A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors
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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.
KeywordsAurora kinase inhibitor Mitosis MSC1992371A Neutropenia Phase l Targeted therapy
The trial was sponsored by Merck Serono S.A., Geneva. Currently, Rigel Pharmaceuticals Inc, CA, USA, owns the rights to MSC1992371A (R763). The authors would like to thank the patients and their families, and the many staff at the hospitals involved, who contributed such valuable work. Editorial and writing assistance was provided by Rob Stepney, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany.
The trial was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations. The study, including the patient-information and consent forms used, was approved by the independent ethics committees of participating centers. Patients provided written informed consent.
Conflict of interest
E Raymond, J Alexandre, S Faivre, T Besse-Hammer, and A Awada have no relevant interests to disclose. F Goldwasser is consultant for Merck Serono S.A., Geneva, Switzerland. A Gianella-Borradori and L Trandafir were employees of Merck Serono S.A., Geneva, Switzerland. N Rejeb and V Jego are current employees of Merck Serono S.A., Geneva, Switzerland.
The study was sponsored by Merck Serono S.A. – Geneva, Geneva, Switzerland. Editorial and writing assistance was funded by Merck KGaA, Darmstadt, Germany.
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