Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

作者：William D. Tap, Zev A. Wainberg, Stephen P. Anthony, Prabha N. Ibrahim, Chao Zhang, John H. Healey, Bartosz Chmielowski, Arthur P. Staddon, Allen Lee Cohn, Geoffrey I. Shapiro, Vicki L. Keedy, Arun S. Singh, Igor Puzanov, Eunice L. Kwak, Andrew J. Wagner, Daniel D. Von Hoff, Glen J. Weiss, Ramesh K. Ramanathan, Jiazhong Zhang, Gaston Habets, Ying Zhang, Elizabeth A. Burton, Gary C. Visor, Laura Sanftner, Paul Severson, Hoa Nguyen, Marie J. Kim, Adhirai Marimuthu, Garson Tsang, Rafe Shellooe, C. M. Gee, Brian L. West, Peter Hirth, K. B. Nolop, Matt van de Rijn, Henry H. Hsu, Charles Peterfy, Paul Lin, Sandra Tong-Starksen, Gideon Bollag · 发表于：New England Journal of Medicine · 年份：2015 · DOI：10.1056/nejmoa1411366 · 被引用次数：588 · 研究领域：Musculoskeletal synovial abnormalities and treatments、Bone Tumor Diagnosis and Treatments、Sarcoma Diagnosis and Treatment

BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of t...