Stereotactic Radiotherapy + Anti PD-1 Therapy in Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma

Phase I/II, multicentre, open label, with no control arm clinical trial of 4-weeks stereotactic radiotherapy followed by nivolumab 3 mg/kg every two weeks in adults with locally advanced pancreatic cancer who does not progress during 4 cycles of standard chemotherapy FOLFIRINOX

Inclusion Criteria:

1. Male and female patients aged ≥18 years

2. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

3. Locally advanced, unresectable, histologically confirmed primary adenocarcinoma of pancreas with no progression during induction chemotherapy (4 cycles of FOLFIRINOX - not a part of trial). Within screening period tumor tissue must be available and sent to the central pathological reviewer in order to confirm the diagnosis.

4. Measurable (one target lesion is sufficient) disease as per RECIST 1.1 criteria

5. Laboratory values:

   1. Aspartate aminotransferase (AST) ≤ 3x ULN (upper limit of normal)
   2. Alanine transaminase (ALT) ≤ 3x ULN
   3. Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome who must have a total bilirubin ≤ 3x ULN)
   4. Creatinine: Serum creatinine ≤ 1.5 ULN or creatinine clearance > 50ml/min (using Cockcroft/Gault formula)
   5. White blood cells ≥ 2000 /ul
   6. Neutrophils ≥ 1500 /ul
   7. Platelets ≥ 100x 103 /ul
   8. Hemoglobin ≥ 9.0 g/l

6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and who is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under age of 55 years must have serum follicle stimulating hormone (FSH) level > 40mIU/ml to confirm menopause.

Exclusion Criteria:

1. Other histology then primary pancreatic adenocarcinoma
2. Resectable disease
3. Distant metastases
4. Progressive disease during induction chemotherapy (4 cycles of FOLFIRINOX)
5. Other previous treatment of the disease except induction chemotherapy (4 cycles of FOLFIRINOX)
6. ECOG performance score of 2 or more
7. Previous therapy of malignant disease in 5 years and less before inclusion to the trial (except skin epithelial tumors)
8. Previous radiotherapy in abdominal region
9. Previous immunological treatment (anti-CTLA-4, anti-PD1 or anti-PD-L1)
10. Active, known or suspected serious autoimmune disease
11. Major surgery less than 28 days prior to the first dose of study treatment
12. Treatment of any investigational medicinal product within 4 weeks before this trial enrolment
13. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency synrome (AIDS)
15. Prisoners or subjects who are involuntarily incarcerated
16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness