Phase II Study Of Tarlatamab Alone Or In Combination With Chemotherapy In Advanced Neuroendocrine Carcinomas Of The Digestive System Or Unknown Primary Origin
Neuroendocrine neoplasms (NENs) comprise a heterogeneous family of neoplasms arising from the neuroendocrine cells localized in endocrine glands or from the diffuse neuroendocrine cells such as in the digestive or lung tract. Treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NEC) is primarily based on chemotherapy regimens, primarily platinum, which achieve limited benefit and a median overall survival of approximately 12 months. Currently, new treatments that activate the immune system to stimulate antitumor responses and prolong survival in patients with NECs are being investigated. Given the high levels of DLL3 expression on the cell surface of neuroendocrine tumor cells and its minimal, primarily cytoplasmic, localization in normal tissues, DLL3 is a promising target for the development of T-cell-directed therapies in NECs. Tarlatamab is a HLE BiTE molecule that combines the binding specificities for DLL3 and CD3, which could activate the immune system to fight NEC cells. The main hypothesis is that treatment with tarlatamab, a bispecific anti-DLL3 and anti-CD3 conjugate, either as a single agent or in combination with standard second-line chemotherapy (FOLFIRI) scheme could be an effective treatment option for patients with advanced neuroendocrine carcinomas of the digestive system or unknown primary origin.
• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent.
• Patient is ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Histologically confirmed neuroendocrine carcinomas (NECs) of the digestive system or unknown primary origin.
• Note: Carcinomas of pulmonary origin are not eligible.
• Ki-67 \>20% or mitotic rate \> 20 per 10 HPF.
• Metastatic or locally advanced unresectable disease in the second-line treatment, after progression to either:
‣ first-line therapy with platinum-based chemotherapy,
⁃ first-line combination of immunotherapy chemotherapy (excluding BITE CD3/DLL3).
• At least one measurable lesion as defined by RECIST V1.1 (Appendix 3).
• 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.
• Adequate organ function as defined below
‣ Neutrophil count (ANC) ≥ 1.5 × 109/L.
⁃ Platelet count ≥ 100 × 109/L.
⁃ Hemoglobin ≥ 9 g/dL.
⁃ 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.
⁃ Serum bilirubin ≤ 1.5 × ULN or 2 X ULN for subjects with liver metastases. Note: patients with Gilbert's disease are excluded.
⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 xULN for patients with liver metastases.
⁃ 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.