Oral TGF-beta Receptor I Inhibitor Vactosertib in SOC Chemoradiotherapy for Esophageal Adenocarcinoma

Inclusion Criteria: * Subjects must have histologically or cytologically confirmed poorly differentiated or Grade 3 adenocarcinoma of the esophagus or gastroesophageal junction, clinical Stage II or III who are appropriate for concurrent chemoradiotherapy with carboplatin and paclitaxel or FOLFOX as per standard of care. Clinical staging appropriate: * cT2 N0 with high-risk lesions including lymphovascular invasion, tumors ≥ 3cm in size, or poorly differentiated histology, or * cT1b-cT2, N+, or * cT3-cT4a, any N * Subjects must be deemed a potential surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform an esophagectomy. * Subjects must NOT have received prior chemotherapy, immunotherapy, or radiation therapy for management of this malignancy (prior ablations or localized therapies for Barrett's metaplasia are acceptable). * Age ≥18 years. Because no dosing or adverse event data are currently available on the use of vVactosertib in subjects ≤18 years of age, children are excluded from this study. * ECOG Performance status ≤2 * Subjects must have normal organ and marrow function as defined below: * Serum total bilirubin \<2 mg/dl. If known Gilbert syndrome, total bilirubin must be \<3mg/dl * AST (SGOT) ≤ 2.5 X institutional upper limit of normal * ALT (SGPT) ≤ 2.5 X institutional upper limit of normal * Serum Creatinine ≤ 1.5 X institutional upper limit of normal * Hemoglobin ≥ 7.5 g/dL * Absolute neutrophil count ≥ 1,500/mcL * Platelet count ≥ 100,000/mcL * Subjects must have no contraindication to receiving recommended concurrent chemotherapy as per standard of care. * Subjects must have no contraindication to receiving radiation as per standard of care. * Women of child-bearing potential and sexually active men with female partners of child-bearing potential must agree to abstain from sexual intercourse for the duration of their participation in the study or agree to use highly effective methods of contraception. This is expected for the entire duration of the study period and up to 6 months after the last dose. Highly effective methods of contraception include: female sterilization (tubal ligation, bilateral oophorectomy, and/or hysterectomy); male sterilization (at least 6 months prior to screening); intrauterine device; and oral, injected, or implanted hormonal contraception AND barrier methods of contraception. Women of child-bearing potential must have documented negative pregnancy test prior to start of investigational treatment regimen. * Subjects must have the ability to understand and the willingness to sign a written informed consent document. * Subjects must be able to swallow oral medication. * Subjects must be willing to undergo endoscopic biopsy and PET CT on trial. Exclusion Criteria: * Subjects receiving any other investigational agents. Proton-beam radiation is acceptable, if it is considered standard of care in the opinion of the treating radiation oncologist. * Subjects with active malignancy within the past 3 years, except if locally curable cancers that have been apparently cured such as non-melanoma cutaneous malignancy, superficial bladder cancer, or carcinoma in situ of the breast or cervix. * History of allergic reactions to carboplatin, paclitaxel or fluorouracil, oxaliplatin, or vactosertib. * Subjects with contraindication to radiation therapy. * Subjects with contraindication to carboplatin and paclitaxel or FOLFOX chemotherapy as per standard of care. * Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant or breastfeeding women are excluded from this study because cytotoxic agents and radiation therapy have the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued if the mother participates in the trial. These potential risks may also apply to other agents used in this study. * HIV-positive patients are ineligible because of the potential for pharmacokinetic interactions with chemotherapeutic agents and because of a potential risk of worsening HIV viral load in response to TGFβ signaling inhibition. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. * Chronic active untreated hepatitis B or C infection. (Assessments should include Hepatitis B Surface AB, Hepatitis B Surface AG, Hepatitis B Core AB - Total, Hepatitis B Core AB, IGM, Hepatitis C AB). * Treated viral hepatitis patients with undetectable viral load are excluded because there is an enhanced risk of reactivation of the virus. Apart from the potential reactivation risk, the hepatitis-induced liver damage may delay or even cause discontinuation of chemotherapy. * Viral hepatitis patients receiving antiviral therapy are ineligible because of the potential for pharmacokinetic interactions with chemotherapeutic agents. * Subject who is taking prohibited medications when using vactosertib as following (refer to APPENDIX III). A minimal washout period of 5 half-lives for the following drugs is recommended prior to the first dosing. * Concurrent use of drugs or foods that are known strong CYP3A4 inhibitors including but not limited to grapefruit juice, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, voriconazole. The topical use of these medications (if applicable), such as 2% ketoconazole cream, may be allowed. * Concurrent use of drugs that are known potent CYP3A4 inducers including but not limited to phenytoin, rifampin, St. John's wort. * Concurrent use of drugs that are CYP3A4, CYP1A2, CYP2B6 substrates with narrow therapeutic indices including but not limited to theophylline, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, sirolimus, tacrolimus, terfenadine (astemizole, cisapride, and terfenadine have been withdrawn from the US market). * Concurrent use of drugs that are sensitive CYP3A4, CYP1A2, CYP2B6 substrates including but not limited to efavirenz, darunavir, dasatinib, everolimus, lopinavir, midazolam, sirolimus, ticagrelor. * QTc interval ≥470 ms calculated from 12-lead ECG at baseline.