A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers

Purpose: To define the maximum tolerated dose (MTD), recommended phase II dose (RD) and dose limiting toxicity (DLT) of liposomal lurtotecan, OSI-211 (formerly known as NX211), given as a short intravenous infusion on days 1, 2, and 3 every three weeks. Experimental design: Thirty-seven patients were enrolled and treated in a dose escalation study from a starting dose of 0.15 mg/m(2) daily x 3 to 2.1 mg/m(2) daily x 3. Detailed pharmacokinetic analyses of blood were done on both days 1 and 3 of the first cycle and toxicity was monitored. Results: Two MTDs were defined; one for patients defined as minimally pretreated and one for those heavily pretreated. Dose limiting toxicity was myelosuppression: primarily thrombocytopenia although neutropenia was also noted. The MTD was 2.1 mg/m(2)/d (total dose of 6.3 mg/m(2)) in minimally pretreated patients and 1.8 mg/m2/d (5.4 mg/m(2) total dose) in heavily pretreated patients. Pharmacokinetics revealed that AUC and C-max increased with dose and were significantly higher than that of free lurtotecan (AUC approx. 100 fold higher). The half life and duration of the active lactone form were also significantly longer than historical data on free drug. Two partial responses were seen, one each in a patient with breast and ovarian cancer. Conclusions: Two Phase II recommended doses were established for OSI-211 given as a daily x 3 schedule every three weeks. The recommended phase II dose is 1.8 mg/m(2) daily x 3 for minimally pretreated patients and 1.5 mg/m(2) for those heavily pretreated. Phase II studies should be initiated in sensitive tumours.