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

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ClinicalTrials.gov Identifier: NCT00095940
Recruitment Status : Completed
First Posted : November 9, 2004
Results First Posted : February 6, 2012
Last Update Posted : May 23, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 9, 2004
First Posted Date  ICMJE November 9, 2004
Results First Submitted Date  ICMJE August 2, 2011
Results First Posted Date  ICMJE February 6, 2012
Last Update Posted Date May 23, 2014
Study Start Date  ICMJE October 2004
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 3, 2012)
  • Relative Phosphorylation of ERBB2 (Molecular Biology Objective) [ Time Frame: 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) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2012)
  • Tumor to Plasma Lapatinib Concentration (Molecular Biology Objective) [ Time Frame: First dose of lapatinib prior to surgery ]
    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.
  • Maximum Concentration of Lapatinib in Plasma (Phase II Objective) [ Time Frame: First dose of lapatinib in course 1 ]
    Serial plasma samples for pharmacokinetic studies of lapatinib will be collected from consenting participants with the first dose of course 1.
  • Number of Participants With Tumors Expressing Total ERBB2 [ Time Frame: Pre-treatment ]
    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.
  • Number of Participants With Tumors Expressing Phosphorylated ERBB2 (Phase II Objective) [ Time Frame: Pre-treatment ]
    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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Lapatinib in Treating Young Patients With Recurrent or Refractory Central Nervous System Tumors
Official Title  ICMJE Molecular Biology and Phase II Study of Lapatinib (GW572016) in Pediatric Patients With Recurrent or Refractory Medulloblastoma, Malignant Glioma or Ependymoma
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • Drug: lapatinib ditosylate
    Given orally
    Other Names:
    • GSK572016
    • GW-572016
    • GW2016
    • Lapatinib
    • Tykerb
  • Procedure: therapeutic conventional surgery
    Undergo surgery
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Procedure: positron emission tomography
    Correlative studies
    Other Names:
    • FDG-PET
    • PET
    • PET scan
    • tomography, emission computed
  • Procedure: magnetic resonance imaging
    Correlative studies
    Other Names:
    • MRI
    • NMR imaging
    • NMRI
    • nuclear magnetic resonance imaging
Study Arms  ICMJE Experimental: 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.

Interventions:
  • Drug: lapatinib ditosylate
  • Procedure: therapeutic conventional surgery
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
  • Procedure: positron emission tomography
  • Procedure: magnetic resonance imaging
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 3, 2012)
52
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE July 2010
Actual Primary Completion Date July 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00095940
Other Study ID Numbers  ICMJE NCI-2012-03007
NCI-2012-03007 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PBTC-016 ( Other Identifier: Pediatric Brain Tumor Consortium )
PBTC-016 ( Other Identifier: CTEP )
U01CA081457 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Maryam Fouladi Pediatric Brain Tumor Consortium
PRS Account National Cancer Institute (NCI)
Verification Date January 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP