Trial of FOLFIRI + Zimberelimab + Domvanalimab vs FOLFIRI With a Hybrid Synthetic Control Arm in Second Line Treatment of Neuroendocrine Carcinoma of Gastro-enteropancreatic or Unknown Origin (REWENEC 01)

NCT07337447 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 69HCL24_07592024-519922-19-00
• Study Type: interventional
• Target: 122
• Locations: 1 country
• Sites: 21

Brief Summary

Background Neuroendocrine carcinomas (NECs) of gastro-entero-pancreatic (GEP) or unknown (UK) origin are rare and highly aggressive diseases. The recommended first-line (L1) treatment is platinum-etoposide combination therapy, which has a progression-free survival (PFS) of only 4-9 months and a median overall survival (OS) of approximately 12 months. All patients experience relapse, often rapidly after this first line of chemotherapy. The standard second-line (L2) chemotherapies recommended by ESMO, ENETS, and NCCN, FOLFIRI and FOLFOX, have modest efficacy with a PFS of 3 months and a median OS of 6 months. The BEVANEC study (PHRCK 2014, NCT02820857) reported no benefit of FOLFIRI + bevacizumab compared to FOLFIRI in a randomized phase II study that enrolled 150 patients in 26 centers over a period of 5 years in France. To date, the most promising efficacy data for this highly aggressive cancer come from clinical trials of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 checkpoint. For example, in France, the non-comparative phase II NIPINEC trial (NCT03591731) randomized patients to receive nivolumab +/- ipilimumab in L2/3 and achieved its primary evaluation criterion (ORR-8 weeks\>10%). Other trials in Europe and worldwide have also reported efficacy data in the context of single-arm studies. Scientific Questions and Unmet Needs:

1. 1.New therapeutic options/perspectives are necessary for patients with GEP/UK NECs given the limited overall survival.
2. 2.Approximately 50% of patients experienced early progression under immunotherapy in the NIPINEC trial and other trials, which may be explained by the absence of chemotherapy combined with immunotherapy and/or the existence of resistance mechanisms.
3. 3.In the GEP/UK NEC indication, the design of these immunotherapy trials has been non-comparative single-arm studies because the realization of randomized comparative trials is considered very difficult for these very rare cancers (incidence \<5/million).

Conditions

Carcinoma, Neuroendocrine

Keywords

Carcinoma, Neuroendocrine; gastro-enteropancreatic or unknown origin; GEP/UK NEC

Outcome Measures

Primary Outcomes (1)

• Overall survival (%) between FOLFIRI and FOLFIRI+Zimberelimab+Domvanalimab

  Length of time from randomization that patients included in the study are still alive. Analyzed in modified intention to treat

  6 months after the start of treatment 12 months after the start of treatment

Secondary Outcomes (10)

• Progression free survival (PFS)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months

• Overall response rate (ORR)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months

• Duration of response (DoR)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months

• Disease control rate

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months

• Evaluation of toxicity

  At the Day 1 of each cycles (each cycle is 4 weeks)

Study Arms (2)

Experimental arm (EA) 61 patients prospectively enrolled to receive the experimental treatment in th

EXPERIMENTAL

FOLFIRI every 14 days + Zimberelimab IV every 28 days + Domvanalimab UV every 28 days

Drug: FOLFIRI + Zimberelimab + Domvanalimab

Hybrid Synthetic Control Arm (HSCA) combines historical data from 45 patients in the BEVANEC trial a

ACTIVE COMPARATOR

45 patients in this group from the BEVANEC trial and 16 patients in this group will be prospectively enrolled and will receive FOLFIRI every 14 days IV every 28 days

Drug: FOLFIRI (standard of care)

Interventions

FOLFIRI + Zimberelimab + Domvanalimab DRUG

FOLFIRI every 14 days + Zimberelimab IV every 28 days + Domvanalimab IV every 28 days

Experimental arm (EA) 61 patients prospectively enrolled to receive the experimental treatment in th

FOLFIRI (standard of care) DRUG

FOLFIRI every 14 days IV every 28 days

Hybrid Synthetic Control Arm (HSCA) combines historical data from 45 patients in the BEVANEC trial a

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Man or woman aged ≥ 18 years old,
• 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,
• Centralized review of the diagnostic by a consulting pathologist specialized in NET (TENPATH network),
• 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,
• Patient presenting at least one measurable target lesion according to the RECIST criteria v.1.1, in an area not previously irradiated,
• General condition ≤ 1 (ECOG-PS),
• 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,
• Patient who signed the informed consent form.
• Patient affiliated to National French social security system

You may not qualify if:

• Well differentiated neuroendocrine tumor whatever the grade,
• First-line chemotherapy other than cisplatin (or carboplatin) and etoposide,
• Prior immunotherapy,
• 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,
• Pregnant or breastfeeding woman,
• Lack of efficient contraception (for men or women of reproductive age),
• 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,
• Patient with asymptomatic brain metastasis or with previously treated brain metastasis relating to the study drugs
• 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,
• Partial and complete dihydropyrimidine dehydrogenase (DPD) deficiency: uracil level ≥ 16 ng/ml,
• Known Gilbert's syndrome,
• 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 ),
• Neutrophils \<1.5x109/l, platelets \<100x109/l, hemoglobin \< 9 g/dl,
• Chronic uncontrolled diarrhea, unresolved intestinal occlusion or subocclusion,
• History of anaphylactic reaction or known intolerance to atropine (sulfate) or to loperamide or to antiemetics administered in association with Folfiri,

Sponsors & Collaborators

• Hospices Civils de Lyon: lead
• Federation Francophone de Cancerologie Digestive: collaborator

Study Sites (21)

CHU Amiens Picardie

Amiens, France

Location

CHU Avicenne APHP

Bobigny, France

Location

CHU Caen Normandie

Caen, France

Location

Hôpital Beaujon

Clichy, France

Location

Hôpital Henri MONDOR

Créteil, France

Location

CHU Dijon

Dijon, France

Location

CHU de Grenoble

Grenoble, France

Location

Centre Oscar Lambret

Lille, France

Location

Service d'Oncologie Médicale - Hôpital Edouard Herriot - Hospices Civils de Lyon

Lyon, France

Location

CHU Timone

Marseille, France

Location

Institut Paoli Calmettes

Marseille, France

Location

CHU Montpellier - Hôpital Saint Eloi

Montpellier, France

Location

HEGP

Paris, France

Location

Hôpital Saint Antoine APHP

Paris, France

Location

Hôpital Saint Louis APHP

Paris, France

Location

CHU de Bordeaux - Hôpital Haut-Leveque

Pessac, France

Location

CHU de Poitiers

Poitiers, France

Location

Hôpital Robert Debré, CHU de Reims

Reims, France

Location

CHU Rouen

Rouen, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Institut Gustave Roussy

Villejuif, France

Location

MeSH Terms

Conditions

Carcinoma, Neuroendocrine

Interventions

zimberelimab; Standard of Care

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Thomas WALTER, MD

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Thomas WALTER, MD

CONTACT

4 72 11 73 98; thomas.walter@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 8, 2025
• First Posted: January 13, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2030
• Last Updated: January 13, 2026

Record last verified: 2026-01

Locations

FR (21)