Topotecan in Treating Young Patients With Neoplastic Meningitis Due to Leukemia, Lymphoma, or Solid Tumors - Full Text View

Sponsor:	Pediatric Brain Tumor Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00112619

Purpose

RATIONALE: Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of topotecan when given by intraventricular infusion in treating young patients with neoplastic meningitis due to leukemia, lymphoma, or solid tumors.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors Carcinoma of Unknown Primary Leukemia Lymphoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: topotecan hydrochloride	Phase I

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children With Neoplastic Meningitis

Resource links provided by NLM:

MedlinePlus related topics: Cancer Hodgkin Disease Leukemia Lymphoma Meningitis

Drug Information available for: Topotecan hydrochloride Topotecan

U.S. FDA Resources

Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:

Estimate the maximum tolerated dose of intraventricular topotecan on this schedule [ Time Frame: First 14 days of therapy ] [ Designated as safety issue: Yes ]
Number of patients with dose-limiting toxicity [ Time Frame: First 14 days of therapy ] [ Designated as safety issue: Yes ]
Estimate the dose of intraventricular topotecan that will result in cerebrospinal fluid lactone concentrations exceeding 1 ng/mL for at least 8 hours after an intrathecal injection [ Time Frame: Day 1 of Week 1 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Number of patients with objective documentation of tumor response to intraventricular topotecan [ Time Frame: Weeks 5, 11 and then every 12 weeks until off study ] [ Designated as safety issue: No ]
MRI of the brain and spine is obtained pre-consolidation, pre-maintenance, and then every 12 weeks in maintenance.
Pharmacokinetics [ Time Frame: Day 1 of Week 1 ] [ Designated as safety issue: No ]
The cerebrospinal fluid (CSF) concentration-time profile for topotecan after intrathecal CSF administration will be modeled from the CSF samples collected on day 1 of week 1. Individual pharmacokinetic parameters estimated will include volume of central compartment, elimination rate constant, half-life, and clearance.
Correlation of imaging parameters with tumor response [ Time Frame: Pre-treatment, week 5, week 11, and then every 12 weeks until off study ] [ Designated as safety issue: No ]
MRI scans of the brain and spine is obtained pre-treament, pre-consolidation, pre-maintenance, and then every 12 weeks on maintenance.

Enrollment:	19
Study Start Date:	August 2005
Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Intervention Details:

Participants receive intraventricular topotecan, .2 mg, administered via an indwelling ventricular reservoir daily for 5 consecutive days during weeks 1 and 3 of the first four weeks of therapy (induction), during weeks 5 and 8 of the next 6 weeks of therapy (consolidation), and during weeks 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, and 51 (maintenance therapy).

Other Name: Hycamptin

Detailed Description:

OBJECTIVES:

Primary

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.

Secondary

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 months.

Eligibility

Ages Eligible for Study:	3 Years to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

Age

3 to 21

Performance status

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

Life expectancy

Not specified

Hematopoietic

Not specified

Hepatic

Not specified

Renal

Calcium ≥ 7 mg/dL

Other

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 reservoir)
No uncontrolled infection
- HIV-positive patients with AIDS-related lymphomatous meningitis are eligible
No other significant uncontrolled systemic medical illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

Recovered from prior biologic therapy or immunotherapy

Chemotherapy

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

Radiotherapy

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

Surgery

Not specified

Other

More than 2 weeks since prior and no other concurrent investigational agents
No other concurrent intra-CSF or systemic therapy for leptomeningeal disease

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00112619

Locations

United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States, 20892-1182
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Dan L. Duncan Cancer Center at Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105

Sponsors and Collaborators

Pediatric Brain Tumor Consortium

National Cancer Institute (NCI)

Investigators

Study Chair:

Susan M. Blaney, MD

Baylor College of Medicine

More Information

No publications provided

Responsible Party:	James M. Boyett, Executive Director Operations and Biostatistics Center, Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:	NCT00112619 History of Changes
Other Study ID Numbers:	CDR0000430504, U01CA081457, PBTC-019
Study First Received:	June 2, 2005
Last Updated:	June 29, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Pediatric Brain Tumor Consortium:

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

Additional relevant MeSH terms:

Carcinoma
Leukemia
Lymphoma
Meningitis
Nervous System Neoplasms
Lymphoma, Non-Hodgkin
Central Nervous System Neoplasms
Neoplasms, Unknown Primary
Meningeal Carcinomatosis
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders

Immune System Diseases
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Neoplasms by Site
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Meningeal Neoplasms
Topotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 09, 2012