First-line Treatment in Locally Advanced or Metastastic Small Bowel Adenocarcinoma

Inclusion Criteria:

Patients are eligible to be included in the trial only if all of the following criteria apply at time of enrollment:

1. Patient's signed informed consent.
2. Patient's age ≥18 years at the time of signing the informed consent.
3. Histologically confirmed small bowel adenocarcinoma.
4. Microsatellite stable tumor or proficient mismatch repair status of the SBA (immunohistochemistry and polymerase chain reaction are both allowed for characterization)
5. Predicted locally advanced irresectable by the local study team or presenting with distant metastases.
6. Patient did not receive antitumor treatment for locally advanced irresetable or metastatic disease.
7. Measurable lesion according to RECIST 1.1.
8. ECOG performance status 0-2. In case of patient's age \>70 years, ECOG has to be 0 or 1 at randomization
9. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:

   * Absolute neutrophil count 1.5 x 109/L (1500/µL)
   * Hemoglobin ≥ 80 g/L (8 g/dL) with or without blood transfusion
   * Platelet count ≥ 100 x109/L (100000/µL) without transfusion
   * Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN)
   * Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) ≤ 2.5 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN
   * Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ≥ 50 mL/min or serum creatinine≤ 1.5x ULN
10. Patients without anticoagulation need to present with an INR\< 1.5x ULN and aPTT \<1.5x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
11. Proficient fluorouracil metabolism as defined:

    * Prior treatment with 5-FU or capecitabine without unusal toxicity or
    * If tested, normal DPD deficiency test according to the standard of the study site or
    * If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%
12. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of study treatment.

A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male partner's sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

For men with female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.

Men with pregnant female partners must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.

Exclusion Criteria:

Patients are excluded from this trial if any of the following criteria apply at time of enrollment:

1. Adenocarcinoma of the ampulla of Vateri
2. Ileus or directly imminent ileus as assessed by the local study team. Patients with treated and resolved ileus are allowed into the trial.
3. Previous chemotherapy for metastatic or irresectable disease.
4. New York Heart Association Class III or greater heart failure by clinical judgement.
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
6. Unstable angina pectoris.
7. Unstable cardiac arrhythmia \>grade 2 NCI CTCAE despite anti-arrhythmic therapy.
8. Ongoing toxicities \>grade 2 NCI CTCAE, in particular peripheral neuropathy.
9. Active uncontrolled infection by investigator's perspective.
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
11. Known hypersensitivity to 5-FU, leucovorin, capecitabine, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
12. Recent or concomitant treatment with brivudine.
13. Peripheral sensitive neuropathy with functional impairment (\> grade 1 acc. to CTCAE version 6.0 (see appendix 2)).
14. Simultaneous application of Johannis herbs preparations.
15. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
16. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization that may interfere with systemic therapy as judged by the investigator.
17. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
18. Medical history of malignant disease other than SBA with the following exceptions:

    18.1. patients who have been disease-free for at least three years before randomization 18.2. patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer 18.3. patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ≥ 80% and does not require active therapy at randomization
19. Known alcohol or drug abuse.
20. Pregnant or breastfeeding females.
21. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
22. Patients dependent on Sponsor, investigator or study site.
23. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
24. Limited legal capacity. Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons.