Protocol Number: 01-C-0123

Title:

A Phase II Study of Intrathecal Topotecan (NSC #609699) in Patients with Refractory Meningeal Malignancies, A COG Group-Wide Study

Number:

01-C-0123

Summary:

This study will test the effects of the anti-cancer drug topotecan in patients with neoplastic meningitis (cancer that has spread to the lining of the brain and spinal cord).

Patients between 1 and 21 years of age with neoplastic meningitis for whom no effective standard treatment is available or effective may be eligible for this study. Candidates will be screened with the following tests, some of which will be repeated at various times throughout the study:

- Complete medical history, physical examination, and neurological examination.

- Blood and urine tests.

- Lumbar puncture (spinal tap). This procedure is done to examine the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. After a local anesthetic is administered, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.

- Magnetic resonance imaging (MRI) of the brain and possibly spine. This diagnostic test uses a strong magnetic field and radio waves to show structural and chemical changes in tissues. During the scan, the patient lies on a table within a narrow cylinder containing a magnetic field. He or she can speak with a staff member via an intercom system at all times during the procedure.

- Bone marrow biopsy. This test looks for evidence of cancer cells in the bone marrow. It is done in patients with leukemia or lymphoma and in certain circumstances in patients with solid tumors. The hip area is anesthetized and a special needle is used to draw bone marrow from the hipbone.

- CSF flow study. This nuclear medicine study examines the CSF circulation. It is done in patients with a solid tumor or leukemia or lymphoma that might be blocking the flow of spinal fluid around the brain and spinal cord.

Study participants will be given infusions of topotecan directly into the CSF over a 10-minute period twice a week for 6 weeks. If the disease has not worsened at the end of 6 weeks, therapy will continue once a week for the next 4 weeks, then twice a month for 4 months and then once a month thereafter for a maximum total of 1 year. Topotecan is given by one of the following methods:

- Lumbar puncture - The drug is administered through the needle used to withdraw the CSF as described above. If needed, additional medication may be given to lessen pain or anxiety.

- Ommaya reservoir or lumbar reservoir - An Ommaya reservoir is a surgically implanted catheter used to inject medicine or withdraw CSF from the ventricles (fluid chambers) within the brain. A lumbar reservoir is a catheter surgically implanted in the lower back to inject medicine or withdraw CSF. The catheters are attached to a small mushroom-shaped chamber (reservoir) beneath the skin. A needle is inserted through the skin and into the reservoir to sample CSF and to administer the topotecan.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Patients must be greater than or equal to 1 and less than or equal to 21.99 years of age at study entry.

Patients must have neoplastic meningitis. Patients with meningeal leukemia/lymphoma must be refractory to conventional therapy (i.e., 2nd or greater relapse). The definition of neoplastic meningitis on this protocol is as follows:

Leukemia/Lymphoma: CSF cell count greater than 5/ul AND evidence of blast cells on cytospin preparation or by cytology;

Solid tumors/Other: Presence of tumor cells on cytospin preparation or cytology OR presence of meningeal disease on MRI scans.

Patients must have a life expectancy of at least 8 weeks.

Patients greater than 10 y.o. should have Karnofsky performance status of greater than or equal to 50% and patients less than or equal to 10 y.o. should have a Lansky performance status of greater than or equal to 50%.

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.

Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy, prior to entering this study and must be without significant systemic illness (e.g. infection). Patients must not have received any systemic CNS-directed therapy within 3 weeks (6 weeks if a prior nitrosourea), or craniospinal irradiation within 8 weeks prior to starting treatment on this study. Patients must not have received intrathecal chemotherapy within 1 week (2 weeks if prior DTC101). Patients who have had IT chemotherapy, e.g. in the - 7 to - 14 day period prior to study entry must have evidence of disease progression, e.g. increasing WBC and percentage blasts in patients with leukemia/lymphoma or increased leptomeningeal enhancements in patients with solid tumors.

Patients must have a platelet count greater than 40,000/ul, with transfusions allowed to achieve this platelet count, within 48 hours prior to intrathecal topotecan treatment.

Patients must have adequate liver function, total bilirubin less than 2.0 mg%; SGPT less than 5 times normal; adequate renal function (serum creatinine less than 1.5 mg); and normal metabolic parameters (serum electrolytes, calcium and phosphorus).

All patients or their legal guardians must sign a written informed consent according to institutional guidelines.

EXCLUSION CRITERIA:

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 chemotherapy to control systemic disease or bulk CNS disease will be eligible, provided the systemic chemotherapy is not a phase I agent, an agent which significantly penetrates the CSF [e.g., high-dose methotrexate (greater than 1 gm/m(2)), thiotepa, high-dose cytarabine, 5-fluorouracil, intravenous 6-mercaptopurine, nitrosoureas, or topotecan], or an agent known to have serious unpredictable CNS side effects. Careful documentation of concurrently administered systemic drugs is required.

Patients with clinical evidence of obstructive hydrocephalus or compartmentalization of the CSF flow as documented by radioisotope Indium(111) or Technitium(99)-DTPA flow study are not eligible for this protocol. If a CSF flow block is demonstrated, focal radiotherapy to the site of block to restore flow and a repeat CSF flow study showing clearing of the blockage is required for the patient to be eligible for the study. [A copy of the institutional CSF flow study report must be submitted to the Primary Study Coordinator, Dr. Susan Blaney, via fax at (832) 824-4039].

Patients with a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt are not eligible for this study unless they are shunt independent and there is evidence that their shunt is nonfunctional; e.g., a CSF flow study demonstrating normal flow.

Patients with leukemia/lymphoma who have a concomitant bone marrow relapse are not eligible for this study.

Women of childbearing age must not be pregnant or lactating because of potential teratogenic effects (e.g. The anti-proliferative activity of the investigational agent may be harmful to the developing fetus or the nursing infant).

Free of uncontrolled infection except HIV (i.e., AIDS-related lymphomatous meningitis).

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 which is known to have delayed toxicities after 7 days or a prolonged half-life.

Patients with impending cord compression, CNS involvement requiring local XRT (e.g. optic nerve), or isolated bulky ventricular or leptomeningeal based lesions are not eligible for this study.

Special Instructions: Currently Not Provided

Keywords:

Leukemia

Lymphoma

Brain Tumor

Solid Tumor

Children

Recruitment Keywords:

Childhood Cancer

Leukemia

Brain Tumor

Lymphoma

Conditions:

Meningeal Cancer

Investigational Drug(s):

Topotecan

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies

Prolongation of drug exposure in cerebrospinal fluid by encapsulation into DepoFoam

A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid

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