Evaluation of Atezolizumab in Patients with Metastatic Urothelial Cancer Experiencing Biochemical Relapse Post-Radical Cystectomy

The primary objective of this study is to evaluate the **complete response (CR)** in patients with **urothelial cancer** following treatment with the investigational agent **atezolizumab**. This treatment is initiated based on a **circulating tumor DNA (ctDNA)** positive status after radical cystectomy, with or without visible metastases on CT imaging. The CR is defined as a ctDNA negative status in the final plasma samples during immuno-oncology treatment, combined with negative CT imaging at the same time point. This objective is clinically relevant as it aims to assess the efficacy of atezolizumab in achieving complete remission, which is crucial for improving patient outcomes in metastatic bladder cancer.

Secondary objectives include: - Duration of freedom from clinical relapse in subjects with decreased or stabilized ctDNA levels post-treatment. - Overall survival and cancer-specific survival after cystectomy in subjects with biochemical relapse. - Recurrence-free survival and cancer-specific survival stratified by predictive biomarkers. - Response rate to the investigational agent stratified by **PD-L1** expression and other biomarkers. - Response rate to neoadjuvant chemotherapy and its correlation with ctDNA levels. - Time to recurrence as seen on imaging. - Quality of life assessment using EORTC QLQ 30 and QLQ-BLM30. - Cost-effectiveness modeling analysis. - Prolonged CR defined by ctDNA negative status and negative imaging 12 months post-treatment without additional oncologic treatment.

The clinical trial focuses on **urothelial cancer** and includes both male and female participants. The study population comprises individuals aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have no suspicion of organ or lymph node metastases above the aortic bifurcation, as determined by preoperative PET/CT scans. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to comply with the trial protocol and have the ability to understand the Participant Information Sheet both orally and in writing. The trial population was selected based on their planned radical cystectomy due to histopathological or clinically documented muscle-invasive urothelial carcinoma, including subtypes, at stage cT2-4a in the urinary bladder following neoadjuvant chemotherapy in cisplatin-fit individuals. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is designed to evaluate the efficacy of **atezolizumab** in the treatment of **urothelial cancer**. This study is a randomized, double-blind, controlled trial with an estimated duration from April 2020 to April 2027. The trial aims to achieve a complete response (CR) after treatment with the investigational agent, initiated by a ctDNA positive status following radical cystectomy. The primary endpoint is defined as a ctDNA negative status in the last plasma samples taken during immunotherapy treatment, combined with negative imaging results at the same time point.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, ECOG performance status, and preoperative imaging results. Following the screening, participants will receive **atezolizumab** via intravenous infusion, with a maximum daily dose of 1200 mg and a total dose not exceeding 21600 mg over a treatment period of up to three months. Follow-up visits will be scheduled to monitor the participants' response to treatment and to ensure compliance with the trial protocol. The end-of-study visit will evaluate the final treatment outcomes and collect data for analysis.

The expected length of participant involvement is approximately seven years, from recruitment to the end-of-study visit. Conditions that may lead to early termination from the study include non-compliance with the trial protocol, adverse reactions to the investigational agent, or withdrawal of consent by the participant. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **atezolizumab**, an investigational medication, for the treatment of metastatic bladder cancer. Atezolizumab is a monoclonal antibody classified under the ATC code L01FF05. It is administered in the form of an intravenous infusion. The pharmaceutical form is designated as PHF00231MIG. The maximum daily dose of atezolizumab is 1200 mg, with a total maximum dose of 21600 mg over the course of the treatment. The treatment period is limited to a maximum of 3 months. Atezolizumab is not a pediatric formulation and is not classified as an orphan drug. The active substance, atezolizumab, is derived from a protein of other origin, and it is also known by the synonym RO5541267.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The administration of atezolizumab is monitored to ensure participant compliance with the dosing schedule. The trial aims to achieve a complete response, defined as a ctDNA negative status in plasma samples and negative imaging results, in participants with metastatic bladder cancer following radical cystectomy. The response will be compared to historical data on PD-1/PD-L1 targeted agents. The trial is authorized and conducted in Denmark, with recruitment having started in April 2020 and expected to end in April 2024.

Efficacy in the clinical trial titled "Treatment Of Metastatic Bladder Cancer at the time Of biochemical reLApse following radical cystectomy - TOMBOLA" will be assessed using the primary endpoint of **complete response (CR)**. This endpoint is defined as achieving a ctDNA negative status in the last plasma samples taken during immuno-oncology (IO) treatment, combined with negative imaging results from CT scans at the same time point after treatment. The trial aims to evaluate the efficacy of the investigational agent, **atezolizumab**, initiated by a ctDNA positive status after radical cystectomy, with or without visible metastases on CT scans.

The assessment of efficacy will involve comparing the data obtained from this study to historical data on responses to PD-1/PD-L1 targeted agents. The complete response is expected to manifest as the absence of visible metastases on CT scans at the time of treatment initiation, or an unchanged status on CT for study subjects without visible metastases at the start of treatment. The trial will utilize ctDNA analysis and CT imaging as tools for measuring the primary endpoint, ensuring a comprehensive evaluation of the investigational agent's efficacy in achieving a complete response in metastatic bladder cancer patients.