A phase I study of TPI 287, a third generation taxane, administered every 21 days in patients with advanced cancer

Abstract

2569 Background: TPI 287 is a third generation taxane engineered to overcome multi-drug resistance and to bind to mutant tubulin. In preclinical studies, TPI 287 suppressed the growth of multiple human tumor xenografts in nude mice, including xenografts that expressed mdr- 1 and that were resistant to other taxanes. The safety and tolerability of TPI 287 when administered every 21 days was examined in this Phase 1 dose escalation study in patients (pts) with advanced neoplasms. Methods: TPI 287 was administered over 1 hour every 21 days in ascending doses to groups of 3 pts. Treatment cohorts were expanded to 6 pts in the face of dose-limiting toxicity (DLT); pts could remain on study until the development of progressive disease or an intolerable adverse event. DLT was defined as Gr 4 heme toxicity lasting 7 days; febrile neutropenia, Gr 3 thrombocytopenia with bleeding, Gr 3 elevation of transaminases lasting 7 days or any other Gr 3/4 toxicity other than nausea or vomiting. Results: 14 pts (M:F 5:9, median age 58.5, range 49 - 77) were enrolled in 5 dose levels ranging from 56 - 185 mg/m2. Pts’ cancers included colorectal (5 pts), esophageal (2), pancreatic (2), NSCLC (2), breast (2) and ovarian (1). All patients had received prior chemotherapy (median no. prior treatments: 3 (range, 2 - 10). Drug related adverse events included mucositis, vomiting, diarrhea, neutropenia, thrombocytopenia, myalgias and peripheral neuropathy. Only 1 pt. experienced Gr 4 neutropenia. DLT of Gr 3 peripheral sensory neuropathy was observed at a dose of 185 mg/m2. At a dose of 160 mg/m2 no DLT was observed. 1 pt with pancreatic cancer had a confirmed response to TPI 287 that has persisted for 2.5 months and continues as of this writing. PK data reveal that AUC is generally dose linear. At a dose of 126 mg/m2, clearance was 24.7 + 12.2 L/hr/m2 and t1/2 was 10.6 + 7.1 hrs. Conclusions: TPI 287 can be safely administered in a dose of 160 mg/m2 every 21 days. The dose limiting toxicity was Gr 3 peripheral neuropathy. Anti-neoplastic activity was seen in a patient with pancreatic cancer. PK is dose linear and predictable. Several Phase 2 studies of TPI 287 are being planned. No significant financial relationships to disclose.