A Phase I Study of Onyx-015, an E1B Attenuated Adenovirus, Administered Intratumorally to Patients with Recurrent Head and Neck Cancer
2000
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.
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