Testing the Combination of Anti-cancer Drugs Atezolizumab and Tiragolumab in People With Advanced Stage Rare Cancers, RARE3 Trial

Inclusion Criteria:

• Patients must have histologically confirmed rare solid tumors that have progressedon standard therapy or for whom there is no standard of care therapy

• Patients must not be eligible for a higher priority study that would befeasible for them to enroll in, such as a disease specific study of phase 2 orhigher or a randomized study. Specifically, patients who are eligible for thePEP-CTN pediatric trial of atezolizumab and tiragolumab in children,adolescents, and young adults with SMARCB1- or SMARCA4-deficient tumors shouldbe excluded

• Patients must have measurable disease as defined by RECIST v1.1, with at least onelesion that can be accurately measured in at least one dimension (longest diameterto be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers byclinical exam)

• Patients must have a tumor site amenable to biopsy

• Age >= 18 years. Because biopsies are mandatory on this trial, patients < 18 yearsof age are excluded

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 institutional upper limit of normal (ULN)

• Patients who receive therapeutic anticoagulation therapy should be on a stabledose

• Total bilirubin =< 1.5 x institutional ULN (however, patients with known Gilbertdisease who have serum bilirubin level of up to 3 mg/dl may be enrolled)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (AST and/or ALT =< 5 x ULN for patients with liverinvolvement)

• Creatinine =< 1.5 x institutional ULN OR creatinine clearance levels >= 30mL/min/1.73 m^2 are permitted as the study agents are not secreted by the kidney

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression formore than >= 1 month after treatment of the brain metastases

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Willingness to provide biopsy samples for research purposes

• Administration of atezolizumab and tiragolumab may have an adverse effect onpregnancy and poses a risk to the human fetus, including embryo-lethality. Femalepatients of child-bearing potential and male patients must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry, for the duration of study participation, and for 5 months (150 days)after the last dose of study agent. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Patients who have had prior monoclonal antibody therapy must have completed thattherapy >= 5 weeks (or 3 half-lives of the antibody, whichever is shorter) prior tostart of treatment (minimum of 1 week between prior therapy and study enrollment)

• Patients must have recovered from clinically-significant adverse events of theirmost recent cancer immunotherapy to grade 1 or less, (with the exception of alopeciaand lymphopenia)

• Patients who are receiving any other investigational agents

• Prior anti-TIGIT therapy is not allowed. However, other prior immune checkpointinhibitor therapy is permitted

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies (i.e., antibodies with generic names ending in "ximab" or "zumab", respectively) or fusion proteins, not resolved by pre-medicationor steroids, leading to subsequent treatment cessation. Patients with a history ofallergic reaction to chimeric or humanized antibodies for which symptoms neverrecurred after subsequent re-challenge may be considered after careful medicalhistory review

• Treatment with systemic immunosuppressive medications (including, but not limitedto, prednisone [> 10 mg/day], cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks priorto Cycle 1, Day 1

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

• The use of inhaled corticosteroids and systemic mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed

• Patients with uncontrolled intercurrent illness, that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because atezolizumab and tiragolumab areinvestigational agents with unknown potential for teratogenic or abortifacienteffects. Because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with atezolizumab, and becauseit is not known if tiragolumab can be excreted in human milk, breastfeeding shouldbe discontinued if the mother is treated with atezolizumab

• History or risk of autoimmune disease, including, but not limited to, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren'ssyndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmunethyroid disease, vasculitis, or glomerulonephritis

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible

• Patients with autoimmune hyperthyroid disease not requiring immunosuppressivetreatment may be eligible

• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimenmay be eligible

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency ororal steroids)

• Patients with active tuberculosis (TB) are excluded

• Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limitedto, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

• Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day

1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinarytract infection or chronic obstructive pulmonary disease) are eligible

• Patients who have undergone major surgical procedures prior to Cycle 1, Day 1 whohave not recovered to ECOG performance status =< 2 (Karnofsky >= 60%)

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 oranticipation that such a live, attenuated vaccine will be required during the studyand up to 5 months after the last dose of atezolizumab

• Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuatedinfluenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time duringthe study