CORE-008: A phase 2, multi-arm, multi-cohort, open-label study to evaluate intravesical cretostimogene grenadenorepvec in participants with high-risk non-muscle invasive bladder cancer.

Abstract

TPS901 Background: 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, 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 with a dual mechanism of action. It selectively replicates and lyses bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations. The subsequent release of virus- and tumor- specific antigens initiate antitumor immune activation amplified by the GM-CSF transgene, a potent cytokine. Cretostimogene received both Fast Track and Breakthrough Therapy Designations by the US FDA for the BCG-Unresponsive HR NMIBC with CIS indication. Given the strength of these data, the CORE-008 clinical trial ( NCT06567743 ) was developed as a Phase 2, multi-arm, multi-cohort trial to further evaluate the safety and efficacy of cretostimogene in patients with HR NMIBC. Methods: Eligibility criteria include pathologic confirmation of HR NMIBC as defined by the American Urologic Association (AUA) Guidelines. Cohort A (BCG-naive) is comprised of 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 n-dodecyl-β-D-maltoside (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. 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. Clinical trial information: NCT06567743 .