PRODIGE 113 (FFCD 2314) – REWENEC – 01 STUDY Randomized trial of FOLFIRI + Zimberelimab + Domvanalimab vs FOLFIRI with a hybrid synthetic control arm in second line treatment of metastatic neuroendocrine carcinoma of gastro-enteropancreatic or unknown origin. Phase II comparative randomized study – multicentric

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospices Civils De Lyon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-02-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

DGOS

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare the overall survival between FOLFIRI and FOLFIRI + Zimberelimab + Domvanalimab.

Secondary objectives 4

1. To compare, between the FOLFIRI + Zimberelimab + Domvanalimab and the FOLFIRI arms: - 12-months and 6-months overall survival - Progression free survival (PFS) - Overall response rate (ORR according to RECIST 1.1) - Duration of Responses (DoR) - Toxicity assessed by NCI CTCAE v5.0 grading, - The Quality of life of patients under treatment per EQ 5D-5L & QLQ-C30 assessment
2. 2. To explore the molecular biomarkers at baseline, assessed by liquid biopsy and the immune biomarkers, assessed by flow cytometry or cytokine dosing, as predictive biomarkers of efficacy in translationnal studies.
3. 3. To explore the pathological characteristics of the tumor and their immune infiltration, their correlation to liquid biomarkers as predictive biomarkers of efficacy in translational studies.
4. 4. To explore the feasibility of collecting toxicity and symptom data reported by patients included in the REWENEC-01 trial (Patients Reported Outcomes, PRO).

Conditions and MedDRA coding

Neuroendocrine carcinoma of gastro-enteropancreatic or unknown origin (GEP/UK NEC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Man or woman aged ≥ 18 years old,
2. Poorly differentiated neuroendocrine carcinoma (NEC) [or mixed tumor with NEC component is > 30%, the patient is eligible] with ki 67 > 20% from a gastrointestinal tract (from esophagus to anal canal) or biliopancreatic primary or an unknown primary cancer, locally advanced and/or metastatic,
3. Centralized review of the diagnostic by a consulting pathologist specialized in NET (TENPATH network), *please submit the pathologist's report and the molecular biology report if available
4. Recommendation of a second-line chemotherapy after progression (documented using the RECIST criteria v.1.1) and after a first-line chemotherapy treatment by cisplatin (or carboplatin) + etoposide or in the event of progression in the 6 months following the discontinuation of this first-line treatment,
5. Patient presenting at least one measurable target lesion according to the RECIST criteria v.1.1, in an area not previously irradiated,
6. General condition ≤ 1 (ECOG-PS),
7. Patient of childbearing age accepting to use a highly effective method of contraception during treatment and until 6 months after discontinuation of chemotherapy and 4 months after the last dose of domvanalimab and zimberelimab. Men sexually active must agree to use a highly effective method of contraception during treatment and for at least 6 months after discontinuation of chemotherapy and 4 months after the last dose of domvanalimab and zimberelimab, (In case of a “urine pregnancy test”, it must be a highly sensitive urine pregnancy test, in accordance with the recommendations of the CTFG regarding pregnancy risk management (Recommendations related to contraception and pregnancy testing in clinical trials)
8. Patient who signed the informed consent form
9. Patient affiliated to National French social security system
10. Patient with asymptomatic and/or previously treated brain metastasis

Exclusion criteria 26

1. Well differentiated neuroendocrine tumor whatever the grade
2. First-line chemotherapy other than cisplatin (or carboplatin) and etoposide
3. Prior immunotherapy, anti-PDL1/PD1 and/or anti-TIGIT and/or anti-CTLA4 type
4. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer
5. pregnant or breastfeeding woman
6. Lack of efficient contraception (for men or women of reproductive age)
7. All medical, geographical, social, and psychological conditions or a legal situation that will not allow the patient to finish the study or sign an informed consent form
8. Patient with symptomatic brain metastasis
9. Any of the following uncontrolled progressive diseases in the 6 months before randomization: liver failure, renal insufficiency, respiratory distress, congestive heart failure (NYHA III-IV), unstable angina, myocardial infarction, significant arrhythmia
10. Partial and complete dihydropyrimidine dehydrogenase (DPD) deficiency: uracil level ≥ 16 ng/ml
11. Known Gilbert's syndrome
12. Total bilirubin level >1.5 x the upper limit of normal (ULN); ASAT and/or ALAT > 5 x ULN; TP < 50 % (Except for patient’s treated with Vitamin K antagonists or direct oral anticoagulants with INR <3 )
13. Neutrophils <1.5x109/l, platelets <100x109/l, hemoglobin < 9 g/dl
14. Chronic uncontrolled diarrhea, unresolved intestinal occlusion or subocclusion
15. History of anaphylactic reaction or known intolerance to atropine (sulfate) or to loperamide or to antiemetics administered in association with Folfiri
16. All treatment with concomitant anticonvulsive agents, CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine); patients with these treatments should have stopped them, for at least 7 days before inclusion in the study
17. Chronic medical condition requiring the ongoing use of supra-physiologic doses of systemic corticosteroids (>10 mg/day of oral prednisone or equivalent) or systemic immunosuppressive medications. Immunosuppressive medications, including chronic systemic corticosteroids at supraphysiologic doses should have been stopped 14 days before the first dose (except for participants who require hormone replacement therapy such as hydrocortisone)
18. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
19. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis
20. Antécédents de pneumonie (non infectieuse) ayant nécessité l'administration de stéroïdes ou pneumonie actuelle
21. Live attenuated vaccines within 28 days prior enrolment
22. Any concurrent anticancer therapy, including chemotherapy, radiotherapy (except palliative radiotherapy), immunotherapy, biologic, or hormonal treatment. Concurrent use of hormones for noncancer-related conditions is permitted
23. Known hypersensitivity to any investigational product (IP), or any excipient contained in the formulations of the study interventions
24. Known immunodeficiency or human immunodeficiency virus (HIV) infection with HIV viral load ≥200 copies/mL or CD4+ T-cell count <350 cells/μL, or taking medications that may interfere with metabolism of study drugs
25. Known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded
26. Serious infection requiring antibiotics within the last 14 days before enrolment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. the overall survival defined as the length of time from randomization, that patients included in the study are still alive. Patients alive at last follow-up will be considered censored.

Secondary endpoints 7

1. 12-months (6-months) overall survival rate defined as the percentage of patients included in the study who are still alive 12-months (6-months) after randomization.
2. Progression-free survival (PFS), defined as the time from randomization to disease progression or death, whatever the cause. Alive and no progressive patients at last follow-up will be considered as censored.
3. Objective response rate (ORR) by local radiological evaluation using RECIST 1.1, defined as the proportion of patients with RECIST 1.1 complete or partial response. Patients with no radiological evaluation and patients with non-evaluable RECIST 1.1 response will be excluded.
4. Duration of Responses (DoR), defined as the time from response (complete or partial) to progression or death, estimated in patients who reached a response and are RECIST 1.1 evaluable.
5. Disease control rate by local radiological evaluation using RECIST 1.1, defined as the proportion of RECIST 1.1 evaluable patients in objective response or with stable disease.
6. Toxicity assessed by NCI CTCAE v5.0 grading,
7. Patients-reported outcomes according to EQ 5D-5L & QLQ-C30 questionnaire for patients recruited prospectively

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospices Civils De Lyon

Sponsor organisation

Hospices Civils De Lyon

Address

3 Quai Des Celestins, Bp 2251 Bp 2251

City

Lyon Cedex 02

Postcode

69229

Country

France

Scientific contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr WALTER

Public contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr WALTER

Locations

1 EU/EEA country · 23 investigational sites

By country

Investigational sites

Results and documents

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

Documents 9 files

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

Application history

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