TY - JOUR
T1 - Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor
AU - Tap, William D.
AU - Wainberg, Zev A.
AU - Anthony, Stephen P.
AU - Ibrahim, Prabha N.
AU - Zhang, Chao
AU - Healey, John H.
AU - Chmielowski, Bartosz
AU - Staddon, Arthur P.
AU - Lee Cohn, Allen
AU - Shapiro, Geoffrey I.
AU - Keedy, Vicki L.
AU - Singh, Arun S.
AU - Puzanov, Igor
AU - Kwak, Eunice L.
AU - Wagner, Andrew J.
AU - Von Hoff, Daniel D.
AU - Weiss, Glen J.
AU - Ramanathan, Ramesh K.
AU - Zhang, Jiazhong
AU - Habets, Gaston
AU - Zhang, Ying
AU - Burton, Elizabeth A.
AU - Visor, Gary
AU - Sanftner, Laura
AU - Severson, Paul
AU - Nguyen, Hoa
AU - Kim, Marie J.
AU - Marimuthu, Adhirai
AU - Tsang, Garson
AU - Shellooe, Rafe
AU - Gee, Carolyn
AU - West, Brian L.
AU - Hirth, Peter
AU - Nolop, Keith
AU - Van De Rijn, Matt
AU - Hsu, Henry H.
AU - Peterfy, Charles
AU - Lin, Paul S.
AU - Tong-Starksen, Sandra
AU - Bollag, Gideon
N1 - Publisher Copyright:
© 2015 Massachusetts Medical Society.
PY - 2015/7/30
Y1 - 2015/7/30
N2 - 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 treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients.
AB - 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 treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients.
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U2 - 10.1056/NEJMoa1411366
DO - 10.1056/NEJMoa1411366
M3 - Article
C2 - 26222558
AN - SCOPUS:84938369565
SN - 0028-4793
VL - 373
SP - 428
EP - 437
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 5
ER -