Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)

Inclusion Criteria for mUC Cohort:

1. Histologically documented, locally advanced or metastatic UC (also termed TCC or urothelial cell carcinoma of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
2. Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status by means of central testing
3. Disease progression during or following treatment with no more than one platinum-containing regimen for inoperable, locally advanced or metastatic UC or disease recurrence
4. ECOG Performance Status of 0 or 1
5. Measurable disease (at least one target lesion) according to RECIST v1.1
6. Adequate hematologic and end-organ function
7. Negative HIV test at screening
8. Negative total hepatitis B core antibody (HBcAb) test and hepatitis C virus (HCV) antibody at screening
9. Tumor accessible for biopsy
10. For women of childbearing potential: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating eggs
11. For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Inclusion Criteria for MIBC Cohorts:

1. ECOG PS of 0 or 1
2. Fit and planned-for cystectomy
3. Histologically documented MIBC (pT2-4, N0, M0), also termed TCC or urothelial cell carcinoma of the urinary bladder
4. N0 or M0 disease by CT or MRI
5. Adequate hematologic and end-organ function
6. Availability of TURBT specimen
7. Negative HIV, HBcAb, and HCV test at screening
8. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm
9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm

Exclusion Criteria for mUC Cohort:

1. Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
2. Prior treatment with any of the protocol-specified study treatments including treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or TIGIT-targeting agents, Trop-2 targeting agents, FAP-directed therapies, 4-1BB (CD137)-directed therapies, or topoisomerase 1 inhibitors
3. Treatment with investigational therapy within 28 days prior to initiation of study treatment
4. Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
5. Eligibility only for the control arm
6. Prior allogeneic stem cell or solid organ transplantation
7. Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment
8. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressant medication during study treatment
9. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
11. Uncontrolled tumor-related pain
12. Uncontrolled or symptomatic hypercalcemia
13. Symptomatic, untreated, or actively progressing CNS metastases
14. History of leptomeningeal disease
15. Active or history of autoimmune disease or immune deficiency
16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
17. History of malignancy other than UC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
18. Active tuberculosis
19. Severe infection within 4 weeks prior to initiation of study treatment
20. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
21. Significant cardiovascular disease
22. Uncontrolled hypertension
23. Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of study treatment
24. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment
25. Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Additional drug-specific exclusion criteria might apply

Exclusion for MIBC Cohorts:

1. Prior treatment with systemic immunostimulatory agents prior to the initiation of study treatment
2. Eligibility only for the control arm
3. Prior allogeneic stem cell or solid organ transplantation
4. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions: Patients who received acute, low-dose, systemic immunosuppressant medications, or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained. Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
5. Severe infection within 4 weeks prior to initiation of study treatment
6. Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Also includes all the mUC exclusion criteria

Additional Exclusion Criteria for Atezo+Tira and Atezo (Atezolizumab) +Tira+Cis (Cisplatin)+Gem (Gemcitabine) in the MIBC Cohorts:

- Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening.

Additional Exclusion Criteria for the Cisplatin-Eligible MIBC Cohort:

1. Patients who decline neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
2. Impaired renal function.