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A Phase I Study Of Seven Day Continuous Intrathecal/Intraventricular Infusion Of Topotecan For Patients With Recurrent, Progressive Or Refractory Leptomingeal Disease

Phase 1
65 Years
Not Enrolling
Brain and Central Nervous System Tumors

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Trial Information

A Phase I Study Of Seven Day Continuous Intrathecal/Intraventricular Infusion Of Topotecan For Patients With Recurrent, Progressive Or Refractory Leptomingeal Disease


- 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.

Inclusion Criteria


- 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



- 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


- 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)


- Bilirubin no greater than 1.5 times normal

- SGOT or SGPT less than 2.5 times upper limit of normal


- Creatinine no greater than 1.5 mg/dL OR

- Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min


- Seizures allowed if well controlled and on anticonvulsants

- CNS toxicity no greater than grade 2


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infections

- HIV allowed


Biologic therapy:

- No concurrent immunomodulating agents (stratum B)

- No stem cell transplantation (stratum A)


- 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


- 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


- Not specified


- Recovered from prior therapy

- At least 7 days since prior investigational drug

- No other concurrent intrathecal or intraventricular therapy for leptomeningeal

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Jonathan L. Finlay, MB, ChB

Investigator Role:

Study Chair

Investigator Affiliation:

New York University School of Medicine


United States: Federal Government

Study ID:




Start Date:

May 2001

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • leptomeningeal metastases
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



NYU School of Medicine's Kaplan Comprehensive Cancer Center New York, New York  10016
Herbert Irving Comprehensive Cancer Center New York, New York  10032