Aflibercept, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme, Gliosarcoma, or Other Malignant Glioma

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of aflibercept when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or recurrent glioblastoma multiforme, gliosarcoma, or other malignant glioma. Aflibercept may stop the growth of tumor cells by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving aflibercept together with radiation therapy and temozolomide may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To define the maximum tolerated dose (MTD) of aflibercept (VEGF Trap) with radiotherapy (RT) and concurrent temozolomide (TMZ) when administered in patients with newly-diagnosed glioblastoma (GBM) or gliosarcoma. II. To define the MTD of aflibercept with adjuvant TMZ administered at 150mg/m2once daily for 5 days every 28 days in patients with stable or recurrent malignant glioma (MG) after RT. III. To define the MTD of aflibercept with adjuvant TMZ administered at 100 mg/m2 once daily for 21 days every 28 days in patients with stable or recurrent MG after RT. IV. To characterize the safety profile of aflibercept in combination with RT and concomitant TMZ in patients with newly-diagnosed GBM. V. To characterize the safety profile of aflibercept in combination with adjuvant TMZ in patients with stable or recurrent MG after RT. SECONDARY OBJECTIVE: I. To characterize the pharmacokinetic profiles of free and bound aflibercept and TMZ in these patients OUTLINE: This is a multicenter, dose-escalation study of aflibercept. Patients are assigned to 1 of 3 treatment groups according to prior treatment and diagnosis. Group 1 (newly diagnosed glioblastoma multiforme or gliosarcoma): Patients undergo involved field partial brain radiotherapy (RT) once daily, 5 days a week (total of 30 fractions) and receive concurrent oral temozolomide (TMZ) once daily for 6 weeks. Beginning 2 weeks after the initiation of RT patients also receive aflibercept IV over 1 hour on days 1 and 15 and continue until the end of RT. Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral TMZ once daily on days 1-5. Treatment with adjuvant TMZ repeats every 28 days for up to 12 courses. Group 2 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1. Patients receive oral TMZ on days 1-5. Treatment repeats every 28 days for up to 12* courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the first day of TMZ treatment. [Note: *The 12 course maximum includes adjuvant TMZ courses administered prior to enrollment.] Group 3 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1. Patients receive oral TMZ on days 1-5. Treatment repeats every 21 days for up to 12* courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the first day of TMZ treatment. [Note: *The 12 course maximum includes adjuvant TMZ courses administered prior to enrollment.] In all groups, treatment continues in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for analysis of pharmacokinetics by ELISA. Tumor biomarkers and plasma angiogenic peptides are analyzed for correlation with response, and tumor MGMT promoter methylation status is determined using methylation-specific PCR. After completion of study treatment, patients are followed every 3 months.

Official Title
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Phase I Trial of Aflibercept (VEGF Trap) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Malignant Glioma

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

Intervention / Treatment
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* Drug: ziv-aflibercept
* Procedure: radiation therapy
* Drug: temozolomide
* Procedure: pharmacological study
* Procedure: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: Creatinine < = 1.5 mg/dL or creatinine clearance = > 60 mL/min At least 28 days since prior major surgery or open biopsy INR < = 1.5 Not pregnant or nursing Negative pregnancy test Karnofsky performance status 60-100% SGOT and SGPT < 2 times upper limit of normal (ULN) Bilirubin < 2 times ULN Life expectancy = > 12 weeks WBC = > 3,000/μL ANC= > 1,500/mm³ Platelet count = > 100,000/mm³ Hemoglobin = > 10 g/dL (transfusion allowed) At least 21 days since prior radiotherapy (groups 2 and 3) No prior Gliadel® wafers No concurrent major surgery Fertile patients must use effective contraception prior to, during, and for at least 6 months after completion of study treatment At least 28 days since prior significant traumatic injury No evidence of bleeding diathesis or coagulopathy No serious or nonhealing wound, ulcer, or bone fracture No history of 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 a minimum of 3 years No history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess gastrointestinal bleeding or diverticulitis within the past 6 months No prior cranial radiotherapy (group 1 only) No prior aflibercept No prior treatment for brain tumors, except concurrent radiotherapy and temozolomide or 2 or fewer 28-day courses of adjuvant temozolomide (groups 2 and 3) No prior or concurrent cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors (group 1 only) No concurrent major surgery No known hypersensitivity to CHO cell products or other recombinant human antibodies No history of hypersensitivity to a recombinant protein whereby reaction occurs during or immediately after infusion No history of allergic reactions attributed to compounds of similar chemical or biological composition to other study agents No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness or social situation that would limit compliance with study requirements No clinically significant cardiovascular disease within the past 6 months, including any of the following: History of ischemic or hemorrhagic stroke Myocardial infarction, coronary artery bypass graft, or unstable angina New York Heart Association class III-IV congestive heart failure, serious cardiac arrhythmia requiring medication, or unstable angina pectoris Clinically significant peripheral vascular disease Pulmonary embolism, deep vein thrombosis, or other thromboembolic event No disease that will obscure toxicity or dangerously alter drug metabolism Recovered from all prior therapy More than 28 days since prior and no concurrent investigational agents More than 7 days since prior core biopsy At least 23 days since prior temozolomide (groups 2 and 3) No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent full-dose anticoagulants (e.g., warfarin or low molecular-weight heparin) Prophylactic doses allowed No concurrent routine prophylactic use of filgrastim (G-CSF) No other concurrent anticancer therapy (including chemotherapy, radiotherapy, hormonal treatment, or immunotherapy) Concurrent enzyme-inducing antiepileptic drugs (EIAED) or non-EIAED allowed Urine protein:creatinine ratio < = 1 or 24-hour urine protein < = 500 mg No significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate therapy

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: Arm 1<br>See Detailed Description | Drug: ziv-aflibercept<br>* Given IV<br>* Other names: Zaltrap;Procedure: radiation therapy<br>* Undergo RT<br>* Other names: therapy, radiation;Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Procedure: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: 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 |
| --- | --- | --- |
| Maximum tolerated dose of aflibercept defined as the dose at which fewer than one-third of patients experience DLT based on the CTC severity grading |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy in terms of antitumor activity based on clinical, radiographic, and biologic assessments | Descriptive analysis will be provided. | Up to 3 months | 
| Plasma aflibercept (VEGF Trap) concentrations and PK parameters such as Cmax, Tmax, area under the plasma concentration-time curve (AUCo-t and AUC), clearance (CL), apparent volume of distribution at steady state (Vdss), and terminal half-life (t1/2) | Will be determined using non-compartmental methods. Dose proportionality in PK parameters will be determined by performing a one-way analysis of variance (ANOVA) on dose-normalized parameters. In addition, summary tables depicting individual patient concentrations and individual and mean PK parameters will be provided. | Baseline and days 15, 16, 22, 29, 57, 85 of course 1 for patients in Arm I; baseline and days 2, 8, 15, 43, 71 of course 1 for patients in Arms 2 and 3 |