Neoadjuvant Regorafenib in Combination with Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer

Inclusion Criteria:

1. Female or Male

2. Age ≥ 18 years old

3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

4. Histologically or cytologically verified adenocarcinoma of the rectum

5. Tumour with distal border below the peritoneal reflection and within 15 cm from theanal verge

6. Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI

7. Absence of distant metastases as shown by baseline computed tomography (CT) of thethorax-abdomen or CT scan of the thorax and MRI of the abdomen

8. Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL

9. Adequate hepatic function as defined by a total bilirubin level ≤1.5 × the upperlimit of normal (ULN) range (excluding subjects with known Gilbert's syndrome) andalanine aminotransferase (ALT) levels ≤2.5 × ULN

10. Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/minaccording to the Cockcroft-Gault or Wright formula

11. Negative serum pregnancy test at screening (up to 7 days before treatment start) forwomen of childbearing potential

12. Women of childbearing potential must agree to use of one highly effective method ofcontraception prior study entry, during the course of the study and at least 5months after the last administration of study treatment.

13. Men with childbearing potential partner must agree to use condom during the courseof this study and for at least 5 months after the last administration of the studytreatment.

14. Absence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule;those conditions should be discussed with the patient before registration in thetrial

15. Absence of clinical conditions that, in the opinion of the investigator, wouldcontraindicate neoadjuvant therapy and/or surgery

16. Life expectancy of at least 3 months

17. Completion of all necessary screening procedures within 28 days prior to enrolment.

18. Signed Informed Consent form (ICF) obtained prior to any study related procedure.

Exclusion Criteria:

1. Any prior or concurrent surgery, chemotherapy, radiotherapy, immunotherapy, biologicor hormonal therapy for rectal cancer. Concurrent use of hormones fornoncancer-related conditions (i.e., insulin for diabetes and hormone replacementtherapy) is acceptable.

2. Any contraindication to pelvic irradiation as evaluated by the investigator

3. Prior organ transplantation, including allogeneic stem cell transplantation

4. Clinically significant acute or chronic infections including, among others:

• known history of testing positive test for human immunodeficiency virus (HIV)or known acquired immunodeficiency syndrome (AIDS)

• known history of testing positive for hepatitis B virus (HBV) surface antigenor anti-hepatitis C virus (HCV) antibody and confirmatory HCV ribonucleic acid (RNA) test

5. Active autoimmune disease that might deteriorate when receiving an immunostimulatoryagent (subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroiddisease not requiring immunosuppressive treatment are eligible)

6. Systemic corticosteroids administered as hormone replacement or asimmunosuppressants at doses exceeding 10 mg/day of prednisone or equivalent. Otherimmunosuppressive medications including, but not limited to methotrexate,azathioprine, and TNF-α blockers. Use of immunosuppressive medications for themanagement of treatment-related AEs or in subjects with contrast allergies isacceptable. A temporary period of steroids is allowed for different indications, atthe discretion of the investigator (i.e., chronic obstructive pulmonary disease,radiation, nausea, etc.). Administration of steroids through a route known to resultin a minimal systemic exposure [topical, intranasal, intro-ocular, or inhalation] isacceptable.

7. Known severe hypersensitivity reactions to the investigational treatments, or anyexcipients or non-investigational medicinal products or concomitant medications

8. Pregnant and/or lactating women

9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke, myocardial infarction, unstable angina, congestive heart failure,uncontrolled arterial hypertension, or serious cardiac arrhythmia requiringmedication

10. Prior myocarditis

11. Known history of immune colitis, immune pneumonitis, pulmonary fibrosis or othermedical conditions (for example, inflammatory bowel disease, uncontrolled asthma),which, in the opinion of the Investigator, might impair the subject's tolerance oftrial treatment

12. Vaccination within 28 days of the first dose of study treatment and while on trial (except for administration of inactivated vaccines)

13. Other invasive malignancy within 2 years except for non-invasive malignancies suchas cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductalcarcinoma in situ of the breast that has/have been surgically cured. Anti-neoplastictreatment received in the past for malignancies cured 2 or more years beforeenrolment are permitted.

14. Any investigational anti-cancer therapy other than the protocol specified therapies.

15. Strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice,itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), strongUGT1A9 inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid), and stronginducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital and St.John's wort) from 28 days before study enrolment up to the end of study treatment.

16. Major surgery within 28 days of the first dose of study treatment

17. Presence of gastrointenstinal perforation of fistula