DENVER--Novel agents have been designed to exploit molecular markers as therapeutic targets in head and neck cancer. Two studies presented at the American Society of Clinical Oncology meeting involved agents targeting the p53 gene, either by eradication of p53-altered tumor cells or restoration of normal gene function. The third study involved a monoclonal antibody targeted at tumor cells with an abnormality of the EGF receptor.
Daniel Von Hoff, MD, of the Cancer Therapy and Research Center and University of Texas Health Science Center, San Antonio, reported on ONYX-015, an attenuated chimeric group C adenovirus construct with a deletion in E1B. The virus efficiently replicates in and lyses p53-deficient tumor cells but not p53-normal cells; p53 is altered in 50% to 70% of head and neck cancer patients.
The phase I study enrolled 27 patients with recurrent squamous cell head and neck cancer and an abnormal p53 status by immunohistochemistry. All patients had failed standard surgery and radiotherapy, with or without chemotherapy.
The patients were given a single intra-lesional injection (107 or 1010 pfu) every four weeks. After safely reaching the 1010 level, the researchers switched to a schedule of 109 and 1010 pfu daily times five.
The therapy was well tolerated with no grade 3 toxicity except for one case of pain on injection. Nineteen single-dose patients were evaluable for antitumor effects, but it was too early to evaluate the eight receiving daily times five dosing.
Antitumor effects were measured in relation to the injected portion of the tumor, not the entire tumor burden. Using this criterion, "there was definite evidence of an antitumor effect," Dr. Von Hoff said.
In one patient with a primary tongue lesion, 50% necrosis of the tumor was observed with three cycles of treatment. "The patient had decreased trismus, improved jaw mobility, and improved swallowing with each successive injection," he said. Another patient with a left temporal primary had 75% tumor necrosis with two treatment cycles. In a third patient, with a tongue primary lesion, 80% of the injected area sloughed off eight days after treatment.
Dr. Von Hoff said that the researchers plan to continue to use the daily times five regimen "to try to address the previously uninjected portions of the tumors." When the desired dose is determined, phase II efficacy trials will begin.
Restoring Normal p53 Function
Researchers from M.D. Anderson have attempted to restore p53 function in patients with advanced recurrent squamous cell carcinoma of the head and neck by intratumoral injections of an adenoviral-mediated p53 gene (ADp53).
In this phase I study, previous chemotherapy for recurrent disease was allowed. The recurrent tumor was evaluated for the presence of p53 mutations by direct DNA sequencing, but mutations were not required for study entry.
All patients received the agent three times weekly for two consecutive weeks. Then patients with resectable disease underwent surgery, with direct injection of ADp53 into the surgical bed. Three days later, an eighth dose was given via retrograde catheter. Patients with nonresec-table disease had tumor biopsy in place of resection. The ADp53 dose was escalated from 106 pfu to 1011 pfu.
Principal investigator Gary L. Clayman, MD, reported on 30 patients, 70% with p53 abnormalities. The treatment was well tolerated, he said, with pain on injection the only grade 3 event.
ADp53 produced objective tumor regression, Dr. Clayman said, particularly at the higher doses. Among the nonresec-table patients, there were no objective responses at lower doses and two partial responses at 1010 and 1011 pfu.
One of the resected patients had a complete histologic response at 107 pfu. "No viable tumor was found in a completely resected neck specimen," he said. Another resected patient treated at 1011 pfu had an approximately 30% reduction. Dr. Clayman noted that phase II studies are scheduled to begin later this year.
Growth factor can be stimulated by epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha). EGF receptor is overexpressed in one third of solid tumors and is thought to play a pivotal role in both initiation and propagation of tumors, said Harlan W. Waksal, MD, chief operating officer, ImClone Systems Inc., New York.
Theoretically, a drug that binds to tyrosine kinase receptor would block access of growth factor to the receptor and ultimately block cell proliferation.
Dr. Waksal reported on a phase Ib/IIa study of a chimerized monoclonal antibody that binds to the EGF receptor with an affinity two- to fivefold higher than that of EGF or TGF-alpha. The antibody, known as C225, was developed by John Mendelsohn, MD, of M.D. Anderson.
In preclinical studies, Dr. Waksal said, C225 was shown to synergize with chemotherapy to inhibit tumor cell division. Thus, in this study of advanced head and neck and non-small-cell lung cancer patients, C225 was combined with cisplatin(Drug information on cisplatin).
The weekly IV C225 dose was escalated from 5 to 400 mg/m². Although patients could not have received any therapy within one month prior to study, all but two had had some prior treatment.
"This was a very well tolerated drug," Dr. Waksal said. There were no dose-limiting toxicities and only one grade 3 toxicity--an anaphylactoid reaction.
At a C255 dose of 200 mg/m², Dr. Waksal said, "we hit what we are calling saturation of clearance." At this dose, he said, the half-life was 7 days and there was dramatic serum accumulation. The pharmacokinetics remained the same at 400 mg/m².
All three patients who received the 100 mg/m² dose had stable disease for 12 weeks. At 200 mg/m², two had stable disease and one had a partial response, although this was unconfirmed because the patient did not have 30-day follow-up. At 400 mg/m², one of three patients had a partial response, which was confirmed at 30-day follow-up as a 57% reduction.
Dr. Waksal noted that both of the patients who responded had received prior radiation therapy but no chemotherapy.
He noted that ImClone is initiating other phase Ib/IIa studies to fine tune the dose level at around 200 mg/m².
Limitations of the Studies
Everett Vokes, MD, the discussant for the papers, said that all three studies had shown "proof of principle." However, he said, the two agents targeting p53 (ONYX-015 and ADp53) may have limited usefulness for two reasons: Because they are local therapies and "reasonable" local therapies already exist for head and neck cancer, and because their efficacy may be limited to p53-altered tumor cells.
He suggested that these agents might be useful in combination with other established modalities. "This is important in view of the contribution of p53 to the determination of resistance to chemotherapy or radiotherapy," he said.
The EGF receptor blocker C255, studied in combination with cisplatin, showed fairly modest activity, he said, and the patients who responded had not received prior chemotherapy. "This kind of activity can certainly be explained by cisplatin alone," he noted.