EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation
This study is currently recruiting participants.
Verified January 2013 by Columbia University
Memorial Sloan-Kettering Cancer Center
Information provided by (Responsible Party):
Andrew Lassman, Columbia University
First received: December 8, 2010
Last updated: January 25, 2013
Last verified: January 2013
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.
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
||Pilot Study of EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation
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 EGFRvIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).
Secondary Outcome Measures:
- 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)
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||December 2013 (Final data collection date for primary outcome measure)
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.
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 (from -2 to +3 days to allow for weekend or holiday or other scheduling difficulties). Tablets should be taken at the same time each week with approximately 200 mL of water at least 1 hour before or 2 hours after a meal. Patients who are unable to swallow tablets may dissolve the tablets in water for administration.
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.
Pre-operative care: 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. Patients will have blood drawn during surgery to determine the concentration of erlotinib in serum at the time of surgery for determination of the concentration of erlotinib and active metabolites in tumor tissue relative to simultaneously collected serum. The date and time of blood collection should be recorded. Patients must undergo a post-operative MRI scan as a new baseline within 96 hours post-operatively.
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.
- In addition, post-operatively, treatment with erlotinib must re-start no later than the 14th day after the post-operative MRI scan.
- 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).
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Patients must have a histologically confirmed intracranial malignant glioma of the following types:
Glioblastoma (GBM) Gliosarcoma (GS) is a subset of GBM and patients with GS are therefore eligible.
Anaplastic astrocytoma (AA) Anaplastic oligodendroglioma (AO) Anaplastic oligoastrocytoma (AOA, also called anaplastic mixed gliomas or AMG) High grade glioma NOS (Not otherwise specified) Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) glioma is made.
- EGFRvIII mutation detected on pretreatment tissue from at least 1 prior surgery, preferably the most recent surgery in patients who have undergone more than 1 resection. EGFR gene amplification alone is insufficient. This MUST BE PERFORMED AT Columbia University Medical Center or Memorial Sloan-Kettering Cancer Center. Any questions should be addressed to the Sponsor.
- At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery. Frozen tissue is also requested if available.
- Before starting study treatment, patients must have recovered from toxic effects of prior therapies and at least 4 weeks must have elapsed since any prior anti-cancer therapy except: at least 6 weeks from nitrosoureas (e.g., BCNU, CCNU) and at least 3 months from prior brain radiotherapy to reduce the likelihood that patients enrolled have pseudoprogression rather than true disease progression.
- 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. The same type of scan, i.e., MRI (or CT for patients who cannot undergo MRI) must be used throughout the period of protocol treatment for tumor measurement. Criteria in section 12 for progression on this study are not mandatory for eligibility if the disease progression is obvious in the opinion of the investigator and the PI or co-PI agrees. Any questions should be addressed to the Sponsor.
- 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 (WBC > or = to 2,000/μl, ANC > or = to 1,500/mm3, platelet count of > or = to 100,000/mm3, and hemoglobin > 10 gm/dl), adequate liver function (SGOT, SGPT and bilirubin < 2 times ULN), and adequate renal function (creatinine < 1.5 mg/dL) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation because the effects of erlotinib on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Women of childbearing potential must have a negative B-HCG 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.
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, progressive disease led to the surgery, and the histology of the most recent surgery documented recurrent/progressive/persistent malignant glioma.
- Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT. If the corticosteroid dose is increased between the date of imaging and registration a new baseline MRI/CT is required. Definition of stable steroids includes patients on no steroids.
- The baseline brain MRI/CT must be performed on the 14th day or less prior to initiation of study treatment. Otherwise it must be repeated.
Cohort B (surgical) specific inclusion criteria:
- Patients must fulfill all of the General Inclusion Criteria.
- An MRI/CT scan showing progression is required. Stable corticosteroids are not required.
- There is no limit on the number or type of prior chemotherapies except:
- Patients must not have received prior treatment with convection enhanced delivery, other catheter based intratumoral treatment, or carmustine (BCNU)/Gliadel wafers because of potential difficulty interpreting brain scans in such patients.
- Patients with prior therapy that included stereotactic radiosurgery (including gamma-knife or cyber-knife) 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. Imaging with MRSpectroscopy, MRPerfusion, PET, or other techniques is not adequate to exclude radiation necrosis for this study. (Clarke et al., 2008).
- Patients may not have received prior treatment with an EGFR inhibitor such as erlotinib,(Tarceva), gefitinib,(Iressa), lapatinib,(Tykerb), vandetanib,(Zactima), or cetuximab (Erbitux), PF299804, or therapy with an anti-EGFR vIII antibody. Any question about the definition of an EGFR inhibitor should be discussed with the Sponsor.
- Patients may not have received prior treatment with direct VEGF/VEGFR inhibitors such as bevacizumab (Avastin), aflibercept (VEGF-Trap), cediranib (AZD2171), or XL-184 (Cabozantinib) because evidence suggests the biology of gliomas following progression on such agents differs, and there is little to no historic control data presently available for such patients.
- 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) defined as:
Carbamazepine (Tegretol, Tegretol XR, Carbatrol) Oxcarbazepine (Trileptal) Phenytoin (Dilantin, Phenytek) Fosphenytoin (Cerebyx) Phenobarbital Primidone (Mysoline) 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 including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with erlotinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. This applies only to patients who have a documented history of HIV and HIV testing is not otherwise required.
- Patients must not have other active concurrent malignancy. Any questions should be addressed to the Sponsor.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01257594
|Memorial Sloan-Kettering at Basking Ridge
|Basking Ridge, New Jersey, United States, 07920 |
|Contact: Ingo Mellinghoff, MD 646-888-3036 |
|Memorial Sloan-Kettering Cancer Center at Commack
|Commack, New York, United States, 11725 |
|Contact: Ingo Mellinghoff, MD 646-888-3036 |
|Memorial Sloan Kettering Cancer Center
|New York, New York, United States, 10065 |
|Contact: Ingo Mellinghoff, MD 646-888-3036 |
|Contact: Christian Grommes, MD 212-639-4058 |
|Columbia University Medical Center
|New York, New York, United States, 10032 |
|Contact: Francine Armentano, NP 212-305-5969 firstname.lastname@example.org |
Memorial Sloan-Kettering Cancer Center
||Andrew Lassman, MD
No publications provided
||Andrew Lassman, Associate Professor of Neurology, Columbia University
History of Changes
|Other Study ID Numbers:
|Study First Received:
||December 8, 2010
||January 25, 2013
||United States: Food and Drug Administration
United States: Institutional Review Board
Keywords provided by Columbia University:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on December 12, 2013
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Central Nervous System Diseases
Nervous System Diseases
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action