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Recurrent Childhood Anaplastic AstrocytomaPhase 1/2NCT00095940

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

A Phase 1/2 study testing lapatinib ditosylate, therapeutic conventional surgery and laboratory biomarker analysis in people with Recurrent Childhood Anaplastic Astrocytoma and Recurrent Childhood Brain Stem Glioma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 21 years
What is being tested?
lapatinib ditosylate, therapeutic conventional surgery and laboratory biomarker analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
1 siteUnited States
Study dates
Oct 2004to Jul 2010
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)
Show all 39Show fewer
  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Pediatric Brain Tumor Consortium

    Memphis, Tennessee, 38105

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

Being tested
lapatinib ditosylate, therapeutic conventional surgery, laboratory biomarker analysis, pharmacological study, positron emission tomography
Medical subject headings
Astrocytoma, Familial ependymoma, Glioblastoma, Medulloblastoma, Oligodendroglioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • lapatinib ditosylateDrug

    Also called GSK572016, GW-572016, GW2016, Lapatinib

    Given orally

  • therapeutic conventional surgeryProcedure or surgery

    Undergo surgery

  • laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • positron emission tomographyProcedure or surgery

    Also called FDG-PET, PET, PET scan, tomography, emission computed

    Correlative studies

  • magnetic resonance imagingProcedure or surgery

    Also called MRI, NMR imaging, NMRI, nuclear magnetic resonance imaging

    Correlative studies

Study groups in NCT00095940
Study groupRoleWhat they receive
Treatment (surgery, lapatinib)ExperimentalMolecular 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.
Receives: Drug: lapatinib ditosylate; Procedure: therapeutic conventional surgery; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: positron emission tomography; Procedure: magnetic resonance imaging

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 7-14 days after starting therapy and prior to surgery

  2. 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.

    Measured: 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 outcomes (4)

  1. 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.

    Measured: First dose of lapatinib prior to surgery

  2. 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.

    Measured: First dose of lapatinib in course 1

  3. 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.

    Measured: Pre-treatment

  4. 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.

    Measured: Pre-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Nov 2004 (estimated)
  2. Study startOct 2004
  3. Primary completionJul 2010
  4. Study completionJul 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
52 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00095940
Sponsor's protocol ID
NCI-2012-03007
Other IDs
NCI-2012-03007, PBTC-016, PBTC-016, U01CA081457
Status last verified
Jan 2013
First submitted
9 Nov 2004
Last updated
23 May 2014

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing lapatinib ditosylate, therapeutic conventional surgery and laboratory biomarker analysis in people with Recurrent Childhood Anaplastic Astrocytoma and Recurrent Childhood Brain Stem Glioma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 39 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 May 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Feb 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Relative Phosphorylation of ERBB2 (Molecular Biology Objective) (time frame: 7-14 days after starting therapy and prior to surgery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00095940.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 May 2014.

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