A PHASE-I TRIAL OF 5-DAY CONTINUOUS-INFUSION CISPLATIN AND INTERFERON-ALPHA

Combination therapy of cisplatin with interferon alpha (IFN) has been shown in several in vitro as well as in vivo models to be synergistic. In order to decrease toxicity seen with cisplatin, 5-day continuous i nfusions, in place of bolus administration, have been introduced. This led us to investigate the combination of 5-day continuous infusion ci splatin with repeated IFN dosing in a phase I cisplatin dose escalatio n study. A group of 17 patients were enrolled in this trial. The maxim um tolerated dose (MTD) of cisplatin was 20 mg/m(2) per day when combi ned with 3 x 10(6) units IFN given three times a week. The dose-limiti ng toxicities seen included thrombocytopenia, leukopenia, and nausea a nd vomiting. Pharmacokinetic analyses of free (unbound or ultra filter able) platinum revealed that the decay curve fitted a monoexponential model. Pharmacokinetic parameters of cisplatin were found to correlate with toxicity. Both increases in the maximum concentration of cisplat in achieved (Cpmax) as well as the area-under-the-curve (AUG) for free platinum, correlated with the incidence of nausea and vomiting (both acute and delayed) and hematological toxicities (leukopenia and thromb ocytopenia). None of the patients exhibited significant changes in ren al function while on this study. The free platinum levels were higher than found in similar studies evaluating comparable cisplatin infusion s alone. The enhanced toxicities seen in this trial may be explained b y the results of an in vitro study using human plasma spiked with cisp latin and IFN that revealed decreased protein binding of cisplatin by 2.5-3.0-fold. Of the 17 patients treated, two non-small cell lung canc er patients obtained a partial response and one malignant melanoma pat ient obtained complete resolution of a malignant pleural effusion. Con sidering the acceptable toxicity seen in this trial, we recommend phas e II trials be conducted with continuous infusion cisplatin with IFN i n the treatment of non-small cell lung cancer.