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3036 Background: The California Cancer Consortium recently completed a Phase I pharmacokinetic (PK) and target validation (TV) trial of E7389. E7389, an analog of the marine compound halichondrin B, inhibits microtubule polymerization by a mechanism that is distinct from all other tubulin-binding agents. Sub- to low-nanomolar levels of E7389 inhibit cancer cell proliferation via induction of a G2/M block, disruption of mitotic spindles, and initiation of apoptosis. Methods: This first-in-man trial included a rapid titration design with real-time PK to guide dose escalation. E7389 was administered as a weekly bolus 3 weeks out of 4, starting at 0.125 mg/m2/wk. During the 1st phase, single patient (pt) cohorts were enrolled with intra- and inter-pt dose-doubling until toxicity was observed. The 2nd phase consisted of a standard 3x3 dose escalation schedule. Once the MTD was determined, a cohort of pts with biopsiable tumors was enrolled for TV studies. Results: A total of 40 (38 evaluable) pts with refractory or advanced solid tumors were entered. Median age was 61 yrs, KPS ≥ 80% in 31/38, and gender was 20/18 (M/F). Most common primary tumor sites were lung (9), breast (4), and bladder (2). Rapid escalation ended with a gr 3 alk phos at 0.5 mg/m2/wk. The 2nd phase ended at 2.0 mg/m2/wk with 2 DLT’s; 1 gr 3 febrile neutropenia and 1 gr 4 neutropenia. Other serious non-heme toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/wk. Responses included 2 PRs (NSCLC; bladder) and 3 MR (NSCLC, breast, and thyroid). SD as best response was seen in 12 pts lasting a median of 4 months (range 2–14). PK results demonstrate a tri-phasic elimination and a prolonged terminal t1/2 of 36–48 hrs. At the MTD, plasma levels of E7389 are above concentrations required for in vitro cytotoxicity for >1 week. A cohort of 13 pts was treated at the MTD and serial tumor biopsies were obtained. Fluorescent IHC analyses of these specimens demonstrate that E7389 disrupts microtubule structure in tumors in vivo Conclusions: Phase II studies of this novel, active agent are ongoing. (Sponsored by CA62505) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai
Synold et al. (Wed,) studied this question.