The study regimen will be administered on an outpatient basis and all medications are administered intravenously (IV). Subjects will receive treatment on Day 1 and Day 15 of each 28-day cycle consisting of the following: nanoliposomal irinotecan at 50 mg/m2, followed by oxaliplatin 60 mg/m2, followed by leucovorin at 400 mg/m2 30 minutes after completion of oxaliplatin, followed by 5-FU 2400 mg/m2 60 minutes after leucovorin completion. Subjects will receive up to 6 cycles of NALIRIFOX then based on response and per physician discretion, de-escalated maintenance treatment with NALIRIFOX minus oxaliplatin may continue. Subjects will continue de-escalated maintenance treatment until progression per RECIST 1.1, intolerable toxicity or physician/subject choice to discontinue.

Inclusion Criteria:

1. Subject has been informed about the nature of the study, and has agreed to participate in the study, and signed the ICF prior to participation in any study-related activities. Also, as determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of ≤ 1 within 28 days prior to registration.

4. Histological or cytologically confirmed small bowel adenocarcinoma per AJCC staging manual, 8th edition that has not been previously treated in the metastatic setting. Subjects treated in the adjuvant setting who completed treatment > 6 months prior to registration and do not have residual toxicities > Grade 1 are eligible. NOTE: Subjects with only localized disease or disease which will likely become resectable after chemotherapy (per investigator discretion) are NOT eligible.

5. Mismatch repair proficient (MMRp) and/or microsatellite stable (MSS) disease per institutional standard of care testing.

6. Subject has one or more metastatic lesion(s) measurable by CT scan (or MRI, if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria. Lesions in a prior radiation field must have progressed subsequent to radiotherapy to be considered measurable.

7. Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration.

   • Platelets (Plt) ≥ 100,000 cells/mm3
   • Absolute Neutrophil Count (ANC) ≥ 1,500 cells/mm3; without the use of hemopoietic growth factors
   • Hemoglobin (Hgb) ≥ 9 g/dL
   • Calculated creatinine clearance ≥ 30 mL/min; Cockcroft-Gault formula for actual body weight should be used for calculation. For subjects with a body mass index (BMI) > 30 kg/m2, adjusted body weight should be used instead
   • Total bilirubin ≤ 1.5 × ULN
   • Aspartate aminotransferase (AST) ≤ 2 × ULN; < 5× with liver metastases
   • Alanine aminotransferase (ALT) ≤ 2 × ULN; < 5× with liver metastases
   • Albumin ≥ 2.5 gm/dL
   • PT/INR and aPTT ≤ 1.5 x ULN; subjects on warfarin or other vitamin K antagonists should be discussed with the sponsor-investigator.
   • Urinalysis: Urinalysis results without clinically significant abnormalities, per the investigator's assessment

8. Electrocardiogram (ECG) without any clinically significant findings (QT interval corrected by Fridericia's formula (QTcF) ≤450 msec and no known arrhythmias) and per the investigator's assessment.

9. Females of childbearing potential must have a negative urine or serum pregnancy test within ≤ 7 days prior to registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

10. Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from penile-vaginal intercourse or use an effective method(s) of contraception. Males able to father a child who are sexually active with a female of childbearing potential must be willing to abstain from penile-vaginal intercourse or use an effective method(s) of contraception.

11. Subjects with known human immunodeficiency virus (HIV) are eligible if they meet all the following criteria:

    • CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications;
    • Probable long-term survival with HIV if cancer were not present;
    • Stable on a highly active antiretroviral therapy (HAART) regimen for ≥ 4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study;
    • HIV is not multi-drug resistant;
    • Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication.

    NOTE: Testing for HIV is not required at screening unless mandated by local policy. If a subject is known to be HIV positive, testing is required as described above to meet eligibility requirements.

12. Subjects with known chronic hepatitis B virus (HBV) infection, must have an undetectable HBV viral load on suppressive therapy, if indicated. Subjects with a history of hepatitis C virus (HCV) infection must have been treated and cured. For subjects with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. NOTE: Testing for HBV and HCV is not required at screening unless mandated by local policy. If a subject is known to have an HBV and/or HCV infection, testing is required as described above to meet eligibility requirements.

Exclusion Criteria:

1. Adenocarcinoma originating in the ampulla or appendix (duodenal tumors that involve the ampulla but originate in the duodenum are eligible).

2. Neuroendocrine or any other histology different than adenocarcinoma.

3. Prior treatment with irinotecan.

4. Prior treatment of small bowel adenocarcinoma (SBA) in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy:

   • Palliative radiotherapy is permitted but lesions in a prior radiation field must have progressed subsequent to radiotherapy to be considered measurable.
   • Placement of biliary stent/tube is permitted.
   • Palliative surgery (for example to treat obstruction)

5. Known history of central nervous system (CNS) metastases. (subjects on a stable or decreasing dose of steroids and deemed clinically stable as per the investigator's assessment are eligible).

6. Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, diarrhea > Grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or bowel obstruction.

7. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the mother is being treated on study.

8. Subjects with an active malignancy in the last 2 years. The following subjects may be eligible: Subjects with prior history of in-situ cancer or basal or squamous cell skin cancer. Subjects with a history of other malignancies but have been continuously disease free for at least 2 years without treatment prior to registration.

9. Known hypersensitivity to any of the components of nanoliposomal irinotecan, other liposomal products, or any components of 5-FU, LV or oxaliplatin.

10. Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease, including:

    • Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before registration
    • High cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year prior to registration
    • New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure

11. Active infection or an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumor fever may be enrolled), which in the investigator's opinion might compromise the subject's participation in the study or affect the study outcome.

12. Major surgery, other than diagnostic surgery, within 4 weeks prior to registration.

13. Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1. Subjects are ineligible if:

    • they are unable to discontinue the use of strong inhibitors of CYP3A, CYP2C8 and UGT1A1 at least 1 week prior to registration;
    • they are unable to discontinue the use of strong CYP3A and CYP2C8 inducers at least 2 weeks prior to registration;

14. There is presence of any contraindications outlined in the Contraindications or Warnings and Precautions sections of the IB for nanoliposomal irinotecan, or in the prescribing information for 5-FU, LV or oxaliplatin.

15. Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of screening.

16. History of systemic connective tissue disorders (e.g. lupus, scleroderma, arteritis nodosa).

17. Subjects who have received a live vaccine within 4 weeks prior to registration.

18. History of the following: interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies, and peripheral artery disease (e.g. claudication, Leo Buerger's disease).

19. Known low or absent dihydropyridine dehydrogenase (DPD) or UGT1A1activity. Testing for DPD or UGT1A1 deficiency is not mandatory but where required by local regulations, testing must be performed using a validated method which is recommended by local health authorities.