Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer.

Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.