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Open Access 01-12-2016 | Study protocol

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme)

Authors: Antonio Avallone, Maria Carmela Piccirillo, Luigi Aloj, Guglielmo Nasti, Paolo Delrio, Francesco Izzo, Elena Di Gennaro, Fabiana Tatangelo, Vincenza Granata, Ernesta Cavalcanti, Piera Maiolino, Francesco Bianco, Pasquale Aprea, Mario De Bellis, Biagio Pecori, Gerardo Rosati, Chiara Carlomagno, Alessandro Bertolini, Ciro Gallo, Carmela Romano, Alessandra Leone, Corradina Caracò, Elisabetta de Lutio di Castelguidone, Gennaro Daniele, Orlando Catalano, Gerardo Botti, Antonella Petrillo, Giovanni M. Romano, Vincenzo R. Iaffaioli, Secondo Lastoria, Francesco Perrone, Alfredo Budillon

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy.

Methods/Design

OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80 % statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [¹⁸F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project.

Discussion

Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response.

EudraCT Number: 2011-004997-27

Trial registration

ClinicalTrials.gove number, NCT01718873

Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.CrossRefPubMed

Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–74.CrossRefPubMed

Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.CrossRefPubMedPubMedCentral

Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.CrossRefPubMed

De Bock K, Mazzone M, Carmeliet P. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Rev Clin Oncol. 2011;8(7):393–404.CrossRefPubMed

Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009;6(9):507–18.CrossRefPubMed

Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(12):2013–9.CrossRef

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.CrossRefPubMed

Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, Stathopoulos J, et al. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology. 2010;78(5–6):376–81.CrossRefPubMed

10.

Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26(6):1201–7.CrossRefPubMed

11.

Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6(6):327–38.CrossRefPubMedPubMedCentral

12.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.CrossRefPubMed

13.

Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science. 2006;312(5777):1171–5.CrossRefPubMed

14.

Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6(6):553–63.PubMed

15.

Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004;64(11):3731–6.CrossRefPubMed

16.

Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res. 2007;13(11):3395–402.CrossRefPubMedPubMedCentral

17.

Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007;13(13):3942–50.CrossRefPubMed

18.

Avallone A, Pecori B, Bianco F, Aloj L, Tatangelo F, Romano C, et al. Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial. Oncotarget. 2015;6(30):30394–407.PubMedPubMedCentral

19.

Zhang D, Hedlund EM, Lim S, Chen F, Zhang Y, Sun B, et al. Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity. Proc Natl Acad Sci U S A. 2011;108(10):4117–22.CrossRefPubMedPubMedCentral

20.

Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14(3):263–73.CrossRefPubMedPubMedCentral

21.

Bertolini F, Shaked Y, Mancuso P, Kerbel RS. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer. 2006;6(11):835–45.CrossRefPubMed

22.

Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.CrossRefPubMed

23.

Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G, et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood. 2006;108(2):452–9.CrossRefPubMedPubMedCentral

24.

Furstenberger G, von Moos R, Lucas R, Thurlimann B, Senn HJ, Hamacher J, et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer. 2006;94(4):524–31.CrossRefPubMedPubMedCentral

25.

Shaked Y, Kerbel RS. Antiangiogenic strategies on defense: on the possibility of blocking rebounds by the tumor vasculature after chemotherapy. Cancer Res. 2007;67(15):7055–8.CrossRefPubMed

26.

Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145–7.CrossRefPubMedPubMedCentral

27.

Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(18):3020–6.CrossRef

28.

Alishekevitz D, Bril R, Loven D, Miller V, Voloshin T, Gingis-Velistki S, et al. Differential therapeutic effects of anti-VEGF-A antibody in different tumor models: implications for choosing appropriate tumor models for drug testing. Mol Cancer Ther. 2014;13(1):202–13.CrossRefPubMed

29.

Avallone A, Di Gennaro E, Delrio P, Aloj L, Tatangelo F, Pecori B, et al. Neoadjuvant multidisciplinary phase II study (BRANCH) of an early bevacizumab schedule plus chemo-radiation therapy in rectal cancer: efficacy, safety, and biomarkers. In: 103rd annual meeting of the American Association for Cancer Research: 2012; Chicago, IL. 2012.

30.

Lanuti P, Rotta G, Almici C, Avvisati G, Budillon A, Doretto P et al. Endothelial progenitor cells, defined by the simultaneous surface expression of VEGFR2 and CD133, are not detectable in healthy peripheral and cord blood. Cytometry A. 2015. doi:10.1002/cyto.a.22730.

31.

Xu L, Duda DG, di Tomaso E, Ancukiewicz M, Chung DC, Lauwers GY, et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 2009;69(20):7905–10.CrossRefPubMedPubMedCentral

32.

Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104(43):17069–74.CrossRefPubMedPubMedCentral

33.

Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(28):4672–8.CrossRef

34.

Schneider BP, Radovich M, Miller KD. The role of vascular endothelial growth factor genetic variability in cancer. Clin Cancer Res. 2009;15(17):5297–302.CrossRefPubMed

35.

Loupakis F, Cremolini C, Fioravanti A, Orlandi P, Salvatore L, Masi G, et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer. 2011;104(8):1262–9.CrossRefPubMedPubMedCentral

36.

Siravegna G, Bardelli A. Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance. Genome Biol. 2014;15(8):449.CrossRefPubMedPubMedCentral

37.

Luo X, Burwinkel B, Tao S, Brenner H. MicroRNA signatures: novel biomarker for colorectal cancer? Cancer Epidemiol Biomark Prev. 2011;20(7):1272–86.CrossRef

38.

Anand S, Cheresh DA. MicroRNA-mediated regulation of the angiogenic switch. Curr Opin Hematol. 2011;18(3):171–6.CrossRefPubMedPubMedCentral

39.

Zheng T, Wang J, Chen X, Liu L. Role of microRNA in anticancer drug resistance. Int J Cancer J Int Cancer. 2010;126(1):2–10.CrossRef

40.

Cascini GL, Avallone A, Delrio P, Guida C, Tatangelo F, Marone P, et al. 18 F-FDG PET is an early predictor of pathologic tumor response to preoperative radiochemotherapy in locally advanced rectal cancer. J Nucl Med. 2006;47(8):1241–8.PubMed

41.

Avallone A, Aloj L, Caraco C, Delrio P, Pecori B, Tatangelo F, et al. Early FDG PET response assessment of preoperative radiochemotherapy in locally advanced rectal cancer: correlation with long-term outcome. Eur J Nucl Med Mol Imaging. 2012;39(12):1848–57.CrossRefPubMed

42.

Lastoria S, Piccirillo MC, Caraco C, Nasti G, Aloj L, Arrichiello C, et al. Early PET/CT scan is more effective than RECIST in predicting outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab. J Nucl Med. 2013;54(12):2062–9.CrossRefPubMed

43.

Avallone A, Di Gennaro E, Delrio P, Aloj L, Tatangelo F, Pecori B, et al. Neoadjuvant multidisciplinary phase II study (BRANCH) of an early bevacizumab schedule plus chemo-radiation therapy in rectal cancer: efficacy, safety, and biomarkers. In: Pro 103rd annual meeting of the American Association for Cancer Research: 2012; Chicago, IL. 2012.

44.

Ferracin M, Lupini L, Salamon I, Saccenti E, Zanzi MV, Rocchi A, et al. Absolute quantification of cell-free microRNAs in cancer patients. Oncotarget. 2015;6(16):14545–55.CrossRefPubMedPubMedCentral

45.

Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795–801.CrossRefPubMedPubMedCentral

46.

Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76.CrossRefPubMed

Title: A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme)
Authors: Antonio Avallone
Maria Carmela Piccirillo
Luigi Aloj
Guglielmo Nasti
Paolo Delrio
Francesco Izzo
Elena Di Gennaro
Fabiana Tatangelo
Vincenza Granata
Ernesta Cavalcanti
Piera Maiolino
Francesco Bianco
Pasquale Aprea
Mario De Bellis
Biagio Pecori
Gerardo Rosati
Chiara Carlomagno
Alessandro Bertolini
Ciro Gallo
Carmela Romano
Alessandra Leone
Corradina Caracò
Elisabetta de Lutio di Castelguidone
Gennaro Daniele
Orlando Catalano
Gerardo Botti
Antonella Petrillo
Giovanni M. Romano
Vincenzo R. Iaffaioli
Secondo Lastoria
Francesco Perrone
Alfredo Budillon
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2102-y

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Methods/Design

Discussion

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