Outcomes for IR and High Risk (HR) Non-muscle Invasive Bladder Cancer (NMIBC) and ctDNA-based Biomarkers for Response and Recurrence in Muscle Invasive Bladder Cancer (MIBC)

This is a multi-center study whose aim is to understand outcomes based on treatment decisions for patients with intermediate and high risk NMIBC and to understand rationale for treatment decisions for patients and providers. The study will also enroll participants with MIBC who will receive longitudinal plasma ctDNA biomarker profiling in addition to their standard-of-care therapy and disease surveillance. The study will explore the use of non-invasive plasma ctDNA biomarkers to capture disease evolution and response to therapy for the potential development of an assay for early detection of recurrence and/or metastatic relapse in patients with MIBC.

• This is a non-interventional, observational, prospective study. (Other): This is a non-interventional, observational prospective study: Arms I-V reflect patient/provider choices, and patients may receive multiple interventions. This is a non-interventional observational study, exposures are not study-assigned interventions.

Primary outcomes

• Arms I-IV: Overall Mortality at 2 years. [36 months]: Kaplan-Meier analysis for recurrence-free and progression free survival at 3, 6, 12, 18, 24, and 36 months.
• Arm V: MIBC patients (Va adjuvant observation and Vb adjuvant therapy) [36 months]: The primary outcome is to demonstrate the association of ctDNA and disease free state (DFS longitudinally )

Secondary outcomes

• Arms I-IV Secondary Outcomes [36 months]: For patients with NMIBC, secondary outcomes include patient-reported health-related quality of life, decision-making for patients and providers, cancer outcomes and treatment choices for difference disease stages.
• Arm V Secondary Outcomes [3 years]: For MIBC, to demonstrate the association of NAT-driven ctDNA clearance with pathologic response.
• Arm V: MIBC Cohort Va Secondary Measures [3 months]: For MIBC patients in Cohort Va, to demonstrate the association of post-RC ctDNA status (positive vs. negative at 3 months post-CX point) with disease-free survival
• Arm V: MIBC Cohort Vb Secondary Outcomes [3 years]: For MIBC patients in Cohort Vb, to demonstrate the association of baseline ctDNA status (positive vs negative) with disease-free survival (DFS). For Cohort Vb, association of longitudinal ctDNA dynamics post-definitive therapy with DFS.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Arms I-IV

* Meet criteria for intermediate risk or high risk (BCG naïve, BCG exposed or BCG unresponsive disease)
* English speakers
* 18 years of age or older
* Ability to understand and the willingness to provide an informed consent
* Pathology documentation from any hospital/clinic/medical center, and
* Predominant urothelial carcinoma histology in the specimen
* Patients undergoing any treatment including observation are eligible for inclusion
* Patients enrolling on clinical trial are eligible for participation
* Any patient previously meeting criteria for BCG unresponsiveness who has a recurrence will be eligible for trial in category of BCG unresponsiveness even if last BCG was more than 1 year ago

Arm V:

* Diagnosed with stage II-IIIB muscle-invasive bladder cancer without evidence of distant metastases
* 18 years of age or older
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Ability to understand and the willingness to provide an informed consent
* Histologically confirmed urothelial carcinoma of the bladder
* The patient is deemed a candidate for and plans to undergo radical cystectomy

Exclusion Criteria:

Arms I-IV

* Any plasmacytoid or small cell (neuroendocrine) component in the pathology (past or current presentation)
* Previous history of cystectomy or radiation therapy for bladder cancer
* Previous history of muscle-invasive bladder cancer or metastatic bladder cancer
* Untreated upper tract urothelial carcinoma
* Incarcerated in a detention facility or in police custody (patients wearing a monitoring device can be enrolled) at baseline/screening
* Unable to provide written informed consent
* Unable to be contacted for research surveys
* Unable to provide Pathology documentation from any hospital/clinic/medical center
* Unable to answer patient questionnaires

Arm V:

* Evidence of metastatic disease at enrollment
* Any small cell (neuroendocrine) component in the pathology (past or current presentation)
* Prior history of radiation therapy for bladder cancer
* Inability or unwillingness to undergo radical cystectomy (e.g., patient opts for primary trimodality therapy).
* Prior systemic therapy for urothelial carcinoma, unless it is the NAT for the current MIBC diagnosis.
* Untreated upper tract urothelial carcinoma.
* Unable to provide written informed consent.
* Not willing or able to adhere with the study procedures
* Active secondary malignancy
* Diagnosis of a malignancy within 3 years of bladder cancer diagnosis, with the exception of low-risk prostate cancer managed with active surveillance, small renal cell carcinoma managed with active surveillance, and skin cancer managed with active surveillance

• Yair Lotan, MD, Principal investigator, University of Texas Southwestern Medical Center