Perioperative or Adjuvant mFOLFIRINOX for Resectable Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
The PREOPANC-3 study is a randomized, multicenter, phase 3 trial. Patients with resectable pancreatic cancer will be randomly assigned (1:1) to 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (arm 1) or to upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX (arm 2). The primary objective of the trial is to determine whether perioperative mFOLFIRINOX improves overall survival compared with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer.

Official Title
-----------------
Perioperative Versus Adjuvant FOLFIRINOX for Resectable Pancreatic Cancer: the PREOPANC-3 Study

Conditions
-----------------
Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma, Resectable Pancreatic Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Leucovorin Calcium
* Drug: Fluorouracil
* Drug: Irinotecan Hydrochloride
* Drug: Oxaliplatin
* Procedure: Resection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically (Bethesda 5 or 6) confirmed pancreatic ductal adenocarcinoma. Resectable tumor according to Dutch Pancreatic Cancer Group criteria: no arterial contact and venous contact with the superior mesenteric vein or portal vein of 90 degrees or less No evidence for metastatic disease WHO performance status of 0 or 1 Ability to undergo surgery and mFOLFIRINOX chemotherapy Leucocytes (WBC) ≥ 3.0 x 10^9/L Platelets ≥ 100 x 10^9/L Hemoglobin ≥ 6.0 mmol/l Renal function: eGFR ≥ 40 ml/min Age ≥ 18 years Written informed consent Exclusion Criteria: Prior radiotherapy, chemotherapy, or surgery for pancreatic cancer. Prior chemotherapy precluding mFOLFIRINOX. Previous malignancy (excluding non-melanoma skin cancer, pancreatic neuroendocrine tumor (pNET) <2cm, and gastrointestinal stromal tumor (GIST) <2cm), unless no evidence of disease and diagnosed more than 3 years before diagnosis of pancreatic cancer, or with a life expectancy of more than 5 years from date of inclusion. Pregnancy or lactation. Serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Perioperative mFOLFIRINOX<br>Patients in the intervention arm (arm 1) start with neoadjuvant mFOLFIRINOX (consisting of oxaliplatin 85 mg/m², irinotecan 150 mg/m², leucovorin 400 mg/m², all at day 1, and fluorouracil continuous IV infusion 2.4 g/m² over 46 hours). Cycles are repeated every 14 days. After eight cycles, surgical resection is performed in the absence of unresectable or metastatic disease. After resection, four cycles of adjuvant mFOLFIRINOX are scheduled. | Drug: Leucovorin Calcium<br>* IV<br>Drug: Fluorouracil<br>* IV<br>Drug: Irinotecan Hydrochloride<br>* IV<br>Drug: Oxaliplatin<br>* IV<br>Procedure: Resection<br>* Open or minimally-invasive pancreatectomy.<br>|
| Active Comparator: Arm 2: Adjuvant mFOLFIRINOX<br>Patients in the comparator arm (arm 2) start with surgery. After resection, 12 cycles of adjuvant mFOLFIRINOX (consisting of oxaliplatin 85 mg/m², irinotecan 150 mg/m², leucovorin 400 mg/m², all at day 1, and fluorouracil continuous IV infusion 2.4 g/m² over 46 hours) are scheduled. | Drug: Leucovorin Calcium<br>* IV<br>Drug: Fluorouracil<br>* IV<br>Drug: Irinotecan Hydrochloride<br>* IV<br>Drug: Oxaliplatin<br>* IV<br>Procedure: Resection<br>* Open or minimally-invasive pancreatectomy.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The time between randomization and death from any cause. Patients alive at last follow-up are censored. | Up to 5 years after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | The time between randomization and locoregional progressive disease before or during treatment (resulting in irresectability), the occurrence of distant metastases, recurrent pancreatic cancer after surgery or death from any cause. Patients alive and free of these events at last follow-up are censored. | Up to 5 years after randomization. | 
| Distant metastases free survival | The time between randomization and the occurrence of distant metastases or death from any cause. Patients alive and free of these events at last follow-up are censored. | Up to 5 years after randomization. | 
| Locoregional progression free survival | The time between randomization and locoregional progression before or during treatment (resulting in irresectability), locoregional recurrence after resection or death from any cause. Patients alive and free of these events at last follow-up are censored. | Up to 5 years after randomization. | 
| Distant metastases free interval | The time between randomization and the occurrence of distant metastases. Distant metastases are considered an event and patients are censored at death or last follow-up when without this event. | Up to 5 years after randomization. | 
| Locoregional progression free interval | The time between randomization and locoregional progression before or during treatment (resulting in irresectability), or locoregional recurrence after resection. Locoregional progressive disease before or during treatment or locoregional recurrence after resection are considered an event and patients are censored at death or last follow-up when free of these events. | Up to 5 years after randomization. | 
| Chemotherapy start rate | The percentage of patients who received at least one cycle of scheduled chemotherapy. | 4 months | 
| Number of chemotherapy cycles received. | The number of mFOLFIRINOX cycles patients received. | 9 months | 
| Chemotherapy completion rate | The percentage of patients who completed all cycles of scheduled chemotherapy. | 9 months | 
| Dose intensity | The amount of drug delivered as a percentage of planned dose according to the protocol. | 9 months | 
| Staging laparoscopy rate | The percentage of patients that actually underwent a staging laparoscopy, regardless whether a surgical exploration or resection was performed. | At the time of surgery. | 
| Laparoscopy yield | The percentage of patients that underwent staging laparoscopy and were diagnosed with metastatic or unresectable disease during this procedure. | At the time of surgery. | 
| Surgical exploration rate | The percentage of patients who underwent a surgical exploration (open or minimally-invasive), regardless whether a resection was performed. | At the time of surgery. | 
| Resection rate | The percentage of patients that underwent a curative-intent resection. | At the time of surgery. | 
| Microscopically margin-negative (R0) resection rate | The percentage of patients that underwent a microscopically margin-negative (R0) resection. The resection is considered R0 if there is no tumor within 1 mm of the margins. | At the time of surgery. | 
| Lymph node-negative (N0) resection rate | The percentage of patients that underwent a resection with negative lymph nodes (N0) in the surgical specimen. | At the time of surgery. | 
| Pathologic response | Tumor regression score in the surgical specimen | At the time of surgery. | 
| Adverse events as assessed by the CTCAE version 5.0 | Adverse events are assessed during neoadjuvant therapy and adjuvant therapy. | Until 30 days after last chemotherapy. | 
| Postoperative complications | According to the Clavien-Dindo classification and by the International Study Group of Pancreatic Surgery and International Study Group of Liver Surgery. | Up to 90 days after surgery. | 
| Serum CA 19-9 and CEA response | The change in carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) after surgery and after 4, 8, and 12 cycles of mFOLFIRINOX compared to baseline. | 9 months | 
| Clinical response rate according to RECIST criteria version 1.1 | Response comparing baseline and restaging after 4 and 8 cycles of mFOLFIRINOX | At the time of surgery. | 
| Patient reported cancer-specific health-related Quality of Life (HRQoL) as assessed using the EORTC QLQ-C30 | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported non-disease specific HRQoL as assessed using the EQ-5D-5L | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported tumor-specific HRQoL as assessed using the EORTC LQPAN26 | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported Quality of Life as assessed using the worry of progression of cancer scale (WOPS) | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported chemotherapy-induced peripheral neuropathy as assessed using the EORTC QLQ-CIPN20 | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported Quality of Life as assessed using the happiness, hospital, anxiety and depression scale (HADS) | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 
| Patient reported Quality of Life as assessed using Exocrine Pancreatic Insufficiency (EPI) questionnaire | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year | Up to 5 years after randomization. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neoadjuvant Therapy, Adjuvant Chemotherapy, Oxaliplatin, Irinotecan, Leucovorin, Fluorouracil, Pancreatic Neoplasms, Pancreatectomy