A Phase II, 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 (NMIBC)
Study Description
In Cohort A, up to 50 participants will be enrolled with pathologically confirmed, CIS-containing, high-risk NMIBC (i.e., CIS with or without concomitant Ta/T1) who are naïve to BCG treatment. Participants will be randomized 1:1 to receive DDM and cretostimogene via the current (Arm 1) or an alternative instillation procedure (Arm 2).
Cretostimogene and DDM 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 and directed TURBT/biopsy (if indicated) every 3 months for the first 2 years after randomization and then every 6 months for a further 2 years or until disease recurrence.
Eligibility
To be eligible for participation in this trial, participants must meet all the following entry criteria. The participant must:
- Be ≥18 years of age (or legal age of majority in the jurisdiction) on day of
signing informed consent.
- Have ECOG performance status of 0 to 2.
- Have pathologically confirmed (WHO grading system employed for tumor grading) (Compérat 2019) BCG-exposed high-risk NMIBC (i.e., HG Ta/T1 disease with or without CIS) within 90 days of treatment allocation.
- Have all Ta and/or T1 disease resected, and all CIS resected or fulgurated, as feasible, within 90 days prior to treatment allocation.
- Refuse radical cystectomy.
- Demonstrate adequate organ function
- Be willing to use barrier contraception during sexual activity, starting at least 14 days prior to Day 1 for women and starting at Day 1 for men through 6 weeks after the last dose of cretostimogene.
- Be willing to comply with all study-mandated cystoscopies, urine cytologies, biopsies, imaging and other procedures (including TURBT or other resection for all Ta/T1 disease) for the duration of the study. Participants who withdraw
consent for these procedures will be withdrawn from the trial.
NOTE: There are no differences in the Exclusion Criteria between Cohort A and Cohort B.
The participant must be excluded from participating in the trial if the participant:
- Has a current or past history of muscle invasive (T2 or higher stage), locally advanced (T3/T4, any N) or metastatic bladder cancer.
- Any HG, non-muscle-invasive urothelial carcinoma (T1, HG Ta, or CIS) in the upper genitourinary tract or prostatic urethra (including CIS of the urethra) within 24 months prior to randomization or treatment allocation OR any history of T2 or higher stage urothelial carcinoma in the upper genitourinary tract (kidneys, renal collecting systems, ureters).
- Has had any prior systemic treatment (except for checkpoint inhibitor therapy), radiation therapy, or surgery (except for TURBT/biopsy/fulguration) for bladder cancer. Previous intravesical therapies are allowed if they do not contravene any other exclusion criteria.
- Has received intravesical therapy within 90 days prior to randomization or treatment allocation except for cytotoxic agents (e.g., mitomycin C, gemcitabine, doxorubicin, and epirubicin) when administered as a single instillation immediately following a TURBT.
- Has had any of the following within the 6 months prior to randomization or treatment allocation: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft
