Five-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 (FUdR) 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 phase I cohort study. A total of 36 patients with refractory solid tumor 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 lower than that previously identified as the MTD [FUdR at 0.2 mg/kg daily with LV at 100 mg q4h and IFN at 2 million units (MU)/m2 daily], three of six patients developed grade 3 mucositis, indicating that the toxicity 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 the 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 dermatitis was observed, indicating no further potentiation of FUdR/LV toxicity with higher IFN doses. However, known toxicities of IFN, including 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 low doses, resulting in increased FUdR toxicity. When the dose of IFN is increased, this FUdR/LV toxicity does not appear to be potentiated further and IFN-related toxicities become dose-limiting.
Vokes
E E
EE
Department of Medicine, University of Chicago, IL 60637.
O'Brien
S M
SM
Vogelzang
N J
NJ
Schilsky
R L
RL
Ratain
M J
MJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D011994:Recombinant Proteins; D013280:Stomatitis / Q000139:chemically induced
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D005467:Floxuridine; D002955:Leucovorin