Abstract A86: A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214629).

Abstract

Abstract Background: LY2523355 is a potent allosteric inhibitor of the motor protein Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study was to determine a Phase 2 dose and schedule of LY2523355 that may be safely administered to patients with advanced malignancy. Methods: Study I1Y-MC-JFBA is an open-label, multicenter, dose-escalation study in patients with advanced malignancy. A modified 3+3 dose-escalation scheme was used, followed by a dose confirmation phase with pre- and post-treatment tumor biopsies. Patients received LY2523355 as a 1hr infusion on days 1, 2 and 3 of a 21-day cycle with determination of the MTD with and without pegfilgrastim administration on day 4. Patients were assessed every other cycle by RECIST. Treatment related PD changes in phosphohistone H3 (pHH3) and Eg5 expression were assessed in skin and tumor biopsies by immunohistochemistry. Results: 46 patients were enrolled in the study as of October 2010. The most frequent related AEs reported (>10%) include leukopenia, neutropenia, fatigue, nausea, stomatitis, vomiting, alopecia, anemia, diarrhea, lymphopenia, pruritis/itching and rash. Dose-limiting toxicities include increased INR, leukopenia, diarrhea, rash (palmar plantar erythrodysesthesia), febrile neutropenia, and mucositis. The single and multiple dose pharmacokinetics of LY2523355 and metabolite were characterized. Dose dependent increase in LY2523355 plasma exposure and a minor degree of intra- and inter-cycle accumulation were observed. An exposure-dependent increase in pHH3 and Eg5 expression and increase in apoptotic cells in tumor and skin biopsies has been demonstrated. One patient with ovarian cancer had a confirmed partial response. Nine other patients had stable disease for at least 2 cycles. Conclusions: The MTD of LY2523355 for this schedule has been established with and without pegfilgrastim at 6mg/m2/d and 4 mg/m2/d, respectively. These doses have shown a quantifiable PD response in skin and tumor biopsies confirming the importance of maximizing exposure intensity for maximum PD response. Dose confirmation is on-going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A86.