Molecular Biology and Phase II Study of Lapatinib (GW572016) in Pediatric Patients With Recurrent or Refractory Medulloblastoma, Malignant Glioma or Ependymoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Relative Phosphorylation of ERBB2 (Molecular Biology Objective)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Treatment (surgery, lapatinib)
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.
干预措施: lapatinib ditosylate (Drug)
Treatment (surgery, lapatinib)
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.
干预措施: therapeutic conventional surgery (Procedure)
Treatment (surgery, lapatinib)
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.
干预措施: laboratory biomarker analysis (Other)
Treatment (surgery, lapatinib)
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.
干预措施: pharmacological study (Other)
Treatment (surgery, lapatinib)
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.
干预措施: positron emission tomography (Procedure)
Treatment (surgery, lapatinib)
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.
干预措施: magnetic resonance imaging (Procedure)
结局指标
主要结局
Relative Phosphorylation of ERBB2 (Molecular Biology Objective)
时间窗: 7-14 days after starting therapy and prior to surgery
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.
Number of Participants With a Sustained Objective Response (Complete or Partial Response) (Phase II Objective)
时间窗: 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)
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.
次要结局
- Tumor to Plasma Lapatinib Concentration (Molecular Biology Objective)(First dose of lapatinib prior to surgery)
- Maximum Concentration of Lapatinib in Plasma (Phase II Objective)(First dose of lapatinib in course 1)
- Number of Participants With Tumors Expressing Total ERBB2(Pre-treatment)
- Number of Participants With Tumors Expressing Phosphorylated ERBB2 (Phase II Objective)(Pre-treatment)