Refractory Advanced diGestive Neuroendocrine Carcinomas Treated With tARlatamab

Inclusion Criteria: 1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent. 2. Patient is ≥ 18 years of age. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 4. Histologically confirmed neuroendocrine carcinomas (NECs) of the digestive system or unknown primary origin. Note: Carcinomas of pulmonary origin are not eligible. 5. Ki-67 \>20% or mitotic rate \> 20 per 10 HPF. 6. Metastatic or locally advanced unresectable disease in the second-line treatment, after progression to either: 1. first-line therapy with platinum-based chemotherapy, 2. first-line combination of immunotherapy chemotherapy (excluding BITE CD3/DLL3). 7. At least one measurable lesion as defined by RECIST V1.1 (Appendix 3). 8. Only patients with tumors positive for DLL3 as determined by the central laboratory are eligible. DLL3 positivity is defined as ≥1% of DLL3-expressing cells. Note: An archival tumor tissue sample (frozen tumor block or 15 unstained formalin fixed, paraffin embedded \[FFPE\] slides) should be available for submission to the central laboratory for the determination of DLL3. Patients will sign a screening ICF and tumor samples will be sent to the central laboratory for assessing DLL3. Patients who do not have archived tumor tissue available should undergo tumor biopsy. 9. Adequate organ function as defined below 1. Neutrophil count (ANC) ≥ 1.5 × 109/L. 2. Platelet count ≥ 100 × 109/L. 3. Hemoglobin ≥ 9 g/dL. 4. Prothrombin time (PT)/INR and Partial Thromboplastin Time (PTT) or Activated Partial Thromboplastin Time (APTT) 1.5 x upper limit of normal (ULN). Patients on chronic anticoagulation therapy who do not meet the criteria above may be eligible to enroll after discussion with the medical monitor. 5. Serum bilirubin ≤ 1.5 × ULN or 2 X ULN for subjects with liver metastases. Note: patients with Gilbert's disease are excluded. 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 xULN for patients with liver metastases. 7. Creatinine clearance (CrCl) ≥ 40 mL/min as estimated by the Cockroft-Gault formula or as measured by 24 hour urine collection (GFR can also be used instead of CrCl) (see Table 10 for Cockcroft-Gault formula). 10\. Female patients must either: a. Be of nonchildbearing potential: i. Postmenopausal \*(defined as at least 1 year without any menses) prior to screening , or i.i. Documented surgically sterile (e.g.hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral tubal occlusion). \*Those who are amenorrheic due to an alternative medical cause are not considered postmenopausal and must follow the criteria for childbearing potential subjects. OR b. If of childbearing potential: i. Agree not to try to become pregnant during the study and for at least 60 days after the last dose of tarlatamab, and 6 months after FOLFIRI. i.i.And have a negative urine or serum pregnancy test within 7 days prior to Day 1, i.i.i. And if heterosexually active, agree to abstinence (if in line with the usual preferred lifestyle of the patient) or consistently use a condom plus 1 form of highly effective birth control (Appendix 4) starting at screening and throughout the study period and for 60 days after the last dose of tarlatamab and 6 months after FOLFIRI. (11) Female patients must agree not to breastfeed or donate ovules starting at screening and throughout the study period, and for 60 days after the last dose of tarlatamab and 6 months after FOLFIRI. (12) Male patients must not donate sperm starting at screening and throughout the study period, and for 60 days after the last dose of tarlatamab and 6 months after FOLFIRI. (13) Male patients with a partner with childbearing potential, or who is pregnant or breastfeeding must agree to abstinence or use a condom plus 1 form of highly effective birth control throughout the study period and for 60 days after the last dose of tarlatamab and 6 months after FOLFIRI. (14) Patient agrees not to participate in another interventional study while on treatment in the present study. Exclusion Criteria: 1. The following endocrine tumor types may not be included: 1. Paraganglioma, adrenal, thyroid parathyroid or pituitary endocrine tumors, 2. Large or small cell lung neuroendocrine carcinoma of the lung, 3. Neuroendocrine tumors (NETs) of the gastrointestinal tract or unknown origin (i.e. well differentiated tumors) 2. History of other malignancy within the past 2 years prior to first dose of tarlatamab except: 1. Malignancy (other than in situ) treated with curative intent and with no known active disease present for 2 years before first dose of tarlatamab and felt to be at low risk for recurrence by the treating physician. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated in situ cancer without evidence of disease. 4. Prostatic intraepithelial neoplasia without evidence of prostate cancer. 5. Adequately treated urothelial papillary non-invasive carcinoma. 3. Prior anti-cancer therapy: at least 28 days must have elapsed between any prior anti-cancer therapy and first dose of tarlatamab. 4. Persistence of any toxicity from prior anti-tumor therapy that has not been resolved to grade ≤ 1 (NCI CTCAE V5.0) or to levels dictated in the eligibility criteria. Note: exception is made with: i) alopecia; ii) grade ≤ 2 neurotoxicity from platinum based chemotherapy or; iii) irreversible toxicities not otherwise described in the exclusion criteria which are stable for ≥ 21 days after consultation with the medical monitor. 5. Major surgery within 28 days of first dose tarlatamab. 6. Radiation therapy \< 2 weeks prior to starting study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated. 7. Myocardial infarction, and/or symptomatic congestive heart failure (New York Heart Association class II) within 12 months of first dose of tarlatamab. 8. Cardiac ejection fraction \< 50%, presence of clinically significant pericardial effusion or clinically significant electrocardiogram findings. 9. History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab. 10. History of solid organ transplantation. 11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of tarlatamab. 12. Patients who experienced severe, life-threatening or recurrent (grade 2 or higher) immune-mediated adverse events or infusion-related reactions from previous treatments. 13. Active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study. 14. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 15. History of hypophysitis or pituitary dysfunction. 16. Acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of tarlatamab. 17. Positive tests for Hepatitis B (HBVsAg) or Hepatitis C ribonucleic acid (HCVab) indicating acute or chronic infection. 18. Live and live-attenuated vaccination are prohibited within 28 days prior to the first dose of tarlatamab treatment and for the duration of study. Note: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination should be avoided during screening at least 14 days prior to the first day of tarlatamab treatment. Monkeypox infection vaccination is allowed during the study (except during cycle 1). 19. Patient has known sensitivity and immediate hypersensitivity to any components of tarlatamab or FOLFIRI. 20. Pregnant or breastfeeding patients, and patients planning to become pregnant during the study period and same windows as scheduled for contraceptive measures. 21. History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or medical monitor, if consulted, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion