Tiragolumab and Atezolizumab Compared to Atezolizumab Alone for the Treatment of Stage II Melanoma In Patients who are ctDNA-Positive After Surgery

Inclusion Criteria

• STEP I: Surgically resected and histologically/pathologically confirmed stage II cutaneous melanoma. No more than 16 weeks may elapse between final surgical resection and randomization. Treatment should start only after complete wound healing from the surgery
• STEP I: Participants must not have been previously treated for melanoma beyond complete surgical resection
• STEP I: At least 18 years of age
• STEP I: Ability to understand and willingness to sign an institutional review board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)
• STEP II: Positive ctDNA test
• STEP II: Absolute neutrophil count >= 1,500/mcL
• STEP II: Lymphocyte count >= 500/mcL
• STEP II: Platelets >= 100,000/mcL
• STEP II: Hemoglobin >= 9.0 g/dL (patients may be transfused to meet this criterion)
• STEP II: Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) or direct bilirubin =< IULN for participants with total bilirubin levels > 1.5 x IULN; patients with known Gilbert disease must have total bilirubin =< 3 x IULN
• STEP II: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x IULN
• STEP II: Alkaline phosphatase =< 2.5 x IULN
• STEP II: Creatinine clearance >= 45 mL/min by Cockcroft-Gault
• STEP II: Serum albumin >= 2.5 g/dL
• STEP II: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x IULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
• STEP II: aPTT =< 1.5 x IULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• STEP II: Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• STEP II: The effects of atezolizumab and tiragolumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, for 90 days after the final dose of tiragolumab, and for 5 months after the final dose of atezolizumab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 90 days after completion of the study

Exclusion Criteria

• STEP I: A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease or malignancies in situ (such as ductal carcinoma in situ [DCIS]), basal cell carcinoma, or localized cutaneous squamous cell carcinomas
• STEP I: Currently receiving any other investigational agents
• STEP I: Prior history of pneumonitis
• STEP I: A history of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab and tiragolumab or other agents used in the study
• STEP I: Significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• STEP I: 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, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the exceptions listed below: * 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 following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** 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
• STEP I: Active tuberculosis
• STEP I: Prior allogeneic stem cell or solid organ transplantation
• STEP I: Positive hepatitis B surface antigen (HBsAb) at screening
• STEP I: Positive hepatitis C virus (HCV) antibody test at screening (unless followed by a negative HCV ribonucleic acid [RNA] test)
• STEP I: Current treatment with anti-viral therapy for hepatitis B (HBV)
• STEP I: Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) test at screening. An EBV polymerase chain reaction (PCR) test should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded
• STEP I: Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-TIGIT, and anti-PD-L1 therapeutic antibodies
• STEP I: History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• STEP I: Patients with human immunodeficiency virus (HIV) are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective antiretroviral therapy (ART) according to The Department of Health and Human Services (DHHS) treatment guidelines is recommended
• STEP II: Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry
• STEP II: Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment, within 90 days after the final dose of tiragolumab, or within 5 months after the final dose of atezolizumab
• STEP II: Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α [TNF-α] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following 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
• STEP II: Major surgical procedure within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• STEP II: 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, in the opinion of the investigator, could impact patient safety
• STEP II: Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• STEP II: Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment