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

In Cohort A, up to 125 participants will be enrolled with pathologically confirmed,

high-risk high-grade non-muscle invasive bladder cancer (NMIBC) NMIBC (i.e., CIS with or

without concomitant Ta or T1 disease OR HG Ta/T1 disease without CIS) which is naïve to

Bacillus Calmette-Guerin (BCG) treatment. Participants with CIS with or without

concomitant Ta/T1 NMIBC at baseline will be randomized 1:1 to receive cretostimogene via

the current (Arm 1) or an alternative instillation procedure (Arm 2). Participants with

papillary-only high-risk NMIBC (i.e., HG Ta/T1 without CIS) at baseline (Arm 3) will

receive cretostimogene via the alternative instillation procedure.

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 Ta or T1 disease OR HG

Ta/T1 disease without CIS) which has 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 Cohort CX, up to 50 participants will be enrolled with pathologically confirmed,

high-risk high-grade NMIBC (i.e., CIS with or without concomitant Ta or T1 disease OR HG

Ta/T1 disease without CIS) which has previously been exposed to or is unresponsive to BCG

treatment. Participants will be randomized 1:1 to receive cretostimogene and gemcitabine

either concurrently or sequentially.

In all cohorts, study treatment 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.