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

Pediatric Brain Tumor Consortium

Status and phase

Terminated

Phase 1

Conditions

Carcinoma of Unknown Primary

Brain and Central Nervous System Tumors

Lymphoma

Leukemia

Unspecified Childhood Solid Tumor, Protocol Specific

Treatments

Drug: topotecan hydrochloride

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00112619

CDR0000430504

U01CA081457 (U.S. NIH Grant/Contract)

PBTC-019

Details and patient eligibility

About

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.

Full 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.

Enrollment

19 patients

Sex

All

Ages

3 to 21 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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