OBJECTIVES:

• Determine the maximum tolerated dose of intrathecal or intraventricular topotecan in patients with recurrent, progressive, or refractory leptomeningeal disease.
• Determine the toxicity of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine the anti-tumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to disease (leukemia or lymphoma vs solid tumor or other malignancy).

Patients receive topotecan intrathecally or intraventricularly continuously on days 1-7. Treatment repeats every 21 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose- limiting toxicity.

Patients are followed for 6 months.

PROJECTED ACCRUAL: A maximum of 50 patients (25 per stratum) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologic or tumor marker confirmation of malignancy at original diagnosis

• Neoplastic meningitis/leptomeningeal metastasis refractory to conventional therapy and other therapies of higher priority, defined as:

  • Stratum A:

    • Small non-cleaved lymphoma (Burkitt's) with any L-3 blast in cerebrospinal fluid (CSF)
    • Any other lymphoma or leukemia with CSF cell count greater than 5/mm3 AND evidence of blast cells by cytology or cytospin preparation OR

  • Stratum B:

    • Solid tumor or other malignancy with presence of tumor cells on cytospin OR positive cytology OR neuroimaging evidence of leptomeningeal tumor by MRI or CT myelogram
• No leptomeningeal leukemia or lymphoma with concurrent bone marrow relapse
• No clinical evidence of untreated obstructive hydrocephalus or compartmentalization of the CSF

PATIENT CHARACTERISTICS:

Age:

• 65 and under

Performance status:

• Lansky 50-100% (age 16 and under)
• Karnofsky 50-100% OR ECOG 0-3 (over age 16)

Life expectancy:

• At least 2 months

Hematopoietic:

• Stratum B:

  • Absolute neutrophil count at least 750/mm^3
  • Platelet count at least 75,000/mm^3 (transfusion independent)
  • Hemoglobin at least 10.0 g/dL (red blood cell transfusions allowed)

Hepatic:

• Bilirubin no greater than 1.5 times normal
• SGOT or SGPT less than 2.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Neurologic:

• Seizures allowed if well controlled and on anticonvulsants
• CNS toxicity no greater than grade 2

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infections
• HIV allowed

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent immunomodulating agents (stratum B)
• No stem cell transplantation (stratum A)

Chemotherapy:

• At least 2 weeks since prior chemotherapy (4 weeks for nitrosoureas)
• No other concurrent cancer chemotherapy (stratum B)

• Other concurrent systemic cancer chemotherapy for leukemia or lymphoma allowed with the following restrictions:

  • No oral or IV topotecan
  • No moderate or high-dose IV or subcutaneous cytarabine (greater than 1.0 g/m2 per day)
  • No moderate or high-dose IV methotrexate (greater than 1 g/m2 per day)
  • No IV thiotepa
  • No myeloablative chemotherapy
  • No intrathecal or intraventricular chemotherapy

Endocrine therapy:

• Concurrent corticosteroids allowed only for treatment of increased intracranial pressure in patients with CNS tumors
• No concurrent intrathecal or intraventricular hydrocortisone

Radiotherapy:

• At least 4 weeks since completion of radiotherapy to the brain or spine and recovered
• Concurrent radiotherapy to localized painful lesions producing acute neurologic dysfunction allowed provided at least 1 measurable lesion is not irradiated
• No concurrent craniospinal or whole-brain radiotherapy

Surgery:

• Not specified

Other:

• Recovered from prior therapy
• At least 7 days since prior investigational drug
• No other concurrent intrathecal or intraventricular therapy for leptomeningeal disease