Bevacizumab and Irinotecan to Treat Brain Tumors

July 6, 2012 updated by: National Cancer Institute (NCI)

A Phase II Trial of Bevacizumab and Irinotecan for Patients With Recurrent High-Grade Gliomas Immediately Following Tumor Progression After Treatment w/Bevacizumab Alone: A Companion Trial to NCI Study 06-C-0064 (NCT00271609)(Bevacizumab Alone for Recurrent Gliomas)

Background:

  • Bevacizumab is a genetically engineered antibody that blocks the growth of new blood vessels in tumors. It has shown activity against human brain tumors in laboratory tests and human clinical trials.
  • Irinotecan causes damage to the deoxyribonucleic acid (DNA) in cancer cells so that the cells cannot reproduce or repair themselves. It is approved for treating patients with colorectal cancer.
  • Bevacizumab and irinotecan in combination are more effective against colon cancer than either drug alone.

Objectives:

  • To determine the safety of bevacizumab and irinotecan and any side effects associated with the combination of the two drugs when given to patients with high grade gliomas.
  • To determine if the combination of bevacizumab and irinotecan can help patients with brain tumors that have grown after treatment with bevacizumab alone.

Eligibility:

-Patients 18 years of age and older who have been treated on National Cancer Institute (NCI) trial 06-C-0064 (NCT00271609), "Bevacizumab Alone for Recurrent Gliomas," and whose tumor has progressed.

Design:

Participants receive infusions of bevacizumab and irinotecan through a vein once every 2 weeks in 4-week treatment cycles, plus the following procedures:

  • History, physical and neurological examinations every 2 weeks for the first treatment cycle and then every 4 weeks
  • Magnetic Resonance Imaging (MRI) scan of the head every 4 weeks.
  • Routine lab every week.
  • Quality-of-life questionnaire every 4 weeks

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Background:

  • Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity (kd = 1.1 nM ). The antibody consists of a human IgG1 framework and the antigen-binding complementarity-determining regions from the murine anti-VEGF MAb A.4.6.1.
  • Irinotecan is a semisynthetic derivative of camptothecin that possesses greater aqueous solubility, greater in vitro and in vivo activity, and is associated with less severe and more predictable toxicity than camptothecin.
  • We now propose treating patients whose tumors progress on our bevacizumab alone protocol with the combination of bevacizumab with irinotecan. We believe that this trial design has significant power to detect a true synergistic effect between the two agents given that the single agent activity of irinotecan is so low in patients with recurrent malignant gliomas (2-5% response rate) and the patients being treated on this trial will have tumors that have already progressed through bevacizumab.

Objective:

  • To establish data and safety regarding the anti-tumor activity of bevacizumab plus irinotecan in patients with recurrent high-grade gliomas that have progressed on bevacizumab alone as determined by objective radiographic response rate.
  • To determine the 6 month progression-free survival of treated patients and to characterize the pattern of changes in the number of endothelial progenitor cells over time and across patients.
  • To obtain preliminary data regarding how response to treatment (stable disease or radiographic response) effects monthly measurements of quality of life while on study.

Eligibility:

  • Patients must have been treated on the National Cancer Institute (NCI) trial 06-C-0064; bevacizumab alone for recurrent gliomas and now have evidence for tumor progression by magnetic resonance imaging (MRI) scan.
  • Patients with histologically proven intracranial malignant glioma.

Design:

-Patients will be treated with bevacizumab by intravenous injection at a dose of 10mg/kg and irinotecan at a dose of 125 mg/m^2 for patients on non-enzyme-inducing anti-epileptic drugs (NEIAED) and 340 mg/m^2 for patients on enzyme-inducing anti-epileptic drugs (EIAED) every two weeks on a 4-week cycle.

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSION CRITERIA:

Patients must have been treated on the National Cancer Institute (NCI) trial 06-C-0064 (NCT00271609); bevacizumab alone for recurrent gliomas and now have evidence for tumor progression by magnetic resonance imaging (MRI) scan.

Patients with histologically proven intracranial malignant glioma will be eligible for this protocol. Malignant glioma include glioblastoma multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified).

Patients must have evidence for tumor progression by MRI or computed tomography (CT) scan. This scan should be performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline magnetic resonance (MR)/CT is required. The same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement.

Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.

All patients or their previously designated durable power of attorney (DPA) (if the patient is deemed by the treating physician to be impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) must sign an informed consent indicating that they are aware of the investigational nature of this study.

Patients must have a Karnofsky performance status of greater than or equal to 60.

Patients must not be more than 4 weeks since their last bevacizumab treatment and may have received no form of treatment (i.e. radiation, chemotherapy, surgery, investigational therapy) for their progressive tumor between their last bevacizumab treatment and enrollment of this companion trial.

Patients must have adequate bone marrow function (white blood cell (WBC) greater than or equal 3,000/microl, absolute neutrophil count (ANC) greater than or equal to1,500/mm^3, platelet count of greater than to or equal 100,000/mm^3), and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (serum glutamic oxaloacetic transaminase (SGOT) and bilirubin less than 2.5 times upper limits of normal (ULN)), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater than or equal to 60 cc/min) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.

Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patients' ability to tolerate this therapy.

This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race.

Urine protein should be screened by dipstick or urine analysis for Urine Protein Creatinine (UPC) ratio. For proteinuria greater than or equal to 1+ or urine protein:creatinine UPC ratio greater than 1.0, 24-hour urine protein should be obtained and the level should be less than 1000 mg for patient enrollment.

Subjects must be willing and able to practice adequate contraception.

EXCLUSION CRITERIA:

Concurrent use of other standard chemotherapeutics or investigative agents.

Patients who have an active infection.

Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy.

Concurrent anti-coagulation or anti-platelet medication (including aspirin, non-steroidal anti-inflammatories, cyclooxygenase-2 (COX-2) inhibitors).

Serious or non-healing wound, ulcer or bone fracture.

History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days.

Invasive procedures defined as follows:

  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
  • Anticipation of need for major surgical procedures during the course of the study
  • Core biopsy within 7 days prior to day (D)1 therapy

Patients with clinically significant cardiovascular disease:

  • History of cerebrovascular accident (CVA) within 6 months
  • Uncontrolled hypertension (greater than 150/100 mmHg)
  • Myocardial infarction or unstable angina within 6 months
  • New York heart association grade II or greater congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Unstable angina pectoris
  • Clinically significant peripheral vascular disease

Clinical evidence of bleeding diathesis or coagulopathy.

Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Bevacizumab & Irinotecan Patients
Bevacizumab - 10 mg/kg intravenous injection Irinotecan - 125 mg/m^2 if patient is on a non-enzyme inducing anti-epileptic drugs 340 mg/m^2 if patient is on enzyme inducing anti-epileptic drugs every two weeks on a 4 week cycle
Biological: Bevacizumab
10 mg/kg intravenous injection
Other Names:
  • rhuMAb VEGF
Drug: Irinotecan hydrochloride
125 mg/m^2 if patient is on a non-enzyme inducing anti-epileptic drugs 340 mg/m^2 if patient is on enzyme inducing anti-epileptic drugs every two weeks on a 4 week cycle
Other Names:
  • Camptosar
  • CPT-11
  • irinotecan hydrochloride trihydrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Radiographic Response Rate (Malignant Glioma Participants)
Time Frame: 23 months (date of first enrollment to 1 month after last progression)
Definition of response: complete response (CR) is the complete disappearance of all measurable and evaluable disease. Partial response (PR) is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. Stable/No response (SD, NR)does not qualify for CR, PR, or progression. Progression is a 25% increase in the sum of products of all measurable lesions (or two target lesions if too numerous over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline.
23 months (date of first enrollment to 1 month after last progression)
Number of Participants With Toxicity as Measured by The National Cancer Institute (NCI) Common Toxicity Criteria v. 3.0.
Time Frame: 23 months (date of first enrollment to 1 month after last progression)
Here is the number of participants with any toxicity, defined as any adverse events possibly, probably or definitely related to the investigational drugs. For the detailed list of investigational new drug (IND)-related toxicities and other serious adverse events, see the adverse event module.
23 months (date of first enrollment to 1 month after last progression)
Radiographic Response Rate (Anaplastic Glioma Participants)
Time Frame: 23 months (date of first enrollment to 1 month after last progression)
Definition of response: complete response (CR) is the complete disappearance of all measurable and evaluable disease. Partial response (PR) is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. Stable/No response (SD, NR)does not qualify for CR, PR, or progression. Progression is a 25% increase in the sum of products of all measurable lesions (or two target lesions if too numerous over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline.
23 months (date of first enrollment to 1 month after last progression)
Radiographic Response Rate (Glioblastoma Multiforme Participants)
Time Frame: 23 months (date of first enrollment to 1 month after last progression)
Definition of response: complete response (CR) is the complete disappearance of all measurable and evaluable disease. Partial response (PR) is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions. Stable/No response (SD, NR)does not qualify for CR, PR, or progression. Progression is a 25% increase in the sum of products of all measurable lesions (or two target lesions if too numerous over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline.
23 months (date of first enrollment to 1 month after last progression)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Howard A Fine, M.D., National Cancer Institute, National Institutes of Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2006

Primary Completion (Actual)

January 1, 2010

Study Completion (Actual)

March 1, 2010

Study Registration Dates

First Submitted

October 25, 2006

First Submitted That Met QC Criteria

October 25, 2006

First Posted (Estimate)

October 26, 2006

Study Record Updates

Last Update Posted (Estimate)

July 13, 2012

Last Update Submitted That Met QC Criteria

July 6, 2012

Last Verified

July 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 060250
  • 06-C-0250

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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