Sustained indomethacin and ranitidine with intermittent continuous infusion interleukin-2 in advanced malignant melanoma: A phase II study

Abstract

Experimental work has shown that, during the development of tumours, host macrophages are triggered to produce high levels of prostaglandin E 2 which inactivates natural killer cells and suppresses lymphokine activated killer cell development. Sustained, uninterrupted indomethacin treatment, when combined with interleukin-2 (IL-2), can totally eradicate experimental metastases. Most trials utilizing high dose IL-2 employ indomethacin and ranitidine in order to alleviate or prevent IL-2 toxicity, but only administer these medications concurrently with IL-2 therapy. A Phase II trial was conducted in patients with advanced melanoma. Patients received 50–75 mg indomethacin three times daily and 150 mg ranitidine twice daily, starting at least 1 week prior to IL-2 and continuing until intolerance or disease progression. Continuous venous infusion IL-2 was administered for three courses, each consisting of 5 days of treatment at 18 × 10 6 iu/m 2//day for the first course with escalation of dose for the subsequent courses if toxicity allowed. Twenty-one patients were eligible to receive all components of therapy. Three patients achieved an objective response (one complete and two partial), giving a response rate of 14%. However, two of these objective responses (one complete and one partial) were achieved on indomethacin and ranitidine alone, prior to the commencement of IL-2 therapy. In this study, indomethacin and ranitidine, without IL-2, have been shown to have antitumour activity in advanced melanoma; continuous infusion IL-2 appeared to add little to the response seen with these two agents.