A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors

Introduction: MSC1992371A is an aurora kinase inhibitor with potential antitumor activity. Methods: This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m2) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19). Results: In both schedules, the 37 mg/m2 dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6-14 months. Conclusion: Oral MSC1992371A can be administered at a MTD of 37 mg/m2 in combination with the standard 1,000 mg/m2 dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD. © Springer Science+Business Media 2013.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A phase i dose-escalation study of msc1992371a, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses

A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses