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
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
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
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
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.
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
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,"
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.