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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00650923

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

6.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Anaplastic Astrocytoma Adult Anaplastic Oligodendroglioma Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Adult Mixed Glioma Recurrent Adult Brain Tumor	Drug: ziv-aflibercept Procedure: radiation therapy Drug: temozolomide Procedure: pharmacological study Procedure: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
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.
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.
To characterize the safety profile of aflibercept in combination with RT and concomitant TMZ in patients with newly-diagnosed GBM.
To characterize the safety profile of aflibercept in combination with adjuvant TMZ in patients with stable or recurrent MG after RT.

SECONDARY OBJECTIVE:

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

61 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2008

Actual Primary Completion Date :

Jun 1, 2013

Actual Study Completion Date :

Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 See Detailed Description	Drug: ziv-aflibercept Given IV Other Names: aflibercept vascular endothelial growth factor trap VEGF Trap Zaltrap Procedure: radiation therapy Undergo RT Other Names: irradiation radiotherapy therapy, radiation Drug: temozolomide Given PO Other Names: SCH 52365 Temodal Temodar TMZ Procedure: pharmacological study Correlative studies Other Names: pharmacological studies Procedure: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Arm 1

See Detailed Description

Drug: ziv-aflibercept

Given IV

Other Names:

aflibercept

vascular endothelial growth factor trap

VEGF Trap

Zaltrap

Procedure: radiation therapy

Undergo RT

Other Names:

irradiation

radiotherapy

therapy, radiation

Drug: temozolomide

Given PO

Other Names:

SCH 52365

Temodal

Temodar

TMZ

Procedure: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Procedure: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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

Efficacy in terms of antitumor activity based on clinical, radiographic, and biologic assessments [Up to 3 months]
Descriptive analysis will be provided.
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) [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]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles (UCLA )	Los Angeles	California	United States	90095
2	UCSF-Mount Zion	San Francisco	California	United States	94115
3	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
4	Adult Brain Tumor Consortium	Baltimore	Maryland	United States	21231-1000
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
6	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129
7	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
8	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15232
9	M D Anderson Cancer Center	Houston	Texas	United States	77030