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

Inclusion Criteria:

• Subjects must have histologically or cytologically confirmed poorly differentiatedor Grade 3 adenocarcinoma of the esophagus or gastroesophageal junction, clinicalstage II or III and must be appropriate for standard of care preoperative therapywith concurrent chemoradiotherapy with carboplatin and paclitaxel or FOLFOX OR withFLOT as per standard of care. Clinical staging appropriate:

• cT2 N0 with high-risk lesions including lymphovascular invasion, tumors ≥ 3cmin 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 radiationtherapy for management of this malignancy (prior ablations or localized therapiesfor Barrett's metaplasia are acceptable)

• Age ≥18 years. Because no dosing or adverse event data are currently available onthe use of vactosertib in subjects ≤18 years of age, children are excluded from thisstudy.

• ECOG Performance status ≤2

• Subjects must have adequate organ and marrow function as defined below:

• Serum total bilirubin <2 mg/dl. If known Gilbert syndrome, total bilirubin mustbe <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 chemotherapy as perstandard of care

• Subjects must have no contraindication to receiving radiation as per standard ofcare, unless the standard of care plan is to receive peri-operative FLOT

• Women of child-bearing potential and sexually active men with female partners ofchild-bearing potential must agree to abstain from sexual intercourse for theduration of their participation in the study or agree to use highly effectivemethods of contraception. This is expected for the entire duration of the studyperiod and up to 6 months after the last dose. Highly effective methods ofcontraception 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 ANDbarrier methods of contraception. Women of child-bearing potential must havedocumented negative pregnancy test prior to start of investigational treatmentregimen

• Subjects must have the ability to understand and the willingness to sign a writteninformed 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 isacceptable, if it is considered standard of care in the opinion of the treatingradiation oncologist

• Subjects with active malignancy within the past 3 years, except if locally curablecancers 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 (if planned for patient asper SOC) or fluorouracil, oxaliplatin, or docetaxel (if planned for patient as perSOC) or vactosertib

• Subjects with contraindication to radiation therapy, unless the standard of careplan is to receive peri-operative FLOT

• Subjects with contraindication to the planned chemotherapy medications (FLOT =fluorouracil, oxaliplatin, docetaxel) or the planned chemoradiation medications (carboplatin and paclitaxel or fluorouracil and oxaliplatin) as per standard of care

• Subjects with uncontrolled intercurrent illness including, but not limited toongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations that wouldlimit compliance with study requirements

• Pregnant or breastfeeding women are excluded from this study because cytotoxicagents and radiation therapy have the potential for teratogenic or abortifacienteffects. Because there is an unknown, but potential risk for adverse events innursing infants secondary to treatment of the mother with chemotherapy,breastfeeding should be discontinued if the mother participates in the trial. Thesepotential risks may also apply to other agents used in this study

• HIV-positive patients are ineligible because of the potential for pharmacokineticinteractions with chemotherapeutic agents and because of a potential risk ofworsening HIV viral load in response to TGFβ signaling inhibition. In addition,these patients are at increased risk of lethal infections when treated with marrowsuppressive therapy

• Chronic active untreated hepatitis B or C infection. (Assessments should includeHepatitis 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 becausethere is an enhanced risk of reactivation of the virus. Apart from the potentialreactivation risk, the hepatitis-induced liver damage may delay or even causediscontinuation of chemotherapy

• Viral hepatitis patients receiving antiviral therapy are ineligible because of thepotential for pharmacokinetic interactions with chemotherapeutic agents

• Subject who is taking prohibited medications when using vactosertib. A minimalwashout period of 5 half-lives for the following drugs is recommended prior to thefirst dosing

• Concurrent use of drugs or foods that are known strong CYP3A4 inhibitorsincluding but not limited to grapefruit juice, itraconazole, ketoconazole,lopinavir/ritonavir, mibefradil, voriconazole. The topical use of thesemedications (if applicable), such as 2% ketoconazole cream, may be allowed

• Concurrent use of drugs that are known potent CYP3A4 inducers including but notlimited to phenytoin, rifampin, St. John's wort

• Concurrent use of drugs that are CYP3A4, CYP1A2, CYP2B6 substrates with narrowtherapeutic indices including but not limited to theophylline, astemizole,cisapride, cyclosporine, dihydroergotamine, ergotamine, sirolimus, tacrolimus,terfenadine (astemizole, cisapride, and terfenadine have been withdrawn fromthe US market)

• Concurrent use of drugs that are sensitive CYP3A4, CYP1A2, CYP2B6 substratesincluding but not limited to efavirenz, darunavir, dasatinib, everolimus,lopinavir, midazolam, sirolimus, ticagrelor

• QTc interval ≥470 ms calculated from 12-lead ECG at baseline.