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[Cancer Research 61, 7464-7472, October 15, 2001]
© 2001 American Association for Cancer Research

Clinical Investigations

A Phase I Trial of CV706, a Replication-competent, PSA Selective Oncolytic Adenovirus, for the Treatment of Locally Recurrent Prostate Cancer following Radiation Therapy1

Theodore L. DeWeese2, Henk van der Poel, Shidong Li, Bahar Mikhak, Renee Drew, Marti Goemann, Ulrike Hamper, Robert DeJong, Nicholas Detorie, Ronald Rodriguez, Thomas Haulk, Angelo M. DeMarzo, Steven Piantadosi, D. C. Yu, Yu Chen, Daniel R. Henderson, Michael A. Carducci, William G. Nelson and Jonathan W. Simons

Divisions of Radiation Oncology [T. L. D., S. L., R. D., N. D., T. H.], Medical Oncology [H. v. d. P., B. M., M. G., M. A. C., W. G. N., J. W. S.], and Biostatistics [S. P.], The Johns Hopkins Oncology Center, Baltimore, Maryland 21231-1000; Departments of Urology [T. L. D., R. R., M. A. C., W. G. N., J. W. S.], Radiology [U. H., R. D.], and Pathology [A. M. D.], The Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, and Calydon, Inc., Sunnyvale, California [D. C. Y., Y. C., D. R. H.]

CV706 is a prostate-specific antigen (PSA)-selective, replication-competent adenovirus that has been shown to selectively kill human prostate cancer xenografts in preclinical models. To study the safety and activity of intraprostatic delivery of CV706, a Phase I dose-ranging study for the treatment of patients with locally recurrent prostate cancer after radiation therapy was conducted. Twenty patients in five groups were treated with between 1 x 1011 and 1 x 1013 viral particles delivered by a real-time, transrectal ultrasound-guided transperineal technique using a three-dimensional plan. The primary end point was the determination of treatment-related toxicity. Secondary objectives included evaluation of the antitumor activity of CV706 and monitoring for other correlates of antineoplastic action. In this study, CV706 was found to be safe and was not associated with irreversible grade 3 or any grade 4 toxicity. No grade >1 alterations in liver function tests associated with CV706 administration were observed. Posttreatment prostatic biopsies and detection of a delayed "peak" of circulating copies of virus provided evidence of intraprostatic replication of CV706. The study defined the timing of CV706 shedding into blood and urine as well as the appearance of circulating Ad5 neutralizing antibodies. Finally, this study documents the serum PSA response of treated patients and reveals a dose response showing that all five patients who achieved a >=50% reduction in PSA were treated with the highest two doses of CV706. This study represents the first clinical translation of a prostate-specific, replication-restricted adenovirus for the treatment of prostate cancer. Taken together, this study documents that intraprostatic delivery of CV706 can be safely administered to patients, even at high doses, and the data also suggest that CV706 possesses enough clinical activity, as reflected by changes in serum PSA, to warrant additional clinical and laboratory investigation.




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