Capecitabine Plus Concomitant Radiation Therapy Followed by Durvalumab as Preoperative Treatment in Rectal Cancer

Inclusion Criteria

1. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and Data Privacy Directive obtained from thepatient/legal representative prior to performing any protocol- related procedures,including screening evaluations.
2. Age > 18 years at time of study entry.
3. Eastern Cooperative Oncology Group (ECOG) 0 or 1.
4. Histological diagnosis of adenocarcinoma of rectum.
5. Clinical stage 2-3 rectal adenocarcinoma, cT3/4N0/M0 or Tx N1-2/M0, assessed by thoraxabdomen pelvis with contrast Computed tomography (CT) scan, pelvi Magnetic resonanceimaging (MRI) scan, pancolonscopy.
6. Able to swallow oral medication.
7. Body weight >30kg.
8. Adequate normal organ and marrow function as defined below:
9. Haemoglobin ≥9.0 g/dL - Absolute neutrophil count (ANC) > 1500 per mm3
10. Platelet count >100.000 per mm3
11. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence ofhaemolysis or hepatic pathology), who will be allowed only in consultation withtheir physician.
12. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
13. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976).
14. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre- menopausal patients. Women of childbaring potential or male patients witha female partner of childbearing potential must agree to use at least 1 highlyeffective method of contraception from the time of screening throughout the totalduration of the drug treatment and the drug washout period (90 days after the lastdose of durvalumab monotherapy) as detailed in section 7.1. Women will be consideredpost-menopausal if they have been amenorrhoeic for 12 months without an alternativemedical cause. The following age-specific requirements apply:
15. Women <50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the post- menopausal range for the institution or underwent surgicalsterilization (bilateral oophorectomy or hysterectomy).
16. Women ≥50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).
17. Patient is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment and scheduled visits and examinations including followup. 11. Must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Previous treatment for local advanced rectum cancer.
2. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study. 3. Any previous treatment with a PD1 or PD-L1 inhibitor,including durvalumab.
3. History of hypersensitivity to fluorouracil.
4. Known Dihydropyrimidine dehydrogenase (DPD) deficiency.
5. History of another primary malignancy except for:
6. Malignancy treated with curative intent and with no known active disease ≥5 yearsbefore the first dose of study drug and of low potential risk for recurrence
7. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease - Adequately treated carcinoma in situ without evidence of diseasee.g., cervical cancer in situ
8. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/day ofprednisone, or an equivalent corticosteroid. The following are exceptions to thiscriterion:
9. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
10. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent
11. Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)
12. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.
13. Major surgical procedure within 28 days prior to the first dose of treatment.
14. History of allogenic organ transplantation.
15. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc]). The following are exceptions to thiscriterion:
16. Patients with vitiligo or alopecia
17. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement - Any chronic skin condition that does not require systemictherapy
18. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician
19. Patients with celiac disease controlled by diet alone
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantially increaserisk of incurring AEs or compromise the ability of the patient to give writteninformed consent
21. History of leptomeningeal carcinomatosis.
22. History of active primary immunodeficiency.
23. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patientswith a past or resolved HBV infection (defined as the presence of hepatitis B coreantibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive forhepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negativefor HCV RNA.
24. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
25. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ highly effective birth controlfrom screening to 90 days after the last dose of durvalumab monotherapy.
26. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.
27. Judgment by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements.
28. Patients unable to follow the Protocol procedures and to sign the informed consent. Inthe case of patients' incapable of giving informed consent, it must be provided andsigned by guardians or legal representative. Patients incapable must also sign theagreement to the extent that they are able to do so.