21 days cycle. Bortezomib was infused 4 hours after FDR gemcitabine since this was established in pre-clinical model to achieve the highest cytotoxicity. Evaluation with radiologic imagings were performed at every two cycles. Results: Dose-limiting toxicities (DLTs) incurred at bortezomib 1.3 mg/m2 and FDR gemcitabine 1,000 and 1,250 mg/m2 with grade 4 thrombocytopenia and neutropenia and grade 3 liver function test abnormalities. Thus, the MTD for this trial is at bortezomib 1 mg/m2 and FDR gemcitabine at 1,250 mg/m2. Median cycles given were 2 (range 1–28). We observed 1 PR with duration of 12 months in breast cancer, and 6 stable disease (SD) out of 29 patients. The median duration of therapy on these 6 patients was 8.5 months (3 -20). SD and PR were at the MTD (or below) with only 1 exception (3 months). Notably, the subset of patients with breast cancer in this study is a heavily pretreated group (all having received at least two prior chemotherapeutic regimens for metastatic disease). Nonetheless, lengthy periods of SD have been observed, with 2 out of 4 patients achieving SD for greater than 11 months. Grade 3/4 toxicities on the 6 evaluable patients treated at the MTD over the course of therapy include anemia (1pts/0pt), neutropenia (3/0), thrombocytopenia (3/1), fatigue (2/0), elevated transaminases (1/0), sensory neuropathy (2/0) and thrombosis (0/1). Conclusions: The combination of FDR gemcitabine with bortezomib may warrant further study in a phase II trial for advanced breast, lung, ovarian and pancreatic cancer patients. The toxicities at the MTD were tolerable. No significant financial relationships to disclose.