Evaluation of Tobemstomig, Tiragolumab, and Atezolizumab in Untreated Locally Advanced or Metastatic Urothelial Cancer Ineligible for Platinum Chemotherapy

The primary objective of this Phase II, randomized, multicenter, open-label, controlled study is to evaluate the **safety** of tobemstomig alone and in combination with tiragolumab, compared to atezolizumab, in patients with previously untreated locally advanced or metastatic **urothelial cancer** who are ineligible for platinum-containing chemotherapy. This evaluation is clinically relevant as it aims to determine the safety profile of novel immunotherapy combinations, which could potentially offer alternative treatment options for patients who cannot undergo standard chemotherapy regimens.

The clinical trial involves a total of **94 participants** diagnosed with **previously untreated locally advanced or metastatic urothelial cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 and histologically or cytologically documented transitional cell carcinoma of the urothelium. The trial includes individuals considered ineligible for platinum-based chemotherapy due to various health factors, such as baseline glomerular filtration rate (GFR) and neuropathy grade. Participants have not received prior chemotherapy for inoperable locally advanced or metastatic urothelial carcinoma and must have measurable disease as defined by RECIST v1.1. The trial also requires the availability of a representative leftover tumor specimen for PD-L1 status determination. The study population includes vulnerable groups, and lifestyle factors such as diet and physical activity are not specified by the sponsor.

The clinical trial is a **Phase II**, randomized, multicenter, open-label, controlled study designed to evaluate the safety of **tobemstomig** alone and in combination with **tiragolumab**, compared to **atezolizumab** in patients with previously untreated locally advanced or metastatic urothelial cancer who are ineligible for platinum-containing chemotherapy. The trial is expected to run from May 31, 2023, to December 30, 2026. Participants will be randomly assigned to receive one of the investigational treatments via **intravenous infusion**. The study will assess the incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, except for Cytokine Release Syndrome, which will be assessed according to the American Society for Transplantation and Cellular Therapy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an Eastern Cooperative Oncology Group Performance Status of ≤ 2 and histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium. The trial will include follow-up visits to monitor the safety and efficacy of the treatments, with the end-of-study visit marking the conclusion of the participant's involvement. The expected length of participant involvement is up to 30 days, corresponding to the maximum treatment period for the investigational products. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's withdrawal of consent.

The clinical trial involves the administration of **Tecentriq**, a **concentrate for solution for infusion** containing the active substance **atezolizumab**. This medication is administered via **intravenous infusion**. The maximum daily dose is 1200 mg, with a total maximum dose of 54 g over a treatment period of 30 days. Tecentriq is manufactured by Roche Registration GmbH and is authorized for use in the European Union. The product undergoes secondary packaging and labeling specifically for clinical trials.

**Tiragolumab** is another investigational product used in this study. It is also a **concentrate for solution for infusion** and is administered through **intravenous infusion**. The maximum daily dose for tiragolumab is 600 mg, with a total maximum dose of 27 g over a 30-day treatment period. This product is developed by F. Hoffmann-La Roche Ltd and is identified by the sponsor product code RO 709-2284/F03-01. Tiragolumab is not yet authorized for marketing and is being evaluated for its safety and efficacy in combination with other treatments.

The third investigational product is **RO7247669**, also known as **tobemstomig**. This product is provided as a **solution for infusion** and is administered via **intravenous infusion**. Similar to tiragolumab, the maximum daily dose is 600 mg, with a total maximum dose of 27 g over a 30-day period. RO7247669 is also developed by F. Hoffmann-La Roche Ltd and is identified by the sponsor product code RO 724-7669/F01-01. This product is being tested for its potential use in combination with other investigational drugs in the treatment of urothelial cancer.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this study. The primary objective is to evaluate the safety of these investigational products, both alone and in combination, in patients with previously untreated locally advanced or metastatic urothelial cancer who are ineligible for platinum-containing chemotherapy.

Efficacy in this clinical trial will be assessed primarily through the incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5). An exception is made for the severity of **Cytokine Release Syndrome (CRS)** events, which will be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The trial involves a Phase II, randomized, multicenter, open-label, controlled study design, comparing the efficacy 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. The study will utilize a controlled approach to ensure the accurate collection and analysis of data related to the primary endpoints. The trial is expected to conclude by December 30, 2026, with recruitment having started on May 31, 2023.