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

Media type: E-Article
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
Contributor: 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.
imprint: Wiley, 2017
Published in: Cancer Medicine
Language: English
DOI: 10.1002/cam4.1140
ISSN: 2045-7634
Keywords: Cancer Research ; Radiology, Nuclear Medicine and imaging ; Oncology
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:p>To establish the maximum tolerated dose (<jats:styled-content style="fixed-case">MTD</jats:styled-content>), dose‐limiting toxicities (<jats:styled-content style="fixed-case">DLT</jats:styled-content>), safety profile, and anti‐tumor efficacy of <jats:styled-content style="fixed-case">RAF</jats:styled-content>265. We conducted a multicenter, open‐label, phase‐I, dose‐escalation trial of <jats:styled-content style="fixed-case">RAF</jats:styled-content>265, an orally available <jats:styled-content style="fixed-case">RAF</jats:styled-content> kinase/<jats:styled-content style="fixed-case">VEGFR</jats:styled-content>‐2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (<jats:styled-content style="fixed-case">PK</jats:styled-content>) analysis, pharmacodynamics (<jats:styled-content style="fixed-case">PD</jats:styled-content>) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]‐fluorodeoxyglucose‐positron‐emission tomography (<jats:styled-content style="fixed-case">FDG</jats:styled-content>‐<jats:styled-content style="fixed-case">PET</jats:styled-content>), tissue biomarkers using immunohistochemistry (<jats:styled-content style="fixed-case">IHC</jats:styled-content>), and modulators of angiogenesis. <jats:styled-content style="fixed-case">RAF</jats:styled-content>265 has a serum half‐life of approximately 200 h. The <jats:styled-content style="fixed-case">MTD</jats:styled-content> 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 <jats:styled-content style="fixed-case">BRAF</jats:styled-content>‐mutant and <jats:styled-content style="fixed-case">BRAF</jats:styled-content> wild‐type (<jats:styled-content style="fixed-case">WT</jats:styled-content>) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On‐treatment versus pretreatment <jats:styled-content style="fixed-case">IHC</jats:styled-content> staining in 23 patients showed dose‐dependent p‐<jats:styled-content style="fixed-case">ERK</jats:styled-content> inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (<jats:styled-content style="fixed-case">sVEGFR</jats:styled-content>‐2) levels in all dose levels. <jats:styled-content style="fixed-case">RAF</jats:styled-content>265 is an oral <jats:styled-content style="fixed-case">RAF</jats:styled-content>/<jats:styled-content style="fixed-case">VEGFR</jats:styled-content>‐2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with <jats:styled-content style="fixed-case">BRAF</jats:styled-content>‐mutant and <jats:styled-content style="fixed-case">BRAF</jats:styled-content>‐<jats:styled-content style="fixed-case">WT</jats:styled-content> disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan‐<jats:styled-content style="fixed-case">RAF</jats:styled-content> inhibitors and modulators of angiogenesis for the treatment of melanoma.</jats:p>
Access State: Open Access

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