Assessement of the Concordance of Genomic Alterations Between Urine and Tissue in High-Risk NMIBC Patients

A Pilot Study to Assess the Concordance of Genomic Alterations Between Urine and Tissue to Develop Precision Medicine-Based Immunotherapy Approaches in High-Risk NMIBC Patients

The analysis of cell-free tumor DNA (cfDNA) in plasma has emerged as a clinically relevant predictive and prognostic biomarker in several metastatic solid malignancies, and even now represents standard-of-care for prescription of some targeted therapies in non-small cell lung cancer (blood-based T790M companion diagnostic test). cfDNA can be detected not only in plasma but also in urine, even in patients with non-invasive disease. Recent studies found that the detection of genomic alterations in plasma of urothelial bladder carcinoma patients was relatively uninformative in the localized setting. However, urine cfDNA has been shown to provide a promising resource for robust whole-genome tumor profiling in clinically localized Muscle invasive Bladder cancer (MIBC) and Non-Muscle Invasive Bladder Cancer (NMIBC). Genomic alterations using a targeted next-generation sequencing (NGS) panel have been recently documented in a series of treatment-naïve high-risk NMIBC.

The investigator's aim is to determine whether liquid biopsies can be used as a new diagnostic assay to guide immunotherapeutic approaches in patients with high-risk NMIBC. The ultimate goal is to develop a "testing decision tree" to segment patients for informing on therapeutic decision and customizing treatment.

Inclusion Criteria:

Common Inclusion Criteria

• Age ≥18 years at the time of screening.
• Capable of giving signed informed consent
• BCG-naïve (patients who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry are eligible).
• No prior radiotherapy to the bladder.
• ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.
• At screening, tumor tissue provision from the initial surgery, formalin-fixed and paraffin-embedded (FFPE) is mandatory for DNA extraction and next-generation sequencing.
• Absence of metastasis, as confirmed by a negative CT or MRI scan of the pelvis, abdomen and chest, no more than 4 weeks prior to the enrolment.
• Life expectancy of at least 12 weeks.
• Must be a candidate for BCG treatment.
• Adequate organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL Absolute neutrophil count ≥1.0 × 109/L Platelet count ≥75 × 109/L Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN Measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight) Males Creatinine CL = (Weight (kg) × (140 - Age))/(72 × serum creatinine (mg/dL)) (mL/min)

Females Creatinine CL = (Weight (kg) × (140 - Age) )/(72 × serum creatinine (mg/dL)) × 0.85 (mL/min) - Being covered by a national health insurance

Specific Inclusion Criteria for Non-Muscle Invasive Bladder Cancer (NMIBC) group

• Local histological confirmation (based on pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa (predominantly urothelial even though mixed histology are allowed). A high-risk tumor is defined as one of the following:
• T1 tumor
• High grade/G3 tumor
• CIS
• Multiple and recurrent and large (with diameter of largest evaluable node ≥3 cm) tumors (all conditions must be met in this point)
• Complete resection of all Ta/T1 papillary disease prior to enrolment, with the most recent TURBT (Trans Urethral Resection of Bladder Tumor) occurring 2 months or less prior to signing informed consent for this study. Patients with residual CIS after TURBT are eligible.
• At least one additional resection of the primary tumor has been performed in case of T1 tumors, or incomplete initial TURB, or in case of doubt about the completeness of a TURB, or if there is no muscle in the specimen (can be omitted if primary CIS (In situ cancer) only was found.)

Specific Inclusion Criteria for Muscle Invasive Bladder Cancer (MIBC) group Patients with histologically proven muscle-invasive bladder cancer (MIBC) scheduled before radical cystectomy.

Non-Inclusion Criteria:

Common Non-inclusion Criteria

• Evidence of lymphovascular invasion of bladder tumor, except if treatment with BCG is deemed to be the only clinically viable treatment (ie, clinical candidates of cystectomy and/or chemotherapy, etc are excluded).
• Known or documented absolute and/or relative contraindication of adjuvant intravesical BCG treatment.
• Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium.
• Any concurrent chemotherapy, Intra Peritoneal, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• Concurrent treatment with systemic immunostimulatory agents prior to the first dose of study treatment.
• History of allogenic organ transplantation. Patients with any history of allogenic stem cell transplantation are also excluded
• History of active primary immunodeficiency
• Pregnant or breastfeeding women
• Being deprived of liberty or under guardianship

Specific Non-inclusion Criteria for NMIBC group

- Evidence of muscle-invasive, locally advanced, metastatic, and/or extra-vesical bladder cancer (ie, T2, T3, T4, and / or stage IV)