An E1B 55 kDa gene-deleted adenovirus,
Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent
head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this
therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria.
Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus
DNA and
neutralizing antibody to adenovirus.
Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in
neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53
tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of
tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53
tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected
tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of
Onyx-015 is feasible, well tolerated, and associated with
biological activity. Further investigation of
Onyx-015, particularly with a more frequent injection protocol and in combination with systemic
chemotherapy, is warranted.