Phase II Randomized Study of FOLFIRI Plus Zimberelimab and Domvanalimab Versus FOLFIRI in Patients With Second-Line Metastatic Gastro-Enteropancreatic or Unknown Origin Neuroendocrine Carcinoma
- Trial ID
- 2024-519922-19-00
- Protocol
- 69HCL24_0759
- Sponsor
- Hospices Civils De Lyon
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare overall survival between the combination of FOLFIRI, Zimberelimab, and Domvanalimab and FOLFIRI alone in patients with second-line metastatic neuroendocrine carcinoma of gastro-enteropancreatic or unknown origin. Secondary objectives include the evaluation of 6-month and 12-month survival rates, progression-free survival, overall response rate according to RECIST 1.1, duration of response, and disease control rate. The study will also assess toxicity using NCI CTCAE v5.0 grading and monitor quality of life via EQ 5D-5L and QLQ-C30 assessments. Additionally, translational research will investigate molecular biomarkers through liquid biopsy, immune biomarkers via flow cytometry or cytokine dosing, and pathological characteristics regarding immune infiltration to identify predictive markers of efficacy. The feasibility of collecting patient-reported outcomes concerning symptoms and toxicity will also be explored. 3
Participants
The sponsor did not provide the total number of participants. The study population consists of adult male and female patients diagnosed with neuroendocrine carcinoma of gastro-enteropancreatic or unknown origin. Eligible participants must have poorly differentiated carcinoma or a mixed tumor with a component greater than 30% and a Ki-67 index exceeding 20%. The primary site may be located within the gastrointestinal tract or the biliopancreatic system. Participants must have locally advanced or metastatic disease and may present with asymptomatic brain metastasis. Inclusion requires a performance status of ≤ 1 according to the ECOG scale and the presence of at least one measurable target lesion based on RECIST criteria. The population includes individuals who have experienced disease progression following first-line treatment with cisplatin or carboplatin and etoposide. Participants must be affiliated with the National French social security system.
Plans and Procedures
This Phase II comparative randomized study is designed to evaluate the efficacy of a combination therapy consisting of irinotecan, fluorouracil, calcium folinate, zimberelimab, and domvanalimab compared to FOLFIRI with a hybrid synthetic control arm. The investigation focuses on the second-line treatment of metastatic neuroendocrine carcinoma of gastro-enteropancreatic or unknown origin. The primary endpoint is overall survival, while secondary endpoints include progression-free survival, objective response rate, duration of responses, disease control rate, toxicity, and patient-reported outcomes. The study involves a screening process to confirm eligibility based on RECIST 1.1 criteria, ECOG performance status, and specific histological requirements. The estimated duration of the study spans from December 2025 to December 2031.
Treatment
The experimental regimen consists of irinotecan hydrochloride administered as an intravenous infusion at a dose of 180 mg/m2. Fluorouracil is also administered via intravenous infusion at a dose of 2800 mg/m2. Calcium folinate is provided as an intravenous injection or infusion at a dose of 200 mg/m2.
The investigational combination includes domvanalimab, supplied as a concentrate for solution for infusion, administered via intravenous infusion at a dose of 1600 mg. Zimberelimab is also administered through intravenous infusion at a dose of 480 mg using a concentrate for solution for infusion.
Efficacy
The primary efficacy endpoint is overall survival, which is defined as the time from randomization until death. Patients who are alive at the final follow-up will be considered censored.
Secondary efficacy parameters include:
- 12-month overall survival rate and 6-month overall survival rate, represented as the percentage of patients alive at those specific timepoints post-randomization.
- Progression-free survival, defined as the interval from randomization to disease progression or death from any cause.
- Objective response rate, determined by local radiological evaluation using RECIST 1.1 to identify the proportion of patients achieving a complete or partial response.
- Duration of response, calculated as the time from the initial response to progression or death in RECIST 1.1 evaluable patients.
- Disease control rate, assessed via local radiological evaluation using RECIST 1.1 to determine the proportion of evaluable patients with either objective response or stable disease.
- Patient-reported outcomes, collected using the EQ 5D-5L and QLQ-C30 questionnaires.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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), *please submit the pathologist's report and the molecular biology report if available
- 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, (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)
- Patient who signed the informed consent form
- Patient affiliated to National French social security system
- Patient with asymptomatic and/or previously treated brain metastasis
Exclusion Criteria
- Well differentiated neuroendocrine tumor whatever the grade
- First-line chemotherapy other than cisplatin (or carboplatin) and etoposide
- Prior immunotherapy, anti-PDL1/PD1 and/or anti-TIGIT and/or anti-CTLA4 type
- 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 symptomatic brain metastasis
- 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
- Antécédents de pneumonie (non infectieuse) ayant nécessité l'administration de stéroïdes ou pneumonie actuelle
- 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
- Serious infection requiring antibiotics within the last 14 days before enrolment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Dec 2025 | 77 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IRINOTECAN | Test | PHF00230MIG | IV INJECTION, IV INFUSION | 180 | 24 | SCP105621456 |
DOMVANALIMAB | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INJECTION, IV INFUSION | 1600 | 24 | PRD9450051 |
FLUOROURACIL | Test | PHF00231MIG | IV INJECTION, IV INFUSION | 2800 | 24 | SCP1165178 |
Zimberelimab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INJECTION, IV INFUSION | 480 | 24 | PRD9450049 |
CALCIUM LEVOFOLINATE | Test | PHF00231MIG | IV INJECTION, IV INFUSION | 200 | 24 | SCP124186993 |