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Aflibercept, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme, Gliosarcoma, or Other Malignant Glioma
This study is not yet open for participant recruitment.
Verified by National Cancer Institute (NCI), April 2009
First Received: April 1, 2008   Last Updated: April 29, 2009   History of Changes
Sponsored by: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00650923
  Purpose

RATIONALE: 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.

PURPOSE: 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.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Biological: aflibercept
Drug: temozolomide
Genetic: DNA methylation analysis
Genetic: polymerase chain reaction
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: adjuvant therapy
Radiation: radiation therapy
Phase I

Study Type: Interventional
Study Design: Treatment
Official Title: Phase I Trial of Aflibercept (VEGF Trap) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Malignant Glioma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of aflibercept [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Toxicity of aflibercept with radiotherapy and temozolomide (TMZ), as well as TMZ alone [ Designated as safety issue: Yes ]
  • Pharmacokinetics of aflibercept [ Designated as safety issue: No ]
  • Correlation of tumor genotype, tumor vascularity, VEGFR and phospho-VEGFR expression, serum free and bound VEGF levels, plasma angiogenic peptides, and tumor MGMT levels with response to therapy with aflibercept [ Designated as safety issue: No ]

Estimated Enrollment: 90
Study Start Date: July 2008
Estimated Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • 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/m^2once 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/m^2 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

  • To characterize the pharmacokinetic profiles of free and bound aflibercept and TMZ in these patients.

Tertiary

  • To correlate tumor genotype, tumor vascularity, vascular endothelial growth factor receptor (VEGFR), and phospho-VEGFR expression, serum free and bound VEGF levels, plasma angiogenic peptides, and tumor O6-methylguanine-DNA-methyltransferase (MGMT) levels with response to therapy with aflibercept.
  • To evaluate the effect of treatment with aflibercept, TMZ, and RT on neurocognitive outcomes in MG 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed intracranial glioblastoma multiforme or gliosarcoma

    • Patients with anaplastic gliomas, including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, or malignant astrocytoma not otherwise specified allowed (groups 2 and 3 only)
    • Newly diagnosed (group 1 only)
    • Stable or recurrent disease allowed (groups 2 and 3 only)
  • No evidence of significant intratumoral or peritumoral hemorrhage on pre-operative MRI or a large amount of peri-operative parenchymal hemorrhage on post-operative MRI

    • Post-operative intracavitary blood allowed

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 60-100%
  • Life expectancy > 12 weeks
  • WBC > 3,000/μL
  • ANC > 1,500/mm³
  • Platelet count > 100,000/mm³
  • Hemoglobin > 10 g/dL (transfusion allowed)
  • SGOT and SGPT < 2 times upper limit of normal (ULN)
  • 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
  • INR ≤ 1.5
  • Not pregnant or nursing
  • Negative pregnancy test
  • 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 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
  • 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 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 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 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 past 3 months
  • 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

PRIOR CONCURRENT THERAPY:

  • 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)
  • At least 28 days since prior major surgery or open biopsy
  • At least 21 days since prior radiotherapy (groups 2 and 3)
  • No prior Gliadel® wafers
  • 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 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00650923

Sponsors and Collaborators
Investigators
Study Chair: Patrick Y. Wen, MD Dana-Farber Cancer Institute
Investigator: John F. deGroot, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Study ID Numbers: CDR0000590174, ABTC-0701, NABTC-0701
Study First Received: April 1, 2008
Last Updated: April 29, 2009
ClinicalTrials.gov Identifier: NCT00650923     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
adult giant cell glioblastoma
adult glioblastoma
adult gliosarcoma
adult anaplastic astrocytoma
adult anaplastic oligodendroglioma
adult mixed glioma
recurrent adult brain tumor

Study placed in the following topic categories:
Glioblastoma
Astrocytoma
Adjuvants, Immunologic
Central Nervous System Neoplasms
Temozolomide
Recurrence
Brain Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neuroepithelioma
Oligodendroglioma
Antineoplastic Agents, Alkylating
Glioma
Glioblastoma Multiforme
Gliosarcoma
Alkylating Agents
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:
Glioblastoma
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Astrocytoma
Antineoplastic Agents
Nervous System Diseases
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Temozolomide
Pharmacologic Actions
Neuroectodermal Tumors
Neoplasms
Neoplasms by Site
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Antineoplastic Agents, Alkylating
Glioma
Neoplasms, Neuroepithelial
Alkylating Agents
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on September 11, 2009