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 tothe 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 includenon-keratinizing histological subtypes (i.e. basaloid, transitional, spheroidal andcloacogenic).
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 welldifferentiated Stage I anal margin cancer are not eligible.
6. Mandatory archival or recent paraffin-fixed (FFPE) tumor biopsy available at baselinefor translational purposes. Fine-needle biopsy is acceptable. Note: If there is no archival tumor tissue or not enough tissue available from thebiopsy at diagnosis, another biopsy may be requested before treatment begins (aftersigning the informed consent).
7. At least one evaluable lesion.
8. Patients should meet the criteria for radical chemoradiotherapy for squamous cellcarcinoma 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 priorto start of the study treatment as defined below:
11. Hemoglobin ≥ 9.0 g/dL (Patients may be transfused to meet this criterion).
12. Absolute neutrophil count (ANC) > 1500 per mm3.
13. Platelet count ≥ 100,000 per mm3.
14. Serum total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN). Thiswill not apply to patients with confirmed Gilbert's syndrome (persistent orrecurrent hyperbilirubinemia that is predominantly unconjugated in the absence ofhaemolysis or hepatic pathology); however, they will be allowed only inconsultation with their physician if total bilirubin ≤ 3 × ULN.
15. Serum transaminases: alanina aminotransferase (ALT), aspartato aminotransferase (AST) and fosfatase alcalina (ALP) ≤ 2.5X ULN.
16. Serum albumin ≥ 25 g/L (2.5 g/dL).
17. Creatinine ≤ 1.5 mg/dL or measured creatinine clearance (CL) > 60 mL/min orCalculated creatinine CL > 60 mL/min by the Cockcroft-Gault formula (Cockcroftand Gault 1976) or by 24-hour urine collection for the determination ofcreatinine 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)
18. Absence of active infection that requires systemic antibiotics.
19. Female subjects of childbearing potential (WOCBP) must provide a negative urinepregnancy test at screening, and must agree to use a medically accepted and highlyeffective birth control method (i.e. those with a failure rate less than 1%) for theduration of the study treatment and for 90 days after the final dose of tiragolumab, 5months after the final dose of atezolizumab, and 6 months after the final dose ofcisplatin / 5-fluorouracil (5-FU). A woman is considered of childbearing potential ( i.e. fertile) following menarche anduntil becoming post-menopausal unless permanently sterile. Women will be consideredpost-menopausal if they have been amenorrhoeic for 12 months without an alternativemedical cause. The following age-specific requirements apply:
20. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments
21. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiollevels in the post-menopausal range
22. Radiation induced oophorectomy with last menses >1 year ago
23. Chemotherapy induced menopause with >1 year interval since last menses
24. Surgical sterilization (bilateral oophorectomy or hysterectomy)
25. Women <50 years of age would be considered post-menopausal if they have beenamenorrheic 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)
26. Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, or underwent surgical sterilization (bilateral oophorectomy,bilateral salpingectomy or hysterectomy).
27. For both male and female patients/partners: Contraceptive use should be consistentwith local regulations regarding the methods of contraception for those participatingin clinical studies. Non-sterile males must be willing to use a highly effectivemethod of birth control for the duration of the study treatment and for 90 days afterthe final dose of tiragolumab, and 6 months after the final dose of cisplatin / 5-FU. A sterile male is defined as:
28. One for whom azoospermia has been previously demonstrated in a semen sampleexamination as definitive evidence of infertility.
29. Males with known "low sperm counts" (consistent with "sub-fertility") are not tobe considered sterile for purposes of this study.
30. Willingness and ability of patients to comply with the protocol for the duration ofthe study including undergoing treatment as well as availability for scheduled visitsand examinations including follow up.

Exclusion Criteria:

1. Previous or pre-planned potentially curative surgery for the anal carcinoma for theduration of the study. Major surgery (i.e. cystectomy) less than 28 days prior to thefirst 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 checkpointblockade therapies, anti-CTLA-4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeuticantibodies are not allowed.
3. History of severe allergic anaphylactic reactions to chimeric or humanized antibodiesor fusion proteins. Known hypersensitivity to Chinese hamster ovary cell products orto 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 notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,or multiple sclerosis. Note: Subjects with the following are not excluded:
6. Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.
7. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.
8. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of the following conditions aremet: i. Rash must cover < 10% of body surface area. ii. Disease is well controlled at baseline and requires only low-potency topicalcorticosteroids. iii. There has been no occurrence of acute exacerbations of the underlying conditionrequiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oral corticosteroids withinthe previous 12 months.
9. Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 14 days prior to thefirst dose of study treatment, with the exceptions:
10. Patients who received acute, low-dose systemic immunosuppressant medication or aone-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours ofcorticosteroids for a contrast allergy) are eligible for the study
11. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroidsfor chronic obstructive pulmonary disease (COPD) or asthma, or low-dosecorticosteroids for orthostatic hypotension or adrenal insufficiency are eligiblefor the study.
12. Treatment with investigational therapy within 42 days prior to initiation of studytreatment. Observational studies are permitted.
13. 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.
14. Not stable treatment with anticoagulant therapies.
15. Severe infection within 4 weeks prior to initiation of study treatment, including, butnot limited to, hospitalization for complications of infection, bacteremia, or severepneumonia, or any active infection that could impact patient safety. Activetuberculosis, Epstein-Barr virus(EBV), Hepatitis C virus (HCV), Hepatitis B virus (HBV), or Human immunodeficiency virus (HIV). Current treatment with antiviral therapyfor 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) Receivingantiretroviral therapy (ART/HAART) for at least 4 weeks prior to study enrollment, andhaving not experienced any HIV-related opportunistic infection for at least 4 weeksprior to study enrollment.
16. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment. Note: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection or chronic obstructive pulmonary disease exacerbation) are eligible for thestudy.
17. Vaccination within 4 weeks of the first dose of study treatment, or anticipation ofneed for such a vaccine while on trial, and 5 months after last dose of atezolizumaband/or 90 days after last dose of tiragolumab is prohibited except for administrationof inactivated vaccines (i.e. SARS-CoV-2 and Influenza vaccines will be permitted).
18. Subject has a history of another uncontrolled malignancy before the first dose ofstudy drug, or any evidence of residual disease from a previously diagnosedmalignancy..
19. Presence of the following conditions within the past 6 months:
20. Uncontrolled diabetes
21. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
22. New York Heart Association class II-IV congestive heart failure
23. Cerebrovascular accident
24. Transient ischemic attack
25. Uncontrolled hypertension
26. Unstable angina
27. Myocardial infarction
28. Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 criteria
29. Uncontrolled tumor-related pain. Patients requiring pain medication must be on astable regimen at study entry
30. Uncontrolled pleural effusion, pericardial effusion, or ascites requiringdrainage procedures
31. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis.
32. Women pregnant or breastfeeding. Fertile and sexually active patients who are notwilling to use the appropriate highly effective contraceptive methods.
33. Any underlying medical or psychiatric disorder, which, in the opinion of theinvestigator, makes the administration of atezolizumab or tiragolumab unsafe orinterferes with the informed consent process or trial procedures.