Introduction:

The current American Urological Association (AUA) guideline recommendation for patients diagnosed with BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer (BCG-UR HR NMIBC) is radical cystectomy. However, many patients are unwilling or unable to undergo such a morbid operative intervention due to patient preference or competing medical risks. While the United States Food and Drug Administration (US FDA) has recently approved therapies in this disease state, a considerable unmet medical need still exists for additional clinically effective, well-tolerated, and readily available bladder-sparing options. This is particularly relevant in the BCG-UR Ta/T1 without CIS population, which may comprise a majority of BCG-UR HR NMIBC patients. 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 received both US FDA Fast Track and Breakthrough Therapy Designations in the BCG-UR HR NMIBC CIS with or without Ta/T1 tumor indication and has demonstrated a consistently favorable safety profile. Based on the strength of these data, the BOND-003 Cohort P study was designed as a multi-national, single-arm, clinical trial to assess the efficacy and safety of intravesical cretostimogene in BCG-UR HR NMIBC patients with Ta/T1 tumors without CIS.

Methods:

Eligibility criteria: age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, histologically confirmed BCG-Unresponsive HG Ta/T1 papillary disease without CIS within 90 days of study enrollment. Patients are required to have previously received adequate BCG by the US FDA definition. Patients who recur with a HG Ta/T1 tumor within six months of the last dose of adequate BCG or who recur with HG T1 after a single induction course of BCG may be eligible. Patients must have no evidence of residual bladder cancer before treatment. Patients will receive intravesical cretostimogene 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, urine cytology, axial imaging, mandatory biopsy at month 12, and centralized review of pathologic samples. The primary outcome measure is all-cause Event Free Survival. Secondary outcome measures include high- and low-grade Recurrence Free Survival, Progression Free Survival, Radical Cystectomy-Free Survival, Bladder Cancer Specific Survival, safety, tolerability, and time to next intervention. Exploratory outcome measures include Health-Related Quality of Life, and biomarker analyses. Descriptive statistics will summarize patient characteristics, treatment administration/compliance, efficacy, safety, and laboratory or exploratory parameters.  Data will also be displayed graphically, where appropriate. It is expected that enrolled patients will result in adequate confidence interval precision for comparisons to historical and published data in the BCG-Unresponsive HG Ta/T1 without CIS disease state, a patient population with considerable unmet medical need.  35+ clinical sites have been selected in the United States and Japan. Screening and patient selection have been initiated. NCT044552591

Results:

Conclusion:

Funding: CG Oncology