Study of NALIRIFOX in Advanced Unresectable Small Bowel Tumors

Inclusion Criteria:

1. Subject has been informed about the nature of the study, and has agreed toparticipate in the study, and signed the ICF prior to participation in anystudy-related activities. Also, as determined by the enrolling physician or protocoldesignee, ability of the subject to understand and comply with study procedures forthe 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 stagingmanual, 8th edition that has not been previously treated in the metastatic setting.Subjects treated in the adjuvant setting who completed treatment > 6 months prior toregistration and do not have residual toxicities > Grade 1 are eligible. NOTE:Subjects with only localized disease or disease which will likely become resectableafter chemotherapy (per investigator discretion) are NOT eligible.

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

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

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

• Platelets (Plt) ≥ 100,000 cells/mm3

• Absolute Neutrophil Count (ANC) ≥ 1,500 cells/mm3; without the use ofhemopoietic growth factors

• Hemoglobin (Hgb) ≥ 9 g/dL

• Calculated creatinine clearance ≥ 30 mL/min; Cockcroft-Gault formula for actualbody 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 Kantagonists 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 intervalcorrected by Fridericia's formula (QTcF) ≤450 msec and no known arrhythmias) and perthe investigator's assessment.

9. Females of childbearing potential must have a negative urine or serum pregnancy testwithin ≤ 7 days prior to registration. If a urine test is done and it is positive orcannot 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 fathera child must be willing to abstain from penile-vaginal intercourse or use aneffective method(s) of contraception. Males able to father a child who are sexuallyactive with a female of childbearing potential must be willing to abstain frompenile-vaginal intercourse or use an effective method(s) of contraception.

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

• CD4 count is ≥350 cells/uL, viral load is undetectable, and not takingprohibited 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 weeksand willing to adhere to their HAART regimen with minimal overlapping toxicityand 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 notinteract 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 tomeet eligibility requirements.

12. Subjects with known chronic hepatitis B virus (HBV) infection, must have anundetectable HBV viral load on suppressive therapy, if indicated. Subjects with ahistory of hepatitis C virus (HCV) infection must have been treated and cured. Forsubjects with HCV infection who are currently on treatment, the HCV viral load mustbe undetectable to be eligible for this trial. NOTE: Testing for HBV and HCV is notrequired at screening unless mandated by local policy. If a subject is known to havean HBV and/or HCV infection, testing is required as described above to meeteligibility requirements.

Exclusion Criteria:

1. Adenocarcinoma originating in the ampulla or appendix (duodenal tumors that involvethe 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 withsurgery, radiotherapy, chemotherapy or investigational therapy:

• Palliative radiotherapy is permitted but lesions in a prior radiation fieldmust 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 ordecreasing dose of steroids and deemed clinically stable as per the investigator'sassessment 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 whilethe mother is being treated on study.

8. Subjects with an active malignancy in the last 2 years. The following subjects maybe eligible: Subjects with prior history of in-situ cancer or basal or squamous cellskin cancer. Subjects with a history of other malignancies but have beencontinuously disease free for at least 2 years without treatment prior toregistration.

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

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

• Severe arterial thromboembolic events (myocardial infarction, unstable anginapectoris, stroke) less than 6 months before registration

• High cardiovascular risk, including, but not limited to, recent coronarystenting 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 thefirst scheduled day of dosing (at the discretion of the investigator, subjects withtumor fever may be enrolled), which in the investigator's opinion might compromisethe 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 areineligible if:

• they are unable to discontinue the use of strong inhibitors of CYP3A, CYP2C8and UGT1A1 at least 1 week prior to registration;

• they are unable to discontinue the use of strong CYP3A and CYP2C8 inducers atleast 2 weeks prior to registration;

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

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

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

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 andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonaryhypersensitivity 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. Testingfor DPD or UGT1A1 deficiency is not mandatory but where required by localregulations, testing must be performed using a validated method which is recommendedby local health authorities.