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A Phase I Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children With Neoplastic Meningitis

Phase 1
3 Years
21 Years
Not Enrolling
Brain and Central Nervous System Tumors, Carcinoma of Unknown Primary, Leukemia, Lymphoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children With Neoplastic Meningitis



- Determine the maximum tolerated dose (MTD) of intraventricular topotecan in young
patients with neoplastic meningitis secondary to leukemia, lymphoma, or solid tumors.

- Determine the toxic effects and dose-limiting toxicity of this drug in these patients.

- Determine whether the MTD of this drug is also the pharmacokinetic optimal dose,
defined by the topotecan lactone concentration in the cerebral spinal fluid (CSF), in
these patients.


- Determine, preliminarily, the antitumor activity of this drug in these patients.

- Determine the pharmacokinetics of this drug in the CSF of these patients.

- Correlate observed effects of post-treatment central review imaging (if feasible) with
response to this drug in these patients.

OUTLINE: This is a non-randomized, dose-escalation, multicenter study.

- Induction therapy (weeks 1-4): Patients receive topotecan intraventricularly* over 5
minutes on days 1-5 in weeks 1 and 3. Patients then proceed to consolidation therapy in
week 5.

NOTE: *Patients who are willing, receive 1 intralumbar (instead of intraventricular) dose of
topotecan on day 1 of week 3 only.

- Consolidation therapy (weeks 5-10): Patients receive topotecan intraventricularly on
days 1-5 in weeks 5 and 8. Patients then proceed to maintenance therapy in week 11.

- Maintenance therapy (weeks 11-54): Patients receive topotecan intraventricularly on
days 1-5 in weeks 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, and 51.

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

Once the MTD is determined, the cohort is expanded to 25 patients and the MTD is declared
the pharmacokinetic optimal dose provided 23 of 25 patients treated at the MTD achieve the
target pharmacokinetic parameter.

PROJECTED ACCRUAL: A total of 28-49 patients will be accrued for this study within 9-24

Inclusion Criteria


- Diagnosis of neoplastic meningitis secondary to leukemia, lymphoma (including
AIDS-related lymphoma), or solid tumor (including primary CNS tumors or carcinomas of
unknown primary site), defined by 1 of the following criteria:

- Cerebral spinal fluid (CSF) cell count > 5/μL AND evidence of blast cells on
cytospin or by cytology (for patients with leukemia or lymphoma)

- Presence of tumor cells on cytospin or cytology OR unequivocal presence of
meningeal disease by MRI (for patients with solid tumor)

- No conventional therapy for neoplastic meningitis exists

- Patients with CNS leukemia or lymphoma must be refractory to conventional
therapy, including radiotherapy (i.e., second or greater relapse)

- Patients with CNS leukemia or lymphoma must have had a negative bone marrow
aspiration within the past 2 weeks

- No clinical evidence of obstructive hydrocephalus

- No compartmentalization of CSF flow by radioisotope indium In 111 or technetium Tc 99
DTPA flow study

- No ventriculoperitoneal or ventriculoatrial shunt unless patient is completely

- No impending spinal cord compression or other CNS involvement (e.g., acute visual
loss secondary to optic nerve involvement) requiring emergent local radiotherapy



- 3 to 21

Performance status

- Lansky 60-100% (≤ 16 years of age) OR

- Karnofsky 60-100% (> 16 years of age)

Life expectancy

- Not specified


- Not specified


- Not specified


- Calcium ≥ 7 mg/dL


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Sodium 125-150 mmol/L

- Magnesium ≥ 0.7 mmol/L

- Must have or be willing to have an intraventricular access device (i.e., Ommaya

- No uncontrolled infection

- HIV-positive patients with AIDS-related lymphomatous meningitis are eligible

- No other significant uncontrolled systemic medical illness that would preclude study


Biologic therapy

- Recovered from prior biologic therapy or immunotherapy


- Recovered from prior chemotherapy

- At least 1 week since prior intra-colony stimulating factory (CSF) chemotherapy (2
weeks for liposomal cytarabine)

- At least 3 weeks since prior systemic chemotherapy for leptomeningeal disease

- Concurrent systemic chemotherapy to control systemic disease or bulk CNS disease
allowed provided the systemic chemotherapy is not an investigational agent OR any of
the following:

- High-dose (> 1 g/m^2) methotrexate

- High-dose (> 1 g/m^2) cytarabine

- Fluorouracil

- Capecitabine

- Thiotepa

- Nitrosoureas

- Topotecan

Endocrine therapy

- Not specified


- See Disease Characteristics

- At least 8 weeks since prior craniospinal radiotherapy and recovered

- No concurrent CNS radiotherapy

- Concurrent radiotherapy to extra-CNS sites (e.g., painful bone metastases not in
the craniospinal axis) allowed


- Not specified


- More than 2 weeks since prior and no other concurrent investigational agents

- No other concurrent intra-CSF or systemic therapy for leptomeningeal disease

Type of Study:


Study Design:

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

Outcome Measure:

Estimate the maximum tolerated dose of intraventricular topotecan on this schedule

Outcome Time Frame:

First 14 days of therapy

Safety Issue:


Principal Investigator

Susan M. Blaney, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Baylor College of Medicine


United States: Food and Drug Administration

Study ID:




Start Date:

August 2005

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Carcinoma of Unknown Primary
  • Leukemia
  • Lymphoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • 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
  • HIV-associated Hodgkin lymphoma
  • stage IV childhood Hodgkin lymphoma
  • stage IV childhood large cell lymphoma
  • stage IV childhood lymphoblastic lymphoma
  • stage IV childhood small noncleaved cell lymphoma
  • primary central nervous system non-Hodgkin lymphoma
  • primary central nervous system Hodgkin lymphoma
  • recurrent childhood acute lymphoblastic leukemia
  • recurrent childhood acute myeloid leukemia
  • unspecified childhood solid tumor, protocol specific
  • childhood grade I meningioma
  • childhood grade II meningioma
  • childhood grade III meningioma
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • childhood high-grade cerebral astrocytoma
  • childhood low-grade cerebral astrocytoma
  • childhood choroid plexus tumor
  • childhood craniopharyngioma
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • recurrent childhood ependymoma
  • recurrent childhood medulloblastoma
  • childhood oligodendroglioma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • leptomeningeal metastases
  • recurrent carcinoma of unknown primary
  • childhood central nervous system germ cell tumor
  • childhood chronic myelogenous leukemia
  • juvenile myelomonocytic leukemia
  • recurrent/refractory childhood Hodgkin lymphoma
  • recurrent childhood grade III lymphomatoid granulomatosis
  • recurrent childhood visual pathway and hypothalamic glioma
  • childhood atypical teratoid/rhabdoid tumor
  • recurrent childhood large cell lymphoma
  • recurrent childhood lymphoblastic lymphoma
  • recurrent childhood small noncleaved cell lymphoma
  • relapsing chronic myelogenous leukemia
  • recurrent childhood pineoblastoma
  • recurrent childhood subependymal giant cell astrocytoma
  • meningeal leukemia
  • secondary central nervous system Hodgkin lymphoma
  • secondary central nervous system non-Hodgkin lymphoma
  • Carcinoma
  • Leukemia
  • Lymphoma
  • Meningitis
  • Nervous System Neoplasms
  • Lymphoma, Non-Hodgkin
  • Central Nervous System Neoplasms
  • Neoplasms, Unknown Primary
  • Meningeal Carcinomatosis



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Duke Comprehensive Cancer Center Durham, North Carolina  27710
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute Boston, Massachusetts  02115
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182
Dan L. Duncan Cancer Center at Baylor College of Medicine Houston, Texas  77030