PIVOT-006: A phase 3, randomized study of cretostimogene grenadenorepvec versus observation for the treatment of intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) following transurethral resection of bladder tumor (TURBT).

Abstract

TPS715 Background: Guidelines for Intermediate Risk Non-Muscle Invasive Bladder Cancer (IR-NMIBC) recommend adjuvant intravesical (IVE) therapy or surveillance. Despite this, 30–60% of patients still recur, and these Guideline recommendations are lacking level-1 evidence. Thus, there is a considerable gap in knowledge and an unmet medical need for improved therapies in the adjuvant setting. Cretostimogene Grenadenorepvec is an oncolytic adenovirus designed to preferentially replicate in and kill cancer cells. The vector is transcriptionally regulated by the E2F promoter that is up-regulated in retinoblastoma (Rb) pathway-defective tumor cells, common in most IR-NMIBC bladder tumors. Additionally, the virus is engineered to selectively express GM-CSF, in order to induce a robust systemic anti-tumor immune response. PIVOT-006 is an open-label, multi-center, randomized Phase 3 study designed to assess the efficacy and safety of intravesical Cretostimogene after TURBT versus TURBT alone. Methods: Eligibility criteria: age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, histologically confirmed IR-NMIBC with absence of nodal or metastatic disease at screening. IR-NMIBC, as defined by American Urologic Association-Society of Urologic Oncology Guidelines on NMIBC, is either a Low Grade (LG) stage Ta tumor that recurs within 12 months of prior LG or High Grade (HG) bladder cancer, a solitary LGTa tumor >3cm in size, multifocal LGTa tumors, primary HGTa lesion < 3cm in size, or a LGT1 tumor. Participants will be stratified by receipt of perioperative chemotherapy and tumor grade. Pts (N~450) will be randomized 1:1 to receive intravesical Cretostimogene (Cohort 1) adjuvant to TURBT or TURBT alone (Cohort 2). Single dose perioperative intravesical chemotherapy at the time of TURBT is permitted. If intravesical NMIBC recurrence is noted in Cohort 2, participants will be eligible to receive intravesical Cretostimogene. In Cohort 1, intravesical Cretostimogene will be instilled in combination with n-dodecyl-B-D-maltoside (DDM, an inactive detergent) for 6 weekly doses during the induction phase, followed by 3 weekly maintenance cycles at months 3 and 6, and culminating in single intravesical doses at months 9 and 12. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and centralized review of pathologic samples. The primary outcome measure is recurrence free survival. Secondary outcome measures include safety, tolerability, progression free survival, and time to next intervention. Exploratory outcome measures include patient-reported quality of life, biomarker analyses, coxsackie adenovirus receptor and E2F promoter expression, neutralizing antibodies, and markers of immunogenicity. Clinical trial information: Pending.