Phase I trials of WR-2721 and cis-platinum

WR-2721 is a sulfhydryl compound which in the animal model improves renal tolerance to cis-platinum (DDP) by factors of 1.3 to 1.7. Phase I trials were initiated to establish the toxicity and dose modification factors when WR-2721 was given prior to escalating doses of DDP. Nineteen patients received 27 courses of WR-2721 (450-910 mg/m2) 20 minutes prior to DDP (50-120 mg/m2). Patients were prehydrated, but no mannitol or other diuretics were administered. Mild, transient nephrotoxicity was observed in only 2 of 15 courses of DDP 80-100 mg/m2 when WR-2721 was given prior to DDP. Although 5 of 9 patients treated with WR-2721 prior to 120 mg/m2 of DDP developed transient nephrotoxicity, their serum creatinines returned to normal baseline values within 1 to 2 weeks. Subsequently, the protocol was modified to include mannitol diuresis. Thirty-four courses of WR-2721 (740 mg/m2) prior to DDP 120-150 mg/m2 with mannitol diuresis were administered. Biweekly serum creatinine and monthly creatinine clearances have remained normal in all patients treated with 120 mg/m2 of platinum and WR-2721. Four of 10 patients treated with 150 mg/m2 of cis-platinum experienced transient nephrotoxicity 5-7 days after treatment. Mild ototoxicity was noted in 4 patients following 150 mg/m2 of DDP. WR-2721 does not appear to protect against the antitumor efficacy of DDP, as 57% of all patients achieved objective partial responses, lasting 1+ to 7+ months. Partial responses occurred in 3/4 (75%) of patients with melanoma and 7/10 (70%) patients with cancer of the head and neck. Compared to retrospective series, our data suggest that WR-2721 may provide some protection against platinum-induced nephrotoxicity, but the dose modification factors remain to be established.