Methotrexate Infusion Into the Fourth Ventricle in Children With Malignant Fourth Ventricular Brain Tumors: A Pilot Study

Catheter Placement:

If you are eligible to take part in this study, you will have surgery to place a catheter
into the ommaya reservoir. The ommaya reservoir is a catheter system that allows drugs to be
administered directly to parts of the brain. In this study, the catheter will be used to
collect about 1 teaspoon of cerebrospinal fluid (CSF - the fluid surrounding the brain and
spinal cord) to check the status of the disease and for the infusion of methotrexate directly
into the 4th ventricle of the brain, which is 1 of the 4 connected fluid-filled cavities in
the brain.

If the study doctor thinks it is necessary, based on the location of the tumor, the tumor may
also be removed while you are already under anesthesia just before the catheter is placed.

Study Drug Administration:

Each cycle is 4 days long and will consist of 4 daily infusions of methotrexate. You will
have at least a 2 week rest period between each cycle.

Methotrexate will be infused through the ommaya reservoir catheter directly into the 4th
ventricle of the brain starting at least 7 days after the catheter placement surgery. The
infusion should last about 3 minutes each time.

You may also be given leucovorin, a drug used to help prevent or treat the side effects of
methotrexate, by intravenous (IV) infusion through a catheter or port you have already had
placed in your arm. If the study doctor thinks it is needed, this infusion will be given
after each cycle to help with the possible side effects you may experience from methotrexate.
The infusion should last about 5 minutes each time.

Study Visits:

Within 72 hours after catheter placement surgery:

- Any updates to your health will be recorded.

- You will have an MRI scan of the brain and spine to check the status of the disease and
the flow of brain fluid.

Within seven (7) days after catheter placement surgery:

- Any updates to your health will be recorded.

- You will have a neurological exam.

- You will have a spinal tap (also called a lumbar puncture). A lumbar puncture is a
procedure where fluid surrounding the spinal cord is removed by inserting a needle into
the lower back. The affected area is numbed with local anesthetic during the procedure.

- You will have a neuropsychological test performed by a neuropsychologist. For this test,
you will be asked questions that will test your memory and brain function. The test
should take about 3 hours.

On Day 1 of each methotrexate infusion for Cycles 1-3:

- You will have a neurological exam.

- Blood (about 1 teaspoon) will be drawn for routine tests.

- If you are able to become pregnant, you will have a urine pregnancy test.

Daily during each methotrexate infusion for Cycles 1-3:

- You will have a neurological exam.

- You will have an Ommaya reservoir tap (a catheter is placed into the Ommaya reservoir to
give the methotrexate infusion).

- CSF (about 1 teaspoon) will be collected for routine tests. Blood (about 1 teaspoon each
time) will be drawn to learn how much methotrexate is in your blood.

After you have completed Cycle 3:

You will have an MRI scan of the brain and spine to check the status of the disease and the
flow of brain fluid.

You will have a spinal tap. You will have a neuropsychological test performed by a
neuropsychologist. For this test, you will be asked questions that will test your memory and
brain function. The test should take about 3 hours.

If the study doctor thinks it is in your best interest, you will continue with additional
cycles of methotrexate therapy, with required tests and procedures. Your doctor may recommend
additional surgery. Your doctor will discuss this with you.

Also, if the study doctor thinks it is in your best interest, methotrexate may be given
together with other chemotherapy after completion of Cycle 3. If you will be receiving other
chemotherapy, the study doctor will speak with you in more detail about what drugs you will
receive and how you will receive them.

Length of Study:

You will receive up to 3 cycles of the methotrexate, or as long as the doctor thinks it is
your best interest. You will no longer be able to receive the study drug if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after you complete the follow-up visits.

Follow-Up Visit:

3 months after the final dose of study drug:

- Any updates to your health will be recorded.

- You will have a neurological exam.

- You will have an MRI scan of the brain and spine to check the status of the disease.

This is an investigational study. Methotrexate is FDA approved and commercially available for
infusion directly into brain tumors. The infusion of methotrexate into the 4th ventricle of
the brain is investigational.

Up to 12 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. There will be a two-step process of eligibility assessment: Step 1: Eligibility for
catheter placement and possible surgical removal of tumor. Step 2: Eligibility for
methotrexate infusion.

2. Step 1 Eligibility (Pre-Operative Eligibility) Includes: Diagnosis and Age - Patients
with tumor originally located within the posterior fossa of the brain: *Patients ≤ age
21 years with recurrent medulloblastoma (PNET) involving the brain and/or spine
*Patients ≤ age 21 years with recurrent ependymoma involving the brain and/or spine
*Patients ≤ age 21 years with recurrent atypical teratoid/rhabdoid tumor (AT/RT)
involving the brain and/or spine.

3. Step 1 Elig.: Life Expectancy - Patients must have a life expectancy of at least 12
weeks as estimated by the treating oncologist and neurosurgeon to be considered for
enrollment.

4. Step 1 Elig: Central Nervous System Function - Patients may be enrolled in the study
if they have an altered neurological status, such as somnolence, which is attributed
to hydrocephalus and/or mass effect from the brain tumor by the treating physicians.
However, after tumor resection and placement of the catheter into the fourth
ventricle, the protocol will only be continued if the patient has adequate central
nervous system function, defined as: patient is not severely somnolent or comatose and
has adequate clinical performance status as defined in protocol section 3.2.2.1.

5. Step 2 Elig. (MTX Infusion Elig.): Clinical Performance Status - Patients must have a
Lansky score of 50 or greater if ≤ 16 years of age and a Karnofsky score of 50 or
greater if they are > 16 years of age to be eligible for enrollment (See Protocol
Section 14.1 for Lansky Play-Performance Scale information; See Protocol Section 14.2
for Karnofsky Performance Scale information).

6. Step 2 Elig: Pregnancy - Female patients who are post-menarchal must have a negative
pregnancy test to be eligible. Pregnant or lactating female patients are ineligible.

7. Step 2 Elig: Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. a.
Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto
this study. b. Hematopoietic Growth Factors: At least 7 days since the completion of
therapy with a growth factor. c. Biologic (anti-neoplastic agent): At least 7 days
since the completion of therapy with a biologic agent. For agents that have known
adverse events occurring beyond 7 days after administration, this period must be
extended beyond the time during which adverse events are known to occur. These
patients must be discussed with the study chair on a case by case basis.

8. Step 2 Elig: Bone Marrow Function - patients must have adequate bone marrow function,
defined as: a. Peripheral absolute neutrophil count (ANC) ≥ 1000/µL b. Platelet count
≥ 30,000/µL (transfusion independent) c. Hemoglobin ≥ 9.0 gm/dL (may receive RBC
transfusions) d. Post-op CSF flow study shows re-establishment of CSF flow.

9. All patients and/or their parents or legal guardians must sign a written informed
consent.

Exclusion Criteria:

1. Patients will be excluded from this study if currently enrolled in another
experimental treatment protocol.

2. Patients will be excluded from this study if they have any evidence of infection, in
any site, at the time of considered enrollment.