Open AccessA 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
Author(s) -
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.
Publication year - 2017
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1140
Subject(s) - medicine , pharmacokinetics , pharmacodynamics , melanoma , response evaluation criteria in solid tumors , vascular endothelial growth factor , mek inhibitor , immunohistochemistry , angiogenesis , angiogenesis inhibitor , adverse effect , progressive disease , oncology , mapk/erk pathway , pharmacology , gastroenterology , cancer research , chemotherapy , kinase , vegf receptors , biology , microbiology and biotechnology
To establish the maximum tolerated dose ( MTD ), dose‐limiting toxicities ( DLT ), safety profile, and anti‐tumor efficacy of RAF 265. We conducted a multicenter, open‐label, phase‐I, dose‐escalation trial of RAF 265, 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. RAF 265 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. RAF 265 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.