Trial Information

Phase I Study of Temozolomide and Intrathecal DepoCyt in Patients With Neoplastic Meningitis

Liposomal cytarabine is a slow-release formulation of cytarabine or Ara-C. It is designed
to slowly release cytarabine to increase exposure of cancer cells to the drug in the
treatment of leptomeningeal disease. Temozolomide is a chemotherapy drug that is designed
to attach to the DNA of rapidly dividing cells (cancer cells). The cells recognize this and
self-destruct.

Tests called an Indium-111 or Technetium 99m-DPTA CSF flow study, where radioactive dye is
injected into the CSF, will be done to make sure the CSF flows freely throughout the spinal
canal. These are done as part of the screening evaluation. If the flow study is okay, you
will be eligible to take part in this study. But if there is a block of the CSF pathway, the
area may be treated (usually with radiation) and then you can be re-evaluated and may still
be enrolled in the study if a repeat flow study shows that the block has been cleared.

If you have a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt in place, you will
have a shunt closure test in which your shunt system will be closed and you will be
monitored for 4 hours for the development of clinical signs of increased intracranial
pressure. The shunt closure test is performed to allow for a long enough time for the shunt
to be closed after liposomal cytarabine is injected. Researchers want to make sure that the
drug will stay in the CSF system long enough to perform its function, without being siphoned
off through the shunt.

An Ommaya Reservoir (a small round plastic pouch with a tube that goes into the brain and
CSF) will be placed under the scalp by a neurosurgeon before starting therapy if you do not
already have one in place. The reservoir will be used to deliver the liposomal cytarabine
and to collect samples of CSF when they are needed.

Liposomal cytarabine will be given through the Ommaya Reservoir once every 14 days on Day 1
for a total of 12 weeks (6 treatments). This is called Induction Treatment. After the first
12 weeks, liposomal cytarabine will be given on Day 1 every 28 days for 40 weeks (10
treatments). This is called Maintenance Treatment. If you are not already taking daily
dexamethasone, you will begin to take dexamethasone by mouth twice a day on the day before
the depocyt starts each course and continuing 5 days after the administration of liposomal
cytarabine.

Temozolomide will be taken by mouth once a day for 7 days (Days 1 - 7) every 14 days
starting from the second treatment of liposomal cytarabine Day 14. You will take it
continuously throughout Induction and Maintenance treatment with liposomal cytarabine.
Your doctor may prescribe an anti-nausea medication to be taken 1 hour before taking
temozolomide. Your doctor will choose the most appropriate anti-nausea medication for you
at that time. You should swallow the temozolomide capsules (usually between 1 and 5) whole
and quickly one after the other. You should not chew the temozolomide capsules. If
vomiting occurs during the course of treatment, no re-dosing will be done before the next
scheduled dose. You should take temozolomide at bedtime and fast (not eat or drink anything
except water) for at least 1 hour before each dose and for 1 hour after each dose.

Three (3) participants at a time will be enrolled in the Phase I portion of this study. The
first group of participants will receive a certain dose of temozolomide. If this dose is
tolerated, then an additional 3 will be treated at this dose. If no more than 1 participant
has a severe side effect, then that will be the dose for the Phase II portion of this study.

During the Phase II portion, if a participant has shown the ability to tolerate the first
dose level, the next dose may be increased, which will be decided by the treating physician
at the next treatment timepoint.

During the study, blood samples (about 1 tablespoon each) for routine tests will be repeated
every week during Induction and then every 2 weeks during the Maintenance period. The
Gd-MRI of the brain and spine will be repeated at Week 6 and 12 and then every 8 weeks.
Within 72 hours of each liposomal cytarabine dosing, vital signs and a physical and
neurological exam will be done. CSF will be removed from the Ommaya Reservoir every 2 weeks
and through lumbar puncture every 6 weeks during Induction and from the Ommaya Reservoir
every 4 weeks and through lumbar puncture every 8 weeks during the Maintenance period to
look for cancer cells in the fluid.

Treatment will continue unless the disease gets worse or unacceptable side effects occur.
Treatment will be given on an outpatient basis. At the end of the study, vital signs, a
complete physical and neurological exam, and routine blood tests (about 1 tablespoon) will
be performed. CSF samples for cytology, protein, glucose, and cell count will be taken. The
Gd-MRI scan will be repeated. You will be asked to complete a questionnaire about how you
are feeling.

After completion of the study, you will have a physical and neurological exam and vital
signs and CSF samples collected every 28 days for 3 months and then every 3 months for up to
1 year. If there are any signs of your tumor getting worse or returning, you will have a
Gd-MRI.

This is an investigational study. Temozolomide is approved by the FDA for the treatment of
some brain tumors and is commercially available. Liposomal cytarabine is authorized for
research use only in the treatment of brain tumors. The use of these two drugs together is
experimental. About 180 patients will take part in this study. About 18 will be enrolled at
UT MD Anderson Cancer Center.