Neratinib and Fam-Trastuzumab Deruxtecan in Advanced Gastro-esophageal Cancer Patients

Inclusion Criteria:

1. Patients must have been diagnosed with histologically or cytologically confirmedgastrointestinal cancer (esophagus, stomach, colon, biliary, pancreas or unknownprimary likely GI), and been deemed unresectable or have at least one site ofmetastatic disease

2. Patients must have evaluable or measurable disease by RECIST 1.1 criteria

3. 4.1.3 Patients' tumors must have HER2-overexpressing:

4. (IHC 3+ or IHC2+/ISH+) advanced gastroesophageal cancer (includinggastroesophageal junction adenocarcinoma).

5. IHC 3+ for other GI cancers

6. Patients must have received at least one prior line of HER2 directed therapy formetastatic/unresectable disease and completed treatment at least 2 weeks prior toC1D1 (only for Gastroesohageal cancers, not for other GI cancers)

7. Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

8. Age > 18 years.

9. ECOG performance status 0-2

10. Patients must have normal organ and marrow function as defined below

• Leukocytes > 3,000/mcL

• Absolute neutrophil count > 1,500/mcL

• Platelets > 90,000/mcL

• Hemoglobin > 9 gm/dl

• Total bilirubin < 2 times institutional normal limits

• AST/ALT (SGOT/SGPT) < 5 times institutional normal limits if liver metastasesand </+ 2 times institutional normal limits otherwise

• Creatinine < 2.0mg/dL OR

• Creatinine clearance > 50 Ml/min/1.73 m2 for patients with creatinine levelsabove institutional normal

9. Left Ventricular Ejection Fraction ≥ 45% or lower limit of normal.

10. Chemotherapy is harmful to the human fetus. For this reason, females of childbearingpotential must be willing to use an effective method of contraception, as outlinedin Section 4.4, for the course of the study through at least 6 months after the lastdose of study medication. Males who have women of childbearing (WOCB) partners mustagree to use an effective method of contraception as outlined in Section 4.4 for thecourse of the study through 8 months after the last dose of study medication.

11. Patients should be willing and able to swallow oral tablet medications

12. Ability to understand and willingness to sign a written informed consent and HIPAAconsent document

Exclusion Criteria:

1. Patients who have had chemotherapy, or radiotherapy within 2 weeks prior to C1D1 orthose who have not recovered from adverse events due to agents administered morethan 2 weeks earlier (secondary hypothyroidism from prior immunotherapy ispermissible if controlled on thyroid hormone replacement). Recovery is defined asany treatment onset adverse events returning to baseline or otherwise deemed notclinically significant.

2. Patients may not be receiving any other investigational agents for advanced cancerand must not have received prior treatment with TDxD

3. Immunotherapy and treatments involving any investigational agents must bediscontinued for >21 days before Cycle 1 Day 1 (C1D1)

4. Patients with known untreated brain metastases are excluded from this study becauseof their poor prognosis and frequent development of neurologic dysfunction thatwould confound the evaluation of neurologic and other adverse events. Treated brainmetastases are allowed (requires stability on MRI at least 4 weeks after initialtreatment). Patients with treated brain metastases are allowed to be treated withsteroid and/or anti-convulsants if the dose remains stable or decreases over thelast 4 weeks prior to C1D1

5. Patients with ongoing diarrhea (> 4 bowel movements/day) unresolved despite medicaland best supportive care in the two weeks preceding therapy

6. Patients will be excluded if they have had interstitial lung disease or pneumonitisor were suspected to have interstitial lung disease or pneumonitis that could not beruled out on imaging at screening or if they had a history of noninfectiousinterstitial lung disease or pneumonitis that had been treated with glucocorticoids.Similarly, patients with clinically significant lung disease requiring O2 support orimpaired lung function per investigator should be excluded

7. History of allergic reactions attributed to compound of similar chemical or biologiccomposition to the agent(s) used in this study

8. Patients receiving any medications or substances that are strong inhibitors orinducers of Neratinib and/or TDxD are ineligible.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

10. Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screeningtriplicate12-lead ECG.

11. Any patients with immune deficiency are at increased risk of lethal infections whentreated with marrow-suppressive therapy, including uncontrolled HIV with CD4 count <200, untreated Hepatitis B are excluded from the study. Patients who have beentreated for hepatitis C definitively with evidence of sustained virologic response,as well as HIV and hepatitis B patients on treatment with undetectable viral loadwill be eligible for inclusion.

12. Pregnant or breast feeding.