Tiraglolumab Atezolizumab and Chemoradiotherapy in Localized Anal Carcinoma (TIRANUS)

Exclusion Criteria39

• 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.
• 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.
• 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.
• History of allogeneic stem cell or solid organ transplant.
• 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:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• 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.
• 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:
• 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
• 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.
• Treatment with investigational therapy within 42 days prior to initiation of study treatment. Observational studies are permitted.
• 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.
• Not stable treatment with anticoagulant therapies.
• 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.
• 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.
• 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).
• 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..
• Presence of the following conditions within the past 6 months:
• Uncontrolled diabetes
• Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN)
• New York Heart Association class II-IV congestive heart failure
• Cerebrovascular accident
• Transient ischemic attack
• Uncontrolled hypertension
• Unstable angina
• Myocardial infarction
• Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 criteria
• Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage procedures
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis.
• Women pregnant or breastfeeding. Fertile and sexually active patients who are not willing to use the appropriate highly effective contraceptive methods.
• 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.