NEW YORK—Researchers 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 Barrett’s 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(Drug information on cisplatin) and fluorouracil(Drug information on 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.
“We’ve 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(Drug information on 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, Barrett’s 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.”
