Phase I study of retelliptine dihydrochloride (SR 95325 B) using a single two-hour intravenous infusion schedule.

Retelliptine dihydrochloride (SR 95325 B, NSC D-626717-W) is an ellipticine derivative having a very high level of antitumor activity in resistant murine solid tumor models. We studied in a Phase I trial escalating doses of retelliptine using a single 2-hour IV infusion schedule. Data from other Phase I studies allowed a starting dose of 80 mg/m2 and a rapid dose escalation. Included were 15 patients (M/F = 13/2) with a median age of 55 (range: 17-72). There were 22 courses delivered at the following dose levels: 80, 180, 700, 900, 1,200, and 1,500 mg/m2. Primary tumor types were kidney (6 patients), colon (3 patients), pancreas (2 patients), and others (4 patients). Mild dose-related visual troubles (blurring, accommodation troubles, oculomotor paresis) occurred in 9/11 patients starting from 700 mg/m2. Asymptomatic EKG anomalies, including significant prolongation of PR and QRS intervals occurred at 1500 mg/m2 (in 3/3 patients) marking the maximum tolerated dose. Both visual and EKG anomalies were spontaneously reversible few minutes to few hours after the end of infusion. Other possible drug-related toxicity occurred sporadically such as somnolence, bronchospasm, dry mouth, and vomiting (2 patients each). There were no significant laboratory anomalies. Neither drug-related deaths nor objective complete or partial responses were observed. The recommended dose for Phase II trial using the 2-hour intravenous infusion schedule is 1,200 mg/m2.