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

June 29, 2011 updated by: Pediatric Brain Tumor Consortium

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Drug: topotecan hydrochloride

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 Type

Interventional

Enrollment (Actual)

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: N/A
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Estimate the maximum tolerated dose of intraventricular topotecan on this schedule Time Frame: First 14 days of therapy	First 14 days of therapy
Number of patients with dose-limiting toxicity Time Frame: First 14 days of therapy	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	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 Time Frame: 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.	Weeks 5, 11 and then every 12 weeks until off study
Pharmacokinetics Time Frame: 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.	Day 1 of Week 1
Correlation of imaging parameters with tumor response Time Frame: 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.	Pre-treatment, week 5, week 11, and then every 12 weeks until off study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Pediatric Brain Tumor Consortium

Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair: Susan M. Blaney, MD, Baylor College of Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2005

Primary Completion (Actual)

August 1, 2010

Study Registration Dates

First Submitted

June 2, 2005

First Submitted That Met QC Criteria