We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status.
- Authors
Izar, Benjamin; Sharfman, William; Hodi, F. Stephen; Lawrence, Donald; Flaherty, Keith T.; Amaravadi, Ravi; Kim, Kevin B.; Puzanov, Igor; Sosman, Jeffrey; Dummer, Reinhard; Goldinger, Simone M.; Lam, Lyhping; Kakar, Shefali; Tang, Zhongwen; Krieter, Oliver; McDermott, David F.; Atkins, Michael B.
- Abstract
To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half-life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment-related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF-mutant and BRAF wild-type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On-treatment versus pretreatment IHC staining in 23 patients showed dose-dependent p-ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) levels in all dose levels. RAF265 is an oral RAF/VEGFR-2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan-RAF inhibitors and modulators of angiogenesis for the treatment of melanoma.
- Subjects
MELANOMA treatment; DRUG dosage; DRUG toxicity; DRUG efficacy; ENDOTHELIAL growth factors; ANTINEOPLASTIC agents; BRAF genes; GENETIC mutation
- Publication
Cancer Medicine, 2017, Vol 6, Issue 8, p1904
- ISSN
2045-7634
- Publication type
Article
- DOI
10.1002/cam4.1140