Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus : a randomized, placebo-controlled phase II AIO trial with serum biomarker program

Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric c
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
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Metadaten
Author:Markus Möhler, Irina Gepfner-Tuma, Annett Maderer, Peter C. Thuss-Patience, Jörn Rüssel, Susanna Hegewisch-Becker, Hansjochen Wilke, Salah-Eddin al- Batran, Mohammad-Reza Rafiyan, Florian Weißinger, Hans-Joachim Schmoll, Frank Kullmann, Ludwig Fischer von Weikersthal, Jens Thomas Siveke, Jens Weusmann, Stephan Kanzler, Carl Christoph Schimanski, Melanie Otte, Lukas Schollenberger, Jochem König, Peter Robert Galle
URN:urn:nbn:de:hebis:30:3-443903
DOI:http://dx.doi.org/10.1186/s12885-016-2736-9
ISSN:1471-2407
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27582078
Parent Title (English):BMC cancer
Publisher:BioMed Central ; Springer
Place of publication:London ; Berlin ; Heidelberg
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/08/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/11/28
Tag:Chemorefractory advanced gastric cancer; FOLFIRI; Sunitinib; Tyrosine kinase inhibitor; VEGF
Volume:16
Issue:Art. 699
Pagenumber:13
First Page:1
Last Page:13
Note:
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS PPN:425198677
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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