Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed small boweladenocarcinoma. Ampullary adenocarcinomas are not eligible. Patients must havemetastatic disease or locally advanced unresectable disease

• Brain metastases are allowed if they have been adequately treated with radiotherapyor surgery and stable for at least 30 days prior to registration. Patients must beneurologically asymptomatic and without corticosteroid treatment for at least 7 daysprior to registration

• Patients must have measurable or non-measurable disease. All scans needed forassessment of measurable disease must be performed within 28 days prior toregistration. Non-measurable disease must be assessed within 42 days prior toregistration. All disease must be assessed and documented on the Baseline TumorAssessment Form

• Patients must have progressed on prior therapy with a fluoropyrimidine and/oroxaliplatin, given either for metastatic/locally advanced disease or as adjuvanttherapy completed within the previous 12 months

• Patients must have completed prior chemotherapy, immunotherapy, or radiation therapyat least 14 days prior to registration and all toxicity must be resolved to grade 1 (with the exception of grade 2 neuropathy) prior to registration. In CommonTerminology Criteria for Adverse Events (CTCAE) version 5.0 grade 2 sensoryneuropathy is defined as "moderate symptoms; limiting instrumental activities ofdaily living (ADLs)"

• Patients must have a complete medical history and physical exam within 28 days priorto registration

• Patients must have a Zubrod performance status of 0 or 1

• Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained within 28 days priorto registration)

• Platelets >= 100,000/mcL (must be obtained within 28 days prior to registration)

• A total bilirubin =< 1.5 x institutional limit normal (IULN) (must be obtainedwithin 28 days prior to registration)

• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x IULN (or 5.0 x IULN if liver metastases are present) (must be obtained within 28 days prior to registration)

• Serum creatinine =< 1.5 x IULN OR calculated creatinine clearance >= 40 mL/min (musthave been obtained within 28 days prior to registration)

• Patient must have urinary protein =< 1+ on dipstick or routine urinalysis (UA)within 28 days prior to registration. If dipstick or routine analysis is >= 2+, a 24

• hour urine collections for protein must demonstrate < 1000 mg of protein in 24hours

• 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

• Patients must not have known dihydropyrimidine dehydrogenase deficiency

• Patients must be offered the opportunity to participate in specimen banking

• Patients must be informed of the investigational nature of this study and must signand give written informed consent in accordance with institutional and federalguidelines

Exclusion Criteria:

• Patients must not have received prior treatment with irinotecan, taxane, orramucirumab for small bowel adenocarcinoma

• Patients must not have had major surgery within 28 days prior to registration, orminor surgery within 7 days prior to registration, and must not be planned forelective major surgery to be performed during protocol treatment

• Patients must not be currently enrolled in or have discontinued within the last 28days a clinical trial involving an investigational product or non-approved use of adrug, or concurrently enrolled in any other type of medical research judged not tobe scientifically or medically compatible with this study. Patients participating insurveys or observational studies are eligible to participate in this study

• Patients must not be receiving chronic antiplatelet therapy, including dipyridamoleor clopidogrel, or similar agents

• Patient must not have a known bleeding diathesis

• Patient must not have uncontrolled or poorly-controlled hypertension (> 160 mmHgsystolic or > 100 mg HG diastolic for > 4 weeks) despite standard medical management

• Patient tumors must not have known deficient mismatch repair (dMMR) ormicrosatellite instability high (MSI-H)

• Patients must not be pregnant or nursing and must have had a negative pregnancy testwithin 4 weeks of starting treatment. Women/men of reproductive potential must haveagreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12consecutive months. In addition to routine contraceptive methods, "effectivecontraception" also includes heterosexual celibacy and surgery intended to preventpregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,bilateral oophorectomy or bilateral tubal ligation. However, if at any point apreviously celibate patient chooses to become heterosexually active during the timeperiod for use of contraceptive measures outlined in the protocol, he/she isresponsible for beginning contraceptive measures

• Patients must not have an active infection requiring systemic therapy

• Patient must not have liver dysfunctions manifested by either (1) Child-Pugh B (orworse) or (2) cirrhosis (any degree) and a history of hepatic encephalopathy orclinically meaningful ascites resulting from cirrhosis. Clinically meaningfulascites is defined as ascites from cirrhosis requiring diuretics or paracentesis

• Patients must not have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosisor superficial venous thrombosis are not considered "significant") during the 90days prior to registration

• Patients must not have experienced any arterial thrombotic event (including but notlimited to myocardial infarction, unstable angina, stable angina markedly limitingordinary physical activity, cerebrovascular accident, or transient ischemic attack)within 120 days prior to registration

• Patients must not have a prior history of gastrointestinal (GI) perforation/fistulaor other risk factors for perforation within 120 days prior to registration

• Patients must not have experienced any grade 3-4 GI bleeding within 90 days prior toregistration

• Patient must not have experienced any serious or non-healing wound, ulcer, or bonefracture within 28 days prior to registration