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EGFR Inhibition Using Weekly Erlotinib for Recurrent Malignant Gliomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01257594
Recruitment Status : Completed
First Posted : December 9, 2010
Last Update Posted : April 23, 2019
Genentech, Inc.
OSI Pharmaceuticals
Information provided by (Responsible Party):
Andrew B Lassman, MD, Columbia University

Tracking Information
First Submitted Date  ICMJE December 8, 2010
First Posted Date  ICMJE December 9, 2010
Last Update Posted Date April 23, 2019
Actual Study Start Date  ICMJE January 7, 2011
Actual Primary Completion Date November 22, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2015)
Clinical Benefit Rate (either radiographic response or at least 6 months of progression-free survival) [ Time Frame: Up to 3 years ]
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 EGFR vIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).
Original Primary Outcome Measures  ICMJE
 (submitted: December 8, 2010)
Explore efficacy of pulsatile dosing [ Time Frame: 2 years ]
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.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2010)
  • signaling through EGFR and related molecules [ Time Frame: 2 years ]
    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 ]
  • intratumoral concentration of erlotinib and active metabolites [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE EGFR Inhibition Using Weekly Erlotinib for Recurrent Malignant Gliomas
Official Title  ICMJE Pilot Study of EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation
Brief Summary The purpose of this study is to test the effectiveness of a drug called erlotinib in treating the tumor. This is a multi-center pilot study that explores efficacy and molecular effects of high dose weekly erlotinib for recurrent EGFR vIII mutant malignant gliomas, and correlate molecular profile of pre-treatment tissue with outcome.
Detailed Description This is a pilot study of erlotinib for subjects who have a brain tumor called a glioblastoma or another malignant glioma, which has continued to grow after treatment. 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 subjects with other cancers (lung cancer or pancreatic cancer). It is not approved for glioblastoma or another malignant glioma. Erlotinib blocks a messenger that tells cancer cells to grow. That messenger is called Epidermal Growth Factor Receptor (EGFR). This type of tumor contains a form of EGFR called variant number 3 (abbreviated EGFR variant III or EGFRvIII for short) that is different from the normal form.Research suggests that erlotinib is particularly effective at stopping 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Brain Cancer
Intervention  ICMJE
  • Drug: erlotinib
    For patients with no cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. For patients with cytoreductive surgery planned, 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.
    Other Name: Tarceva
  • Procedure: Cytoreductive Surgery
    Standard procedure
Study Arms  ICMJE
  • 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.
    • Drug: erlotinib
    • Procedure: Cytoreductive Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 8, 2010)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 31, 2018
Actual Primary Completion Date November 22, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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 not otherwise specified (NOS).
  • 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.
  • Recovered from toxic effects of prior therapies.
  • Able to undergo contrast enhanced MRI scans (or CT scans for patients unable to tolerate MRI).
  • 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 = 18 years.
  • Karnofsky Performance Status > or = 60%.
  • Life expectancy of > 8 weeks.
  • 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.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Ability to swallow the tablets.

Cohort A (medical) specific inclusion criteria:

  • 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.
  • 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:

  • Fulfill all of the general inclusion criteria.
  • An MRI/CT scan showing progression is required.

Exclusion Criteria:

  • Received prior treatment with convection enhanced delivery, other catheter based intratumoral treatment, or carmustine (BCNU)/Gliadel wafers.
  • 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.
  • Prior treatment with an EGFR inhibitor.
  • Received prior treatment with direct Vascular endothelial growth factor (VEGF)/Vascular Endothelial Growth Factor Receptors (VEGFR) inhibitors.
  • Smoking or plan to smoke tobacco or marijuana during study therapy.
  • Receiving any other investigational agents concurrently with study treatment.
  • 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.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib.
  • Uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Have HIV and are receiving combination antiretroviral therapy.
  • Other active concurrent malignancy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older 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 NCT01257594
Other Study ID Numbers  ICMJE AAAJ7500
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Andrew B Lassman, MD, Columbia University
Study Sponsor  ICMJE Andrew B Lassman, MD
Collaborators  ICMJE
  • Genentech, Inc.
  • OSI Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Andrew Lassman, MD Columbia University
PRS Account Columbia University
Verification Date April 2019

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