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Carcinoma, NeuroendocrinePhase 2REWENEC 01NCT07337447

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)

A Phase 2 study testing FOLFIRI + Zimberelimab + Domvanalimab in people with Carcinoma, Neuroendocrine, run by Hospices Civils de Lyon at 21 sites in France.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Neuroendocrine
What is being tested?
FOLFIRI + Zimberelimab + Domvanalimab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
122 participants
Where
21 sitesFrance
Study dates
Apr 2026to Apr 2030
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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),
Show all 9Show fewer
  • 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

Who cannot join

  • 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),
Show all 25Show fewer
  • 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,
  • 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,
  • 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).
  • 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.
  • History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
  • History of severe hypersensitivity reaction to any monoclonal antibody (mAb) therapy.
  • Live attenuated vaccines within 28 days prior enrolment.
  • 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.
  • Known hypersensitivity to any investigational product (IP), or any excipient contained in the formulations of the study interventions.
  • 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.
  • 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.

Trial locations and contacts

21 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Thomas WALTER, MD contact

4 72 11 73 98 ext. +33

thomas.walter@chu-lyon.fr

21 sites in 1 country

France21 sites

  • CHU Amiens Picardie

    Amiens

    Vincent HAUTEFEUILLE, MD

    Vincent HAUTEFEUILLE, MD

  • CHU Avicenne APHP

    Bobigny

    Florence MARY, MD

    Florence MARY, MD

  • CHU Caen Normandie

    Caen

    Karine BOUHIER-LEPORRIER, MD

    Karine BOUHIER-LEPORRIER, MD

  • Hôpital Beaujon

    Clichy

    Olivia HENTIC, MD

    Olivia HENTIC, MD

  • Hôpital Henri MONDOR

    Créteil

    Charlotte FENIOUX, MD

    Charlotte FENIOUX, MD

  • CHU Dijon

    Dijon

    Côme LEPAGE, MD

    Côme LEPAGE, MD

  • CHU de Grenoble

    Grenoble

    Christelle D'ENGREMONT, MD

    Christelle D'ENGREMONT, MD

  • Centre Oscar Lambret

    Lille

    Elisabeth GAYE, MD

    Elisabeth GAYE, MD

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

    Lyon

    Thomas WALTER, MD

    Thomas WALTER, MD

  • CHU Timone

    Marseille

    Laetitia DAHAN, MD

    Laetitia DAHAN, MD

  • Institut Paoli Calmettes

    Marseille

    Sandrine OZIEL TAIEB, MD

    Sandrine OZIEL TAIEB, MD

  • CHU Montpellier - Hôpital Saint Eloi

    Montpellier

    Eric ASSENAT, MD

    Eric ASSENAT, MD

  • HEGP

    Paris

    Celine LEPERE, MD

    Celine LEPERE, MD

  • Hôpital Saint Antoine APHP

    Paris

    Pauline AFCHAIN, MD

    Pauline AFCHAIN, MD

  • Hôpital Saint Louis APHP

    Paris

    Nelson LOURENCO, MD

    Nelson LOURENCO, MD

  • CHU de Bordeaux - Hôpital Haut-Leveque

    Pessac

    Eric TERREBONNE, MD

    Eric TERREBONNE, MD

  • CHU de Poitiers

    Poitiers

    Nicolas ISAMBERT, MD

    Nicolas ISAMBERT, MD

  • Hôpital Robert Debré, CHU de Reims

    Reims

    Marine PERRIER, MD

    Marine PERRIER, MD

  • CHU Rouen

    Rouen

    Frederic DI FIORE, MD

    Frederic DI FIORE, MD

  • Centre Paul Strauss

    Strasbourg

    Mehrer BEN ABDELGHANI, MD

    Mehrer BEN ABDELGHANI, MD

  • Institut Gustave Roussy

    Villejuif

    Julien HADOUX, MD

    Julien HADOUX, MD

Other trials in France

About this study

Official title: 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 Neuroendocrine Carcinoma of Gastro-enteropancreatic or Unknown Origin. Phase II Comparative Randomized Study - Multicentric

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.

Read more

Scientific Questions and Unmet Needs:

  1. New therapeutic options/perspectives are necessary for patients with GEP/UK NECs given the limited overall survival.
  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. 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).

Rationale for the REWENEC-01 Trial The DURIGAST PRODIGE 59 study, conducted by the FFCD, demonstrated the feasibility and safety of the FOLFIRI + double immune checkpoint inhibitor (anti-PD-1 and anti-CTLA4) combination, as well as for the combination Folfox-Domvanalimab-Zimberelimab (anti-PD-1 and anti-TIGIT). In a translational study of the immune phenotype in patients with NECs treated with the anti-PD1 pembrolizumab, an increase in TIGIT expression was observed after pembrolizumab treatment and higher TIGIT expression on T cells in the blood of patients with high Ki67 expression in their tumors. These data suggest that TIGIT is a potential complementary therapeutic target to PD-1/PD-L1 checkpoint inhibition in GEP/UK NECs. Domvanalimab has been developed as an anti-TIGIT monoclonal antibody and zimberelimab as an anti-PD-1.

Design and primary objective of the REWNEC-01 Trial The REWENEC-01 trial is a comparative phase II trial that will randomize GEP/UK NEC patients between an experimental arm FOLFIRI+Zimberelimab + Domvanalimab and a control arm FOLFIRI in L2. The FOLFIRI arm will be a "hybrid" synthetic control arm composed of patients from historical/external data from the FOLFIRI arm of BEVANEC and French retrospective studies RBNEC and CEPD, mixed with patients recruited prospectively during the trial and randomized to the control arm. The randomization ratio for patients included prospectively during the trial will be 4:1 (4 patients assigned to FOLFIRI+Zimberelimab + Domvanalimab for 1 patient assigned to FOLFIRI). The randomization algorithm will take into account "external" patients assigned progressively to the control arm to obtain a 1:1 ratio between the trial arms, with balanced distributions of stratification factors between the two arms.

With 77 patients to be included, this strategy will provide statistical power equivalent to that of a trial including 122 patients, sufficient to demonstrate an advantage in overall survival rate at 12 months from 32% to 50%.

The hypotheses related to efficacy criteria are formulated a priori, as recommended by the FDA guidance document on trials with synthetic/external control arms. The proof of concept has been reported at ESMO 2023. The primary judgment criterion will be the overall survival rate at 12 months because it is a strong and significant criterion for translating the clinical benefit of the Chemotherapy + Zimberelimab + Domvanalimab combination. The design with a hybrid synthetic control arm allows for the consideration of a randomized comparative study in a cancer as rare as neuroendocrine carcinoma.

Being tested
FOLFIRI + Zimberelimab + Domvanalimab, FOLFIRI (standard of care)
Keywords
Carcinoma, Neuroendocrine, gastro-enteropancreatic or unknown origin, GEP/UK NEC
Medical subject headings
Carcinoma, Neuroendocrine

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FOLFIRI + Zimberelimab + DomvanalimabDrug

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

  • FOLFIRI (standard of care)Drug

    FOLFIRI every 14 days IV every 28 days

Study groups in NCT07337447
Study groupRoleWhat they receive
Experimental arm (EA) 61 patients prospectively enrolled to receive the experimental treatment in thExperimentalFOLFIRI every 14 days + Zimberelimab IV every 28 days + Domvanalimab UV every 28 days
Receives: Drug: FOLFIRI + Zimberelimab + Domvanalimab
Hybrid Synthetic Control Arm (HSCA) combines historical data from 45 patients in the BEVANEC trial aActive comparator45 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
Receives: Drug: FOLFIRI (standard of care)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

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

Secondary outcomes (10)

  1. Progression free survival (PFS)

    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

    Measured: 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

  2. Overall response rate (ORR)

    local radiological evaluation using RECIST 1.1

    Measured: 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

  3. Duration of response (DoR)

    Time from response (complete or partial) to progression or death, estimated in patients who reached a response and are RECIST 1.1 evaluable

    Measured: 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

  4. Disease control rate

    Defined as the proportion of RECIST 1.1 evaluable patients in objective response or with stable disease.

    Measured: 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

  5. Evaluation of toxicity

    assessed by NCI CTCAsE v5.0

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

  6. Evaluation of toxicity

    assessed by NCI CTCAsE v5.0

    Measured: at the Day 15 of each cycles (each cycle is 4 weeks)

  7. Questionnaire Quality of life QLQ-C30

    Questionnaire QLQ-C30

    Measured: at the day 1 of Cycle 2 (1 cycle is 4 weeks)

  8. Questionnaire Quality of life EQ 5D-5L

    Questionnaire EQ 5D-5L

    Measured: at the day 1 of Cycle 2 (1 cycle is 4 weeks)

  9. Questionnaire Quality of life

    Questionnaire QLQ-C30

    Measured: Every 8 weeks through study completion, an average of 2 years

  10. Questionnaire Quality of life

    Questionnaire EQ 5D-5L

    Measured: Every 8 weeks through study completion, an average of 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Jan 2026
  2. Study startApr 2026 (estimated)
  3. Primary completionApr 2029 (estimated)
  4. Study completionApr 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
122 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07337447
Sponsor's protocol ID
69HCL24_0759
Other IDs
2024-519922-19-00
Acronym
REWENEC 01
Status last verified
Jan 2026
First submitted
8 Dec 2025
Last updated
13 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing FOLFIRI + Zimberelimab + Domvanalimab in people with Carcinoma, Neuroendocrine, run by Hospices Civils de Lyon at 21 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 13 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 21 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Thomas WALTER, MD (4 72 11 73 98 ext. +33, thomas.walter@chu-lyon.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall survival (%) between FOLFIRI and FOLFIRI+Zimberelimab+Domvanalimab (time frame: 6 months after the start of treatment 12 months after the start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07337447.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2026.

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