MFOLFIRINOX And Stereotactic Radiotherapy (SBRT) for Pancreatic Cancer With High Risk and Locally Advanced Disease

Study Overview
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Brief Summary
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This is a prospective, multicentre randomised, phase II clinical trial, with randomisation 2:1 by minimisation and stratification by tumour stage, planned chemotherapy and institution.

Detailed Description
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This is a prospective, multicentre randomised, phase II clinical trial to evaluate safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in patients with high-risk and borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). High risk defined as any patient with tumour >4cm, extrapancreatic extension or node positive disease.

Official Title
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MASTERPLAN: A Randomised Phase II Study of MFOLFIRINOX And Stereotactic Radiotherapy (SBRT) for Pancreatic Cancer With High Risk and Locally Advanced Disease

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Radiation: Stereotactic Radiotherapy (SBRT)
* Drug: mFOLFIRINOX
* Drug: Gemcitabine + Nab-paclitaxel
* Drug: Gemcitabine + Capecitabine
* Procedure: Pancreatoduodenectomy (Whipple procedure)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults, aged between 18-75 years, with histological confirmation of pancreatic adenocarcinoma Any of the following T3 (tumour >4 cm) Extrapancreatic extension Node positive (stage IIB) Borderline resectable pancreatic cancer, locally advanced pancreatic cancer Measurable disease according to RECIST v1.1 ECOG performance status 0-1 Adequate renal and haematological function Adequate hepatic function. Defined as bilirubin <1.5 X ULN (Upper Limit of Normal), AST + ALT <3.0 X ULN. In patients who have had a recent biliary drainage and whose bilirubin is descending, a value of ≤ 3 X N is acceptable Study treatment planned to start within 14 days of registration Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments Signed, written informed consent Exclusion Criteria: Tumour size greater than 70mm Prior abdominal radiotherapy Evidence of metastatic disease on baseline radiologic investigations History of another malignancy within 2 years prior to randomisation, except adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial transitional cell carcinoma of the bladder, or any Stage 1 endometrial carcinoma. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years after definitive primary treatment Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety Neuroendocrine pancreatic carcinoma Life expectancy of less than 3 months Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must use a reliable means of contraception Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Option 1: fluorouracil(5-FU)/leucovorin/irinotecan/oxaliplatin (mFOLFIRINOX) (6 cycles) Option 2: gemcitabine + nab-paclitaxel (3 cycles) Resectable patients receive surgery 6 weeks post completion of initial chemotherapy Unresectable patients continue with ongoing chemotherapy (option 1 or option 2) Unresectable patients with locoregional progression or metastatic disease, chemotherapy treatment at the discretion of treating medical oncologist Adjuvant chemotherapy for resectable patients to begin within 8 weeks after surgery For patients who received option 1 chemotherapy: 12 weeks of mFOLFIRINOX For patients who received option 2 chemotherapy: 12 weeks of mFOLFIRINOX or 12 additional weeks of gemcitabine/capecitabine | Drug: mFOLFIRINOX<br>* Day 1: oxaliplatin 85mg/m2 + irinotecan 150mg/m2 + leucovorin 50mg 5-FU 2400mg/m2 continuous IV infusion, 46 hour continuous infusion 14-day cycle, 6 cycles<br>* Other names: modified regimen of oxaliplatin, leucovorin, irinotecan, and fluorouracil (5-FU);Drug: Gemcitabine + Nab-paclitaxel<br>* Day 1, Day 8 and Day 15 gemcitabine 1000mg/m2 + nab-paclitaxel 125mg/m2 28-day cycle, 3 cycles<br>* Other names: Gemcitabine + Abraxane;Drug: Gemcitabine + Capecitabine<br>* Week 1, 2 and 3, qw: 1000 mg/m2 gemcitabine 21 days continuous: 830 mg/m2 oral capecitabine + 7 days rest 28-day cycle, 3 cycles<br>* Other names: GemCap;Procedure: Pancreatoduodenectomy (Whipple procedure)<br>* R0 resection. When the tumour is within the head of the pancreas, a standard Whipple's procedure and level 2/3 dissection with modification to obtain margin clearance will be offered. For lesions in the tail, a standard modular resection will be offered.<br>* Other names: Whipple;|
| Experimental: Arm B<br>Option 1: fluorouracil(5-FU)/leucovorin/irinotecan/oxaliplatin (mFOLFIRINOX) (6 cycles) Option 2: gemcitabine + nab-paclitaxel (3 cycles) Stereotactic Radiotherapy (SBRT) to commence within 3 weeks of completing initial chemotherapy: 40 Gray (Gy) in 5 fractions over 2 weeks Resectable patients receive surgery 6 weeks post completion of initial chemotherapy Unresectable patients continue with ongoing chemotherapy (option 1 or option 2) Unresectable patients with locoregional progression or metastatic disease, chemotherapy treatment at the discretion of treating medical oncologist Adjuvant chemotherapy for resectable patients to begin within 8 weeks after surgery For patients who received option 1 chemotherapy: 12 weeks of mFOLFIRINOX For patients who received option 2 chemotherapy: 12 weeks of mFOLFIRINOX or 12 additional weeks of gemcitabine/capecitabine | Radiation: Stereotactic Radiotherapy (SBRT)<br>* 40 Gray (Gy) in 5 fractions, 2-3 fractions per week over two weeks, 8 Gy per fraction<br>* Other names: Stereotactic Body Radiotherapy;Drug: mFOLFIRINOX<br>* Day 1: oxaliplatin 85mg/m2 + irinotecan 150mg/m2 + leucovorin 50mg 5-FU 2400mg/m2 continuous IV infusion, 46 hour continuous infusion 14-day cycle, 6 cycles<br>* Other names: modified regimen of oxaliplatin, leucovorin, irinotecan, and fluorouracil (5-FU);Drug: Gemcitabine + Nab-paclitaxel<br>* Day 1, Day 8 and Day 15 gemcitabine 1000mg/m2 + nab-paclitaxel 125mg/m2 28-day cycle, 3 cycles<br>* Other names: Gemcitabine + Abraxane;Drug: Gemcitabine + Capecitabine<br>* Week 1, 2 and 3, qw: 1000 mg/m2 gemcitabine 21 days continuous: 830 mg/m2 oral capecitabine + 7 days rest 28-day cycle, 3 cycles<br>* Other names: GemCap;Procedure: Pancreatoduodenectomy (Whipple procedure)<br>* R0 resection. When the tumour is within the head of the pancreas, a standard Whipple's procedure and level 2/3 dissection with modification to obtain margin clearance will be offered. For lesions in the tail, a standard modular resection will be offered.<br>* Other names: Whipple;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional control (Locoregional Response Rate LRR) | To determine if the addition of SBRT to chemotherapy improves locoregional control; | Within 12 months of randomisation; | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (NCI CTCAE v5.0) | Compare acute and late side effects from chemotherapy +/- SBRT | Safety Assessment before each cycle of chemotherapy, post chemotherapy treatment, following SBRT and surgery (if applicable) then at 3, 6, 9 and 12 months post-randomisation and 6 monthly during year 2, 3 and 4 | 
| Surgical morbidity/mortality (Clavien grading system) | Length of stay, death within 30 days, frequency and severity of adverse events. Hospital admission during surgery will be calculated from day of surgery to date of discharge from acute care hospitalisation. The length of stay in acute hospital care will include intensive care admissions. | At discharge post-surgery, 30 days and 90 days post surgery, up to 4 years | 
| Radiological response rates (RECIST v1.1) | Compare radiologic response rates for chemotherapy +/- SBRT | at baseline. In SBRT arm, post-initial chemotherapy (prior to SBRT). In both arms, 4-6 weeks post completion of initial treatment (prior to surgery), 3 ,6, 9 and 12 monthly during year 2, 3 and 4. | 
| Progression Free Survival (PFS) (RECIST v1.1) | Compare 12-month progression free survival | From randomisation to the time of first documented clinical or imaging relapse or date of death from any cause, whichever occurs first; up to 4 years | 
| Pathological response rates (College of American Pathology Tumour Regression Grade TRG) | Compare pathologic response rates of chemotherapy +/- SBRT | At SRBT/surgery compared to baseline; | 
| Surgical resection rates (Guidelines for the Evaluation of Resectability and Histology) | Compare rates of surgical resection | At surgery | 
| R0 resection rates (>1mm) (Synoptic PC histology reporting as outlined in Royal College of Pathologists of Australasia (RCPA) | Compare R0 resection rates (>1 mm) | At surgery | 
| Quality of Life (EORTC QLQ C30 and PAN26 QOL) | To assess the impact of the regimens on quality of life of patients | Baseline, Day 1 of each cycle of chemotherapy, prior to SBRT, post initial chemotherapy +/- SBRT, prior to surgery, 30 days post end of treatment, at months 3, 6,9 and 12 post randomisation 6 monthly in years 2, 3 and 4. | 
| Deterioration-Free Survival (DFS) (EORTC QLQ C30) | To assess overall net clinical benefit of treatment | The time until the first of the following events: a 10-point deterioration in health status from baseline, disease progression, death, or treatment discontinuation;up to 4 years | 
| Overall Survival (OS) | OS is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known alive. Participants will be censored at the date of commencement of the subsequent anti-cancer therapy. | From the date of randomisation to date of death from any cause, or the date of last known alive; up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stereotactic body radiotherapy, SBRT, chemotherapy, radiotherapy, surgery