5-DAY INFUSIONAL FLUORODEOXYURIDINE WITH ORAL LEUCOVORIN AND ESCALATING DOSES OF INTERFERON-ALPHA-2B - A PHASE-I STUDY

In a previous phase I study we identified the maximally tolerated dose (MTD) of a continuous intravenous infusion of fluorodeoxyuridine (FUd R) to be 0.3 mg/kg daily for 5 days when combined with oral leucovorin (LV) given at 100 mg q4h. In an attempt to modulate FUdR further, we added escalating doses of interferon alpha-2b (IFN) to FUdR/LV in a ph ase I cohort study. A total of 36 patients with refractory solid tumor s were treated at two dose levels of FUdR and five dose levels of IFN. Although the initial patient cohort was treated with a dose of FUdR l ower than that previously identified as the MTD [FUdR at 0.2 mg/kg dai ly with LV at 100 mg q4h and IFN at 2 million units (MU)/m2 daily], th ree of six patients developed grade 3 mucositis, indicating that the t oxicity of FUdR/LV was increased in the presence of low doses of IFN. After decreasing the FUdR dose to 0.1 mg/kg daily, we could increase t he dose of IFN from 2 to 30 MU/m2 daily in five additional cohorts of patients. With increasing IFN doses, no increase in mucositis or derma titis was observed, indicating no further potentiation of FUdR/LV toxi city with higher IFN doses. However, known toxicities of IFN, includin g transient myelosuppression and hepatic transaminase elevation, were observed more frequently at IFN doses of 15 and 30 MU/m2 daily, where they became dose-limiting. We conclude that IFN modulates FUdR/LV at l ow doses, resulting in increased FUdR toxicity. When the dose of IFN i s increased, this FUdR/LV toxicity does not appear to be potentiated f urther and IFN-related toxicities become dose-limiting.