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Selective Replication and Oncolysis in p53 Mutant Tumors with ONYX-015, an E1B-55kD Gene-deleted Adenovirus, in Patients with Advanced Head and Neck Cancer: A Phase II Trial

US Oncology, Dallas, Texas 75246[J. N., P. M.]; Baylor University Medical Center, Dallas, Texas [J. N., J. K., T. M., S. L.]; Beatson Cancer Institute, Glasgow, Scotland [I. G., S. K.]; M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030 [F. K.]; Albany Regional Cancer Center, Albany, New York [J. A.]; Onyx Pharmaceuticals Incorporated, Richmond, California [L. R., B. R., T. R., D. K.]

ONYX-015 is an E1B-55kDa gene-deleted adenovirus engineered to selectively replicate in and lyse p53-deficient cancer cells. To evaluate the selectivity of ONYX-015 replication and cytopathic effects for the first time in humans, we carried out a Phase II clinical testing of intratumoral and peritumoral ONYX-015 injection in 37 patients with recurrent head and neck carcinoma. Patients received ONYX-015 at a daily dose of 1 x 10¹⁰ plaque-forming units (pfu) via intratumoral injection for 5 days during week 1 of each 3-week cycle (n = 30; cohort A), or 1 x 10¹⁰ pfu twice a day for 10 days during weeks 1 and 2 of each 3-week cycle. Posttreatment biopsies documented selective ONYX-015 presence and/or replication in the tumor tissue of 7 of 11 patients biopsied on days 5–14, but not in immediately adjacent normal tissue (0 of 11 patients; P = 0.01). Tissue destruction was also highly selective; significant tumor regression (>50%) occurred in 21% of evaluable patients, whereas no toxicity to injected normal peritumoral tissues was demonstrated. p53 mutant tumors were significantly more likely to undergo ONYX-015-induced necrosis (7 of 12) than were p53 wild-type tumors (0 of 7; P = 0.017). High neutralizing antibody titers did not prevent infection and/or replication within tumors. ONYX-015 is the first genetically engineered replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. This agent demonstrates the promise of replication-selective viruses as a novel therapeutic platform against cancer.

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