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

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.

• Stereotactic Radiotherapy (SBRT) (Radiation), also known as SBRT, Stereotactic Body Radiotherapy: 40 Gray (Gy) in 5 fractions, 2-3 fractions per week over two weeks, 8 Gy per fraction
• mFOLFIRINOX (Drug), also known as modified regimen of oxaliplatin, leucovorin, irinotecan, and fluorouracil (5-FU): * 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
• Gemcitabine + Nab-paclitaxel (Drug), also known as Gemcitabine + Abraxane: * Day 1, Day 8 and Day 15 gemcitabine 1000mg/m2 + nab-paclitaxel 125mg/m2 * 28-day cycle, 3 cycles
• Gemcitabine + Capecitabine (Drug), also known as GemCap: * 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
• Pancreatoduodenectomy (Whipple procedure) (Procedure), also known as Whipple: 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.

Primary outcomes

• Locoregional control (Locoregional Response Rate LRR) [Within 12 months of randomisation;]: To determine if the addition of SBRT to chemotherapy improves locoregional control;

Secondary outcomes

• Safety (NCI CTCAE v5.0) [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]: Compare acute and late side effects from chemotherapy +/- SBRT
• Surgical morbidity/mortality (Clavien grading system) [At discharge post-surgery, 30 days and 90 days post surgery, up to 4 years]: 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.
• Radiological response rates (RECIST v1.1) [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.]: Compare radiologic response rates for chemotherapy +/- SBRT
• Progression Free Survival (PFS) (RECIST v1.1) [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]: Compare 12-month progression free survival
• Pathological response rates (College of American Pathology Tumour Regression Grade TRG) [At SRBT/surgery compared to baseline;]: Compare pathologic response rates of chemotherapy +/- SBRT
• Surgical resection rates (Guidelines for the Evaluation of Resectability and Histology) [At surgery]: Compare rates of surgical resection
• R0 resection rates (>1mm) (Synoptic PC histology reporting as outlined in Royal College of Pathologists of Australasia (RCPA) [At surgery]: Compare R0 resection rates (>1 mm)
• Quality of Life (EORTC QLQ C30 and PAN26 QOL) [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.]: To assess the impact of the regimens on quality of life of patients
• Deterioration-Free Survival (DFS) (EORTC QLQ C30) [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]: To assess overall net clinical benefit of treatment
• Overall Survival (OS) [From the date of randomisation to date of death from any cause, or the date of last known alive; up to 4 years]: 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.

Other outcomes

• Exploratory biomarker analysis of blood [baseline, prior to SBRT (Arm B only), insertion of fiducial markers (Arm B, optional), post initial treatment, at surgery (optional, at selected sites), 6 and12 months post randomisation and at progression, up to 5 years]: The list of blood biomarkers and their measurement will be updated when confirmed.
• Exploratory biomarker analysis of tissue [Diagnosis (archival tissue), at time of fiducial insertion (Arm B, optional), surgical resection (for resectable patients) and at time of progression (optional), up to 5 years.]: The list of tissue biomarkers and their measurement will be updated when confirmed.
• ePRO Acceptability [Baseline, Day 1 of each cycle of chemotherapy, 2 weeks post initial chemotherapy(SBRT arm), 4-6 weeks post initial chemotherapy +/- SBRT, 30 days post end of treatment, at months 3, 6,9 and 12 post randomisation 6 monthly in years 2, 3 and 4.]: Proportion of patients who are willing to use electronic device vs. paper format, Analysis of demographic data and assessing data quality between the group

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Adults, aged between 18-75 years, with histological confirmation of pancreatic adenocarcinoma
* Any of the following

  1. T3 (tumour >4 cm)
  2. Extrapancreatic extension
  3. Node positive (stage IIB)
  4. 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

• Andrew Oar, Study chair, ICON Gold Coast University Hospital, Southport, Queensland, AUS