Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS)

Inclusion Criteria: 1. Male or female subjects ≥ 18 years old. 2. Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 4. Histologically confirmed squamous cell carcinoma of the anal canal. This may include non-keratinizing histological subtypes (i.e. basaloid, transitional, spheroidal and cloacogenic). 5. Locoregional squamous cell carcinoma of the anal canal with no distant metastasis: stages I, II, IIIA, and IIIB according to the American Joint Cancer Committee (AJCC) Cancer Staging Handbook Seventh Edition (T1-4, N0-1, M0). Patients with well differentiated Stage I anal margin cancer are not eligible. 6. Mandatory archival or recent paraffin-fixed (FFPE) tumor biopsy available at baseline for translational purposes. Fine-needle biopsy is acceptable. Note: If there is no archival tumor tissue or not enough tissue available from the biopsy at diagnosis, another biopsy may be requested before treatment begins (after signing the informed consent). 7. At least one evaluable lesion. 8. Patients should meet the criteria for radical chemoradiotherapy for squamous cell carcinoma of the anal canal following international guidelines. 9. Normal life expectancy, excluding cancer mortality risk 10. Patients with adequate normal organ and marrow function assessed within 14 days prior to start of the study treatment as defined below: 1. Hemoglobin ≥ 9.0 g/dL (Patients may be transfused to meet this criterion). 2. Absolute neutrophil count (ANC) \> 1500 per mm3. 3. Platelet count ≥ 100,000 per mm3. 4. Serum total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician if total bilirubin ≤ 3 × ULN. 5. Serum transaminases: alanina aminotransferase (ALT), aspartato aminotransferase (AST) and fosfatase alcalina (ALP) ≤ 2.5X ULN. 6. Serum albumin ≥ 25 g/L (2.5 g/dL). 7. Creatinine ≤ 1.5 mg/dL or measured creatinine clearance (CL) \> 60 mL/min or Calculated creatinine CL \> 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance: Males: Creatinine CL (mL/min) = (Weight (kg) × (140 - Age))/ 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = ((Weight (kg) × (140 - Age) ×0.85))/72 x serum creatinine (mg/dL) 11. Absence of active infection that requires systemic antibiotics. 12. Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%) for the duration of the study treatment and for 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, and 6 months after the final dose of cisplatin / 5-fluorouracil (5-FU). A woman is considered of childbearing potential ( i.e. fertile) following menarche and until becoming post-menopausal unless permanently sterile. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: 1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments 2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range 3. Radiation induced oophorectomy with last menses \>1 year ago 4. Chemotherapy induced menopause with \>1 year interval since last menses 5. Surgical sterilization (bilateral oophorectomy or hysterectomy) 6. Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) 7. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 13. For both male and female patients/partners: Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study treatment and for 90 days after the final dose of tiragolumab, and 6 months after the final dose of cisplatin / 5-FU. A sterile male is defined as: 1. One for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. 2. Males with known "low sperm counts" (consistent with "sub-fertility") are not to be considered sterile for purposes of this study. 14. Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up. Exclusion Criteria: 1. Previous or pre-planned potentially curative surgery for the anal carcinoma for the duration of the study. Major surgery (i.e. cystectomy) less than 28 days prior to the first dose of study treatment. 2. Prior treatment for the control of the squamous cell carcinoma of the anal canal. Prior radiotherapy, chemotherapy or treatment with CD137 agonists or immune checkpoint blockade therapies, anti-CTLA-4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies are not allowed. 3. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the tiragolumab or atezolizumab formulation. 4. History of allogeneic stem cell or solid organ transplant. 5. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis. Note: Subjects with the following are not excluded: 1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. 2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. 3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: i. Rash must cover \< 10% of body surface area. ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids. iii. There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. 6. Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment, with the exceptions: 1. Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study 2. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. 7. Treatment with investigational therapy within 42 days prior to initiation of study treatment. Observational studies are permitted. 8. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2) within 28 days or 5 drug-elimination half-lives (whichever is longer) prior to first study treatment administration. 9. Not stable treatment with anticoagulant therapies. 10. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety. Active tuberculosis, Epstein-Barr virus(EBV), Hepatitis C virus (HCV), Hepatitis B virus (HBV), or Human immunodeficiency virus (HIV). Current treatment with antiviral therapy for HBV. Note: HIV-positive patients may be eligible if they are stable as defined by (a) CD4+ count ≥ 300/μL. (b) Undetectable viral load per standard of care assay. (c) Receiving antiretroviral therapy (ART/HAART) for at least 4 weeks prior to study enrollment, and having not experienced any HIV-related opportunistic infection for at least 4 weeks prior to study enrollment. 11. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Note: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 12. Vaccination within 4 weeks of the first dose of study treatment, or anticipation of need for such a vaccine while on trial, and 5 months after last dose of atezolizumab and/or 90 days after last dose of tiragolumab is prohibited except for administration of inactivated vaccines (i.e. SARS-CoV-2 and Influenza vaccines will be permitted). 13. Subject has a history of another uncontrolled malignancy before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy.. 14. Presence of the following conditions within the past 6 months: 1. Uncontrolled diabetes 2. Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN) 3. New York Heart Association class II-IV congestive heart failure 4. Cerebrovascular accident 5. Transient ischemic attack 6. Uncontrolled hypertension 7. Unstable angina 8. Myocardial infarction 9. Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 criteria 10. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry 11. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage procedures 15. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis. 16. Women pregnant or breastfeeding. Fertile and sexually active patients who are not willing to use the appropriate highly effective contraceptive methods. 17. Any underlying medical or psychiatric disorder, which, in the opinion of the investigator, makes the administration of atezolizumab or tiragolumab unsafe or interferes with the informed consent process or trial procedures.