Comparison of mFOLFIRINOX Versus Platinum-Etoposide in First-Line Chemotherapy for Metastatic Grade 3 Gastroenteropancreatic Neuroendocrine Carcinoma
- Trial ID
- 2024-515300-39-00
- Protocol
- PRODIGE69
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival** (PFS) between the mFOLFIRINOX regimen and the platinum-etoposide regimen in patients with metastatic grade 3 poorly differentiated neuroendocrine carcinoma of gastro entero pancreatic and unknown primary. This comparison is conducted according to the investigator's assessment using RECIST v1.1 criteria. The clinical relevance of this objective lies in determining the more effective first-line chemotherapy regimen, which could potentially improve patient outcomes by delaying disease progression.
Secondary objectives include:
- PFS according to centralized review using RECIST v1.1 criteria.
- Best objective response rate (ORR).
- Median overall survival (OS).
- Safety assessment according to NCI CTC V4.0.
- Evaluation of dose reductions.
- Quality of life assessed by EORTC QLQ-C30 and EQ-5D-5L.
- Establishment of a molecular profile within 2 months after tumor sample submission and provision of a molecular tumor board report to the treating physician.
- Frequency of Rb loss in G3 NEC irrespective of the SC or LC subtype.
- Correlation of ORR, PFS, and OS with molecular alterations (Rb, TP53, MSH2, etc.) under both chemotherapy regimens.
Participants
The clinical trial involves participants diagnosed with **metastatic grade 3 poorly differentiated neuroendocrine carcinoma** of gastro-entero-pancreatic origin or with an unknown primary. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have no prior chemotherapy or systemic therapy for the management of metastatic disease or the primary tumor. The sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include having at least one measurable lesion as assessed by CT-scan or MRI according to RECIST 1.1 guidelines and meeting specific laboratory value thresholds for bilirubin, AST, ALT, ANC, platelet count, and hemoglobin levels. Participants must also agree to use effective contraception if of childbearing potential and be beneficiaries of the social security system.
Plans and Procedures
The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy of two chemotherapy regimens in patients with **metastatic grade 3 poorly differentiated neuroendocrine carcinoma** of gastro entero pancreatic and unknown primary origin. The primary objective is to compare progression-free survival (PFS) between the mFOLFIRINOX regimen and the platinum-etoposide regimen, assessed using RECIST v1.1 criteria. The trial is expected to run until March 31, 2029, with recruitment having commenced on October 20, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and laboratory values. Following randomization, participants will attend regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments such as imaging studies, laboratory tests, and quality of life questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final evaluations will be conducted.
The expected duration of participant involvement is up to 24 months, depending on the treatment regimen and individual response. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants will receive intravenous infusions of the study drugs, including **cisplatin**, **oxaliplatin**, **irinotecan hydrochloride trihydrate**, **fluorouracil**, and **etoposide**, with dosing adjusted according to body surface area and clinical guidelines.
Treatment
The clinical trial involves the administration of several **experimental medications**. The first medication is **Cisplatin**, marketed as Cisplatine Teva 1 mg/ml, which is provided as a concentrate for solution for infusion. This pharmaceutical form is specifically designed for **intravenous perfusion use**. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a total dose not exceeding 100 mg/m². The treatment period for Cisplatin is set at a maximum of 24 weeks.
Another experimental medication used in the trial is **Oxaliplatin**, available as OXALIPLATINE HOSPIRA 5 mg/ml, solution à diluer pour perfusion. This solution for infusion is administered via **IV infusion**. The dosing regimen allows for a maximum daily dose of 85 mg/m², with the total dose also capped at 85 mg/m². The treatment duration for Oxaliplatin is up to 24 weeks.
**Irinotecan Hydrochloride Trihydrate** is also included in the study, marketed as Irinotecan Kabi 20 mg/ml concentrate for solution for infusion. This medication is administered through **intravenous infusion**. The dosing schedule permits a maximum daily dose of 150 mg/m², with a total dose not exceeding 150 mg/m². The treatment period for Irinotecan is limited to 6 weeks.
The trial further incorporates **Fluorouracil**, provided as FLUOROURACILE TEVA 1000 mg/20 ml, solution à diluer pour perfusion. This solution for injection is administered via **intravenous infusion**. The dosing regimen allows for a maximum daily dose of 1200 mg/m², with a total dose not exceeding 2400 mg/m². The treatment duration for Fluorouracil is up to 24 weeks.
Lastly, **Etoposide** is used in the trial, marketed as ETOPOSIDE TEVA 200 mg/10 ml, solution injectable pour perfusion. This solution for injection/infusion is administered through **intravenous infusion**. The dosing schedule permits a maximum daily dose of 100 mg/m², with a total dose capped at 300 mg/m². The treatment period for Etoposide is set at a maximum of 24 weeks.
All medications are of chemical origin and are not formulated for pediatric use. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the **progression-free survival (PFS)** between two treatment regimens: mFOLFIRINOX and platinum-etoposide. The evaluation will be conducted according to the investigator's assessment using the RECIST v1.1 criteria. The primary endpoint is the comparison of PFS between the two regimens. Secondary endpoints include PFS as per centralized review, best objective response rate (ORR), median overall survival (OS), safety according to NCI CTC V4.0, dose reductions, and quality of life assessed by EORTC QLQ-C30 and EQ-5D-5L. Additionally, a molecular profile will be established for each patient within two months after tumor sample submission, and a molecular tumor board report will be provided to the treating physician. The frequency of Rb loss in G3 NEC and the correlation of ORR, PFS, and OS with molecular alterations such as Rb, TP53, and MSH2 will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Grade 3 neuroendocrine carcinoma (Ki67>20%) or high grade MiNEN with a grade 3 poorly differentiated neuroendocrine carcinoma
- Primary gastro-entero-pancreatic or unknown primary
- Small cell or large cell or non-small cell or non- typeable neuroendocrine carcinoma
- Metastatic disease
- ECOG performance status ≤ 1
- First line treatment for metastatic disease. No prior chemotherapy or systemic therapy for management of metastatic disease or primary tumor
- At least one measurable lesion as assessed by CT-scan or MRI according to RECIST 1.1 guidelines
- Available tumor block
- ANC ≥ 1.5x109/l, platelet ≥ 100x109/l and haemoglobin > 8 g/dl
- Total bilirubin ≤ 1.5N, AST ≤ 2.5N, ALT≤ 2.5N or AST and ALT ≤ 5N in case of liver metastasis.
- Age ≥ 18 years
- Signed and dated informed consent, and willing and able to comply with protocol requirements.
- Women of childbearing potential, as well as men (who have sexual relations with women of childbearing potential) must agree to use an effective method of contraception throughout this study and during the 15 months following administration of the last dose of the study medicinal product
- Patient who is a beneficiary of the Social security system
Exclusion Criteria
- Grade 3 well differentiated neuroendocrine tumor according to WHO 2017 classification
- Severe renal impairment (creatinine clearance less than 30 mL/min, Cockroft and Gault)
- ECOG performance status > 1
- Partial or complete Dihydropyrimidine Dehydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL)
- Known Gilbert's syndrome
- Pre-existing permanent neuropathy (NCI CTC V4.0 grade ≥2)
- Previously treated by chemotherapy or targeted therapy
- Symptomatic brain metastases patient with asymptomatic brain metastases or under stable corticosteroid doses for at least 2 weeks before randomization can be included.
- Combination with sorivudine and others analogues of dihydropyrimidine dehydrogenase)
- Treatment with St John's Wort (Hypericum perforatum)
- Pregnant women or breastfeeding mother
- Known or historical active infection with HIV, or known active infection untreated with hepatitis B or hepatitis C
- History of prior malignancy in the three yars before randomization, except for cured non-melanoma skin cancer and cured in situ cervical carcinoma.
- Active or suspected acute or chronic uncontrolled disease that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
- vaccinations (live vaccine) within 30 days prior to start of study drugs
- Patient under guardianship and/or deprived of his/her freedom
- QTc interval > 450 msec for male and > 470 msec for female at EKC.
- K+ < LLN, Mg²+ < LLN, Ca²+ < LLN
- History or know hypersensitivity to any of the study chemotherapy agents, or their excipients.
- Patient already participating in another clinical trial who is currently being treated or whose treatment was completed less than four weeks prior to inclusion.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 20 Oct 2020 | 218 |
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 |
|---|---|---|---|---|---|---|
OXALIPLATINE HOSPIRA 5 mg/ml, solution à diluer pour perfusion | Test | SOLUTION À DILUER POUR PERFUSION | IV INFUSION | 85 | 24 | PRD1169372 |
Irinotecan Kabi 20 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 150 | 6 | PRD10702430 |
ETOPOSIDE TEVA 200 mg/10 ml, solution injectable pour perfusion | Test | SOLUTION INJECTABLE POUR PERFUSION | INTRAVENOUS INFUSION | 100 | 24 | PRD724180 |
FLUOROURACILE TEVA 1000 mg/20 ml, solution à diluer pour perfusion | Test | SOLUTION À DILUER POUR PERFUSION | INTRAVENIOUS INFUSION | 1200 | 24 | PRD674455 |
Cisplatine Teva 1 mg/ml concentraat voor oplossing voor infusie. | Test | CONCENTRAAT VOOR OPLOSSING VOOR INFUSIE | INTRAVENOUS PERFUSION USE | 100 | 24 | PRD3752346 |