Trial Information

Clinical Protocol for Wild Type p53 Gene Induction in Premalignancies of Squamous Epithelium of the Oral Cavity and Oral Pharynx Via an Adenoviral Vector [NCI Supplied Agent Ad-p53, (INGN 201) (Advexin®) NSC 683550, IND# 7135]

Some cancers that occur in the mouth may in some way be due to a defect in a gene called the
p53 gene. In this study, an adenovirus is used as a tool (a "vector") to deliver the normal
p53 gene into cells. The parts of the adenovirus that allow it to reproduce and promote
infection are removed, and the experimental gene (p53) is added.

Prior to beginning this study, all participants will have a complete medical history and
physical exam, including measurement of vital signs and weight. Participants will have an
electrocardiogram (ECG), a urine test, and blood tests, including an HIV test. At
mid-cycle, another white blood cell count will have to be drawn. Women able to have
children must have a negative blood pregnancy test. Participants will be asked what
medications have been taken in the past 30 days. Additionally, a chest x-ray will be
performed.

All participants will undergo a complete head and neck examination. This includes both
visual [direct as well as mirror (and fiberoptic if required)] of all mucosal sites from the
nasal and lip areas to the back of the throat. The physician will manually examine areas of
the skin, salivary glands, the neck, and thyroid bed. Also, the doctor will make sure the
cranial nerves are working properly. Location and size of lesion(s) will be recorded and
measured in two dimensions. All lesions present will be photographed prior to the start of
the intervention.

Physical examination including a fiberoptic exam, is the established standard of evaluating
pre-cancerous lesion(s). Only if a concern for cancer is present , or symptoms are beyond
those findings of the physical examination will a CT or MRI be prescribed. These tests (CT
and MRI) should not have to be done since they have no established role in the evaluation,
management, or follow-up of these lesion(s). If utilized, a CT (computerized tomography)
scan is a special test using x-ray along with a computer to give detailed pictures of parts
of the body. An MRI (magnetic resonance imaging) is a special test using a strong magnetic
field and radio frequency signals to give detailed pictures of parts of the body. An x-ray
shows a 2-dimensional picture while a CT scan or an MRI shows 3 dimensions.

Each study course includes one week of treatment followed by three weeks of observation.
The length of the study is 6 months (6 courses) for most participants. Participants will
return to the clinic twice a day for Days 2 - 5 for each month of participation, and should
expect to spend a total of about 6 hours a day at the clinic.

Participants in this study will receive INGN 201 in two ways. The first way will be by
injection in the area of the lesion. The second way will be by mouth rinse. Vital signs
will be checked each time before participants receive INGN 201. The injection will be given
on the first day of each week of the course, after a numbing (anesthetic) medication is
applied to prevent discomfort.

The mouth rinse will be given one time on the first day and two times on Days 2 - 5 of each
course of INGN 201. The injection and rinse (first day of each cycle), or the two rinses
(Days 2 - 5 of each cycle), will be separated by at least two hours. There will be a 30
second rinse with 5% acetic acid, a raspberry flavored, vinegar-like liquid, followed by a
tap water rinse just before participants receive INGN 201. Participants will be asked to
hold the INGN 201 in their mouth for 30 minutes. Eating and drinking should be avoided for
one hour after receiving the mouth rinse. The injection and rinse series will be repeated
on a monthly basis for a period of six months.

Participants will be requested to have two biopsies (small tissue samples) of the
premalignant lesion taken on Day 5 of the 1st and 6th courses. These biopsies will
contribute to the understanding of how the experimental agent works on pre-cancerous cells.
In particular, the biopsies will help to determine if the experimental agent is effective in
killing pre-cancerous cells (this process is called apoptosis). These studies will also
determine if the gene therapy injections have been effective in delivering the gene (p53) to
the precancerous cells.

Participants will be observed for three more weeks after the sixth course of treatment. At
the end of the study, 28 days after the last dose of INGN 201, participants will have a
physical exam, including measurement of weight and vital signs. Participants will have a
medical history and blood and urine tests. These tests are done to monitor the effects of
the study treatment.

Participants who develop severe side effects will be taken off study, though they may
continue to receive follow-up evaluations to monitor their health. Participants will be
counseled by their physician should the lesion(s) progress to cancer during the study or
follow up period. After counseling, participant may choose to have surgery to remove the
precancerous lesion(s), laser surgery, or observation. The participant will then be
monitored closely.

Study participants will be followed for five years, and must agree to stay in contact with
their personal doctor or the doctor responsible for this study even if they move after the
study ends. The participant's personal doctor may be asked to provide information about any
anticancer treatments received after the study's completion, as well as information about
the patient's overall health.

This is an investigational study. This experimental use of human genes is an example of
gene therapy. This is the first time that adenovirus gene therapy has been used for a
pre-cancerous condition. This is the first study to use INGN 201 as a mouth rinse. A total
of 20 patients will be enrolled at M. D. Anderson. A maximum of 51 subjects will be entered
in this multi-center study.