CAPOX, Bevacizumab and Trastuzumab for Patients With HER2-Positive Metastatic Esophagogastric Cancer

Summary

The purpose of this study is to determine the safety and effectiveness of a combination of chemotherapy, capecitabine and oxaliplatin, plus the antibodies bevacizumab and trastuzumab. Trastuzumab (also called Herceptin) is an antibody that attacks HER2 protein in tumor cells. Bevacizumab (also called Avastin) works by slowing or stopping the growth of cells in cancer tumors by decreasing the blood supply of the tumors. If blood supply is decreased, oxygen and nutrients that are needed for tumor growth are decreased. The chemotherapy used in this trial is called CAPOX, which is an abbreviation of capecitabine and oxaliplatin.

Timeline

Start

2011-02

Primary completion

2021-12

Completion

2024-08

Publications

• Background Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
• Background Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005 Jan 19;97(2):142-6. doi: 10.1093/jnci/dji024.
• Background Cancer Genome Atlas Research Network; Analysis Working Group: Asan University; BC Cancer Agency; Brigham and Women's Hospital; Broad Institute; Brown University; Case Western Reserve University; Dana-Farber Cancer Institute; Duke University; Greater Poland Cancer Centre; Harvard Medical School; Institute for Systems Biology; KU Leuven; Mayo Clinic; Memorial Sloan Kettering Cancer Center; National Cancer Institute; Nationwide Children's Hospital; Stanford University; University of Alabama; University of Michigan; University of North Carolina; University of Pittsburgh; University of Rochester; University of Southern California; University of Texas MD Anderson Cancer Center; University of Washington; Van Andel Research Institute; Vanderbilt University; Washington University; Genome Sequencing Center: Broad Institute; Washington University in St. Louis; Genome Characterization Centers: BC Cancer Agency; Broad Institute; Harvard Medical School; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; University of North Carolina; University of Southern California Epigenome Center; University of Texas MD Anderson Cancer Center; Van Andel Research Institute; Genome Data Analysis Centers: Broad Institute; Brown University:; Harvard Medical School; Institute for Systems Biology; Memorial Sloan Kettering Cancer Center; University of California Santa Cruz; University of Texas MD Anderson Cancer Center; Biospecimen Core Resource: International Genomics Consortium; Research Institute at Nationwide Children's Hospital; Tissue Source Sites: Analytic Biologic Services; Asan Medical Center; Asterand Bioscience; Barretos Cancer Hospital; BioreclamationIVT; Botkin Municipal Clinic; Chonnam National University Medical School; Christiana Care Health System; Cureline; Duke University; Emory University; Erasmus University; Indiana University School of Medicine; Institute of Oncology of Moldova; International Genomics Consortium; Invidumed; Israelitisches Krankenhaus Hamburg; Keimyung University School of Medicine; Memorial Sloan Kettering Cancer Center; National Cancer Center Goyang; Ontario Tumour Bank; Peter MacCallum Cancer Centre; Pusan National University Medical School; Ribeirao Preto Medical School; St. Joseph's Hospital &Medical Center; St. Petersburg Academic University; Tayside Tissue Bank; University of Dundee; University of Kansas Medical Center; University of Michigan; University of North Carolina at Chapel Hill; University of Pittsburgh School of Medicine; University of Texas MD Anderson Cancer Center; Disease Working Group: Duke University; Memorial Sloan Kettering Cancer Center; National Cancer Institute; University of Texas MD Anderson Cancer Center; Yonsei University College of Medicine; Data Coordination Center: CSRA Inc.; Project Team: National Institutes of Health. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017 Jan 12;541(7636):169-175. doi: 10.1038/nature20805. Epub 2017 Jan 4.
• Background Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. doi: 10.1056/NEJMoa073149.
• Background Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5.
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• Background Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB 3rd, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017 Feb;35(4):446-464. doi: 10.1200/JCO.2016.69.4836. Epub 2016 Nov 14.
• Background Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. doi: 10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19.
• Background Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K, Kang YK. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018 Oct;19(10):1372-1384. doi: 10.1016/S1470-2045(18)30481-9. Epub 2018 Sep 11.
• Background Zhao D, Klempner SJ, Chao J. Progress and challenges in HER2-positive gastroesophageal adenocarcinoma. J Hematol Oncol. 2019 May 17;12(1):50. doi: 10.1186/s13045-019-0737-2.
• Background Janjigian YY, Kawazoe A, Yanez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. doi: 10.1038/s41586-021-04161-3. Epub 2021 Dec 15.
• Background Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-39. doi: 10.1016/S0140-6736(13)61719-5. Epub 2013 Oct 3.
• Background Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. doi: 10.1016/S1470-2045(14)70420-6. Epub 2014 Sep 17.
• Background Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. doi: 10.1200/JCO.2011.36.2236. Epub 2011 Aug 15.
• Background Cleary JM, Horick NK, McCleary NJ, Abrams TA, Yurgelun MB, Azzoli CG, Rubinson DA, Brooks GA, Chan JA, Blaszkowsky LS, Clark JW, Goyal L, Meyerhardt JA, Ng K, Schrag D, Savarese DMF, Graham C, Fitzpatrick B, Gibb KA, Boucher Y, Duda DG, Jain RK, Fuchs CS, Enzinger PC. FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial. Cancer. 2019 Jul 1;125(13):2213-2221. doi: 10.1002/cncr.32029. Epub 2019 Mar 26.
• Background Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):420-435. doi: 10.1016/S1470-2045(18)30791-5. Epub 2019 Feb 1.
• Background Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, Peng Yong W, Langer B, Delmar P, Scherer SJ, Shah MA. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2119-27. doi: 10.1200/JCO.2011.39.9824. Epub 2012 May 7.
• Background Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001 Jun;21(12):3995-4004. doi: 10.1128/MCB.21.12.3995-4004.2001.
• Background Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 2004 Mar 1;10(5):1706-16. doi: 10.1158/1078-0432.ccr-0951-3.
• Background Singh R, Kim WJ, Kim PH, Hong HJ. Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing gastric cancer xenografts than individual blockade. Exp Mol Med. 2013 Nov 1;45(11):e52. doi: 10.1038/emm.2013.111.
• Background Liu K, Chen H, You Q, Shi H, Wang Z. The siRNA cocktail targeting VEGF and HER2 inhibition on the proliferation and induced apoptosis of gastric cancer cell. Mol Cell Biochem. 2014 Jan;386(1-2):117-24. doi: 10.1007/s11010-013-1850-0. Epub 2013 Oct 26.
• Background Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, Gydush G, Reed SC, Rotem D, Rhoades J, Loginov D, Livitz D, Rosebrock D, Leshchiner I, Kim J, Stewart C, Rosenberg M, Francis JM, Zhang CZ, Cohen O, Oh C, Ding H, Polak P, Lloyd M, Mahmud S, Helvie K, Merrill MS, Santiago RA, O'Connor EP, Jeong SH, Leeson R, Barry RM, Kramkowski JF, Zhang Z, Polacek L, Lohr JG, Schleicher M, Lipscomb E, Saltzman A, Oliver NM, Marini L, Waks AG, Harshman LC, Tolaney SM, Van Allen EM, Winer EP, Lin NU, Nakabayashi M, Taplin ME, Johannessen CM, Garraway LA, Golub TR, Boehm JS, Wagle N, Getz G, Love JC, Meyerson M. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017 Nov 6;8(1):1324. doi: 10.1038/s41467-017-00965-y.
• Background Pectasides E, Stachler MD, Derks S, Liu Y, Maron S, Islam M, Alpert L, Kwak H, Kindler H, Polite B, Sharma MR, Allen K, O'Day E, Lomnicki S, Maranto M, Kanteti R, Fitzpatrick C, Weber C, Setia N, Xiao SY, Hart J, Nagy RJ, Kim KM, Choi MG, Min BH, Nason KS, O'Keefe L, Watanabe M, Baba H, Lanman R, Agoston AT, Oh DJ, Dunford A, Thorner AR, Ducar MD, Wollison BM, Coleman HA, Ji Y, Posner MC, Roggin K, Turaga K, Chang P, Hogarth K, Siddiqui U, Gelrud A, Ha G, Freeman SS, Rhoades J, Reed S, Gydush G, Rotem D, Davison J, Imamura Y, Adalsteinsson V, Lee J, Bass AJ, Catenacci DV. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov. 2018 Jan;8(1):37-48. doi: 10.1158/2159-8290.CD-17-0395. Epub 2017 Oct 4.
• Background Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L. HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice. World J Gastroenterol. 2016 Jul 14;22(26):5879-87. doi: 10.3748/wjg.v22.i26.5879.
• Background Zhang L, Hamdani O, Gjoerup O, Cho-Phan C, Snider J, Castellanos E, Nimeiri H, Frampton G, Venstrom JM, Oxnard G, Klempner SJ, Schrock AB. ERBB2 Copy Number as a Quantitative Biomarker for Real-World Outcomes to Anti-Human Epidermal Growth Factor Receptor 2 Therapy in Advanced Gastroesophageal Adenocarcinoma. JCO Precis Oncol. 2022 Jan;6:e2100330. doi: 10.1200/PO.21.00330.

Drugs

Indications