Introduction:

Treatment for patients with High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) consists of Transurethral Resection of Bladder Tumor (TURBT) followed by intravesical Bacillus Calmette–Guérin (BCG). Despite high initial response rates, over 50% of patients will recur and 20-40% are at risk for progression. Treatment of HR NMIBC is challenged by the BCG shortage and limited bladder-sparing options for patients who do not meet the strict definition of BCG-unresponsive disease by the US FDA. Thus, there exists a need for clinically effective, well-tolerated, and readily available treatment options for patients with HR NMIBC. Cretostimogene grenadenorepvec is an oncolytic immunotherapy designed to selectively replicate in bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, commonly found in BCG-UR HR NMIBC. In addition, cretostimogene also expresses GM-CSF adding to local and systemic cancer control. Cretostimogene has received Fast Track and Breakthrough Therapy Designations by the US FDA for the BCG-Unresponsive HR NMIBC with CIS indication. Given the strength of recently presented data, the CORE-008 clinical trial was developed as a Phase 2, multi-arm, multi-cohort trial to further evaluate the safety and efficacy of cretostimogene in both BCG-naive and BCG-exposed patients with HR NMIBC.

Methods:

Eligibility criteria require pathologic confirmation of HR NMIBC as defined by the American Urologic Association (AUA) Guidelines, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Cohort A (BCG-naive) will comprise CIS +/- HG Ta/T1 participants who have not received prior BCG. Cohort B (BCG-exposed) will consist of CIS +/- HG Ta/T1 or papillary-only patients who have received prior BCG and recurred either immediately after induction therapy (BCG-resistant) or recurred at a delayed timepoint, after adequate or inadequate BCG. Intravesical cretostimogene will be instilled in combination with DDM, a transduction agent, adjuvant to TURBT for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through month 12, then every six months through month 36. Re-induction is permitted. Primary disease assessments include serial cystoscopy with directed TURBT/biopsy (if indicated), urine cytology, axial imaging, and retrospective central review of pathologic samples. The primary endpoint for the CIS population is Complete Response (CR) at any time. High-Grade Event Free Survival is the primary endpoint for papillary-only participants. Secondary endpoints will include Duration of Response, all-cause Event-Free Survival, Bladder Cancer Specific Survival, Radical Cystectomy Free Survival, and safety. Exploratory outcome measures include Health-Related Quality of Life, Overall survival, and biomarker assessments. Additional HR NMIBC cohorts are under development. Multiple clinical sites have been identified and Cohort B has received collaborative support from the Society of Urologic Oncology-Clinical Trials Consortium (SUO-CTC). The study has been submitted to Clinicaltrials.gov.

Results:

Conclusion:

Funding: CG Oncology