Bladder Cancer Clinical Trials

• Age ≥18 years at the time of consent.

• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Able and willing to provide written informed consent.

• Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.

• Non-muscle-invasive bladder cancer

‣ Cohort A: CIS +/- high grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.

⁃ Cohort B: High grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.

• Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible. NOTE: Pathology report required for documentation purposes.

• Patients can have BCG-unresponsive or BCG-exposed NMIBC11. Adequate BCG therapy is defined as completing at least induction BCG (≥ 5 doses) and the first round of maintenance or second induction course BCG (≥ 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG.

‣ BCG-unresponsive is defined as high grade persistent or recurrent NMIBC that has not achieved a disease-free status after an adequate course of BCG therapy. This includes patients with:

• Persistent or recurrent high-grade tumors (Ta/T1) or carcinoma in situ (CIS) within 6 to 12 months of completing adequate BCG therapy.

∙ Recurrent high-grade papillary disease within 6 months of BCG therapy.

∙ High-grade T1 disease found at the first evaluation after BCG induction therapy alone.

⁃ BCG-exposed is defined as high grade NMIBC that has recurred after an initial response or is still present after initial treatment, but recurrence is never too late to be considered BCG-unresponsive. This includes patients with:

• High-grade recurrence between 12 and 24 months after adequate BCG therapy.

∙ Recurrence within 24 months of inadequate BCG therapy.

∙ High-risk recurrence at the 3-month mark after an initial BCG induction.

∙ High grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible. The recurrence must be within 6 months of the last BCG dose.

• Patients may have received up to 2 lines of prior therapy (including chemotherapy or other approved agents) for NMIBC (NOTE: prior PD-1/PD-L1 blockade is prohibited).

• Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should be documented in the medical record.

• All visible tumor must be completely resected within 60 days prior to registration (residual pure CIS is permitted).

‣ All patients must have had a cystoscopy (or TURBT with complete resection) without papillary tumor and negative urine cytology within 28 days prior to registration (positive cytology is allowed in patients with CIS).

⁃ All patients with T1 tumors must undergo restaging TURBT within 60 days prior to registration.

∙ There must be uninvolved muscularis propria in the restaging TURBT specimen.

‣ The initial TURBT prior to the restaging TURBT may be \> 60 days prior to registration.

⁃ Patients must have baseline tumor tissue from either initial or repeat TURBTs for submission of a minimum of 2 and up to 10 unstained slides for translational study objectives. If archival tissue is not available, the subject is not eligible.

⁃ Adequate organ function as defined by ALL of the following within 28 days prior to registration:

∙ Absolute neutrophil count ≥ 1500/µL

‣ Platelets ≥ 100,000/µL

‣ Hemoglobin ≥ 9 g/dL

‣ Aspartate aminotransferase/alanine aminotransferase ≤ 1.5× upper limit of normal (ULN)

‣ Total serum bilirubin ≤ 1.5×ULN\*; \*Patients with Gilbert's disease: ≤ 3×ULN

‣ International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN unless the patient is on therapeutic anticoagulation.

‣ Creatinine clearance ≥ 40 mL/min by Cockcroft-Gault estimation. The patient's estimated CrCl will be calculated by the local laboratory (for eligibility purposes) using screening/baseline height (m), actual weight (kg), and serum creatinine:

⁃ Males: CrCl = ((140 - age in years) × weight (kg)) / (72× serum creatinine (mg/dL)) Females: CrCl = ((140 - age in years) × weight (kg) ×0.85) / (72× serum creatinine (mg/dL))

⁃ Females of childbearing potential (FOCBP) must have a negative urine or serum pregnancy test within 7 days of registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. FOCBP must agree to use contraception during the study.

⁃ Men capable of fathering a child must agree to use contraception during the study.

⁃ Must have a life expectancy of at least 12 weeks.