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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Confirmed HER2-positive esophageal, GE junction or gastric adenocarcinoma that is metastatic or unresectable.
* All patients must have available tumor sample (either paraffin block or 15 freshly cut, unstained slides) prior to study entry.

Part II: Patient must have primary esophagogastric tumor in place or other tumor that is accessible for mandatory biopsy.

* Measurable disease, defined in RECIST 1.1
* 18 years of age or older
* Life expectancy of greater than 12 weeks
* ECOG performance status of 0 or 1
* Organ and marrow function as outlined in the protocol
* Women of child-bearing potential and men must agree to use adequate contraception during study participation and for 30 days from the date of the last study drug administration.
* Part II only: Participant agrees to undergo mandatory pre and post loading dose of trastuzumab biopsy for correlative science.

Exclusion Criteria:

* Prior therapy with any of the following; capecitabine, oxaliplatin, bevacizumab or trastuzumab is not allowed. May have received and completed adjuvant therapy at least 6 months prior to study entry or one prior therapy for metastatic disease as long as it did not include any of the above agents.
* Chemotherapy or radiotherapy to greater then 25% of bone marrow within 4 weeks prior to entering the study.
* Palliative radiation therapy to isolated bone metastasis within 2 weeks of initiating therapy.
* Major surgery, open biopsy, significant traumatic injury within 4 weeks prior to study entry,.
* Minor surgery, including placement of vascular access device within 7 days prior to the first dose of bevacizumab.
* Residual toxicity from prior chemotherapy and/or radiation therapy of Grade 2 or greater.
* Participants may not be receiving any concurrent investigational agents
* Active brain or other CNS metastasis by history or clinical examination.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to capecitabine, bevacizumab or trastuzumab. No known allergy or hypersensitivity to Chinese hamster ovary, or any of the study agents. No known DPD deficiency.
* Warfarin is prohibited; anticoagulation using low molecular weight heparin is allowed.
* Uncontrolled, intercurrent illness
* Patients with a history of other malignancy are not eligible except for the following circumstances: disease-free for at least 3 years and are deemed to be at low risk for recurrence of that malignancy; cervical cancer in situ, basal cell or squamous cell carcinoma of the skin that was treated with curative intent within the past 5 years.
* Known HIV seropositivity, hepatitis C, acute or chronic hepatitis B or other serious active infection
* LVEF less than 50% as determined by MUGA scan or echocardiogram within 28 days prior to initiation of therapy
* Inadequately controlled hypertension
* History of prior hypertensive crisis or hypertensive encephalopathy
* History of any arterial thrombosis, CVA, TIA, MI or unstable angina in past 6 months.
* Evidence of bleeding diathesis or coagulopathy
* Serious, unhealed wounds, bone fractures or skin ulcers
* Pregnant or breast feeding
* Greater than grade 1 peripheral neuropathy at baseline
* Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.

• BACKGROUNDSung 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. PMID 33538338
• BACKGROUNDPohl 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. PMID 15657344
• BACKGROUNDCancer 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.