NEW YORKResearchers have seen encouraging early results in head
and neck and other cancers with use of the attenuated adenovirus,
ONYX-015, David H. Kirn, MD, vice president of clinical research,
Onyx Pharmaceuticals, (Richmond, Calif), said at Current Concepts in
Cancer Therapy II, a symposium sponsored by Long Ridge Associates.
Initial trials of the agent were in refractory head and neck cancers,
and pivotal studies for this indication are expected to begin by the
end of the year, Dr. Kirn said. Investigations of possible efficacy
in pancreatic cancer, liver metastases from colorectal carcinoma,
oral leukoplakia, and Barretts esophagus are at earlier stages.
Genetically modified to replicate selectively in cells that
have lost p53 tumor-suppression function, ONYX-015 spares normal
tissue, Dr. Kirn said. Mutation of the p53 gene is found in
about half of all cancers, and its pathway is inactivated by other
mechanisms in most of the rest. Studies show ONYX-015 to be active in
both circumstances, he said.
Within 48 to 72 hours, the agent produces thousands of copies of
itself, which spill from lysed cells to infect adjacent tumor cells.
Early clinical data, he added, confirm that infection with ONYX-015
has the potential to induce tumor necrosis and eradication.
Head and Neck Cancer
In the phase I study in patients with recurrent, refractory
head and neck cancer, one tumor regressed completely with just one
cycle of ONYX-015 given over 22 days, Dr. Kirn reported.
The patient had failed prior surgery, radiation, and
chemotherapy, he said, and the recurrent 4 cm ulcerated
tumor that was injected with ONYX-015 was partially wrapped around
the carotid artery.
The phase II trials used ONYX-015 with standard chemotherapy for
recurrent head and neck cancer. ONYX-015 was given in intratumoral
injections for 5 consecutive days, Dr. Kirn said, and standard
cisplatin and fluorouracil were administered in the same time period.
All agents were repeated every 3 weeks.
In the 30 evaluable patients, Dr. Kirn reported, the
overall response rate of 63% contrasted with the 30% to 40% seen
historically with cisplatin and fluorouracil in combination. The
complete response rate is very encouraging at 27%, compared with 5%
to 10% historically. Approximately 83% of patients had no tumor
progression at 6 months. Some patients are out almost a year
now without tumor progression, he observed.
In nine patients with more than one tumor, only the largest lesion
was injected with ONYX-015. Responses were seen in 7 of the 9
injected tumors but in uninjected lesions in only three patients.
Weve shown that the antitumoral activity is superior to
both historical and internal controls and has a very favorable safety
profile, Dr. Kirn said.
Biopsies on days 5 and 15 after treatment initiation showed early and
late viral replication with associated necrosis. This is an
important concept, he said, because theoretically
chemotherapy could have blocked replication. The only adverse
symptoms that could be linked directly to ONYX-015, he said, were
injection site pain and low-grade fevers.
The protocol for a randomized phase III study hinges on discussions
with the FDA, but Dr. Kirn said the study would aim to assess the
impact of ONYX-015 given with standard chemotherapy. Half of
the 350 to 450 patients expected to be enrolled, he said,
would receive only standard chemotherapy and half would also
get ONYX-015. In this trial, he said, we would inject all
tumors in these patients to maximize the clinical benefit.
A phase II trial of ONYX-015 is underway in pancreatic cancer.
The phase I study showed that it was safe to inject a
replicating virus into the pancreas, Dr. Kirn said, and
we saw encouraging biologic activity.
ONYX-015 is injected into pancreatic tumor masses via
ultrasound-guided endoscopy. It will be tried alone and in
combination with gemcitabine (Gemzar).
In a phase I-II study in liver metastases from colorectal cancer,
ONYX-015 is being delivered via hepatic artery perfusion. Begun in
January, the trial has enrolled 10 patients to date.
The theoretical basis for using ONYX-015 to eradicate the
precancerous lesions, Barretts esophagus and oral leukoplakia,
is that p53 mutations often occur before invasive tumors develop.
The first two leukoplakia patients treated with an oral rinse
containing ONYX-015 both had a complete response, Dr. Kirn
said. These are early data, he said, but they are
exciting early data.