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

Phase 2

Completed

Conditions: Adult Giant Cell Glioblastoma
Recurrent Adult Brain Tumor
Adult Anaplastic Oligodendroglioma
Adult Gliosarcoma
Adult Anaplastic Astrocytoma

Interventions: Biological: ziv-aflibercept
Other: pharmacological study
Other: laboratory biomarker analysis

Registration Number: NCT00369590

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 58

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
All Study Patients	pharmacological study	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.
All Study Patients	ziv-aflibercept	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.
All Study Patients	laboratory biomarker analysis	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) at 6 Months	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	Start to End of treatment 39 cycles or 1yr 7.5months (78 weeks)	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	Approximately 1 year (start of treatment - end of treatment)	number of patients who experienced toxicity that led to being taken off treatment

Secondary Outcome Measures

Name	Time	Method
Response Rate Associated With VEGF Trap Therapy Defined as Proportions of Patients Experiencing Complete or Partial Response	Up to 2 years	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	up to 3 years	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	3 years	all patients alive as of the last contact were censored for survival on the basis of that contact date

Trial Locations

Locations (7): Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States
University of California Los Angeles
🇺🇸
Los Angeles, California, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of California San Francisco
🇺🇸
San Francisco, California, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States