Erlotinib and Sorafenib in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme
Primary Purpose
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
erlotinib hydrochloride
sorafenib tosylate
pharmacological study
Sponsored by
About this trial
This is an interventional treatment trial for Adult Giant Cell Glioblastoma
Eligibility Criteria
Inclusion Criteria:
- Patients must have histologically confirmed supratentorial glioblastoma multiforme which is progressive or recurrent after radiation therapy ± chemotherapy; patients with previous low grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have a high grade glioma are eligible
- Patients must have tissue specimens available and agree to have their blood and tissue blocks (or slides) submitted for the combined correlative studies
- Patients must have measurable contrast enhancing progressive or recurrent glioblastoma multiforme by MRI or CT imaging (Within 14 days before starting treatment)
- Patients must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy, while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen; NOTE: For a non-cytotoxic, FDA approved agents (i.e. Celebrex, thalidomide, etc.) therapy could be started 2 weeks after discontinuing this agent provided the patient has fully recovered from all toxicity associated with the agent; for investigational, non-cytotoxic agents a minimum of 3 weeks must have elapsed before the patient will be eligible for this study
- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
- Absolute Neutrophil Count >= 1500/mm^3
- Platelets >= 100,000/mm^3
- Creatinine =< 1.7mg/dl
- Total Bilirubin within normal institutional limits
- Transaminases =< 2.5 times above the upper limits of the institutional norm
- PT, PTT ≤ institutional norm
- Patients must be able to provide written informed consent
- Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception; women of childbearing potential must have a negative serum pregnancy test; (the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant)
- Patients must have a Mini Mental State Exam score >= 15
Exclusion Criteria:
- Patients with serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety; (examples of medical illnesses are [but not limited to] the following: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements)
- Patients with uncontrolled hypertension; hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled hypertension are eligible
- Patients who are pregnant or breast-feeding (the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant)
- Patients who have received more than two prior treatments
- Patients who have had prior therapy with erlotinib or sorafenib or any other agent targeting EGFR
- Patients receiving concurrent therapy for their tumor (with the exception of steroids)
- Patients undergoing major surgery or sustaining a significant traumatic injury within 21 days prior to treatment are ineligible
- Patients with a concurrent malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients with a prior malignancy are ineligible unless they have been free of disease for >= five years
- Patients must not have any evidence of bleeding diathesis or coagulopathy
- Patients with PT INR > 1.5 are excluded, unless the patient is on full dose warfarin
Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met:
- The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
- The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
- NOTE: Patients on a full dose of anticoagulants will a different schedule for PT/INR evaluations
- Prophylactic anticoagulation (i.e. low dose warfarin) are eligible provided their coagulation parameter levels are as follows: prothrombin time (INR; International Normalized Ratio of prothrombin time) < 1.1 x institutional upper limit of normal
- Patients with known abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) are excluded
- Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills are excluded
- Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) and must not have taken them for at least 10 days
- Patients may not have allergies to or a history of allergic reactions attributed to erlotinib and/or sorafenib
- Eligibility of patients receiving any other medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of erlotinib or sorafenib will be determined following review of their case by the Principal Investigator
- HIV patients receiving combination anti-retroviral therapy will be excluded
Sites / Locations
- University of Alabama at Birmingham
- Moffitt Cancer Center
- Emory University
- Johns Hopkins University
- Massachusetts General Hospital
- Henry Ford Hospital
- Wake Forest University Health Sciences
- Cleveland Clinic
- University of Pennsylvania
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment
Arm Description
Patients receive oral erlotinib hydrochloride 150mg once daily and oral sorafenib tosylate 400mg twice daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Other: pharmacological study
Outcomes
Primary Outcome Measures
Overall Survival
death. measured by time of first day of treatment until date of death, assessed up to 2 years.
Secondary Outcome Measures
6months -Progression-free Survival Rate
defined patient started treatment is alive and progression free at the time of 26-week (6 months) follow-up
Full Information
NCT ID
NCT00445588
First Posted
March 7, 2007
Last Updated
March 25, 2016
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00445588
Brief Title
Erlotinib and Sorafenib in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme
Official Title
A Phase II Trial of Erlotinib (OSI-774) and Sorafenib (BAY 43-9006) for Patients With Progression or Recurrent Glioblastoma Multiforme
Study Type
Interventional
2. Study Status
Record Verification Date
March 2016
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
August 2009 (Actual)
Study Completion Date
August 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase II trial is studying how well giving erlotinib together with sorafenib works in treating patients with progressive or recurrent glioblastoma multiforme. Erlotinib and sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving erlotinib together with sorafenib may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES:
I. The primary objective of this trial is to estimate the overall survival rate associated with this combined regimen in treating adult patients with recurrent glioblastoma multiforme.
SECONDARY OBJECTIVES:
I. To assess and estimate the toxicities. II. Tumor response rate. III. To estimate 6-month progression free survival. IV. To describe the pharmacokinetics of this route of administration. V. For the Molecular Targeted Combinations Correlative (MTC2) Study Initiative: To determine the relationship between tumor and blood biomarkers and clinical outcome of patients treated with the combination of targeted agents.
OUTLINE: This is a multicenter, open-label, phase II study.
Patients receive oral erlotinib hydrochloride once daily and oral sorafenib tosylate twice daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
Tumor tissue and blood samples are collected prior to beginning treatment. Samples are analyzed by immunohistochemistry, gene expression, and DNA mutation and genomic analyses of the epidermal growth factor receptor, ras-raf-ERK, and PI3K-Akt-mTOR pathways to identify markers that correlate with patient outcomes. Blood samples are also collected on day 15 of course 1 for pharmacokinetic studies. Samples are analyzed by reversed-phase isocratic high-performance liquid chromatography with electrospray ionization mass spectrometry to determine the concentration of erlotinib hydrochloride and sorafenib tosylate and its known metabolites.
After completion of study therapy, patients are followed every 2 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
56 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment
Arm Type
Experimental
Arm Description
Patients receive oral erlotinib hydrochloride 150mg once daily and oral sorafenib tosylate 400mg twice daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
Other: pharmacological study
Intervention Type
Drug
Intervention Name(s)
erlotinib hydrochloride
Other Intervention Name(s)
OSI-774
Intervention Description
150mg Given orally once daily
Intervention Type
Drug
Intervention Name(s)
sorafenib tosylate
Other Intervention Name(s)
BAY 3-9006
Intervention Description
400mg Given orally twice daily
Intervention Type
Other
Intervention Name(s)
pharmacological study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Overall Survival
Description
death. measured by time of first day of treatment until date of death, assessed up to 2 years.
Time Frame
Time of first day of the treatment to death, assessed up to 2 years
Secondary Outcome Measure Information:
Title
6months -Progression-free Survival Rate
Description
defined patient started treatment is alive and progression free at the time of 26-week (6 months) follow-up
Time Frame
At 6 months- defined as patient started treatment is alive and progression free at the time of 26-week (6 months) follow-up
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients must have histologically confirmed supratentorial glioblastoma multiforme which is progressive or recurrent after radiation therapy ± chemotherapy; patients with previous low grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have a high grade glioma are eligible
Patients must have tissue specimens available and agree to have their blood and tissue blocks (or slides) submitted for the combined correlative studies
Patients must have measurable contrast enhancing progressive or recurrent glioblastoma multiforme by MRI or CT imaging (Within 14 days before starting treatment)
Patients must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy, while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen; NOTE: For a non-cytotoxic, FDA approved agents (i.e. Celebrex, thalidomide, etc.) therapy could be started 2 weeks after discontinuing this agent provided the patient has fully recovered from all toxicity associated with the agent; for investigational, non-cytotoxic agents a minimum of 3 weeks must have elapsed before the patient will be eligible for this study
Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
Absolute Neutrophil Count >= 1500/mm^3
Platelets >= 100,000/mm^3
Creatinine =< 1.7mg/dl
Total Bilirubin within normal institutional limits
Transaminases =< 2.5 times above the upper limits of the institutional norm
PT, PTT ≤ institutional norm
Patients must be able to provide written informed consent
Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception; women of childbearing potential must have a negative serum pregnancy test; (the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant)
Patients must have a Mini Mental State Exam score >= 15
Exclusion Criteria:
Patients with serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety; (examples of medical illnesses are [but not limited to] the following: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements)
Patients with uncontrolled hypertension; hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled hypertension are eligible
Patients who are pregnant or breast-feeding (the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant)
Patients who have received more than two prior treatments
Patients who have had prior therapy with erlotinib or sorafenib or any other agent targeting EGFR
Patients receiving concurrent therapy for their tumor (with the exception of steroids)
Patients undergoing major surgery or sustaining a significant traumatic injury within 21 days prior to treatment are ineligible
Patients with a concurrent malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients with a prior malignancy are ineligible unless they have been free of disease for >= five years
Patients must not have any evidence of bleeding diathesis or coagulopathy
Patients with PT INR > 1.5 are excluded, unless the patient is on full dose warfarin
Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met:
The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
NOTE: Patients on a full dose of anticoagulants will a different schedule for PT/INR evaluations
Prophylactic anticoagulation (i.e. low dose warfarin) are eligible provided their coagulation parameter levels are as follows: prothrombin time (INR; International Normalized Ratio of prothrombin time) < 1.1 x institutional upper limit of normal
Patients with known abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) are excluded
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills are excluded
Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) and must not have taken them for at least 10 days
Patients may not have allergies to or a history of allergic reactions attributed to erlotinib and/or sorafenib
Eligibility of patients receiving any other medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of erlotinib or sorafenib will be determined following review of their case by the Principal Investigator
HIV patients receiving combination anti-retroviral therapy will be excluded
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Peereboom, MD
Organizational Affiliation
New Approaches to Brain Tumor Therapy Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
23328813
Citation
Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S, Nabors LB, Rosenfeld MR, Mikkelsen T, Grossman SA; New Approaches to Brain Tumor Therapy Consortium. NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol. 2013 Apr;15(4):490-6. doi: 10.1093/neuonc/nos322. Epub 2013 Jan 17.
Results Reference
result
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Erlotinib and Sorafenib in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme
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