RAGNAR: Refractory Advanced diGestive Neuroendocrine carcinomas treated with tARlatamab

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Tumores Neuroendocrinos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Dec 2025 → ongoing

Decision date (initial)

2025-09-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Primary Objective in the First Part:
The primary aim of the first part of the study is to seek for the best tarlatamab-based
treatment approach in terms of prevention of progression of the disease.

Primary Objective in the Second Part:
The primary aim of this study is to evaluate the efficacy of tarlatamab, either as a single
agent or in combination with FOLFIRI scheme, in patients with neuroendocrine carcinomas of
the digestive system or unknown primary origin, assessed in terms of overall survival (OS).

Secondary objectives 4

1. To evaluate clinical outcomes such as objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression free survival (PFS) of tarlatamab for patients with neuroendocrine carcinomas of the digestive system or unknown primary origin.
2. To evaluate the correlation of risk factors in the efficacy of tarlatamab treatment for neuroendocrine carcinomas of the digestive system or unknown primary origin.
3. To evaluate the quality of life of patients with neuroendocrine carcinomas of the digestive system or unknown primary origin treated with tarlatamab.
4. To evaluate safety of the intended treatment regimen based on the frequency and severity of adverse events and Treatment-emergent adverse events (TEAEs) assessed by NCI CTCAE v5.0. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) will be assessed specifically according to the American Society for Transplantation and Cellular Therapy (ASTCT) grading system.

Conditions and MedDRA coding

Advanced neuroendocrine carcinomas (NECs) of the digestive system or unknown primary origin.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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.
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: a. first-line therapy with platinum-based chemotherapy, b. first-line combination of immunotherapy chemotherapy (excluding BITE CD3/DLL3).
7. At least one measurable lesion as defined by RECIST V1.1
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.
9. 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)
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 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.
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 21

1. 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)
2. 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.
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.
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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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).
2. 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.

Secondary endpoints 11

1. Objective response rate (ORR) according to RECIST V1.1 criteria
2. Disease control rate (DCR).
3. Duration of the response (DoR).
4. Progression-free survival (PFS).
5. Overall survival (OS).
6. 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
7. 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.
8. Frequency and severity of adverse events and Treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0.
9. Blood biomarkers.
10. Correlation between clinical and molecular determinants and efficacy of tarlatamab.
11. Frequency of AEs leading to treatment discontinuation.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Tumores Neuroendocrinos

Sponsor organisation

Grupo Espanol De Tumores Neuroendocrinos

Address

Calle De Velazquez 7 Planta 3

City

Madrid

Postcode

28001

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

A responsible person designated by the Sponsor

Public contact point

Organisation

Grupo Espanol De Tumores Neuroendocrinos

Contact name

A responsible person designated by the Sponsor

Locations

2 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications