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A Phase II Study of Intrathecal Topotecan (NSC #609699) in Patients With Refractory Meningeal Malignancies

Phase 2
1 Year
21 Years
Not Enrolling
AIDS-related Diffuse Large Cell Lymphoma, AIDS-related Diffuse Mixed Cell Lymphoma, AIDS-related Diffuse Small Cleaved Cell Lymphoma, AIDS-related Immunoblastic Large Cell Lymphoma, AIDS-related Lymphoblastic Lymphoma, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Primary CNS Lymphoma, AIDS-related Small Noncleaved Cell Lymphoma, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, HIV-associated Hodgkin Lymphoma, Leptomeningeal Metastases, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Large Cell Lymphoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Small Noncleaved Cell Lymphoma, Recurrent/Refractory Childhood Hodgkin Lymphoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase II Study of Intrathecal Topotecan (NSC #609699) in Patients With Refractory Meningeal Malignancies


I. Determine the therapeutic activity of intrathecal topotecan, in terms of response rate
and time to central nervous system (CNS) progression, in pediatric patients with recurrent
or refractory neoplastic meningitis.

II. Determine the safety and toxicity of this regimen in these patients. III. Evaluate the
concentration of matrix metalloproteinases (MMPs) in the cerebrospinal fluid (CSF) of these

OUTLINE: Patients are stratified according to disease type (acute lymphoblastic leukemia vs.
other leukemia/lymphoma vs medulloblastoma vs other solid tumors). (Recurrent CNS acute
lymphoblastic leukemia stratum only open to accrual as of 11/30/04)

INDUCTION: Patients receive topotecan hydrochloride intrathecally (IT) over 5 minutes twice
weekly for 6 weeks.

CONSOLIDATION: Beginning 1 week after completion of induction, patients receive topotecan
hydrochloride IT over 5 minutes weekly for 4 weeks in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Beginning 2 weeks after completion of consolidation, patients receive topotecan
hydrochloride IT over 5 minutes twice monthly for 4 months and then monthly through year 1.

After completion of study treatment, patients are followed up monthly for 3 months, every 3
months for 1 year, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 14-77 patients will be accrued for this study.

Inclusion Criteria:

- Histologically proven refractory leukemia, lymphoma, or other solid tumor thathas
overt meningeal involvement (Recurrent CNS acute lymphoblastic leukemia stratum only
open to accrual as of 11/30/04)

- Definition of meningeal disease:

- Leukemia/lymphoma (including acute lymphoblastic leukemia)

- CSF cell count greater than 5/mm^3 AND evidence of blast cells
oncytospin preparation or by cytology

- Refractory to conventional therapy, including radiotherapy (i.e., in
second or greater relapse)

- No concurrent bone marrow relapse

- Solid tumors (including medulloblastoma)

- Presence of tumor cells on cytospin preparation or cytology OR
presence ofmeningeal disease on MRI scans

- No clinical evidence of obstructive hydrocephalus or compartmentalization ofCSF flow
as documented by radioisotope indium In 111 or technetium Tc 99 DTPAflow study

- If CSF flow block is demonstrated, focal radiotherapy must be administered
tosite of block to restore flow and a repeat CSF flow study must show clearing
of blockage

- No ventriculoperitoneal or ventriculoatrial shunt unless:

- Patient is shunt independent and there is evidence that the shunt is

- CSF flow study demonstrates normal flow

- No impending cord compression, CNS involvement requiring local radiotherapy(e.g.,
optic nerve), or isolated bulky ventricular or leptomeningeal basedlesions

- Performance status - Lansky 50-100% (age 10 and under)

- Performance status - Karnofsky 50-100% (over age 10)

- At least 8 weeks

- Platelet count greater than 40,000/mm^3 (transfusions allowed)

- Bilirubin less than 2.0 mg/dL

- SGPT less than 5 times normal

- Creatinine less than 1.5 mg/dL

- Electrolytes, calcium, and phosphorus normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No significant illness (e.g., uncontrolled infection, except HIV [i.e., AIDS-related
lymphomatous meningitis])

- Prior immunotherapy allowed and recovered

- At least 3 weeks since systemic CNS directed chemotherapy (6 weeks for nitrosoureas)
and recovered

- At least 1 week since prior intrathecal (IT) chemotherapy (2 weeks for cytarabine

- No prior IT chemotherapy on days -14 to -7 before study entry unless 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) (Recurrent CNS acute lymphoblastic leukemia stratum only open to accrual as
of 11/30/04)

- Concurrent chemotherapy to control systemic disease or bulk CNS disease allowed if
the systemic chemotherapy is not a phase I study agent that significantly penetrates
the CSF (e.g., high-dose systemic methotrexate [greater than 1 g/m^2], thiotepa,
high-dose cytarabine, temozolomide, IV mercaptopurine, nitrosourea, or topotecan) or
an agent known to have serious unpredictable CNS side effects

- Concurrent dexamethasone or prednisone allowed if part of a systemic chemotherapy

- See Disease Characteristics

- At least 8 weeks since prior cranial irradiation and recovered

- No concurrent whole brain or craniospinal irradiation

- At least 7 days since prior investigational drug

- Time period should be extended if patient has received any investigational
agent that is known to have delayed toxic effects after 7 days or a prolonged

- No other concurrent investigational agents

- No concurrent therapy (IT or systemic) for leptomeningeal disease

- No other concurrent systemic agents that significantly penetrate the blood-brain

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For the leukemia and lymphoma patients, an objective response rate, defined to be the proportion of Complete Responses of less than 0.10

Outcome Time Frame:

Up to 54 months

Safety Issue:


Principal Investigator

Susan Blaney

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

April 2000

Completion Date:

February 2009

Related Keywords:

  • AIDS-related Diffuse Large Cell Lymphoma
  • AIDS-related Diffuse Mixed Cell Lymphoma
  • AIDS-related Diffuse Small Cleaved Cell Lymphoma
  • AIDS-related Immunoblastic Large Cell Lymphoma
  • AIDS-related Lymphoblastic Lymphoma
  • AIDS-related Peripheral/Systemic Lymphoma
  • AIDS-related Primary CNS Lymphoma
  • AIDS-related Small Noncleaved Cell Lymphoma
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Immunoblastic Large Cell Lymphoma
  • HIV-associated Hodgkin Lymphoma
  • Leptomeningeal Metastases
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Childhood Large Cell Lymphoma
  • Recurrent Childhood Lymphoblastic Lymphoma
  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Small Noncleaved Cell Lymphoma
  • Recurrent/Refractory Childhood Hodgkin Lymphoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Medulloblastoma
  • Neoplasm Metastasis
  • Lymphoma, Large-Cell, Immunoblastic
  • Meningeal Neoplasms
  • Meningeal Carcinomatosis



Children's Oncology Group Arcadia, California  91006-3776