A phase I study of TPI 287, a novel taxane, administered every 21 days in patients (pts) with advanced cancer

Abstract

13510 Background: TPI 287 is a novel taxane engineered to overcome multi-drug resistance. In preclinical studies, TPI 287 suppressed the growth of multiple human tumor xenografts in nude mice, including xenografts that expressed mdr-1 and 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 pts with advanced cancers. 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. The maximum tolerated dose (MTD) was defined as the dose at which < 2/3 of pts experienced DLT. Results: 21 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 (7 pts), pancreatic (2), NSCLC (2), breast (2) and one each carcinoid, cholangiosarcoma, esophageal, gastric, ovarian, and an unknown primary. Twenty pts had received prior chemotherapy (median #: 4 (range, 2 - 11). Pts received a median of 3 cycles (range 1–13). All patients experienced adverse events during the study, the most common being neuropathy (48%) anemia (38%), diarrhea (29%), nausea (29%), and neutropenia (24%). DLTs consisted of Gr 3 peripheral sensory neuropathy (3 pts) and neutropenia (2 Gr 3, 1 Gr 4). One pt with pancreatic cancer had a confirmed partial response (51% by RECIST) that lasted for 9 months and one patient with breast cancer had stable disease for over 6 months. Peak plasma concentrations (Cmax) and area under the curve (AUC) were generally dose linear at the 3 highest doses administered, and these parameters as well as the terminal elimination half life (HL) of TPI 287 were similar to values reported for paclitaxel infused for 1 or 3 hours at clinically relevant dose levels ranging from 135 to 175 mg/m2. Conclusions: TPI 287 can be safely administered in a dose of 160 mg/m2 every 21 days. The DLTs consisted of neuropathy and neutropenia. Anti-tumor activity was seen in two pts with pancreatic and breast cancers, respectively. PK is dose linear and predictable. Several Phase 2 studies using TPI 287 in this dose and schedule have been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Tapestry Pharmaceuticals, Inc. Tapestry Pharmaceuticals, Inc.