Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS)

The peculiarity of anal cancers, with well-established radical chemoradiotherapy that allows tumor-neoantigen formation with platinum-based chemotherapy and radiotherapy with radio-sensitizing chemotherapy could create the perfect environment for immunotherapy in this setting, not only to increase the probability of pathological complete response (CCR) but also creating neoantigen exposure and immune-prevention to reduce the relapse after surgery. TIRANUS trial is a Phase II, single-arm, open-label, non randomized, non controlled recruiting treatment-naive localized squamous cell carcinoma of the anal canal and are candidates for radical chemoradiotherapy. The trial hypothesizes that the addition of immunotherapy (atezolizumab and tiragolumab) to standard chemoradiotherapy in localized squamous cell carcinoma of the anal canal may improve the CCR at the end of consolidation phase. The study will assess, as the primary endpoint, the CCR, defined as the percentage of patients who have achieved complete response (CR), disappearance of all target lesions and no presence of residual disease assessed by biopsy at the end of consolidation phase. Secondary objectives include survival, safety of the combination, patient reported quality of life, and a substudy of molecular biomarkers determined in tumor biopsy and blood samples. The main question\[s\] it aims to answer are: 1. To determine the efficacy of atezolizumab plus tiragolumab concomitantly with chemoradiotherapy in patients with localized squamous cell carcinoma of the anal canal evaluating the clinical response to treatment. 2. To evaluate safety of the intended treatment regimen and Health-related quality of life (HRQoL) in this treatment regimen All patients will receive atezolizumab plus tiragolumab for 2 cycles in concomitance with the 6 weeks of standard scheduled chemoradiotherapy. (cisplatin, 5-Fluorouracil and radiotherapy). After the concomitant phase, patients will enter a consolidation phase and will receive atezolizumab in combination with tiragolumab up to 24 weeks. Patients will discontinue treatment in case of confirmed progression, toxicity, patient criteria, or physician criteria.

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 \ 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.