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VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide

Primary Purpose

Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ziv-aflibercept
pharmacological study
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Anaplastic Astrocytoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: International Normalized Ratio (INR) < = 1.5 Platelet count => 100,000/mm³ Hemoglobin => 10 g/dL (transfusion allowed) Serum glutamic oxaloacetic transaminase (SGOT)/Serum glutamic pyruvic transaminase (SGPT) < = 2 times upper limit of normal (ULN) Not pregnant or nursing Negative pregnancy test No previous Vascular endothelial growth factor (VEGF) Trap At least 4 weeks since chemotherapy, surgery, or open biopsy At least 2 weeks since vincristine At least 6 weeks since carmustine, lomustine, fotemustine, or radiation therapy At least 42 days since prior nitrosoureas At least 3 weeks since procarbazine No previous Gliadel wafers or bevacizumab Tumor did not respond to previous radiation therapy and temozolomide Karnofsky performance status (KPS) 60-100% Life expectancy = > 8 weeks White blood count (WBC) = >3,000/mm³ Absolute neutrophil count = > 1,500/mm³ Bilirubin < = 2 times ULN Creatinine < = 1.5 mg/dL OR creatinine clearance= > 60 mL/min Urine protein:creatinine ratio < = 1 OR 24-hour urine protein < = 500 mg/dL Fertile patients must use effective contraception prior to, during, and for = > 6 months after completion of study treatment No significant medical illnesses that, in the opinion of the investigator, cannot be adequately controlled with appropriate therapy or would preclude compliance with study treatment No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No history of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study No history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for = >3 years At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin [radiosensitizer does not count]) At least 7 days since prior core biopsy At least 28 days since prior investigational agents No prior bevacizumab or vascular endothelial growth factor receptor inhibitors No concurrent full-dose anticoagulants (e.g., warfarin or low molecular-weight heparin) No clinically significant cardiovascular disease, including any of the following: Cerebrovascular accident within the past 6 months Uncontrolled hypertension, defined as blood pressure (BP) > 140/90 mm Hg or systolic BP > 180 mm Hg if diastolic BP < 90 mm Hg, on ≥ 2 repeated determinations on separate days within the past 3 months Myocardial infarction, coronary artery bypass graft (CABG), or unstable angina pectoris within the past 6 months New York Heart Association class III-IV congestive heart failure No serious cardiac arrhythmia requiring medication Clinically significant peripheral vascular disease within the past 6 months Pulmonary embolism, deep vein thrombosis, or other thromboembolic event within the past 6 months No evidence of bleeding diathesis or coagulopathy No more than 1 prior chemotherapy regimen (initial treatment and treatment for 1 relapse) Surgical resection for relapsed disease with no anticancer therapy instituted for up to 12 weeks followed by another surgical resection is considered 1 relapse If prior therapy for a grade 3 glioma was given, surgical diagnosis of a high-grade glioma is considered the first relapse Prior surgical, interstitial brachytherapy, or stereotactic radiosurgery not considered prior therapy If prior therapy included interstitial brachytherapy or stereotactic radiosurgery, must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) scan, thallium scanning, Magnetic Resonance (MR) spectroscopy, or surgical documentation of disease Must show unequivocal radiographic evidence of tumor progression by MRI Recent resection of recurrent or progressive tumor allowed Residual disease not required Temozolomide-resistant recurrent glioblastoma is defined as tumor progression or tumor recurrence during or after treatment with temozolomide-based chemotherapy regimens Recovered from prior therapy No other disease that would obscure toxicity or dangerously alter drug metabolism No uncontrolled intercurrent illness, including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situations that would limit compliance with study requirements No serious or nonhealing wound, ulcer, or bone fracture No history of intracerebral or intratumoral hemorrhage No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No significant traumatic injury within the past 28 days At least 28 days since prior cytotoxic therapy Histologically confirmed diagnosis of 1 of the following: Intracranial glioblastoma or gliosarcoma Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic mixed oligoastrocytoma Malignant astrocytoma not otherwise specified NOTE: If original histology was grade 3 glioma, subsequent histological diagnosis of 1 of these diseases is allowed provided no prior diagnosis of grade 2 glioma At least 20 unstained slides OR 1 tissue block available from original diagnostic biopsy/surgery or from biopsy/surgery at recurrence Patients presenting at the time of first recurrence or relapse, defined as progression after initial therapy (i.e., radiotherapy +/- chemotherapy if that was used as initial therapy) are eligible No other concurrent investigational drugs No other concurrent investigational drugs No concurrent cytotoxic or noncytotoxic therapy, including chemotherapy, radiotherapy, hormonal therapy, or immunotherapy No concurrent major surgery No concurrent combination antiretroviral therapy for HIV-positive patients Concurrent anticonvulsant therapy allowed

Sites / Locations

  • University of California Los Angeles
  • University of California San Francisco
  • Dana-Farber Cancer Institute
  • Memorial Sloan-Kettering Cancer Center
  • University of Pittsburgh
  • M D Anderson Cancer Center
  • University of Wisconsin Hospital and Clinics

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

All Study Patients

Arm Description

Patients receive VEGF Trap (ziv-aflibercept) IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Other: pharmacological study; laboratory biomarker analysis.

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS) at 6 Months
This design yields 85% power to detect a true 30% 6-month PFS rate, while maintaining .91 probability of rejecting for a true 15% 6-month PFS rate. pts had MRIs at screening and at the 3rd and 5th cycles then every 8 weeks until progression. Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Safety Profile - Toxicities
number of cycles patient was able to have before developing a toxicity that required removing the patient from treatment. Treatment: Aflibercept 4mg/kg intravenously on day 1 of every 14-day cycle - 2 week cycle.
Safety Profile - Events That Discontinued Treatment
number of patients who experienced toxicity that led to being taken off treatment

Secondary Outcome Measures

Response Rate Associated With VEGF Trap Therapy Defined as Proportions of Patients Experiencing Complete or Partial Response
pts had MRIs at screening and at the 3rd and 5th cycles then every 8 weeks until progression. All responders were centrally reviewed for confirmation Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Progression Free Survival (PFS) Rate for Subjects With Radiographic Response
pts with confirmed radiographic response and their rate of progression (PFS). Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Overall Survival
all patients alive as of the last contact were censored for survival on the basis of that contact date

Full Information

First Posted
August 24, 2006
Last Updated
August 31, 2015
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00369590
Brief Title
VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide
Official Title
Phase II Single Arm Trial of VEGF Trap in Patients With Recurrent Temozolomide-Resistant Malignant Gliomas
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
October 2012 (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 VEGF Trap works in treating patients with recurrent malignant or anaplastic gliomas that did not respond to temozolomide. VEGF Trap may stop the growth of malignant or anaplastic gliomas by blocking blood flow to the tumor.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the therapeutic efficacy of VEGF Trap in patients with temozolomide-resistant malignant gliomas at first recurrence as measured by 6-month progression-free survival (PFS). II. Determine the safety profile of VEGF Trap in these patients. SECONDARY OBJECTIVES: I. Determine the efficacy of this regimen as measured by radiographic response, PFS, time to progression, and overall survival. II. Characterize the single-dose and repeated-dose pharmacokinetic profiles of VEGF Trap in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to histology (glioblastoma vs anaplastic glioma). Patients receive VEGF Trap IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell 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
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
All Study Patients
Arm Type
Experimental
Arm Description
Patients receive VEGF Trap (ziv-aflibercept) IV over 1 hour on day 1. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Other: pharmacological study; laboratory biomarker analysis.
Intervention Type
Biological
Intervention Name(s)
ziv-aflibercept
Other Intervention Name(s)
aflibercept, vascular endothelial growth factor trap, VEGF Trap, Zaltrap
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacological study
Intervention Description
correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
correlative studies
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS) at 6 Months
Description
This design yields 85% power to detect a true 30% 6-month PFS rate, while maintaining .91 probability of rejecting for a true 15% 6-month PFS rate. pts had MRIs at screening and at the 3rd and 5th cycles then every 8 weeks until progression. Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Time Frame
6 months
Title
Safety Profile - Toxicities
Description
number of cycles patient was able to have before developing a toxicity that required removing the patient from treatment. Treatment: Aflibercept 4mg/kg intravenously on day 1 of every 14-day cycle - 2 week cycle.
Time Frame
Start to End of treatment 39 cycles or 1yr 7.5months (78 weeks)
Title
Safety Profile - Events That Discontinued Treatment
Description
number of patients who experienced toxicity that led to being taken off treatment
Time Frame
Approximately 1 year (start of treatment - end of treatment)
Secondary Outcome Measure Information:
Title
Response Rate Associated With VEGF Trap Therapy Defined as Proportions of Patients Experiencing Complete or Partial Response
Description
pts had MRIs at screening and at the 3rd and 5th cycles then every 8 weeks until progression. All responders were centrally reviewed for confirmation Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Time Frame
Up to 2 years
Title
Progression Free Survival (PFS) Rate for Subjects With Radiographic Response
Description
pts with confirmed radiographic response and their rate of progression (PFS). Response determined by modified MacDonald Criteria Complete Response (CR): Complete disappearance of all measurable and evaluable disease, no new lesions. no steroids Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable lesions. no new lesions. steroid dose no > than maximum dose used in first 8 weeks of treatment. Stable: Does not qualify for CR, PR, or progression steroid dose no > than maximum dose used in first 8 weeks of treatment. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no increase) Clear clinical worsening.
Time Frame
up to 3 years
Title
Overall Survival
Description
all patients alive as of the last contact were censored for survival on the basis of that contact date
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: International Normalized Ratio (INR) < = 1.5 Platelet count => 100,000/mm³ Hemoglobin => 10 g/dL (transfusion allowed) Serum glutamic oxaloacetic transaminase (SGOT)/Serum glutamic pyruvic transaminase (SGPT) < = 2 times upper limit of normal (ULN) Not pregnant or nursing Negative pregnancy test No previous Vascular endothelial growth factor (VEGF) Trap At least 4 weeks since chemotherapy, surgery, or open biopsy At least 2 weeks since vincristine At least 6 weeks since carmustine, lomustine, fotemustine, or radiation therapy At least 42 days since prior nitrosoureas At least 3 weeks since procarbazine No previous Gliadel wafers or bevacizumab Tumor did not respond to previous radiation therapy and temozolomide Karnofsky performance status (KPS) 60-100% Life expectancy = > 8 weeks White blood count (WBC) = >3,000/mm³ Absolute neutrophil count = > 1,500/mm³ Bilirubin < = 2 times ULN Creatinine < = 1.5 mg/dL OR creatinine clearance= > 60 mL/min Urine protein:creatinine ratio < = 1 OR 24-hour urine protein < = 500 mg/dL Fertile patients must use effective contraception prior to, during, and for = > 6 months after completion of study treatment No significant medical illnesses that, in the opinion of the investigator, cannot be adequately controlled with appropriate therapy or would preclude compliance with study treatment No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No history of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study No history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for = >3 years At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin [radiosensitizer does not count]) At least 7 days since prior core biopsy At least 28 days since prior investigational agents No prior bevacizumab or vascular endothelial growth factor receptor inhibitors No concurrent full-dose anticoagulants (e.g., warfarin or low molecular-weight heparin) No clinically significant cardiovascular disease, including any of the following: Cerebrovascular accident within the past 6 months Uncontrolled hypertension, defined as blood pressure (BP) > 140/90 mm Hg or systolic BP > 180 mm Hg if diastolic BP < 90 mm Hg, on ≥ 2 repeated determinations on separate days within the past 3 months Myocardial infarction, coronary artery bypass graft (CABG), or unstable angina pectoris within the past 6 months New York Heart Association class III-IV congestive heart failure No serious cardiac arrhythmia requiring medication Clinically significant peripheral vascular disease within the past 6 months Pulmonary embolism, deep vein thrombosis, or other thromboembolic event within the past 6 months No evidence of bleeding diathesis or coagulopathy No more than 1 prior chemotherapy regimen (initial treatment and treatment for 1 relapse) Surgical resection for relapsed disease with no anticancer therapy instituted for up to 12 weeks followed by another surgical resection is considered 1 relapse If prior therapy for a grade 3 glioma was given, surgical diagnosis of a high-grade glioma is considered the first relapse Prior surgical, interstitial brachytherapy, or stereotactic radiosurgery not considered prior therapy If prior therapy included interstitial brachytherapy or stereotactic radiosurgery, must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) scan, thallium scanning, Magnetic Resonance (MR) spectroscopy, or surgical documentation of disease Must show unequivocal radiographic evidence of tumor progression by MRI Recent resection of recurrent or progressive tumor allowed Residual disease not required Temozolomide-resistant recurrent glioblastoma is defined as tumor progression or tumor recurrence during or after treatment with temozolomide-based chemotherapy regimens Recovered from prior therapy No other disease that would obscure toxicity or dangerously alter drug metabolism No uncontrolled intercurrent illness, including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situations that would limit compliance with study requirements No serious or nonhealing wound, ulcer, or bone fracture No history of intracerebral or intratumoral hemorrhage No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No significant traumatic injury within the past 28 days At least 28 days since prior cytotoxic therapy Histologically confirmed diagnosis of 1 of the following: Intracranial glioblastoma or gliosarcoma Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic mixed oligoastrocytoma Malignant astrocytoma not otherwise specified NOTE: If original histology was grade 3 glioma, subsequent histological diagnosis of 1 of these diseases is allowed provided no prior diagnosis of grade 2 glioma At least 20 unstained slides OR 1 tissue block available from original diagnostic biopsy/surgery or from biopsy/surgery at recurrence Patients presenting at the time of first recurrence or relapse, defined as progression after initial therapy (i.e., radiotherapy +/- chemotherapy if that was used as initial therapy) are eligible No other concurrent investigational drugs No other concurrent investigational drugs No concurrent cytotoxic or noncytotoxic therapy, including chemotherapy, radiotherapy, hormonal therapy, or immunotherapy No concurrent major surgery No concurrent combination antiretroviral therapy for HIV-positive patients Concurrent anticonvulsant therapy allowed
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John de Groot, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Wisconsin Hospital and Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21606416
Citation
de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, Mehta MP, Lassman AB, Deangelis LM, Yung WK, Chen A, Prados MD, Wen PY. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol. 2011 Jul 1;29(19):2689-95. doi: 10.1200/JCO.2010.34.1636. Epub 2011 May 23.
Results Reference
background
PubMed Identifier
21632852
Citation
de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI, Lassman A, DeAngelis L, Camphausen K, Chen A, Yung WK, Prados M, Wen PY, Heymach JV. Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res. 2011 Jul 15;17(14):4872-81. doi: 10.1158/1078-0432.CCR-11-0271. Epub 2011 Jun 1.
Results Reference
derived

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VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide

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