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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Recurrent Adult Brain Tumor

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Patrick Wen

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00678

NCT ID:

NCT00650923

Start Date:

July 2008

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Recurrent Adult Brain Tumor
  • Astrocytoma
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma

Name

Location

Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617
University of PittsburghPittsburgh, Pennsylvania  15261
M D Anderson Cancer CenterHouston, Texas  77030
University of California San Francisco Medical Center-Mount ZionSan Francisco, California  94115
University of California at Los Angeles (UCLA )Los Angeles, California  90095
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Adult Brain Tumor ConsortiumBaltimore, Maryland  21231-1000