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

Adult Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00650923
• Other study ID #: NCI-2009-00678
• Secondary ID: NCI-2009-00678CD
• Status: Completed
• Phase: Phase 1
• First received: April 1, 2008
• Last updated: May 29, 2014
• Start date: July 2008
• Est. completion date: December 2013

Study information

• Verified date: April 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: December 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• ziv-aflibercept
Given IV

Procedure:
• radiation therapy
Undergo RT

Drug:
• temozolomide
Given PO

Procedure:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Adult Brain Tumor Consortium	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Charlestown	Massachusetts
United States	M D Anderson Cancer Center	Houston	Texas
United States	University of California at Los Angeles (UCLA )	Los Angeles	California
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	UCSF-Mount Zion	San Francisco	California
United States	University of California San Francisco Medical Center-Parnassus	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Efficacy in terms of antitumor activity based on clinical, radiographic, and biologic assessments	Descriptive analysis will be provided.	Up to 3 months	No
Secondary	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	No