RATIONALE: Lapatinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

PURPOSE: Phase I/II trial to study the effectiveness of lapatinib in treating young patients who have recurrent or refractory CNS tumors.

Condition	Treatment or Intervention	Phase
childhood brain tumor childhood meningioma childhood spinal cord tumors	Drug: lapatinib  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase I Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the maximum tolerated dose and dose-limiting toxicity of lapatinib in pediatric patients with recurrent or refractory malignant CNS tumors who are or are not receiving steroids.
• Determine the toxic effects of this drug in these patients.
• Determine the inhibition of ERBB receptor signaling by this drug in these patients.
• Determine the objective response rate (complete response and partial response) in patients treated with this drug.

Secondary

• Determine the plasma and tissue pharmacokinetics of this drug in these patients.
• Determine the effect of steroids on the pharmacokinetics of this drug in these patients.

OUTLINE: This is a multicenter, phase I, dose-escalation study followed by an open-label phase II study. Patients in the phase I portion of the study are stratified according to concurrent corticosteroid use (no vs yes)*. Patients in the phase II portion of the study are stratified according to histology (medulloblastoma/primitive neuroectodermal tumor vs high-grade glioma vs ependymoma).

NOTE: *Stratum 1 (patients not receiving corticosteroids) open to accrual; stratum 2 (patients receiving corticosteroids) temporarily closed to accrual as of 1/10/05, pending toxicity evaluation.

• Patients receive oral lapatinib twice daily on days 1-28. Treatment repeats every 28 days for up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity. Cohorts of 2-6 patients per stratum receive escalating doses of lapatinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 25% of patients experience dose-limiting toxicity. Once the MTD is determined, the phase II portion of the study is initiated.
• Phase II: Patients receive lapatinib as in phase I at the MTD. Patients in the phase I portion of the study are followed for at least 30 days. Patients in the phase II portion of the study are followed for survival.

PROJECTED ACCRUAL: A total of 8-24 patients (4-12 per stratum) will be accrued for the phase I portion of the study. A total of 43-72 patients (7-32 with medulloblastoma/primitive neuroectodermal tumors, 13-20 with high-grade glioma, and 13-20 with ependymoma) will be accrued for the phase II portion of this study.

Ages Eligible for Study:  up to  21 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Phase I study:
• Histologically confirmed malignant CNS tumor
• Recurrent or refractory disease
• Histological diagnosis is not required for diffuse intrinsic brain stem gliomas
• Phase II study:
• Histologically confirmed diagnosis of 1 of the following:
• Medulloblastoma/primitive neuroectodermal tumor
• High-grade glioma (anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, or anaplastic oligodendroglioma)
• Ependymoma
• Recurrent or refractory disease
• Measurable disease

PATIENT CHARACTERISTICS: Age

• 21 and under

Performance status

• Karnofsky 50-100% (> 16 years of age) OR
• Lansky 50-100% (≤ 16 years of age)

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3*
• Platelet count ≥ 100,000/mm^3*
• Hemoglobin ≥ 8.0 g/dL* NOTE: *Transfusion independent

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
• ALT < 2.5 times ULN for age
• Albumin ≥ 2 g/dL
• No overt hepatic disease

Renal

• Creatinine ≤ 1.5 times ULN for age OR
• Glomerular filtration rate ≥ 70 mL/min
• No overt renal disease

Cardiovascular

• No overt cardiac disease
• Shortening fraction ≥ 27% by echocardiogram OR
• Ejection fraction ≥ 50% by gated radionuclide study

Pulmonary

• Pulse oximetry > 94%
• No dyspnea at rest
• No exercise intolerance
• No overt pulmonary disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Neurological deficits allowed provided they remain stable ≥ 1 week before study entry
• Seizure disorders allowed provided symptoms are well controlled
• Body surface area ≥ 0.4 m^2 (phase I only)
• No uncontrolled infection
• No other significant medical illness not adequately controlled with appropriate therapy or that would preclude study participation
• No other disease that would obscure toxicity or dangerously alter drug metabolism

PRIOR CONCURRENT THERAPY: Biologic therapy

• More than 3 weeks since prior myelosuppressive anticancer biologic therapy
• At least 6 months since prior allogeneic bone marrow transplantation
• At least 3 months since prior autologous bone marrow or stem cell transplantation
• At least 2 weeks since prior hematopoietic growth factors (filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)

Chemotherapy

• More than 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

Endocrine therapy

• Concurrent corticosteroids allowed provided dose is stable or decreasing for ≥ 1 week before study entry

Radiotherapy

• At least 3 months since prior craniospinal irradiation (≥ 18 Gy)
• At least 4 weeks since prior local radiotherapy to primary tumor
• At least 2 weeks since prior focal irradiation to symptomatic metastatic sites

Surgery

• Not specified

Other

• At least 2 weeks since prior enzyme-inducing anticonvulsant drugs (EIACDs)
• At least 1 week since prior and no concurrent CYP3A4 inhibitors
• At least 2 weeks since prior and no concurrent CYP3A4 inducers, except dexamethasone
• Concurrent cimetidine, ranitidine, or omeprazole is allowed only in conjunction with corticosteroids given for increased intercranial pressure
• Concurrent antacids allowed provided they are administered > 1 hour before and > 1 hour after lapatinib administration
• No concurrent EIACDs
• No other concurrent anticancer or experimental agents or therapy

California
      UCSF Comprehensive Cancer Center, San Francisco,  California,  94143,  United States; Recruiting
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States; Recruiting
Illinois
      Children's Memorial Hospital - Chicago, Chicago,  Illinois,  60614,  United States; Recruiting
Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States; Recruiting
Massachusetts
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States; Recruiting
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104-4318,  United States; Recruiting
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
Tennessee
      St. Jude Children's Research Hospital, Memphis,  Tennessee,  38105-2794,  United States; Recruiting
Texas
      Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital, Houston,  Texas,  77030-2399,  United States; Recruiting
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States; Recruiting

Study chairs or principal investigators

Maryam Fouladi, MD,  Study Chair,  St. Jude Children's Research Hospital   
Richard J. Gilbertson, MD, PhD,  St. Jude Children's Research Hospital   

Study ID Numbers:  CDR0000393490; PBTC-016; NCT00095940
Record last reviewed:  January 2005
Last Updated:  April 4, 2005
Record first received:  November 9, 2004
ClinicalTrials.gov Identifier:  NCT00095940
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08