Preclinical studies in our laboratory have demonstrated that prior exposure to
hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent
gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of
hydroxyurea given over 24 h followed by a 30-min infusion of
gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of
hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of
gemcitabine. The initial dose level of
gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9.
Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years).
Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The
gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9.
Hydroxyurea had no effect on the plasma pharmacokinetics of
gemcitabine. These results suggest that
hydroxyurea followed by
gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with
platinum-resistant
head and neck cancer.