Bevacizumab (Avastin™) for Metastatic Colorectal Cancer: Treatment Referral Center Protocol

National Cancer Institute
Friday, 1 August 2003

Key Points:

  • A Treatment Referral Center Protocol has been established to study the use of bevacizumab for people with locally advanced or metastatic colorectal cancer.

  • Bevacizumab, an investigational agent, will be combined with 5-fluorouracil (5-FU) and leucovorin, two standard drugs.

  • This study is for people who have already received standard chemotherapy combinations and have progressive disease.

  • The study will be carried out at NCI-designated Clinical and Comprehensive Cancer Centers and other selected institutions across the country.

The National Cancer Institute (NCI) has opened a Treatment Referral Center Protocol that will evaluate bevacizumab in patients who are no longer benefiting from standard treatments for locally advanced or metastatic colorectal cancer.

1. What is bevacizumab?

Bevacizumab, whose brand name is Avastin™, is an investigational drug. It is a monoclonal antibody produced from genetically engineered cells. Bevacizumab is designed to specifically block the action of a protein called vascular endothelial growth factor (VEGF).

Bevacizumab belongs to a family of drugs called antiangiogenic agents, or angiogenesis inhibitors. Angiogenesis inhibitors prevent the formation of new blood vessels that surround and "feed" cancer cells the oxygen and nutrients they need to grow. By depriving cancer cells of their blood supply, angiogenesis inhibitors may be able to reduce tumor cell growth and cause cancerous tumors to grow more slowly or to become smaller.

2. What is a Treatment Referral Center Protocol?

A Treatment Referral Center (TRC) Protocol is a mechanism by which the National Cancer Institute makes an investigational drug available at NCI-designated Clinical and Comprehensive Cancer Centers and other institutions selected to provide wide geographic availability. A TRC protocol is established when clinical evidence suggests that a new agent should be made available to patients even though it is not yet approved by the Food and Drug Administration.

3. Who can participate in the study?

This study is open to people with locally advanced or metastatic colorectal cancer. It is specifically for people who have already had treatment with oxaliplatin- and irinotecan-containing chemotherapy regimens and who are no longer benefiting from these treatments. Treatment for patients who have already had two different forms of treatment is known as "third-line" therapy.

4. What does the treatment in this study involve?

Participants in this study will receive the investigational agent, bevacizumab, in combination with 5-fluorouracil (5-FU) and leucovorin. Most patients who are eligible for this study will have had 5-FU and leucovorin during previous treatment and, therefore, would be unlikely to benefit from more chemotherapy alone. The purpose of this trial is to find out whether the addition of bevacizumab to these two chemotherapy agents will be effective. The drugs will be given in a treatment cycle that is 8 weeks long.

Patients who benefit from their first 8-week treatment cycle will receive treatment as long as they continue to benefit. Benefit is defined as a complete response (disappearance of tumors), a partial response (significant shrinkage of tumors), stable disease (no significant shrinkage or growth), and no new tumors. Patients who do not benefit from the initial 8-week treatment cycle will be counseled about other options. (See Question 11.)

5. How will the doctors know if study participants are benefiting from the new treatment?

The doctors will monitor participants closely to track changes in their tumors and to check their general health. Monitoring procedures may include chest x-rays, computed tomograpy (CT or CAT) scanning, and/or magnetic resonance imaging (MRI). For tumors that can be seen and felt on the skin or in lymph nodes, the study staff may use a ruler and color photography. Participants will also have lab tests and physical examinations.

6. Why do the doctors think this drug combination might work?

In earlier "first-line" therapy trials (involving people who had not yet received treatment for their metastatic colorectal cancer), investigators saw longer survival and tumor control among those who received bevacizumab along with a standard chemotherapy called IFL (irinotecan, 5-FU, and leucovorin) than among those who received IFL without bevacizumab. Results are pending for a "second-line" treatment study (involving patients who were no longer responding to their first course of treatment for metastatic colorectal cancer) comparing standard therapy plus bevacizumab versus standard therapy.

7. Does bevacizumab cause side effects?

In earlier trials, most patients tolerated bevacizumab well although serious adverse events have been observed. Side effects can include mild to moderate high blood pressure, nose bleeds, fever, headache, rash, and chills. In addition, this new agent may be associated with blood clots and bleeding. In rare cases, bevacizumab increased the risk of life-threatening complications such as perforation of the wall of the colon.

8. Where will the study take place?

The TRC protocol will be carried out at NCI-designated Cancer Centers as well as at certain other institutions to ensure wide geographic availability. Up-to-date information about institutions that are enrolling patients is available from the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER. (See Question 17.)

9. Who is sponsoring the study?

The NCI's Cancer Therapy Evaluation Program (CTEP) is sponsoring this trial in collaboration with Genentech, Inc., the manufacturer of bevacizumab.

10. Is there enough of bevacizumab for all of the patients who want to receive it?

The supply of bevacizumab is limited. After the initial 125 patients enter the trial, a process that randomly selects eligible patients similar to a lottery may be needed, but only if demand exceeds supply. If a lottery is established and the patient is not selected in the first week, the person's name will be automatically re-entered for following lotteries, provided the patient still qualifies for the study and wants to participate.

11. What if this treatment doesn't work? Are other treatments available to patients with advanced colorectal cancer?

Some patients with advanced colorectal cancer may be eligible to participate in other clinical trials. Links to listings of ongoing trials for advanced colorectal can be found at http://cancer.gov/clinicaltrials/digestpage/bevacizumab on the Internet. Other patients may decide to have no further cancer therapy and to receive only therapy to control their symptoms.

12. Can patients receive bevacizumab from their own doctor?

Patients can receive bevacizumab only from the doctor at the participating institution. In some cases, patients may receive the other drugs from their own doctor.

13. When will the study begin? When will it end?

The study will begin at a participating institution as soon as the study has been approved by the local institution's IRB (Institutional Review Board). Patients will be able to join the study until about one month after the FDA approves bevacizumab for marketing, and the drug becomes available locally. Even after the drug has been approved, patients who are in the study will continue to receive treatment at the TRC institution.

14. Can patients receive bevacizumab if they do not participate in this study?

Bevacizumab is still under investigation and is available only in clinical trials. A link to a listing of ongoing trials involving bevacizumab for several types of cancer can be found at http://www.cancer.gov/clinicaltrials/digestpage/bevacizumab on the Internet. This information is also available by calling 1-800-4-CANCER. (See Question 17.)

15. How can a person apply to get into the Treatment Referral Center Protocol?

The patient's doctor can contact the nearest participating site if the patient appears to meet the eligibility criteria for this study. (See Question 3.) The National Cancer Institute's Cancer Information Service at 1-800-4-CANCER can provide up-to-date information about institutions that are enrolling patients. (See Question 17.)

16. Will patients have to pay for their treatment in the Treatment Referral Center Protocol?

The NCI will provide bevacizumab to study participants free of charge through an agreement with the bevacizumab manufacturer, Genentech, Inc. If bevacizumab becomes commercially available, there is a possibility that patients may be asked to purchase subsequent supplies. However, every effort will be made to provide adequate supplies of bevacizumab free of charge to patients to complete the study even after bevacizumab is commercially available. Patients or their insurers, however, will have to pay for the other drugs and costs associated with their treatment. Patients should check with their insurer about coverage of these costs before they begin treatment.

17. Where can patients find out more about their disease and its treatment?

Patients can find out more about colorectal cancer and its treatment by contacting the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). For callers with TTY equipment, the number is 1-800-332-8615. The NCI's Cancer.gov Web site also provides information about colorectal cancer at http://cancer.gov/cancerinfo/types/colon-and-rectal.

For more information, or to contact National Cancer Institute, see their website at: www.cancer.gov

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