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

Sponsor

Pediatric Brain Tumor Consortium (Other)

Overall Status

Terminated

CT.gov ID

NCT00112619

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

1.7

Patients Per Site

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Carcinoma of Unknown Primary Leukemia Lymphoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: topotecan hydrochloride	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2005

Actual Primary Completion Date :

Aug 1, 2010

Outcome Measures

Primary Outcome Measures

Estimate the maximum tolerated dose of intraventricular topotecan on this schedule [First 14 days of therapy]
Number of patients with dose-limiting toxicity [First 14 days of therapy]
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 [Day 1 of Week 1]

Secondary Outcome Measures

Number of patients with objective documentation of tumor response to intraventricular topotecan [Weeks 5, 11 and then every 12 weeks until off study]
MRI of the brain and spine is obtained pre-consolidation, pre-maintenance, and then every 12 weeks in maintenance.
Pharmacokinetics [Day 1 of Week 1]
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 [Pre-treatment, week 5, week 11, and then every 12 weeks until off study]
MRI scans of the brain and spine is obtained pre-treament, pre-consolidation, pre-maintenance, and then every 12 weeks on maintenance.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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