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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Brain and Central Nervous System Tumors, Carcinoma of Unknown Primary, Leukemia, Lymphoma, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: topotecan hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: topotecan hydrochloride|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).|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Pre-treatment, week 5, week 11, and then every 12 weeks until off study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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