114 - Phase 3, Randomized, Placebo Controlled Clinical Trial of CAN-2409+Prodrug in Combination with Standard of Care External Beam Radiation (EBRT) for Newly Diagnosed Localized Prostate Cancer
Presenter(s)
G. Gejerman1, A. Manzanera2, T. Wheeler3, J. E. Sylvester4, T. M. Schroeder5, G. Chesnut6, D. Song7, M. Chang8, S. Liauw9, T. Facelle10, C. Pieczonka11, M. Goody2, J. Vogt2, S. Rao2, M. L. Silva Polanco2, F. Barone2, W. Nichols2, P. P. Tak2, and T. L. DeWeese7; 1New Jersey Urology - Saddle Brook, Saddle Brook, NJ, United States, 2Candel Therapeutics, Inc., Needham, MA, United States, 3Baylor College of Medicine, Houston, TX, United States, 4Independent Researcher, Nokomis, FL, 5University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, 6Walter Reed National Military Medical Center, Bethesda, MD, 7Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 8Hunter Holmes McGuire VA Medical Center, Richmond, VA, 9Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, 10United Urology, Owings Mills, MD, United States, 11Associated Medical Professionals, Syracuse, NY
Purpose/Objective(s):
Previous preclinical and clinical studies showed that CAN-2409, a replication-defective adenovirus encoding the HSV-tk gene, induces immunogenic cell death after intraprostatic injection and prodrug (valacyclovir) administration in men with prostate cancer (PrCa). We conducted a randomized ph 3, double blind, placebo (PBO)-controlled clinical trial (NCT01436968) aiming to improve disease-free survival (DFS) in localized PrCa patients (pts) treated with standard of care, leveraging the synergy between CAN-2409+prodrug and EBRT.Materials/Methods:
745 pts with intermediate or select high risk (single NCCN risk factor only, no T3b) localized PrCa were randomized 2:1 (496 to CAN-2409; 249 to PBO); randomization was stratified by NCCN risk group and short term ADT (<6 mos vs no ADT). Approximately 26% received hypofractionated EBRT and 74% standard EBRT. Three intraprostatic injections of CAN-2409 (5x1011v/2mL) or PBO, each followed by 14 days of prodrug were administered before and during EBRT. Primary endpoint was DFS, defined as time from randomization to PrCa recurrence (local/regional failure or distant metastasis) or death in the intent-to-treat population (ITT). Blinded independent central pathologists assessed baseline and post-treatment prostate biopsies to evaluate biological response to treatment and determine proportion with pathologic complete response (pCR).Results:
Treatment with CAN-2409 reduced the risk of PrCa recurrence or death by 30% (HR 0.7, 95% CI 0.52 to 0.94, p=0.0155) after median 50.3 mos of follow up. PrCa-specific DFS (excluding non PrCa deaths) demonstrated even greater effect with a 38% decreased risk in the CAN-2409 arm vs. PBO (HR 0.62, 95% CI 0.44 to 0.87, p=0.0046). CAN-2409 improved DFS in important subgroups, including hypo- or standard fractionated EBRT, with or without ADT. Post treatment biopsies (451) were collected 16-73 mos after treatment; pCR was observed in 77.7% (233/300) of all available samples in the CAN-2409 arm vs 66.2% in PBO (100/151), p=0.0091. In the 2-year biopsies (22-26 months), pCR in the CAN-2409 and PBO arms were 80.4% and 63.6%, respectively (p=0.0015). Dense aggregates of lymphocytes were observed in prostate biopsies after treatment with CAN-2409. CAN-2409+prodrug was generally well-tolerated; transient, mild flu-like symptoms were common. Treatment-related SAEs occurred in 1.7% of CAN-2409 and 2.3% of PBO-treated pts.Conclusion:
CAN-2409+prodrug significantly improved DFS by 30% compared to placebo when added to hypofractionated or conventional EBRT +/- ADT, with a good tolerability profile. We observed a significant decrease in tumor presence in post treatment biopsies. This therapeutic regimen may represent the first significant advance for localized PrCa in over 20 years.