A phase I pharmacokinetic and target validation study of the novel anti-tubulin agent E7389: A California Cancer Consortium trial

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 refracto...