SOUTH SAN FRANCISCO, Calif. — December 11th, 2009 — Genentech, Inc., a member of the Roche Group, has been informed that the U.S. Food and Drug Administration (FDA) is allowing enrollment to resume into a Phase III clinical trial (E5103) evaluating Avastin® (bevacizumab) in combination with anthracycline, cyclophosphamide and paclitaxel chemotherapy in women with early-stage HER2-negative breast cancer. E5103 is sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between the NCI and Genentech, and is being conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG).
Enrollment in the trial was temporarily suspended on September 25, 2009, because six cases of clinical congestive heart failure (CHF) were reported during a pre-planned cardio-toxicity analysis of the first 200 patients enrolled in the two study groups receiving Avastin plus anthracycline, cyclophosphamide and paclitaxel chemotherapy. The trial’s protocol specified enrollment should be suspended if six or more cases of CHF were reported in the first 200 patients randomized to receive Avastin plus chemotherapy.
Genentech has been informed that, after detailed review of available safety data, the study’s Data Safety Monitoring Board (DSMB) concluded the risk-benefit assessment of Avastin in combination with anthracycline, cyclophosphamide and paclitaxel chemotherapy in this trial remains unchanged. The company was informed the observed rate of CHF in this trial is consistent with previously reported rates for Avastin and rates described in its U.S. prescribing information.
New patients enrolling in the study will be made fully aware of the CHF rate observed in this trial through an amendment to the consent form. Patients already enrolled were informed at the time enrollment was suspended. E5103 began enrollment in November 2007 and 3,487 of the planned 4,950 patients have been enrolled to date.
The Avastin U.S. prescribing information states that the rate of CHF among patients who received prior anthracyclines for HER2-negative metastatic breast cancer was 3.8 percent for patients who received Avastin plus paclitaxel compared with 0.6 percent for patients who received paclitaxel alone.
Genentech is committed to patient safety and will continue to work with those involved in this study, and other clinical trials evaluating Avastin in combination with anthracyclines, to closely monitor safety.
E5103 is a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial evaluating Avastin plus chemotherapy as adjuvant treatment following surgery in women with either lymph node-positive or high-risk, lymph node-negative, breast cancer. The primary endpoint of the study is disease-free survival (reducing the risk of the cancer returning following surgery). Secondary endpoints include safety, including cardiac toxicity, overall survival and efficacy of short-term versus long-term Avastin use. Following surgery, patients in the trial are randomized to one of three arms:
A: Doxorubicin, cyclophosphamide plus placebo (4 cycles) followed by paclitaxel plus placebo (4 cycles)
B: Doxorubicin, cyclophosphamide plus Avastin (4 cycles) followed by paclitaxel plus Avastin (4 cycles)
C: Doxorubicin, cyclophosphamide plus Avastin (4 cycles) followed by paclitaxel plus Avastin (4 cycles) followed by Avastin alone (10 cycles)
Avastin is a solution for intravenous infusion and is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF). VEGF plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. Avastin does not bind to receptors on normal or cancer cells. The tumor blood supply is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). For more information about angiogenesis, visit http://www.gene.com.
Avastin is indicated for previously untreated, metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression-free survival (PFS). Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.
BOXED WARNINGS and Additional Important Safety Information
People treated with Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:
Gastrointestinal (GI) perforation: Treatment with Avastin can result in the development of a potentially serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine or large intestine. In clinical trials, this event occurred in more people who received Avastin than in the comparison group (0.3 percent to 2.4 percent). In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs.
Surgery and wound healing problems: Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality. Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of wound healing problems following surgery has not been determined. Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with wound healing problems following surgery that require medical treatment.
Severe bleeding: Treatment with Avastin can result in serious bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds and vaginal bleeding. These events occurred up to five times more often in people who received Avastin. Across cancer types, 1.2 percent to 4.6 percent of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin should be permanently stopped if serious bleeding occurs (i.e., requiring medical attention).
In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group. The formation of an abnormal passage from parts of the body to another part (non-GI fistula formation) was seen in 0.3 percent or less of people. Severe to life-threatening stroke or heart problems were seen in 2.4 percent of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1 percent of people. Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included severe to life-threatening high blood pressure, which was seen in 5 percent to 18 percent of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1 percent of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3 percent of people and severe reactions occurred in 0.2 percent of people.
Common side effects that occurred in more than 10 percent of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain and inflammation of the skin (exfoliative dermatitis). Across all trials, treatment with Avastin was permanently stopped in 8.4 percent to 21 percent of people because of side effects.
Avastin may impair fertility. Patients who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for at least six months following the last dose of Avastin.
In the E2100 metastatic breast cancer trial, there was a 20.5 percent increase in severe to life-threatening and fatal side effects for Avastin plus paclitaxel chemotherapy vs. paclitaxel alone. Because mild side effects of Avastin plus paclitaxel were not studied, they are not known. Severe to life-threatening side effects that increased by 2 percent or more in people who received Avastin plus paclitaxel were numbness and tingling in the fingers and toes (24 percent vs. 18 percent), high blood pressure (16 percent vs. 1 percent), tiredness (11 percent vs. 5 percent), infection without reduced white blood cell counts (9 percent vs. 5 percent), white blood cells that contained harmful bacteria (6 percent vs. 3 percent), vomiting (6 percent vs. 2 percent), diarrhea (5 percent vs. 1 percent), bone pain (4 percent vs. 2 percent), headache (4 percent vs. 1 percent), nausea (4 percent vs. 1 percent), stroke (3 percent vs. 0 percent), dehydration (3 percent vs. 1 percent), infection (3 percent vs. 0.3 percent), rash (3 percent vs. 0.3 percent) and too much protein in the urine (3 percent vs. 0 percent). The most common severe to life-threatening and fatal side effects that increased by 5 percent or more in people who received Avastin plus paclitaxel vs. paclitaxel alone included numbness and tingling in fingers and toes (24 percent vs. 18 percent), high blood pressure (16 percent vs. 1 percent) and tiredness (11 percent vs. 5 percent). Congestive heart failure was seen in more people who received Avastin plus paclitaxel vs. paclitaxel alone (2.2 percent vs. 0.3 percent). Among people receiving prior anthracyclines, congestive heart failure was more common in people who received Avastin plus paclitaxel vs. paclitaxel alone (3.8 percent vs. 0.6 percent). Deaths due to side effects were seen in 1.7 percent (6 of 363) of people who received Avastin plus paclitaxel. Causes of death were the development of a hole in the stomach, small intestine or large intestine (2), heart attack (2) and diarrhea/abdominal pain/weakness/low blood pressure (2).
For full Prescribing Information and Boxed WARNINGS on Avastin please visit http://www.avastin.com.
Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.