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

Phase 1
18 Years
Not Enrolling
Neoplastic Meningitis

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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

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

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

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.

Inclusion Criteria:

1. Patients must be >/=18 years of age

2. All patients with the exception of those with primary brain tumors, must have
histologic diagnosis of systemic malignancy. Patients must have the presence of
malignant cells in CSF (+CSF) or clinical signs and symptoms of leptomeningeal
disease and radiographic abnormalities without malignant cells identified in the CSF
(-CSF). Clinical signs/symptoms include cerebral hemispheric, cranial nerve, and/or
spinal cord/root dysfunction.

3. Patients must have Karnofsky performance status of >/=60%. Patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purposes of the performance score.

4. Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy, before entering the study and must be without
significant systemic illness. Patients must not have received any systemic therapy
for Leptomeningeal disease (LMD) within 3 wks (6 wks if a nitrosourea), intrathecal
chemotherapy within 1 wk, or irradiation within 8 wks prior to treatment on this
study. Patients previously receiving craniospinal irradiation must have positive
cytology or progression of meningeal disease on MRI scan. Patients must not have
received whole brain or focal CNS radiotherapy within 1 wk of treatment.

5. Patients must have a platelet count >/= 75,000/mm(3) and ANC >/= 1500/mm(3) within 72
hours prior to intrathecal DepoCyt and temozolomide treatment.

6. Patients must have adequate liver function, total bilirubin < 2.0 mg%; SGPT < 5 times
normal; adequate renal function (serum creatinine parameters (serum electrolytes, calcium, magnesium, and phosphorus).

7. All patients or their legal guardians must sign a document of informed consent
indicating their awareness of the investigational nature and the risks of this study.

8. Ventricular access devices (e.g. an Ommaya reservoir) are mandatory.

Exclusion Criteria:

1. Patients receiving other therapy (either intrathecal or systemic) designed
specifically to treat their leptomeningeal disease are not eligible for this study.
However, patients receiving concomitant non-cytotoxic therapy (hormonal or cytostatic
therapy) to control systemic disease or bulk CNS disease will be eligible, provided
the therapy is not a phase I agent, an agent which significantly penetrates the CSF
or an agent known to have serious unpredictable CNS side effects.

2. (1. continued) No other cytotoxic chemotherapies are allowed (non-cytotoxic therapies
such as herceptin, tarceva, arimidex etc are allowed at the investigator's
discretion). Careful documentation of concurrently administered systemic drugs is

3. Patients with clinical evidence of obstructive hydrocephalus or compartmentalization
of the CSF flow as documented by radioisotope Indium-(111) (Technetium(99) -DTPA when
Indium-(111) unavailable) flow study are not eligible for this protocol. CSF
obstruction will be determined by routine nuclear medicine CSF flow study parameters.
If patients have evidence of block that is subsequently proven to be relieved after
focal XRT, these patients can enroll immediately after repeat flow study shows block
to be relieved.

4. Patients with a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt must have an
on/off device in their shunt systems to be eligible for the study. Patients must be
able to tolerate shunt closure for >/= 4 hours without development of clinical signs
of increased intracranial pressure. Patients unable to tolerate shunt closure for >/=
4 hours will not be eligible for the study.

5. Women of childbearing potential (females who are not surgically sterile or who have
had a period in the last 12 months) must have a negative serum pregnancy test and
must not be lactating.

6. Patients with any uncontrolled infection (life-threatening infection resistant to
treatment after 7 days) are not eligible for this study, except those with HIV and
AIDS-related lymphomatous meningitis).

7. Use of any other investigational drug within 7 days prior to study entry. This period
should be extended if the patient has received any investigational agent that is
known to have delayed toxicities after 7 days or a prolonged half-life.

8. Patients not able to undergo magnetic resonance testing. i.e. pacemaker.

9. Patients may not have had prior treatment with Temozolomide.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) for the combination of Temozolomide and DepoCyt

Outcome Description:

The MTD is the dose at which 0/3 or 1/6 participants experience Dose Limiting Toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 participants encountering DLT. MTD based on the assessment of DLT during the first 28 days of treatment on the regimen.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Morris D. Groves, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

February 2006

Completion Date:

June 2009

Related Keywords:

  • Neoplastic Meningitis
  • Neoplastic Meningitis
  • Leptomeningeal Disease
  • Temozolomide
  • Temodar
  • DepoCyt
  • Liposomal Cytarabine
  • Liposomal ara-C
  • Meningitis
  • Meningeal Carcinomatosis



U.T.M.D. Anderson Cancer Center Houston, Texas  77030