Neoadjuvant PD-1 Plus TIGIT Blockade in Patients With Cisplatin-Ineligible Operable High-Risk Urothelial Carcinoma

Inclusion Criteria:

1. Signed Informed Consent Form

2. Age >18 years at time of signing Informed Consent Form

3. Ability to comply with the study protocol

4. Histologically or cytologically confirmed proof of muscle invasive urothelialcancer. This may include any patient requiring cystectomy (or nephroureterectomy toresect tumors), including muscle invasive disease (cT2-4aN0M0). Patients with thefollowing high-risk features who are not candidates for traditional neoadjuvantchemotherapy will be included for this trial: micropapillary, sarcomatoid andplasmacytoid features; 3-D mass on exam under anesthesia (EUA); lymphovascularinvasion; hydronephrosis (unless in the opinion of the treating physician, this isnot due to tumor); high grade (grade 3) tumors of the ureter, renal pelvis, ortumors in these areas with radiographic abnormality large enough to recognize as anabnormal mass by CT or MRI imaging5; direct invasion of the prostatic stroma or thevaginal wall (i.e. cT4a disease). For patients in whom eligibility is unclear, finalarbitration will be determined by the Principal Investigator.

5. Subjects must be considered cisplatin ineligible as per treating physician (EasternCooperative Oncology Group performance status (ECOG-PS) 2, creatinine clearance (CrCl) <60 mL/min, grade > 2 hearing loss, grade > 2 neuropathy, or New York HeartAssociation (NYHA) class III heart failure. See FDA draft guidance n adjuvanttherapy in bladder cancer https://www.fda.gov/media/142544/download) or have refusedcisplatinbased chemotherapy as a neoadjuvant therapy.

6. Tissue resected by transurethral resection of bladder tissue (TURBT) at the MDAnderson Cancer Center; if completed TURBT at the outside facility, it must bewithin three months and must transfer outside TURBT tumor tissues to MD Anderson forcorrelative research on this trial.

7. Eligible for R0 resection with curative intent at the time of screening, asconfirmed by the operating attending surgeon and involved medical oncologist priorto study enrollment

8. Adequate pulmonary function to be eligible for surgical resection with curativeintent, as assessed by PFTs performed within 6 months of planned resection andrepeated at screening, if clinically indicated, including lung volumes, spirometry,and a diffusion capacity; and meeting at least one of the following criteria:

9. Predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) andppo diffusion capacity of the lung for carbon monoxide (DLCO) >40%

10. Maximal oxygen consumption (VO2max) >15 mL/kg/min

11. If either ppoFEV1 or ppoDLCO is <40% or a pneumonectomy is planned, cardiopulmonaryexercise testing must be performed and VO2max >15 mL/kg/min.

12. If PFTs were performed before 6 months of planned resection or have not beenpreviously performed, they must be performed during the screening period.

13. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

14. Normal life expectancy, excluding lung cancer mortality risk

15. Adequate hematologic and -end organ and marrow function, defined by the followinglaboratory test results, obtained within 14 days prior to initiation of studytreatment:

16. ANC > 1.5 x 109 /L (1500/µL) without granulocyte colony-stimulating factor support

17. Lymphocyte count >0.5 x 109 /L (500/µL)

18. Platelet count >100 x109 /L (100,000/µL) without transfusion

19. Hemoglobin >90 g/L (9 g/dL)

20. Patients may be transfused to meet this criterion. e. AST, ALT, and ALP <2.5 x upperlimit of normal (ULN) f. Total bilirubin <1.5 xULN with the following exception:Patients with known Gilbert disease (>3 xULN): who must have a baseline totalbilirubin <3.0 mg/dL g. Creatinine clearance >45 mL/min (calculated using theCockcroft-Gault formula) h. Serum albumin >25 g/L (2.5 g/dL)

21. For patients not receiving therapeutic anticoagulation: INR and aPTT <1.5 xULN

22. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

23. Negative HIV test at screening

24. Negative hepatitis B surface antigen (HBsAg) test at screening

25. Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAbat screening accompanied by either of the following:

a. Negative total hepatitis B core antibody (HBcAb) b. Positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA< 500 IU/mL. The HBV DNA test will be performed only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. c. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.

19. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraception, and agreement to refrain fromdonating eggs, as defined below:

a. Women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for up to 23 weeks after the last dose of study drugs dose. Women must refrain from donating eggs during this same period. b. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. c. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

d. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. e. Women who would like to become pregnant after study treatment discontinuation should seek advice on oocyte cryopreservation prior to initiation of study treatment.

20. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below:

21. With a female partner of childbearing potential, men who are not surgically sterilemust remain abstinent or use a condom plus an additional contraceptive method thattogether result in a failure rate of <1% per year during the treatment period, forup to 90 days after the final dose of the study drugs. Men must refrain fromdonating sperm during this same period.

22. With a pregnant female partner, men must remain abstinent or use a condom during thetreatment period for 90 days after the final dose of the study drugs to avoidexposing the embryo.

23. The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not adequate methods of contraception. If required per localguidelines or regulations, locally recognized adequate methods of contraception andinformation about the reliability of abstinence will be described in the localInformed Consent Form.

24. Men who would like to father a child after study treatment initiation should beadvised regarding the conservation of sperm prior to treatment because of thepossibility of irreversible infertility resulting from drugs used in this study.

Exclusion Criteria:

1. Illness or condition that may interfere with a patient's capacity to understand,follow, and/or comply with study procedures

2. Any prior therapy for urothelial cancer, including immunotherapy, chemotherapy, orradiotherapy

3. History of leptomeningeal disease

4. 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-Barrésyndrome, or multiple sclerosis (see Appendix 4 for a more comprehensive list ofautoimmune diseases and immune deficiencies), with the exceptions listed below.

5. Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.

6. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

7. 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 following conditions aremet: i. Rash must cover <10% of body surface area ii. Disease is well controlled atbaseline and requires only low-potency topical corticosteroids iii. No occurrence ofacute exacerbations of the underlying condition requiring psoralen plus ultravioletA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,or high-potency or oral corticosteroids within the previous 12 months

8. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest CT scan

9. Active tuberculosis

10. Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

11. Major surgical procedure, within 4 weeks prior to initiation of study treatment, oranticipation of need for a major surgical procedure during the study

12. History of malignancy other than urothelial cancer within 5 years prior toscreening, with the exception of malignancies with a negligible risk of metastasisor death (e.g., 5-year OS rate >90%), such as adequately treated carcinoma in situof the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductalcarcinoma in situ, or Stage I uterine cancer

13. Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia, or any active infection that, in the opinion of the investigator,could impact patient safety

14. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment a. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection or chronic obstructive pulmonary disease exacerbation) are eligible forthe study.

15. Prior allogeneic stem cell or solid organ transplantation

16. Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

17. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy 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 thefinal dose of atezolizumab

18. Current treatment with anti-viral therapy for HBV

19. Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) testat screening a. An EBV PCR test should be performed as clinically indicated to screen for acuteinfection or suspected chronic active infection. Patients with a positive EBV PCRtest are excluded.

20. Treatment with investigational therapy within 42 days prior to initiation of studytreatment

21. 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.

22. Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever islonger) prior to initiation of study treatment

23. Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andantitumor necrosis factor- [TNF-] agents) within 2 weeks prior to initiation ofstudy treatment, or anticipation of need for systemic immunosuppressive medicationduring study treatment, with the following exceptions:

24. Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study after INDMedical Monitor confirmation has been obtained

25. Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose (< 10mg prednisone equivalent per day) corticosteroids for orthostatichypotension or adrenal insufficiency are eligible for the study.

26. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

27. Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab or tiragolumab formulation.

28. Pregnancy or breastfeeding, or intention of becoming pregnant during studytreatment, within 90 days after the final dose of tiragolumab, 5 months after thefinal dose of atezolizumab. Women of childbearing potential must have a negativeserum pregnancy test result within 14 days prior to initiation of study treatment.