Evaluation of DDR Gene Alterations in Predicting Response to Platinum-Based Chemotherapy in Metastatic or Locally Advanced Urothelial Cancer

The primary objective of this study is to assess whether patients with **metastatic or locally advanced urothelial cancer** harboring DDR genes alterations exhibit an increased response to platinum-based chemotherapy compared to those without such genetic alterations. This evaluation is clinically relevant as it may inform personalized treatment strategies, potentially improving therapeutic outcomes for patients with these specific genetic profiles.

Secondary objectives include:

• Evaluating the efficacy of first-line therapy in patients with or without DDR genes alterations.
• Assessing survival rates in patients with or without DDR gene alterations.
• Comparing the response in patients with or without DDR genes alterations between those treated with carboplatin or cisplatin.
• Evaluating disease control in patients with or without DDR genes alterations between those treated with carboplatin or cisplatin.
• Assessing the safety profile of chemotherapy in patients with or without DDR genes alterations.
• Describing the incidence of DDR alteration in metastatic urothelial cancer (mUC).
• Describing the expression of Nectin4, PDL1, Trop2, and Her2 proteins in tumor tissue.

The clinical trial involves participants diagnosed with **metastatic or locally advanced urothelial cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate bone marrow, liver, and renal function, and must be eligible for standard chemotherapy with cisplatin or carboplatin combined with gemcitabine. The trial does not include a vulnerable population. Participants must have a life expectancy of at least six months and measurable disease according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The selection process for the trial population is not specified, as the sponsor has not provided information on the total number of participants. Lifestyle considerations such as diet and physical activity are not detailed in the available data. Key inclusion criteria include the ability to provide informed consent, histological or cytological documentation of urothelial cancer, and available tumor tissue for analysis. Participants must also agree to use adequate contraception during the study and for a specified period after the last dose of chemotherapy and avelumab.

The clinical trial is designed to evaluate the predictive role of DDR gene alterations in response to **platinum-based chemotherapy** in patients with metastatic or locally advanced **urothelial cancer**. This is a Phase IV, single-arm, multicenter, low-intervention trial. The trial will involve the administration of standard-of-care chemotherapy, including **cisplatin**, **carboplatin**, and **gemcitabine hydrochloride**, with the addition of **avelumab** in some cases. The trial is expected to commence on December 2, 2024, and conclude by December 2, 2026, with an estimated duration of 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate organ function and measurable disease. Following the screening, eligible participants will receive treatment according to the trial protocol. The treatment period will last up to 18 months for chemotherapy agents and up to 24 months for avelumab. Study visits will include regular follow-up assessments to monitor treatment response and adverse events, with evaluations conducted according to RECIST 1.1 criteria. The primary endpoint is to assess the overall response rate (ORR) to the chemotherapy regimen, while secondary endpoints include progression-free survival (PFS), overall survival (OS), and the incidence of treatment-related adverse events.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or withdraw consent. The expected length of participant involvement is approximately 24 months, including follow-up. The trial aims to provide insights into the efficacy of DDR gene alterations as predictive markers for chemotherapy response in this patient population.

The clinical trial involves the administration of several **antineoplastic agents** in the form of concentrates for solution for infusion. **Carboplatin** is one of the experimental medications used in this study. It is administered via **intravenous infusion** with a maximum daily dose of 750 mg and a total dose of 750 mg over a treatment period of up to 18 weeks. The active substance, carboplatin, is a chemical compound classified under platinum compounds.

**Gemcitabine Hydrochloride** is another experimental medication included in the trial. It is also administered as a concentrate for solution for infusion through intravenous infusion. The dosing regimen allows for a maximum daily dose of 1000 mg/m² and a total dose of 2000 mg over a maximum treatment period of 18 weeks. Gemcitabine hydrochloride is a chemical compound categorized as a pyrimidine analogue.

**Avelumab** is utilized in the trial as a monoclonal antibody, administered via intravenous infusion. The maximum daily and total dose is 800 mg, with a treatment period extending up to 24 weeks. Avelumab is a protein-based therapeutic agent, specifically classified under other antineoplastic agents.

**Cisplatin** is also part of the experimental treatment regimen. It is administered as a concentrate for solution for infusion through intravenous infusion. The dosing schedule permits a maximum daily dose of 70 mg/m² and a total dose of 140 mg over a treatment period of up to 18 weeks. Cisplatin is a chemical compound, classified under platinum compounds.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the Overall Response Rate (ORR), defined as the percentage of patients who achieve a Partial Response (PR) or Complete Response (CR) as measured by RECIST 1.1 criteria. This will be evaluated in patients with metastatic or locally advanced urothelial cancer, with or without DDR gene alterations, undergoing platinum-based chemotherapy. Radiological confirmation of the response is not required.

Secondary endpoints include the evaluation of Progression-Free Survival (PFS), which is the time from the start of investigational treatment to the documentation of disease progression or death from any cause, whichever occurs first. Overall Survival (OS) will also be assessed, defined as the time from the start of treatment to death from any cause. Additionally, the ORR will be evaluated in patients treated with either carboplatin or cisplatin, and the Disease Control Rate (DCR) will be measured, defined as the percentage of patients achieving stable disease, PR, or CR according to RECIST 1.1 criteria.

The incidence of chemotherapy-related adverse events will be monitored and graded according to NCI CTCAE version 5.0. Translational endpoints include the description of DDR gene alterations found in Next-Generation Sequencing (NGS) analysis and the expression of proteins such as Nectin4, PDL1, Trop2, and Her2 in tumor tissue. These assessments will provide comprehensive data on the efficacy of the treatment regimen in the specified patient population.