Topotecan in Treating Patients With Recurrent, Progressive, or Refractory Cancer That is Metastatic to the Lining Around the Brain

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

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the effectiveness of intrathecal or intraventricular topotecan in treating recurrent, progressive, or refractory cancer that is metastatic to the lining around the brain.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: topotecan hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75651
    • CHU Pitié-Salpêtrière
• United States
  • New York
    • New York, New York, United States, 10016
      • NYU School of Medicine's Kaplan Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Jonathan L. Finlay, MB, ChB, NYU Langone Health

Study record dates

Study Major Dates

• Study Start: May 1, 2001
• Primary Completion (Actual): October 1, 2003

Study Registration Dates

• First Submitted: October 11, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): November 9, 2012
• Last Update Submitted That Met QC Criteria: November 8, 2012
• Last Verified: March 1, 2003

More Information

Terms related to this study

• Keywords: leptomeningeal metastases
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Topotecan
• Other Study ID Numbers: CDR0000068949; NYU-0005H; NYU-0041H; NCI-G01-2018