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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Single Arm Trial of VEGF Trap in Patients With Recurrent Temozolomide-Resistant Malignant Gliomas

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

Intervention / Treatment
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* Biological: ziv-aflibercept
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Study Patients<br>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. | Biological: ziv-aflibercept<br>* Given IV<br>* Other names: Zaltrap;Other: pharmacological study<br>* correlative studies<br>Other: laboratory biomarker analysis<br>* correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 
| 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. | Start to End of treatment 39 cycles or 1yr 7.5months (78 weeks) | 
| Safety Profile - Events That Discontinued Treatment | number of patients who experienced toxicity that led to being taken off treatment | Approximately 1 year (start of treatment - end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 2 years | 
| 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. | up to 3 years | 
| Overall Survival | all patients alive as of the last contact were censored for survival on the basis of that contact date | 3 years |