A Study Evaluating Different Immunotherapies (LAG-3 and PD-1 With or Without TIGIT, Compared to PD-L1 Alone) in Participants With Untreated Locally Advanced Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of tobemstomig alone or in combination with tiragolumab compared with atezolizumab in participants with previously untreated, locally advanced or metastatic urothelial cancer (mUC) who are ineligible to receive a platinum containing chemotherapy.

Official Title
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A Phase II, Randomized, Multicenter, Open-Label, Controlled Study of Tobemstomig Alone or in Combination With Tiragolumab Versus Atezolizumab in Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer Who Are Ineligible for Platinum-Containing Chemotherapy

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Tobemstomig
* Drug: Tiragolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. Participants with squamous, sarcomatoid, micropapillary, and glandular variant histologies are eligible for inclusion in the study, provided that a urothelial component is present in the tumor specimen. Participants with other variant histologies or pure variant histologies are not eligible for inclusion in this study Ineligible (unfit) to receive platinum-based chemotherapy No prior chemotherapy for inoperable locally advanced or metastatic or recurrent urothelial carcinoma (UC) Measurable disease; at least one measurable lesion as defined by response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) Availability of a representative leftover tumor specimen that is suitable for determination of PD-L1 status as assessed by a central laboratory Adequate hematologic and end organ function Negative for hepatitis B and hepatitis C virus (HCV) Adequate cardiovascular function Exclusion Criteria: Pregnancy or breastfeeding GFR <15 mL/min/1.73 m2 Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases History of leptomeningeal disease Uncontrolled tumor-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Uncontrolled or symptomatic hypercalcemia Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan Active tuberculosis (TB) or acute Epstein-Barr virus (EBV) Significant cardiovascular/cerebrovascular disease within 3 months prior to initiation of study treatment Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study History of another primary malignancy other than urothelial carcinoma within 2 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death Severe infection within 4 weeks prior to initiation of study treatment Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease [COPD] exacerbation), or who are receiving oral antibiotics to treat a urinary tract infection are eligible for the study Prior allogeneic stem cell or solid organ transplantation Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment or within 5 months after the final dose of atezolizumab, 4 months after the final dose of tobemstomig, or 90 days after the final dose of tiragolumab Current treatment with anti-viral therapy for HBV Treatment with any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-TIGIT and anti-LAG3 therapeutic antibodies or pathways targeting agents Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Participants will receive intravenous (IV) atezolizumab every 3 weeks (Q3W). | Drug: Atezolizumab<br>* Participants will receive 1200 mg IV atezolizumab Q3W.<br>|
| Experimental: Arm B<br>Participants will receive IV tobemstomig Q3W. | Drug: Tobemstomig<br>* Participants will receive 600 mg IV tobemstomig Q3W.<br>* Other names: RO7247669;|
| Experimental: Arm C<br>Participants will receive IV tobemstomig + IV tiragolumab Q3W. | Drug: Tobemstomig<br>* Participants will receive 600 mg IV tobemstomig Q3W.<br>* Other names: RO7247669;Drug: Tiragolumab<br>* Participants will receive 600 mg IV tiragolumab Q3W.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) |  | Up to approximately 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) |  | Up to approximately 30 months | 
| Overall Survival (OS) |  | Up to approximately 30 months | 
| Duration of Response (DOR) |  | Up to approximately 30 months | 
| PFS |  | 6 months and 12 months | 
| OS |  | 6 months, 12 months, and 18 months | 
| Disease Control Rate (DCR) |  | Up to 12 weeks | 
| Time to Confirmed Deterioration (TTCD) |  | Baseline up to 3 weeks | 
| Change from Baseline in European Organisation for Research and Cancer Treatment Item Library 187 (EORTC IL 187) Scores |  | Up to approximately 30 months | 
| Maximum Concentration (Cmax) of Tobemstomig |  | Up to approximately 30 months | 
| Time of Maximum Concentration (Tmax) of Tobemstomig |  | Up to approximately 30 months | 
| Clearance (CL) of Tobemstomig |  | Up to approximately 30 months | 
| Volume of Distribution at Steady State (Vss) of Tobemstomig |  | Up to approximately 30 months | 
| Area Under the Curve (AUC) of Tobemstomig |  | Up to approximately 30 months | 
| Half-Life (T1/2) of Tobemstomig |  | Up to approximately 30 months | 
| Maximum serum concentration (Cmax) of tiragolumab |  | Up to approximately 30 months | 
| Minimum serum concentration (Cmin) of tiragolumab |  | Up to approximately 30 months | 
| Cmax of atezolizumab |  | Up to approximately 30 months | 
| Cmin of atezolizumab |  | Up to approximately 30 months | 
| Incidence of Anti-Drug Antibodies (ADAs) |  | Up to approximately 30 months |