EASTERN COOPERATIVE GROUP TRIAL OF INTERFERON-GAMMA IN METASTATIC MELANOMA - AN INNOVATIVE STUDY DESIGN

IFN-gamma is a potent immunomodulator, which has activity against mela noma in vitro and in murine models, However, preclinical data suggests that the optimal therapeutic and immunomodulatory dose may not be the maximally tolerated clinical dose, We conducted a Phase II/III trial in good prognosis patients with metastatic melanoma to determine wheth er a therapeutic and immunomodulatory dose-response curve of IFN-gamma could be identified, and whether the two could be correlated. Ninety- eight patients with metastatic melanoma were randomized to one of seve n dose levels of IFN-gamma ranging from 0.01 to 0.90 mg/m(2), All pati ents were required to have s.c., skin, soft tissue, or nodal disease, although visceral disease was also allowed, and no more than one prior chemotherapy regimen, Patients received IFN-gamma as a 1-h i.v. infus ion three times per week for at least 8 weeks or until progressive dis ease. Ninety-five patients were eligible for toxicity evaluation; 81 w ere eligible for tumor response, Four patients responded to therapy (r esponse rate, 5%) at three dose levels: two patients at 0.01 mg/m(2) a nd one each at 0.5 and 0.9 mg/m(2), The duration of response ranged fr om 5 to 58 weeks, Toxicities were typical of IFNs and included flu-lik e constitutional symptoms, No dose-response relationship was identifie d for efficacy, A dose-response relationship for toxicity was observed only for fever and chills (p = 0.035) and hepatic toxicity (p = 0.034 ). IFN-gamma has minimal activity in metastatic melanoma, and a therap eutic dose-response curve could not be identified, Although potent dos e-dependent effects on immunomodulation were identified (J. M. Kirkwoo d, J. Bryant, J. H. Schiller, M. M. Oken, E. C. Borden, and T. L. Whit eside, Immunomodulatory function of interferon gamma in patients with metastatic melanoma: results of a phase IIB trial in subjects with met astatic melanoma: ECOG Study E4987, submitted for publication), this b iological activity does not translate into therapeutic activity in the metastatic disease setting in this trial.