Since patients with (borderline) resectable pancreatic cancer have a limited life expectancy, it is important to improve treatment strategies. Therefore, the objective of this study is to investigate whether neoadjuvant triple treatment with chemotherapy (mFOLFIRINOX), immunotherapy (pembrolizumab and stereotactic radiotherapy, followed by adjuvant surgery and chemotherapy and immunotherapy, improves survival in patients with (borderline) resectabel pancreatic cancer.

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the pancreas (WHO VI or VII)
• Male or female participants who are at least 18 years of age on the day of signing informed consent
• Primary resectable or borderline resectable disease (DPCG criteria)
• ECOG performance status 0 or 1
• Ability to undergo surgery, radiotherapy, chemotherapy and immunotherapy
• Leucocytes (WBC) ≥ 3.0 X 10*9/l, Platelets ≥ 100X 10*9 /l, Hemoglobin ≥ 6 mmol/l, Renal function: E-GFR > 50 ml/min, Bilirubin < 50 µmol/l or planned for biliary drainage
• A male participant must agree to use a contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 18 weeks after the last dose of study treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant (see Appendix 6), not breastfeeding, and at least one of the following conditions applies: Not a:

woman of childbearing potential (WOCBP) OR WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 18 weeks after the last dose of study treatment Written informed consent

Exclusion criteria

• Metastatic or locally advanced (i.e. unresectable) pancreatic cancer.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents for pancreatic cancer.
• Has received prior radiotherapy within 2 weeks of start of study intervention.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
• Complete dihydropyrimidine dehydrogenase deficiency. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Has 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 (e.g., thyroxine, insulin, or physiologic corticosteroid re placement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection.
• Has had an allogenic tissue/solid organ transplant.
• Serious concomitant systemic disorders that would compromise the safety of the patient or their ability to complete the study, at the discretion of the investigator.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of treatment (see Appendix 6). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit until 18 weeks after the last dose of trial treatment.
• Has contra-indications for MRI (only for Amsterdam UMC and RAKU)
• Pacemakers or implanted defibrillators, deep brain stimulators, cochlear implants.
• Patients who have a metallic foreign body in their eye, or who have an aneurysm clip in their brain, cannot have an MRI scan since the magnetic field may dislodge the metal.
• Patients with severe claustrophobia not able to tolerate an MRI scan