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

Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00112619
• Other study ID #: CDR0000430504
• Secondary ID: U01CA081457PBTC-
• Status: Terminated
• Phase: Phase 1
• First received: June 2, 2005
• Last updated: June 29, 2011
• Start date: August 2005

Study information

• Verified date: June 2011
• Source: Pediatric Brain Tumor Consortium
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 19
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Carcinoma
• Carcinoma of Unknown Primary
• Central Nervous System Neoplasms
• Leukemia
• Lymphoma
• Meningeal Carcinomatosis
• Meningitis
• Neoplasms
• Neoplasms, Unknown Primary
• Nervous System Neoplasms
• Unspecified Childhood Solid Tumor, Protocol Specific

Intervention

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).

Locations

Country	Name	City	State
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	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Dan L. Duncan Cancer Center at Baylor College of Medicine	Houston	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Pediatric Brain Tumor Consortium	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Estimate the maximum tolerated dose of intraventricular topotecan on this schedule		First 14 days of therapy	Yes
Primary	Number of patients with dose-limiting toxicity		First 14 days of therapy	Yes
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No