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.
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 Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
19
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).
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Duke Comprehensive Cancer Center
Durham, North Carolina, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Dan L. Duncan Cancer Center at Baylor College of Medicine
Houston, Texas, United States
...and 1 more locations
Estimate the maximum tolerated dose of intraventricular topotecan on this schedule
Time frame: First 14 days of therapy
Number of patients with dose-limiting toxicity
Time frame: 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
Time frame: Day 1 of Week 1
Number of patients with objective documentation of tumor response to intraventricular topotecan
MRI of the brain and spine is obtained pre-consolidation, pre-maintenance, and then every 12 weeks in maintenance.
Time frame: Weeks 5, 11 and then every 12 weeks until off study
Pharmacokinetics
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.
Time frame: Day 1 of Week 1
Correlation of imaging parameters with tumor response
MRI scans of the brain and spine is obtained pre-treament, pre-consolidation, pre-maintenance, and then every 12 weeks on maintenance.
Time frame: Pre-treatment, week 5, week 11, and then every 12 weeks until off study
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.