A Phase I Safety Study of Doxifluridine and Interferon-α-2a in Patients with Advanced Neoplastic Disease

Abstract

Aims and Background

Doxifluridine (RO 21-9738, 5′-dFUR) is a fluoropyrimidine derivative with proven antitumor activity in different experimental models. On the basis of experimental evidence, several clinical trials have been carried out to define the optimal 5′-dFUR dose and route of administration. In general, the maximum monthly dose of 5′-dFUR was 36-38 g. According to these clinical data, we explored the feasibility of a combination of 5′-dFUR and interferon-alpha-2a (IFN-alpha-2a). The aim of the protocol was to confirm the maximum tolerated dose (MTD) of the drug in combination with a settled dose of IFNα2a.

Methods

An open-label phase I study with intravenous 5′-dFUR was carried out in 12 patients with a histologically proven diagnosis of advanced gastrointestinal or breast cancer refractory to previous conventional hormone-chemotherapy. Escalating doses of 5′-dFUR were administered as a 2-h intravenous infusion, once a week for at least 4 weeks in groups of 3 patients. IFN-alpha-2a was administered as an intramuscular injection of 3 MU 3 times a week for 4 consecutive weeks. Physical and laboratory parameters were assessed at baseline and then weekly until the end of treatment.

Results

The treatment with 5′-dFUR was stopped at 5 g/m², since this level corresponded to the maximum monthly dosage reported in the literature (36-38 g). No severe toxicity was recorded up to this drug level.

Conclusions

The combination of 5′-dFUR plus IFN-alpha-2a was well tolerated at the level of 5 g/m². Although the MTD was not reached, it can be stated that the dosage administered in this study could be explored in a larger trial.