TARLATAMAB for Neuroendocrine carcinoma of the digestive system | Neuroendocrine carcinoma of unknown primary origin

Inclusion criteria

• {"criterion_text":"- Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent.\n- Female patients must either: a. Be of nonchildbearing potential: i. Postmenopausal (defined as at least 1 year without any menses) prior to screening , or ii. Documented surgically sterile (e.g.hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral tubal occlusion). 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. ii. And have a negative urine or serum pregnancy test within 7 days prior to Day 1, iii. 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 starting at screening and throughout the study period and for 60 days after the last dose of tarlatamab and 6 months after FOLFIRI.\n- 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.\n- 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.\n- 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.\n- Patient agrees not to participate in another interventional study while on treatment in the present study.\n- Patient is ≥ 18 years of age.\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2\n- Histologically confirmed neuroendocrine carcinomas (NECs) of the digestive system or unknown primary origin.\n- Ki-67 >20% or mitotic rate > 20 per 10 HPF.\n- Metastatic or locally advanced unresectable disease in the second-line treatment, after progression to either: a. first-line therapy with platinum-based chemotherapy, b. first-line combination of immunotherapy chemotherapy (excluding BITE CD3/DLL3).\n- At least one measurable lesion as defined by RECIST V1.1\n- 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.\n- Adequate organ function as defined below: a. Neutrophil count (ANC) ≥ 1.5 × 10^9/L. b. Platelet count ≥ 100 × 10^9/L. c. Hemoglobin ≥ 9 g/dL. d. 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. e. Serum bilirubin ≤ 1.5 × ULN or 2 X ULN for subjects with liver metastases. f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 xULN for patients with liver metastases. g. 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)"}

Exclusion criteria

• {"criterion_text":"- The following endocrine tumor types may not be included: a. Paraganglioma, adrenal, thyroid parathyroid or pituitary endocrine tumors, b. Large or small cell lung neuroendocrine carcinoma of the lung, c. Neuroendocrine tumors (NETs) of the gastrointestinal tract or unknown origin (i.e. well differentiated tumors)\n- History of solid organ transplantation.\n- 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.\n- Patients who experienced severe, life-threatening or recurrent (grade 2 or higher) immune-mediated adverse events or infusion-related reactions from previous treatments.\n- 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.\n- Evidence of interstitial lung disease or active, non-infectious pneumonitis.\n- History of hypophysitis or pituitary dysfunction.\n- Acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of tarlatamab.\n- Positive tests for Hepatitis B (HBVsAg) or Hepatitis C ribonucleic acid (HCVab) indicating acute or chronic infection.\n- Live and live-attenuated vaccination are prohibited within 28 days prior to the first dose of tarlatamab treatment and for the duration of study.\n- Patient has known sensitivity and immediate hypersensitivity to any components of tarlatamab or FOLFIRI.\n- History of other malignancy within the past 2 years prior to first dose of tarlatamab except: a. 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. b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated in situ cancer without evidence of disease. d. Prostatic intraepithelial neoplasia without evidence of prostate cancer. e. Adequately treated urothelial papillary non-invasive carcinoma.\n- Pregnant or breastfeeding patients, and patients planning to become pregnant during the study period and same windows as scheduled for contraceptive measures.\n- 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.\n- Prior anti-cancer therapy: at least 28 days must have elapsed between any prior anti-cancer therapy and first dose of tarlatamab.\n- 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.\n- Major surgery within 28 days of first dose tarlatamab.\n- 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.\n- Myocardial infarction, and/or symptomatic congestive heart failure (New York Heart Association class II) within 12 months of first dose of tarlatamab.\n- Cardiac ejection fraction < 50%, presence of clinically significant pericardial effusion or clinically significant electrocardiogram findings.\n- History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint for the first part of this study will be the Progression-free Survival (PFS) rate, defined as the percentage of patients without progression as defined by RECIST V1.1 criteria or death. PFS rate will be calculated for each treatment arm separately once 38 PFS events are reported in the first 54 patients included (27 per treatment arm).","definition_or_measurement_approach":"PFS rate defined as percentage of patients without progression per RECIST V1.1 or death; calculated separately for each treatment arm once 38 PFS events are reported among the first 54 patients (27 per arm)."}
• {"endpoint_text":"- The primary endpoint will be the 12-months Overall Survival (OS) rate, defined as the percentage of patients alive after 12 months from the first dose of study treatment. OS will consider death from any cause as an event. Patients alive and free of events at the date of the analysis will be censored at their last known contact. OS will be calculated for each treatment arm separately.","definition_or_measurement_approach":"12-month Overall Survival (OS) rate: percentage of patients alive 12 months after first dose; death from any cause is an event; censoring at last known contact; calculated per treatment arm."}

Secondary endpoints

• {"endpoint_text":"- Objective response rate (ORR) according to RECIST V1.1 criteria","definition_or_measurement_approach":"ORR assessed per RECIST V1.1"}
• {"endpoint_text":"- Disease control rate (DCR).","definition_or_measurement_approach":"DCR as reported in protocol (no further measurement detail provided)"}
• {"endpoint_text":"- Duration of the response (DoR).","definition_or_measurement_approach":"DoR as reported in protocol (no further measurement detail provided)"}
• {"endpoint_text":"- Progression-free survival (PFS).","definition_or_measurement_approach":"PFS assessed per RECIST V1.1 or death (see primary endpoint definition)"}
• {"endpoint_text":"- Overall survival (OS).","definition_or_measurement_approach":"OS measured from first dose to death from any cause; censoring at last contact"}
• {"endpoint_text":"- Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3","definition_or_measurement_approach":"HRQoL assessed using EORTC QLQ-C30 v3 questionnaire"}
• {"endpoint_text":"- Efficacy variables will be reported for subgroups to find potential correlation between patient characteristics (i.e. age, gender, ECOG, AJCC stage, differentiation, or previous treatments) and the clinical outcomes to tarlatamab.","definition_or_measurement_approach":"Subgroup analyses correlating baseline characteristics with efficacy outcomes (no further detail provided)"}
• {"endpoint_text":"- Frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0.","definition_or_measurement_approach":"Safety assessed by NCI CTCAE v5.0; CRS and ICANS assessed per ASTCT grading system"}
• {"endpoint_text":"- Blood biomarkers.","definition_or_measurement_approach":"Blood biomarker assessments (no further detail provided)"}
• {"endpoint_text":"- Correlation between clinical and molecular determinants and efficacy of tarlatamab.","definition_or_measurement_approach":"Correlation analyses between clinical/molecular determinants and efficacy (no further detail provided)"}
• {"endpoint_text":"- Frequency of AEs leading to treatment discontinuation.","definition_or_measurement_approach":"Count and frequency of adverse events resulting in treatment discontinuation (no further detail provided)"}

France

Earliest CTIS Part Ii Submission Date

27-08-2025

Latest Decision Or Authorization Date

12-09-2025

Processing Time Days

16

Number Of Sites

9

Number Of Participants

43

Spain

Earliest CTIS Part Ii Submission Date

18-06-2025

Latest Decision Or Authorization Date

10-09-2025

Processing Time Days

84

Number Of Sites

11

Number Of Participants

44

Primary sponsor

Full Name

Grupo Espanol De Tumores Neuroendocrinos

Organisation Type

Patient organisation/association

Country Of Registered Address

Spain