Futibatinib With Paclitaxel and Ramucirumab for the Treatment of Locally Advanced or Unresectable Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma

Patients must have histologically or cytologically confirmed locally advanced/unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma that is microsatellite stable and HER2 negative. (American Joint Committee on Cancer \[AJCC\] staging criteria; https://pmc.ncbi.nlm.nih.gov/articles/PMC5387145/)

* Note: Histological or cytological test reports from external laboratories outside of Northwestern University (NU) will also be accepted

Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

* Note: Patients must have documented unresectable and/or metastatic disease on CT or MRI imaging completed prior to registration. Imaging must have been completed within 90 days prior to registration for participants with measurable disease

Patients must not have received more than 1 prior line of therapy in the metastatic setting.

* Note: Patients who have received neoadjuvant or adjuvant therapy must have completed therapy a year prior to registration in this study. Exception: patients with neoadjuvant or adjuvant therapy who have progressed within 6 months

Patients must be age ≥ 18 years

Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Leukocytes (white blood cells \[WBC\]) ≥ 2,000/mcL

Absolute neutrophil count (ANC) ≥ 1500/mcL

Hemoglobin (Hgb) ≥ 9 g/dL (transfusions within 1 week of registration are not allowed to meet cutoff)

Platelets (PLT) ≥ 100,000/mcL (transfusions within 1 week of registration are not allowed to meet cutoff)

Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x institutional ULN (unless liver metastases are present, in which case they must be ≤ 5 x ULN)

Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN (unless liver metastases are present, in which case they must be ≤ 5 x ULN)

Creatinine ≤ 1.5 x Institutional ULN or meeting creatinine clearance (CrCl) criteria below

Creatinine clearance per the Cockcroft-Gault formula or 24-hour urine collection) ≥ 45 mL/min

Phosphate \< ULN

International normalized ratio (INR) \< 1.5

Patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA) within 28 days of registration.

* Note: Random analysis of urine protein with a normal value is sufficient. If urine dipstick or routine analysis indicated proteinuria ≥ 2+, then a 24-hour urine is to be collected and demonstrate \< 1000 mg of protein in 24 hours to allow participation in the study

For patients with a known history of human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have a viral load undetectable for 6 months prior to registration.

* Please note: this lab is not a requirement for eligibility, however, if it has been completed previously as part of the patient's health care, it should be documented for eligibility

Patients with known history of chronic hepatitis B virus (HBV) infection must be on suppressive therapy with an undetectable viral load.

* Please note: this lab is not a requirement for eligibility, however if it has been completed previously as part of the patient's health care, it should be documented for eligibility

Patients with treated brain metastases must not have any evidence of progression on the follow-up brain imaging after central nervous system (CNS)-directed therapy.

* Note: All treatment for brain metastases must have been completed at least 28 days prior to registration

Futibatinib and other therapeutic agents used in this trial are known to be teratogenic. For this reason, patients of child-bearing potential (POCBP) and their partners with sperm-producing reproductive capacity must agree to use adequate contraception from time of informed consent, for the duration of study participation, and for 3 months following completion of study drug therapy. Should a POCBP become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must also agree to use adequate contraception with partners of childbearing potential from time of informed consent, for the duration of study participation, and 3 months after completion of study drug administration

* Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria:

* Has not undergone a hysterectomy or bilateral oophorectomy

* Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

POCBP must have a negative pregnancy test prior to registration on study

Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements

Patients must have the ability to swallow, retain and absorb oral medications

What this study is about