Phase 2 Study to Evaluate Safety and Efficacy of Cretostimogene Grenadenorepvec in High-Risk NMIBC

This is a Phase 2, Multi-Arm, Multi-Cohort, Open-Label Study to Evaluate the Safety and Efficacy of Cretostimogene Grenadenorepvec in Participants with High-Risk Non-Muscle-Invasive Bladder Cancer.

In Cohort A, up to 50 participants will be enrolled with pathologically confirmed, carcinoma in situ (CIS)-containing, high-risk non-muscle invasive bladder cancer (NMIBC) (i.e., CIS with or without concomitant Ta/T1) who are naïve to Bacillus Calmette-Guerin (BCG) treatment. Participants will be randomized 1:1 to receive cretostimogene via the current (Arm 1) or an alternative instillation procedure (Arm 2).

In Cohort B, up to 150 participants will be enrolled with pathologically confirmed, high-risk high-grade NMIBC (i.e., CIS with or without concomitant HG Ta or T1 disease OR HG Ta/T1 disease without CIS) who have previously been exposed to BCG treatment. Participants with CIS-containing pathology at baseline will be recruited into Arm 1 and participants with papillary-only pathology at baseline will be recruited into Arm 2. Both Cohort B Arms 1 and 2 will receive cretostimogene via the alternative instillation procedure.

In both cohorts, cretostimogene will be administered as a weekly induction course for the first 6 weeks with a reinduction course administered to patients who have CIS and/or high-grade Ta disease at the 3-month evaluation. Following induction, if no high-grade disease is detected, maintenance treatment will begin. This consists of a cycle of three weekly treatments every three months during the first year, and every six months during the second year, with an optional extension to the third year following the same six-month schedule.

Disease status will be assessed using urine cytology, complete bladder visualization (e.g., cystoscopy), upper tract assessment and directed resection/biopsy (if indicated) every 3 months for the first 2 years and then every 6 months for a further 2 years or until disease recurrence.

Eligibility Criteria:
Cohort A Key Inclusion Criteria:

• Pathologically confirmed BCG-naïve, CIS-containing (i.e., CIS with or without concomitant HG Ta/T1) high-risk NMIBC within 90 days of randomization.

Participants with BCG-naïve NMIBC should have either:

* No prior treatment with BCG OR
* No treatment with BCG within the past 24 months prior to current pathological diagnosis OR
* A maximum of 1 or 2 doses of BCG within the past 24 months prior to current pathological diagnosis.
* All visible disease must be resected, and all CIS resected or fulgurated, as feasible within 90 days prior to randomization.
* Acceptable baseline organ function.

Cohort B Key Inclusion Criteria:

* Pathologically confirmed BCG-exposed high-risk high-grade NMIBC (i.e., CIS with or without Ta/T1 disease or high-grade Ta/T1 papillary-only disease without CIS) within 90 days of treatment allocation.
* All visible disease must be resected, and all CIS resected or fulgurated, as feasible within 90 days prior to randomization.
* Acceptable baseline organ function.

Key Exclusion Criteria (Both Cohorts):

* Current or past history of muscle-invasive, locally advanced or metastatic bladder cancer.
* High-grade disease in the upper urinary tract or prostatic urethra within 24 months of randomization or any history of muscle-invasive, locally advanced or metastatic disease in the upper urinary tract.
* Significant immunodeficiency.
* Pregnant or breastfeeding.