Phase I trial of extracellular adenosine 5′-triphosphate in patients with advanced cancer

Abstract

Adenosine 5′‐triphosphate (ATP) has antineoplastic activity in vitro and in murine tumor systems, but there are no data in humans defining its potential use as an antineoplastic agent. We conducted a Phase I study to determine the spectrum of toxicity, maximum safely tolerated dose (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with advanced cancer received 96‐hour infusions of ATP once monthly in doses ranging from 50 to 100 μg/kg/minute. Toxicity was assessed by standard National Cancer Institute (NCI) criteria, cardiac function was monitored serially by two‐dimensional echocardiography, and whole blood ATP was measured serially in a subset of patients. ATP was generally well tolerated and no significant hematologic toxicity was noted. The dose‐limiting toxicity was a cardiopulmonary reaction characterized by chest tightness and dyspnea that resolved within seconds of discontinuing ATP. Dose‐limiting cardiopulmonary toxicity occurred in 3 of 3 patients at 100 μg/kg/minute, in 3 of 6 patients at 75 μg/kg/minute, and 4 of 11 patients at 50 μg/kg/minute. Whole blood ATP levels significantly increased with treatment, reaching a steady state by 24 hours and returning to or near baseline by 1 week after treatment. Plateau levels were 63%, 67%, and 116% above baseline at 50, 75, and 100 μg/kg/min, respectively. We conclude that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 μg/kg/minute is both the MTD and the most appropriate dose rate for subsequent Phase II testing of 96‐hour infusions of ATP in patients with advanced cancer.