Preoperative Chemoradiotherapy With CApecitabine and Temozolomide in MGMT Silenced, MSS, Locally Advanced RecTal Cancer

Inclusion Criteria: * Written informed consent to study procedures; * Willing and able to comply with the protocol; * Age ≥ 18 years; * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1; * Life expectancy of at least 5 years (excluding diagnosis of cancer); * Histologically confirmed diagnosis of rectal adenocarcinoma, with centrally confirmed mismatch repair proficiency (MSS) by PCR, lack of MGMT expression by IHC and MGMT promoter methylation by pyrosequencing; * Locally advanced, resectable disease defined by the presence of at least one of the following features: 1. Distal tumor margin at \<15 cm from the anal verge; 2. cT3N0 or cT1-3N1 (with the definition of a clinically positive lymph node being any node ≥ 1 cm); 3. Less than four lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease; 4. No evidence of enlarged lateral pelvic clinically positive lymph node (\> 1 cm); 5. No evidence of extramural vascular invasion (EMVI); 6. No evidence of metastatic disease by CT scan of the chest and abdomen and total body fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan; 7. No clear indication of involvement of the pelvic side walls by imaging; * Tumor must be amenable to curative resection (curative resection can include pelvic exenteration); * Hematopoietic: absolute neutrophil count ≥1500/mm3; platelet count ≥ 100,000/mm3; haemoglobin level ≥ 10 g/dL; * Hepatic total bilirubin ≤1.5 time upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST and ALT ≤ 2.5 times ULN Serum creatinine ≤ 1.5 × ULN or renal creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula (or local institutional standard methods); * Availability of an adequate archival tumor sample (Formalin Fixed Paraffin-embedded \[FFPE\]) for central tissue screening. If the tumor block is not available, a minimum of twenty-five (25) 3-micron unstained sections of tumor will be required (5 of those on standard non charged slides for immunochemistry, the others on charged slides); * Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception) contraception starting with the first dose of study therapy, through 180 days after the last dose of treatment; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for these subject. * Women of childbearing potential must have a negative blood pregnancy test at the baseline visit and must be willing to use an effective means of contraception and to continue its use for the duration of the study and for 180 days after the last infusion of study treatment. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Exclusion Criteria: * Dihydropyrimidine dehydrogenase (DPD) deficiency; * Previous pelvic RT; * Any of the following in the 6 months prior to treatment start: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (≥ New York Heart Association Classification Class II), cerebrovascular accident/stroke, transient ischemic attack, serious cardiac arrhythmia requiring medication or symptomatic pulmonary embolism; * Uncontrolled coagulopathy; * Active infection requiring systemic therapy; * Infection with human immunodeficiency virus (HIV) plus CD4 cells \<200/mm3 or AIDS-defining conditions despite HAART; * Known prior severe hypersensitivity to investigational product or any component in its. formulations; * Lack of upper gastrointestinal tract integrity or malabsorption syndrome; immune colitis; active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic); * Presence of metastatic disease, recurrent rectal cancer or history of invasive rectal malignancy, regardless of disease-free interval; * Other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell or cloacogenic carcinoma) or synchronous colon cancer; * Patients with prior malignancies, including invasive colon cancer, are eligible provided they have been disease-free for ≥ 3 years and are deemed by their physician to be at low risk for recurrence (patients with effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum are eligible even if diagnosed less than 3 years before study enrollment); * Other severe acute or chronic medical conditions including immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study; * Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies; * Pregnant or lactating women.