Background: Eg5, a mitotic motor kinesin, plays an essential role in bipolar spindle formation. Clinical studies on LY2523355 (Litronesib), an allosteric Eg5 inhibitor, were ongoing in several countries. This Phase I study evaluated the tolerability, safety and pharmacokinetics of LY2523355 in Japanese patients with refractory solid tumors to determine the recommended dose for further studies.

Methods: This was an open-label, dose-escalation study. LY2523355 was intravenously administered over 60 min on days 1, 2, and 3 every 3 weeks at 1 of 3 dose levels: 2, 4, and 5 mg/m2/day. Doses were escalated in a classic 3 + 3 design. Toxicity was assessed with NCI-CTCAE. Tumor responses were assessed according to the RECIST. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for >7 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring platelet transfusion, a neutrophil count of <500/μL with a fever of >38.5°C that lasted for >2 days, or grade ≥3 non-hematologic toxicity. G-CSF was used to treat grade 4 neutropenia or grade 3 febrile neutropenia.

Results: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. The male-to-female ratio was 7:5 and the median age was 61.5 years. The tumor types were non-small cell lung cancer (n = 2), colorectal cancer (n = 3), small cell lung cancer (n = 2), angiosarcoma (n = 1), breast cancer (n = 1), esophageal cancer (n = 1), gastric cancer (n = 1), and ovarian cancer (n = 1). The main toxicities were neutropenia and leukopenia (100%). Grade 4 neutropenia was observed in 83% of patients; neutrophil levels recovered to >500/μL within 7 days with G-CSF support in all patients. Grade 3 febrile neutropenia was observed in 2 (66%) patients at 4 mg/m2/day and in 6 (100%) patients at 5 mg/m2/day, but these were manageable with appropriate antibiotics administration. DLT was not noted up to 5 mg/m2/day, the dose used in parallel overseas Phase II studies. In pharmacokinetic analysis, exposure of LY2523355 increased dose-proportionally across these doses. None of the predictive factors, including gender, were associated with pharmacokinetic parameters or toxicity. The pharmacokinetic parameters were similar to those observed in Western populations. No objective tumor responses were observed.

Conclusions: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day on days 1, 2, and 3 with a manageable safety profile in Japanese patients with refractory solid tumors.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C68.

Citation Format: Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Wakui, Shinji Nakamichi, Hidenori Mizugaki, Satoru Kitazono, Hironori Kanda, Kohei Suzuki, Shiro Akinaga, Tomohide Tamura. Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C68.