Clinical trial NCT00112619: Topotecan in Treating Young Patients With Neoplastic Meningitis Due to Leukemia, Lymphoma, or Solid Tumors
Official title: A Phase I Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children With Neoplastic Meningitis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Carcinoma of Unknown Primary
Leukemia
Lymphoma
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-06-03
Enrollment: 19
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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

* 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

Primary outcomes:
measure: Estimate the maximum tolerated dose of intraventricular topotecan on this schedule
timeFrame: First 14 days of therapy
measure: Number of patients with dose-limiting toxicity
timeFrame: First 14 days of therapy
measure: 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
timeFrame: Day 1 of Week 1
Secondary outcomes:
measure: Number of patients with objective documentation of tumor response to intraventricular topotecan
timeFrame: Weeks 5, 11 and then every 12 weeks until off study
measure: Pharmacokinetics
timeFrame: Day 1 of Week 1
measure: Correlation of imaging parameters with tumor response
timeFrame: Pre-treatment, week 5, week 11, and then every 12 weeks until off study
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Dan L. Duncan Cancer Center at Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
Study officials:
affiliation: Baylor College of Medicine
name: Susan M. Blaney, MD
role: STUDY_CHAIR
References: