Lapatinib in Treating Young Patients With Recurrent or Refractory Central Nervous System Tumors

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies lapatinib to see how well it works in treating young patients with recurrent or refractory central nervous system (CNS) tumors. Lapatinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To estimate the MTD and describe the DLT of oral lapatinib (GW572016) administered twice daily for 28 days to children with recurrent or refractory malignant brain tumors who are not receiving steroids (Stratum 1) and to describe toxicities in those who are receiving steroids (Stratum 2). II. To test the ability of lapatinib (GW572016) to inhibit ERBB receptor signaling in recurrent or refractory: medulloblastoma/PNET, high-grade glioma or ependymomas. III. To estimate the sustained objective response rates (CR plus PR sustained for 8 weeks) to lapatinib (GW572016) administered continuously at the MTD (900 mg/m2/dose bid) to children with recurrent or refractory: medulloblastoma/PNET, high-grade glioma or ependymoma. SECONDARY OBJECTIVES: I. To characterize the plasma pharmacokinetics of lapatinib (GW572016) and tumor tissue lapatinib (GW572016) concentration in children. II. To assess the effect of steroids on the pharmacokinetics of lapatinib (GW572016). III. To explore the pharmacogenetic polymorphisms in lapatinib (GW572016) metabolizing enzymes and relate these polymorphisms to the drug pharmacokinetics. IV. To estimate the incidence of ERBB1, ERBB2, ERBB3 and ERBB4 expression and pathway activation in recurrent or refractory CNS tumors of childhood, including ependymoma, medulloblastoma/PNET and glioma. V. To identify additional genes both within and outside the canonical ERBB pathway that might act as determinants of response to lapatinib (GW572016). VI. To explore changes in PET and correlative magnetic resonance imaging in children receiving lapatinib. Imaging studies may be combined across similar PBTC protocols to increase the power for detecting correlations among scans and associations with outcome. OUTLINE: This is an open-label, multicenter study. Patients are stratified according to histology (medulloblastoma/primitive neuroectodermal tumor vs high-grade glioma vs ependymoma). Molecular Biology Phase: Patients randomized to receive lapatinib prior to surgery receive oral lapatinib twice daily for 7-14 days. Surgery is performed after 7-14 days of lapatinib treatment. For patients randomized to not receive lapatinib, surgery is performed within 3 weeks of registration. After surgical resection, all molecular biology participants start lapatinib treatment within 10 days post-surgery. The first dose of lapatinib post-surgery initiates course 1. 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. Lapatinib Continuation/Phase II: 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. After completion of study treatment, patients are followed for at least 30 days.

Official Title
-----------------
Molecular Biology and Phase II Study of Lapatinib (GW572016) in Pediatric Patients With Recurrent or Refractory Medulloblastoma, Malignant Glioma or Ependymoma

Conditions
-----------------
Recurrent Childhood Anaplastic Astrocytoma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Ependymoma, Recurrent Childhood Giant Cell Glioblastoma, Recurrent Childhood Glioblastoma, Recurrent Childhood Gliosarcoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Oligodendroglioma

Intervention / Treatment
-----------------
* Drug: lapatinib ditosylate
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: positron emission tomography
* Procedure: magnetic resonance imaging


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PHASE I TRIAL: All patients with recurrent or refractory malignant CNS tumors; a histological diagnosis of malignant CNS tumor from either the initial presentation or at the time of recurrence is required for all patients, but those with brain stem gliomas MOLECULAR BIOLOGY TRIAL: Patients must have recurrent or refractory disease with a histological diagnosis from either the initial presentation or at the time of recurrence of one of the following: Recurrent or refractory medulloblastoma/PNET Recurrent or refractory high grade glioma, (anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglioma) Recurrent or refractory ependymoma Patients for whom surgical resection is clinically indicated and are amenable to receiving GW572016 for 7-14 days prior to their resection PHASE II TRIAL: Patients must have recurrent or refractory disease with a histological diagnosis from either the initial presentation or at the time of recurrence of one of the following: Recurrent or refractory medulloblastoma/PNET, Recurrent or refractory high grade glioma, (anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglioma) Recurrent or refractory ependymoma Patients must have measurable disease Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration Karnofsky performance scale (KPS for > 16 yrs of age) or Lansky performance score (LPS for =< 16 years of age) >= 50 assessed within two weeks prior to registration Evidence of recovery from prior chemotherapy; no myelosuppressive anticancer chemotherapy within 3 weeks and no biological therapy or other non-myelosuppressive investigational agent =< 7 days prior to study registration (6 weeks if a nitrosourea or mitomycin C agent) prior to registration >= 3 months prior to registration for craniospinal irradiation (>= 18 Gy); >= 4 weeks for local radiation to primary tumor; and >= 2 weeks prior to registration for focal irradiation to symptomatic metastatic sites >= 6 months prior to registration for allogeneic bone marrow transplants and >= 3 months prior to registration for autologous bone marrow/stem cell transplants Patients with seizure disorder may be enrolled if well controlled; patients receiving enzyme inducing anticonvulsants are not eligible for this study; patients must be off EIACD for at least 2 weeks prior to registration Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to registration; patients enrolled in the molecular biology and phase II components of the study will not be stratified based on steroid use; however, use of steroids should be reported as a concomitant medication in the database; in the phase I component of the study, patients on corticosteroids will be eligible for stratum 2 of the study; patients with ACTH deficiency who are on physiological replacement doses of hydrocortisone (or other corticosteroid) will be eligible for stratum 1 of the study Off all colony forming growth factor(s) >= 2 weeks prior to registration (G-CSF, GM-CSF, Erythropoietin) Patients must not have received: CYP3A4 inhibitors within seven (7) days prior to registration on protocol and for the duration of the study; however, amiodarone, another CYP3A4 inhibitor, should have been discontinued 6 months prior to registration and for the duration of the study CYP3A4 inducers within fourteen (14) days prior to registration and for the duration of the study Cimetidine within 48 hours prior to registration and for the duration of the study Patients must be in adequate general condition for study Absolute neutrophil count >= 1000/microliter Platelets >= 100,000/microliter (transfusion independent) Hemoglobin >= 8.0 g/dL (transfusion independent) Serum creatinine =< 1.5 times upper limit of institutional normal for age or GFR >= 70 ml/min/1.73m^2 Bilirubin =< 1.5 times upper limit of normal for age SGPT (ALT) < 2.5 x institutional upper limit of normal Albumin >= 2 g/dL No overt renal, hepatic, biliary, cardiac or pulmonary disease Adequate cardiac function, assessed within 2 weeks prior to registration, defined as: shortening fraction of >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study Adequate pulmonary function, assessed within 2 weeks prior to registration, defined as: no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study Signed informed consent according to institutional guidelines must be obtained Exclusion Criteria: Patients with any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy Patients with any disease that would obscure toxicity or dangerously alter drug metabolism Patients with uncontrolled infection

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (surgery, lapatinib)<br>Molecular Biology Phase: Patients randomized to receive lapatinib prior to surgery receive oral lapatinib twice daily for 7-14 days. Surgery is performed after 7-14 days of lapatinib treatment. For patients randomized to not receive lapatinib, surgery is performed within 3 weeks of registration. After surgical resection, all molecular biology participants start lapatinib treatment within 10 days post-surgery. The first dose of lapatinib post-surgery initiates course 1. 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. Lapatinib Continuation/Phase II: 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. | Drug: lapatinib ditosylate<br>* Given orally<br>* Other names: Tykerb;Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: positron emission tomography<br>* Correlative studies<br>* Other names: tomography, emission computed;Procedure: magnetic resonance imaging<br>* Correlative studies<br>* Other names: nuclear magnetic resonance imaging;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Phosphorylation of ERBB2 (Molecular Biology Objective) | Lapatinib may be able to control the growth of tumor cells. To assess the ability of lapatinib to block a molecule, the ERBB2 receptor, that signals tumor cells to divide, fresh frozen tissue from the surgical resection is processed by quantitative western blot analysis to assess the phosphorylation of ERBB2. The relative phosphorylation is a ratio of the phosphorylated ERBB2 measured in the tumor normalized to the level of total receptor protein and housekeeping protein. Lower values suggests more inhibition of the ERRB2 receptor signal and a decreased ability for tumor cell division. | 7-14 days after starting therapy and prior to surgery | 
| Number of Participants With a Sustained Objective Response (Complete or Partial Response) (Phase II Objective) | A complete response is defined as complete disappearance of all tumor accompanied by a stable or improving neurologic exam, and a partial response is defined as 50% or more reduction in the tumor size by bi-dimensional measurement and a stable or improving neurologic exam. The response must be sustained for at least 8 weeks. The number of patients with a sustained objective response will be reported separately for each of the three disease groups. | From start of therapy until the earliest of disease progression, death or end of the fourth course (recurrent medulloblastoma and recurrent high grade glioma) or end of the sixth course (recurrent ependymoma) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor to Plasma Lapatinib Concentration (Molecular Biology Objective) | For participants randomized to receive lapatinib 7-14 days prior to surgery, plasma samples will be obtained with the first dose of lapatinib prior to surgery. The lapatinib concentration is measured in both the plasma samples and the tumor tissue obtained at surgery. Reported is the concentration of lapatinib observed in the tumor expressed as a percentage of the concentration observed in plasma. | First dose of lapatinib prior to surgery | 
| Maximum Concentration of Lapatinib in Plasma (Phase II Objective) | Serial plasma samples for pharmacokinetic studies of lapatinib will be collected from consenting participants with the first dose of course 1. | First dose of lapatinib in course 1 | 
| Number of Participants With Tumors Expressing Total ERBB2 | Total ERBB2 expression is assessed in participants enrolled in both the molecular biology trial and the phase II trial who provided pre-treatment formalin fixed paraffin embedded tumor material. The tumor material is analyzed by immunohistochemistry for expression of total ERBB2. Low, moderate, and intense expression are combined into one group vs. no total ERBB2 expression. | Pre-treatment | 
| Number of Participants With Tumors Expressing Phosphorylated ERBB2 (Phase II Objective) | Phosphorylated ERBB2 expression is assessed in patients who provided pre-treatment formalin fixed paraffin embedded tumor material. The tumor material is analyzed by immunohistochemistry for expression of phosphorylated ERBB2. Low, moderate, and intense expression are combined into one group vs. no phosphorylated ERBB2 expression. | Pre-treatment |