A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors.

PURPOSE

PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors.

METHODS

Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated.

RESULTS

Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses > or = 550 mg/m(2). The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species.

CONCLUSIONS

PR-104 was well tolerated at a dose of 1,100 mg/m(2) administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway.