This phase II trial studies how well giving irinotecan hydrochloride together with oxaliplatin and capecitabine works as first-line therapy in treating patients with metastatic or unresectable locally advanced small bowel cancer. Drugs used in chemotherapy, such as irinotecan hydrochloride, oxaliplatin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PRIMARY OBJECTIVE:

To assess the confirmed tumor response of the combination of oxaliplatin, irinotecan (irinotecan hydrochloride), and capecitabine in patients with advanced adenocarcinoma of the small bowel when dosed according to UGT1A1 genotype.

SECONDARY OBJECTIVES:

1. To assess the toxicity of this regimen in these groups of patients.
2. To gain preliminary data on whether microsatellite instability influences outcome within this arm.
3. To gain preliminary data on whether evidence of celiac disease may affect toxicity and outcome.
4. To gain preliminary data on whether site of tumor origin (duodenal, jejunal, or ileal) affects response or survival.

OUTLINE: Patients are assigned to 1 of 3 treatment groups based on UGT1A1 genotype.

GROUP 1 (6/6 UGT1A1 genotype): Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (BID) on days 2-15.

GROUP 2 (6/7 UGT1A1 genotype): Patients receive irinotecan hydrochloride as in group 1. They also receive oxaliplatin and capecitabine as in group 1 but at lower doses.

GROUP 3 (7/7 UGT1A1 genotype): Patients receive irinotecan hydrochloride, oxaliplatin, and capecitabine as in group 1 but at lower doses.

In all groups, treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed every 6 weeks for 2 years and then periodically thereafter.

Inclusion Criteria

• Confirmation UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A1) TA indel genotype of 6/6, 6/7, or 7/7 after pre-registration but prior to registration

• Patient willingness to provide a serum sample for analysis for celiac disease (tissue transglutaminase antibodies)

• Small bowel adenocarcinoma, either metastatic or locally advanced and not surgically resectable; NOTE: periampullary carcinoma and appendiceal cancer are not eligible

• Histologic or cytologic confirmation of adenocarcinoma consistent with small bowel origin; biopsy can be of primary tumor or can be from a metastatic site if there is a primary small bowel tumor currently or previously present

• Measurable disease; for patients with lesions >= 1 cm but < 2 cm, spiral computed tomography (CT) scan imaging must be used for tumor assessments

• Life expectancy >= 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

• >= 4 weeks since prior major surgery to time of registration

• >= 2 weeks from completion of any radiation treatment

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelets >= 100,000/mm^3

• Serum glutamic oxaloacetic transaminase (SGOT) =< 5 x upper normal limit (UNL); =< 2.5 x UNL if no liver metastases

• Total bilirubin:

  • For 6/6 patients: =< upper limit of normal (ULN)
  • For 6/7 or 7/7 patients: =< 2.0 x ULN

• Hemoglobin >= 9.0 g/dL

• Creatinine =< 1.5 x UNL (if > 1.5 x UNL, calculated creatinine clearance should be checked.; if it is > 60 mL/min, then the patient is eligible for the study)

• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

Exclusion Criteria

• Prior chemotherapy regimen for advanced small bowel cancer (prior adjuvant chemotherapy with fluorouracil (5FU)/leucovorin is permitted if last dose was administered >= 3 months prior to registration); prior oxaliplatin or irinotecan use as adjuvant therapy is not permitted
• Prior radiotherapy to > 25% of bone marrow
• Active or uncontrolled infection
• Evidence of serious intercurrent illness (e.g., unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia)
• Pregnant women; women of child-bearing potential and men must agree to use adequate contraception (diaphragm, birth control pills, injections, foams, intrauterine device [IUD], or abstinence, etc.) for the duration of study participation; if a woman becomes pregnant or suspects that she is pregnant while participating in this study, she should inform her treating physician immediately and all study treatment discontinued
• Nursing women; breast-feeding should be discontinued when the mother is treated with these agents
• Men or women of childbearing potential who are unwilling to employ adequate contraception
• Current evidence of other malignancy besides small bowel adenocarcinoma, with exception of non-melanoma skin cancer
• Known central nervous system metastases or carcinomatous meningitis
• Preexisting sensory neuropathy >= grade 2 from any cause interfering with function
• Concurrent therapy with sorivudine, brivudine, lamivudine, or stavudine