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EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Genentech, Inc.
OSI Pharmaceuticals
Memorial Sloan-Kettering Cancer Center
Information provided by (Responsible Party):
Andrew Lassman, Columbia University
ClinicalTrials.gov Identifier:
NCT01257594
First received: December 8, 2010
Last updated: August 29, 2014
Last verified: August 2014

December 8, 2010
August 29, 2014
December 2010
December 2014   (final data collection date for primary outcome measure)
Clinical Benefit Rate (either radiographic response or at least 6 months of progression-free survival) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

All patients will have their tumor measurements recorded at baseline and at the time of each MRI/CT scan.

Clinical efficacy of pulsatile dosing with the EGFR Tyrosine Kinase Inhibitor erlotinib in patient with EGFRvIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).

Explore efficacy of pulsatile dosing [ Time Frame: 2 years ] [ Designated as safety issue: No ]
All patients will continue weekly pulsatile erlotinib until either disease progression (assessed by routine brain MRI approximately every 2 cycles with a cycle defined as 28 days) or intolerable agent related toxicity defined as moderate, severe, or life-threatening drug related toxicity (≥ Common Toxicity Criteria grade 3) despite dose modification.
Complete list of historical versions of study NCT01257594 on ClinicalTrials.gov Archive Site
  • Cmax and AUC blood concentration levels of Erlotinib [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
    Pharmacokinetics will be measured, including intratumoral concentration of erlotinib and active metabolites. Blood samples will be drawn at indicated timepoints in order to assess the Cmax blood concentration levels of Erlotinib for subjects on treatment.
  • Immunohistochemistry Score (4 point scale, 0 to 3) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Evaluation of the in vivo biological activity of protocol therapy will be explored by a within patient comparison of EGFR activation (measured by pEGFR), PI3K/AKT/mTOR/S6K signaling (measured by pS6K and pAKT and related molecules), RAS/RAF/MEK/ERK signaling (measured by pERK and related molecules) and cell proliferation (measured by Ki-67 immunostaining to estimate the proliferation index as the % of tumor cells staining per high power field) in pre-treatment archived tissue versus the tissue acquired during treatment for patients in cohort B. Slides analyzed by immunohistochemistry will be scored for staining on a 4 point scale (0-3)
  • signaling through EGFR and related molecules [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Evaluation of the in vivo biological activity of protocol therapy will be explored by a within patient comparison of EGFR activation (measured by pEGFR), PI3K/AKT/mTOR/S6K signaling (measured by pS6K and pAKT and related molecules), RAS/RAF/MEK/ERK signaling (measured by pERK and related molecules) and cell proliferation (measured by Ki-67 immunostaining to estimate the proliferation index as the % of tumor cells staining per high power field) in pre-treatment archived tissue versus the tissue acquired during treatment for patients in cohort B.
  • tumor cell proliferation [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • intratumoral concentration of erlotinib and active metabolites [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation
Pilot Study of EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation

The purpose of this study is to test the effectiveness of a drug called erlotinib in treating the tumor.

The study drug, erlotinib (also called Tarceva) is a pill (taken by mouth) that has been approved by the U.S. Food and Drug Administration (FDA) for the patients with other cancers (lung cancer or pancreatic cancer). It is considered investigational in brain tumors. Erlotinib blocks a messenger that tells cancer cells to grow. That messenger is called "epidermal growth factor receptor" which is abbreviated "EGFR." The tumor contains a form of EGFR called variant number 3 (abbreviated EGRR variant III or EGFRvIII for short) that is different from the normal form. Research suggests that erlotinib is particularly effective at stopping the EGFRvIII. Research also suggests that high doses of erlotinib taken once per week may be more effective than low doses of erlotinib taken once per day.

Not Provided
Interventional
Not Provided
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain Cancer
  • Drug: erlotinib
    For patients with no cytoreductive surgery planned. All doses of erlotinib will be self-administered in an open-label, unblinded manner. During the treatment period, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. Patients who are unable to swallow tablets may dissolve the tablets in water for administration.
    Other Name: Tarceva
  • Drug: erlotinib
    For patients with cytoreductive surgery planned. All erlotinib doses except the immediate pre-operative dose will be self-administered in an open-label, unblinded manner. During the treatment period, patients will receive single-agent erlotinib at a starting dose of 2000 mg day 1 of every 7 days (+/- 2 days). One pre-operative dose of 2000 mg erlotinib will be administered in an open-label, unblinded manner, administered in the hospital "on call" to the operating room. Resection will occur within approximately 3 hours after the pre-operative dose. Following recovering from surgery, treatment with erlotinib post-operatively should resume no sooner than the 8th post-operative day and no later than 28th post-operative day.
    Other Name: Tarceva
  • Experimental: No cytoreductive surgery planned
    Patients who are not candidates for surgery as part of their routine care will enroll into the medical arm of the trial. They will initiate pulsatile erlotinib dosing and continue therapy until either disease progression or intolerable toxicity.
    Intervention: Drug: erlotinib
  • Experimental: Cytoreductive surgery planned
    Patients scheduled for "salvage" resection as part of their routine care will be considered for this cohort. They will receive 1 pre-operative dose of 2000 mg erlotinib. Resection will occur ≤ 3 hours after the pre-operative dose. After recovery from surgery, patients will resume pulsatile erlotinib dosing.
    Intervention: Drug: erlotinib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
22
December 2014
December 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have a histologically confirmed intracranial malignant glioma of the following types: Glioblastoma (GBM), Gliosarcoma (GS), Anaplastic astrocytoma (AA), Anaplastic oligodendroglioma (AO), Anaplastic oligoastrocytoma (AOA, also called anaplastic mixed gliomas or AMG), High grade glioma NOS (Not otherwise specified).
  • EGFRvIII mutation detected on pretreatment tissue from at least 1 prior surgery.
  • At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery.
  • Patients must have recovered from toxic effects of prior therapies.
  • Patients must be able to undergo contrast enhanced MRI scans (or CT scans for patients unable to tolerate MRI).
  • Patients must have shown unequivocal evidence for contrast enhancing tumor progression by MRI (or CT for patients who cannot tolerate MRI) in comparison to a prior scan.
  • Age > or = to 18 years.
  • Karnofsky Performance Status > or = to 60%
  • Life expectancy of greater than 8 weeks.
  • Patients must have normal organ and marrow function, adequate liver function and adequate renal function before starting therapy.
  • Women of child-bearing potential and men must agree to use adequate contraception.
  • Women of childbearing potential must have a negative pregnancy test documented within 7 days prior to treatment.
  • Women must agree not to breast feed.
  • Patients must have the ability to understand and the willingness to sign a written informed consent document.
  • Patients must have the ability to swallow the tablets.

Cohort A (medical) specific inclusion criteria:

  • Patients must fulfill all of the General Inclusion Criteria.
  • MRI/CT must demonstrate measurable enhancing tumor of at least 1cm2 in cross-sectional area to allow assessment of radiographic response, unless: measurable disease is not present because the patient underwent gross total resection as the most recent anti-tumor therapy.
  • At least 3 months have elapsed between any prior brain radiotherapy and initiation of study therapy.
  • MRI/CT must demonstrate measureable enhancing tumor at least 1cm by 1cm squared in cross-sectional area to allow assessment of radiographic response.
  • Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT.
  • The baseline MRI/CT must be performed on the 14th day or less prior to initiation of study treatment.

Cohort B (surgical) specific inclusion criteria:

  • Patients must fulfill all of the General Inclusion Criteria.
  • An MRI/CT scan showing progression is required.

Exclusion Criteria:

  • Patients must not have received prior treatment with convection enhanced delivery, other catheter based intratumoral treatment, or carmustine (BCNU)/Gliadel wafers.
  • Patients with prior therapy that included stereotactic radiosurgery during therapy for newly diagnosed or recurrent disease, or re-irradiation of any type, must have confirmation of true progressive disease rather than radiation necrosis based upon surgical documentation of recurrent/progressive disease.
  • Patients may not have received prior treatment with an EGFR inhibitor.
  • Patients may not have received prior treatment with direct VEGF/VEGFR inhibitors.
  • Patients may not smoke or plan to smoke tobacco or marijuana during study therapy.
  • Patients may not be receiving any other investigational agents concurrently with study treatment.
  • Patients must not be taking Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an EIAED, the patient must be off of it for at least two weeks prior to study treatment.
  • Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib.
  • Patients must not have uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Patients with HIV who are receiving combination antiretroviral therapy.
  • Patients must not have other active concurrent malignancy.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01257594
AAAJ7500
Yes
Andrew Lassman, Columbia University
Andrew Lassman
  • Genentech, Inc.
  • OSI Pharmaceuticals
  • Memorial Sloan-Kettering Cancer Center
Principal Investigator: Andrew Lassman, MD Columbia University
Columbia University
August 2014

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