Study of Cretostimogene Given in Patients With Non-Muscle Invasive Bladder Cancer ,Unresponsive to Bacillus-Calmette-Guerin

Cohort C Inclusion Criteria

In order to be eligible for participation in this trial, the patient must:

• Be ≥18 years of age (or legal age of majority in the jurisdiction) on day of signinginformed consent.

• Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Have pathologically confirmed (WHO grading system employed for tumor grading) (Compérat 2019) BCG unresponsive CIS. Patients with BCG unresponsive CIS are thoseunlikely to benefit from, and who will not be receiving, further intravesical BCG.There is no maximum limit to the amount of prior BCG treatment, but maintenance BCGshould be administered on a schedule consistent with standard induction-maintenanceprotocols (e.g., BCG weekly × 6 then weekly × 3 weeks administered at Months 3, 6, 12, 18, 24, and 36). Specifically, the definition of BCG unresponsive CIS will alsorequire the following:

• Pathologically confirmed relapsed or persistent CIS (with or without HG Ta orHG T1 disease) within 12 months of completion (last dose) of adequate BCGtreatment for HGUC (e.g., CIS, HG Ta, HG T1, or a combination of these HGUCpathologies).

• Completion of qualifying BCG treatment (e.g., "5+2" minimum exposure) within 12months of the initial qualifying dose of BCG (e.g., induction and initialmaintenance or re-induction cycle must be completed over no more than a 12-month period of time).

• Pathological confirmation of BCG unresponsive CIS within 8 weeks of studyenrollment.

• CIS specimen must be predominantly urothelial (transitional cell) and have lessthan 50% variant (e.g., sarcomatoid, squamous etc. component) histology.

• No maximum limit to the amount of BCG administered but maintenance BCG shouldbe administered on a schedule consistent with the SWOG 8507 regimen (Lamm 2000).

• Have all Ta and/or T1 disease resected and all CIS resected or fulgurated, asfeasible, prior to study treatment (e.g., prior to Day 1 treatment).

• Ineligible to receive radical cystectomy (medically unfit) or refusal of radicalcystectomy according to Investigator assessment.

• Demonstrate adequate organ function

• Patients must be willing to comply with study mandated cystoscopies, urine cytology,urograms, biopsies, and other procedures (including TURBT or other resection for allTa/T1 disease) for the duration of the study. Patients who withdraw consent forthese procedures will be withdrawn from the trial

Cohort P Inclusion Criteria

• Be ≥18 years of age (or legal age of majority in the jurisdiction) on day of signinginformed consent

• Have ECOG performance status of 0 to 2.

• Have pathologically confirmed (WHO grading system employed for tumor grading) (Compérat 2019) BCG-unresponsive HG Ta/T1 papillary disease without CIS. Patientswith BCG-unresponsive HG Ta/T1 papillary disease are those unlikely to benefit fromand who will not be receiving further IVE BCG. There is no maximum limit to theamount of prior BCG treatment, but maintenance BCG should be administered on aschedule consistent with standard induction-maintenance protocols. Specifically, thedefinition of BCG unresponsive HG Ta/T1 papillary disease without CIS will alsorequire the following:

• Pathologically confirmed recurrent HG Ta/T1 papillary disease without CISwithin 6 months of completion (last dose) of adequate BCG treatment for HGUC (e.g., CIS, HG Ta, HG T1, or a combination of these HGUC pathologies).

• Patients with HG Ta: Completion of qualifying BCG treatment (e.g., "5+2"minimum exposure) within 12 months of the initial qualifying dose of BCG (e.g.,induction and initial maintenance or re-induction cycle must be completed overno more than a 12-month period of time).

• Patients with HG T1: Patients may be eligible after the initial induction alone (5 of 6 doses of an induction course) as the qualifying BCG treatment.

• Completion (last dose) of qualifying BCG treatment within 12 months of studyenrollment.

• Pathological confirmation of BCG-unresponsive HG Ta/T1 papillary diseasewithout CIS within 14 days of study enrollment.

• All pathology specimens must be predominantly urothelial (transitional cell)and have less than 50% variant (e.g., sarcomatoid, squamous etc. component)histology.

• No maximum limit to the amount of BCG administered; however, there should be nomore than 12 months between cycles of BCG

• Have all Ta and/or T1 disease resected, prior to study treatment (e.g., prior to Day 1 treatment).

• Ineligible to receive radical cystectomy (medically unfit) or refusal of radicalcystectomy based on Investigator assessment.

• Demonstrate adequate organ function,

• Patients must be willing to comply with study-mandated cystoscopies, urine cytology,imaging, biopsies, and other procedures for the duration of the trial

Cohort C and Cohort P Key Exclusion Criteria:

• Has current or past history of muscle invasive (T2 or higher stage) or locallyadvanced (T3/T4, any N) or metastatic bladder cancer.

• Any HGUC as T1, HG Ta, or CIS in the upper genitourinary tract or prostatic urethra (including CIS of the urethra) within 24 months prior to enrollment OR any historyof T2 or higher stage urothelial carcinoma in the upper genitourinary tract (kidneys, renal collecting systems, ureters).

• Has received systemic anti-cancer therapy, including investigational agents, within 4 weeks of Day 1.

• Has had prior systemic treatment (with the exception of checkpoint inhibitortherapy), radiation therapy, or surgery for bladder cancer other than TURBT orbladder biopsies.

• Has any of the following within the 6 months prior to starting study treatment:myocardial infarction, severe/unstable angina, coronary/peripheral artery bypassgraft, cerebrovascular accident, pulmonary embolus, uncontrolled hypertension, oruncontrolled congestive heart failure.

• Cannot tolerate study-related biopsies, IVE administration, or 1-hour bladder holdof cretostimogene.

• IVE therapy within 8 weeks prior to beginning study treatment with the exception ofcytotoxic agents (e.g., Mitomycin C, gemcitabine, doxorubicin and epirubicin) whenadministered as a single instillation immediately following a TURBT procedure whichis permitted 14 or more days prior to beginning study treatment