Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study

BMC Cancer

Study Protocol

John B.A.G. Haanen¹  Alfons J.M. van den Eertwegh²  Daniel S. Peeper³  Ronald Boellaard⁴  Bernies van der Hiel⁵  Marcel P.M. Stokkel⁵  Bart A. van de Wiel⁶  Jos H. Beijnen⁷  Connie R. Jimenez⁸ 

[1] Department of Medical Oncology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands;Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands;Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands;Department of Nuclear Medicine, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, PO Box 90203, 1006, Amsterdam, BE, The Netherlands;Department of Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands;Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands;Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands;

关键词: Stage IIIc/IV melanoma;    Resistance;    BRAF inhibitor;    MEK inhibitor;    F-FDG;    F-FLT;    PET/CT;   

DOI  :  10.1186/s12885-017-3626-5

 received in 2016-03-29, accepted in 2017-08-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundIn patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment.Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3′-deoxy-3’L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG.MethodsThis phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks.Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.DiscussionThe results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment.Trial registrationClinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

【 授权许可】

CC BY   
© The Author(s). 2017