A PHASE-I STUDY OF RECOMBINANT INTERFERON-ALPHA ADMINISTERED AS A 7-DAY CONTINUOUS VENOUS INFUSION AT CIRCADIAN-RHYTHM MODULATED RATE IN PATIENTS WITH CANCER

A Phase I trial of interferon-alpha (IFN-alpha) administered at circad ian-rhythm modulated rate was carried out to evaluate maximum tolerate d dose (MTD) and toxicity in patients with advanced malignancies. Reco mbinant IFN-alpha-2b was administered as a 7-day continuous venous inf usion with maximum delivery between 6 p.m. and 3 a.m. Entry dose level s were 0.2, 2 and 4 MU/m2/day. The dose was escalated by an amount equ al to the starting dose until a maximum of 6 entry dose levels was ach ieved, with a 1-week rest between each cycle. The maximal daily dose o f IFN-alpha administered was 24 MU/m2/day. A programmable-in-time ambu latory pump was used, so that all patients could receive their treatme nt at home. Eighteen patients were entered in the study and 16 were ev aluable for toxicity. Toxicity was mild to moderate except for two pat ients who developed WHO grade III toxicity. No significant decline in performance status was associated with treatment. Two objective respon ses were observed in patients with previously treated metastatic renal cell carcinoma. As compared to standard s.c./i.m. administration or c ontinuous nonchronomodulated i.v. infusion of IFN-alpha, this circadia n schedule has allowed to deliver high doses of drug with acceptable t oxicity.