EGFR Inhibition Using Weekly Erlotinib for Recurrent Malignant Gliomas

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Genentech, Inc.
OSI Pharmaceuticals
Memorial Sloan Kettering Cancer Center
Information provided by (Responsible Party):
Columbia University
ClinicalTrials.gov Identifier:
NCT01257594
First received: December 8, 2010
Last updated: July 14, 2015
Last verified: July 2015
  Purpose

The purpose of this study is to test the effectiveness of a drug called erlotinib in treating the tumor. This will be a multi-center pilot study that will explore 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.


Condition Intervention
Brain Cancer
Drug: erlotinib
Procedure: Cytoreductive Surgery

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • 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 EGFR vIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).



Secondary Outcome Measures:
  • Cmax blood concentration level 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)


Enrollment: 22
Study Start Date: January 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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
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

Detailed Description:

Following informed consent, patients will be enrolled into one of two study arms based on their eligibility for tumor resection:

  • Cohort A (medical cohort) 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.
  • Cohort B (surgical cohort) 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.

Accrual to either Cohort A or B may continue and exceed 11 participants provided the total accrual to the study does not exceed 22 participants.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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.
  • 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 VEGF/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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01257594

Locations
United States, New Jersey
Memorial Sloan-Kettering at Basking Ridge
Basking Ridge, New Jersey, United States, 07920
United States, New York
Memorial Sloan-Kettering Cancer Center at Commack
Commack, New York, United States, 11725
Columbia University Medical Center
New York, New York, United States, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Columbia University
Genentech, Inc.
OSI Pharmaceuticals
Memorial Sloan Kettering Cancer Center
Investigators
Principal Investigator: Andrew Lassman, MD Columbia University
  More Information

Additional Information:
No publications provided

Responsible Party: Columbia University
ClinicalTrials.gov Identifier: NCT01257594     History of Changes
Other Study ID Numbers: AAAJ7500
Study First Received: December 8, 2010
Last Updated: July 14, 2015
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Columbia University:
Gliomas
Erlotinib
Glioblastoma
GBM
Gliosarcoma
Glioma

Additional relevant MeSH terms:
Erlotinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 30, 2015