Introduction:

Patients with High-Risk NMIBC whose disease trajectory falls outside the strict FDA guidance of BCG-Unresponsive represent a significant unmet need, often lacking access to clinical trials or evidence-based treatment options. Cretostimogene grenadenorepvec is a tumor-selective oncolytic immunotherapy with a dual mechanism of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, releasing virus- and tumor-specific antigens that initiate anti-tumor immune response, further enhanced by the GM-CSF transgene. Cretostimogene received Fast Track and Breakthrough Therapy Designations by the US FDA for HR BCG-Unresponsive NMIBC with CIS. The CORE-008 clinical trial (NCT06567743) was developed as a Phase 2, multi-arm, multi-cohort trial to evaluate the efficacy and safety of cretostimogene in patients with HR NMIBC, across BCG-naïve, BCG-exposed, and BCG-unresponsive disease states. Here, we describe Cohort B of CORE-008, which examines the efficacy and safety of cretostimogene in BCG-exposed NMIBC.

Methods:

Cohort B eligibility criteria include pathologic confirmation of HR NMIBC, CIS containing and papillary only, as defined by the AUA/SUO guidelines, and recurrence after prior BCG (BCG-exposure). BCG-exposed NMIBC is defined as high-grade recurrence in patients who are BCG-resistant (recurrence after at least 5 of 6 induction doses), or who experience delayed relapse within 24 months following either adequate BCG (≥5 induction doses plus ≥2 reinduction or maintenance doses) but outside the defined BCG-Unresponsive window or following inadequate BCG (3–6 doses). Intravesical cretostimogene will be instilled in combination with DDM, an excipient that enhances adenoviral delivery, 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 at Month 3, if persistent HG Ta or CIS is noted at biopsy. Response assessment include serial cystoscopy with directed biopsy (as indicated), urine cytology, and CT/MR urogram. The primary endpoint for the CIS population is Complete Response (CR) at any time and HG-EFS for patients with papillary-only disease. Secondary endpoints include Duration of Response, all-cause Event-Free Survival, Bladder Cancer Specific Survival, Progression-Free Survival, Cystectomy-Free Survival, safety, and tolerability. Exploratory outcome measures consist of Health-Related Quality of Life, Overall Survival, and biomarker assessments. Cohort B is now open for enrollment in collaboration with the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC).

Results:

Conclusion:

Funding: CG Oncology, Inc