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Cancer Med. 2017 Aug;6(8):1904-1914. doi: 10.1002/cam4.1140. Epub 2017 Jul 18.

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.

Author information

1
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
2
Center for Cancer Precision Medicine/Dana-Farber Cancer Institute and the Broad Institute, Boston, Massachusetts.
3
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
4
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
5
Dana Farber Cancer Institute, Boston, Massachusetts.
6
Massachusetts General Hospital, Boston, Massachusetts.
7
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
8
California Pacific Medical Center Research Institute, San Francisco, California.
9
Vanderbilt-Ingram Cancer Center, Vanderbilt, Tennessee.
10
University Hospital, Zurich, Switzerland.
11
Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.
12
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
13
Novartis Pharma AG, Basel, Switzerland.
14
Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia.

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.

KEYWORDS:

BRAF wild-type; BRAF-mutant; Biomarker analysis; RAF265; metastatic melanoma

PMID:
28719152
PMCID:
PMC5548886
DOI:
10.1002/cam4.1140
[Indexed for MEDLINE]
Free PMC Article

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