A PHASE-I CLINICAL-TRIAL OF IMIQUIMOD, AN ORAL INTERFERON INDUCER, ADMINISTERED DAILY

Imiquimod is an orally active interferon inducer with anti-tumour acti vity in experimental animals. In this study the tolerability, toxicity and biological effects of daily oral imiquimod administration were in vestigated in 21 patients with refractory cancer. Patients were treate d with doses of 25 mg, 50 mg, 100 mg or 200 mg on a projected 112 day course. Only three patients completed the course, all at the 50 mg dos e. Treatment toxicities were dose related and mainly comprised flu-lik e symptoms, nausea and lymphopenia. Of the 21 patients, five received dose reductions and in five treatment was discontinued because of trea tment-related toxicity. The biological activity of imiquimod was confi rmed by significant and sustained rises in peripheral blood mononuclea r cell (PBMC) 2-5A synthetase (2-5AS) levels at all doses. At 100 mg a nd 200 mg these occurred within the first 24 h of administration. Leve ls of neopterin and beta(2)-microglobulin (beta(2)M) were also signifi cantly elevated when assessed after three weeks' treatment. Interferon production was not demonstrated within the first 24 h of the initial dose but, following repeated doses, ten of the patients developed dete ctable serum interferon concentrations with a maximum value of 5600 IU ml(-1) recorded. Administration of imiquimod did not have any signifi cant effect on serum levels of tumour necrosis factor (TNF) or interle ukin 1 (IL-1), nor did it lead to development of detectable levels of antibodies to interferon. One mixed clinical response was observed aft er 4 weeks' treatment at 100 mg in a patient with renal cell cancer. D aily administration of imiquimod causes activation of the interferon p roduction system but at higher doses results in unacceptable toxicity. Further investigation of imiquimod as an interferon-inducing agent in cancer patients is suggested at either the lower dose levels or emplo ying alternative dosing schedules.