PHASE IB TRIAL AT PICIBANIL (OK-432) AS AN IMMUNOMODULATOR IN PATIENTS WITH RESECTED HIGH-RISK MELANOMA

The microbial immunostimulant OK-432 has been studied intensively in p reclinical systems and has shown promise as an anticancer agent in tri als that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the Univer sity of Pittsburgh Cancer Institute Melanoma Center, establishing 30 K E as the maximal tolerable dosage, on the basis of cutaneous reactions , Subsequently, 48 patients with resected high-risk melanoma participa ted in a phase IB study of OK-432. This study has evaluated the immuno modulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of th e treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participate d in this trial had a significant depression of OK-432-inducible cytok ine production (interleukin-1 beta, interferon gamma, and tumor necros is factor alpha) at baseline. Treatment with OK-432 reversed this defi cit for interferon gamma (IFN gamma) production in a dose-dependent ma nner, and mitigated the inhibition for interleukin-l (IL-1) across all dosage groups. The impact of OK-432 upon other immunological function s of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16(+) cell co unts and natural killer activity with early tumor progression and deat h due to melanoma. Favorable prognosis is associated with monocyte cap acity to produce tumor necrosis factor (TNF), and polymorphonuclear le ukocyte formylmethionyl-leucylphenylalanine-inducible superoxide relea se. This study reveals several new immunological correlates of tumor p rogression and lethal outcome in resected highrisk melanoma. It demons trates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study ha s defined treatment and dose response patterns of immunomodulation ass ociated with one of the most complex immunological agents yet evaluate d in phase IB trials, in a well-defined population of high-risk patien ts with resected melanoma.