litronesib and Leukopenia

Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.. LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia.. Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed.. The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.

Topics: Adult; Aged; Allosteric Regulation; Antineoplastic Agents; Cancer Care Facilities; Chemotherapy-Induced Febrile Neutropenia; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drugs, Investigational; Enzyme Inhibitors; Female; Half-Life; Humans; Japan; Kinesins; Leukopenia; Male; Middle Aged; Neoplasm Proteins; Neoplasms; Severity of Illness Index; Sulfonamides; Thiadiazoles