Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor Journal Article
| Authors: | Tap, W. D.; Wainberg, Z. A.; Anthony, S. P.; Ibrahim, P. N.; Zhang, C.; Healey, J. H.; Chmielowski, B.; Staddon, A. P.; Lee Cohn, A.; Shapiro, G. I.; Keedy, V. L.; Singh, A. S.; Puzanov, I.; Kwak, E. L.; Wagner, A. J.; Von Hoff, D. D.; Weiss, G. J.; Ramanathan, R. K.; Zhang, J.; Habets, G.; Zhang, Y.; Burton, E. A.; Visor, G.; Sanftner, L.; Severson, P.; Nguyen, H.; Kim, M. J.; Marimuthu, A.; Tsang, G.; Shellooe, R.; Gee, C.; West, B. L.; Hirth, P.; Nolop, K.; van de Rijn, M.; Hsu, H. H.; Peterfy, C.; Lin, P. S.; Tong-Starksen, S.; Bollag, G. |
| Article Title: | Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor |
| Abstract: | 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. © 2015 Massachusetts Medical Society. |
| Keywords: | adult; controlled study; human tissue; protein expression; aged; middle aged; unclassified drug; major clinical study; clinical trial; fatigue; neutropenia; area under the curve; diarrhea; dose response; drug dose reduction; drug efficacy; drug safety; drug withdrawal; side effect; solid tumor; treatment duration; drug targeting; antineoplastic agent; prospective study; metabolism; phase 2 clinical trial; anemia; tumor volume; nausea; cohort analysis; drug potency; tumor regression; pathology; dose-response relationship, drug; drug discovery; drug development; drug selectivity; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; lymphocytopenia; hair color; alanine aminotransferase; aspartate aminotransferase; hyponatremia; drug mechanism; tumor burden; multicenter study; drug response; patient compliance; crystallography, x-ray; adenosquamous carcinoma; time to maximum plasma concentration; phase 1 clinical trial; receptor blocking; drug half life; cancer control; periorbital edema; pyrroles; structure analysis; x ray crystallography; salivary gland carcinoma; soft tissue neoplasms; lymphocyte count; pyrrole derivative; dysgeusia; giant cell tumor; international normalized ratio; giant cell tumors; tenosynovial giant cell tumor; tendon; tendons; colony stimulating factor 1 receptor; colony stimulating factor receptor; receptor, macrophage colony-stimulating factor; faintness; hand pain; humans; human; male; female; priority journal; article; antagonists and inhibitors; aminopyridines; aminopyridine derivative; 5 [[5 chloro 1h pyrrolo(2,3 b)pyridin 3 yl]methyl] n [[6 (trifluoromethyl)pyridin 3 yl]methyl]pyridin 2 amine; 5-((5-chloro-1h-pyrrolo(2,3-b)pyridin-3-yl)methyl)-n-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine |
| Journal Title: | New England Journal of Medicine |
| Volume: | 373 |
| Issue: | 5 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2015-07-30 |
| Start Page: | 428 |
| End Page: | 437 |
| Language: | English |
| DOI: | 10.1056/NEJMoa1411366 |
| PUBMED: | 26222558 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work