St Marks Hospitals

Brain & Colon Cancer Health: Avastin May Stop Cancer Spread

August 26, 2008 – 10:19 am

Avastin Shows Promise As Aggressive Brain Cancer Drug

Phase II trials of Avastin (bevacizumab) for the treatment of aggressive brain cancer have shown promising results, said Genentech, makers of the drug, who presented their findings at the 12th Annual Scientific Meeting of the Society for Neuro-Oncology that took place between 15th and 18th November, in Dallas, Texas.

Avastin (bevacizumab) is a monoclonal antibody that inhibits the growth of tumours by blocking the production of new blood vessels (angiogenesis) that would feed the tumour. The drug, which has been described as a “blockbuster” cancer drug, was one of the first clinically available angiogenesis inhibitors in the US.

Given alone or with irinotecan chemotherapy in a randomized, multi-center, phase II trial, the drug showed an encouraging six-month progression-free survival (PFS) and objective response rate in patients with the most common and aggressive type of brain cancer, relapsed glioblastoma multiforme (GBM). According to the American Cancer Society (ACS), only 3 per cent of patients with GBM survive longer than 5 years, and this figure has not altered in 25 years. The Society estimates that in 2007 there will be 20,500 new cases of brain cancer and 12,740 brain cancer deaths in the US.
36 per cent (31 out of 85) patients treated with Avastin alone, and 51 per cent (42 out of 82) treated with Avastin combined with chemotherapy, lived without the disease advancing within six months, reported Genentech, who said the results were “assessed by independent radiological review”. Genentech researchers said they observed no new or unexpected safety events related to Avastin. Dr Timothy Cloughesy, lead researcher of the study, and director of the Neuro-Oncology Program of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA) said that:

“Historical estimates suggest that only 15 percent of patients with this aggressive type of brain cancer live without their cancer progressing within six months.” “The findings suggested that at six months, more patients had lived without their cancer advancing when Avastin was administered as a single-agent or in combination with chemotherapy, than what we would normally expect,” he added.

In this phase II, open-label, multicenter, randomized, non-comparative study, Cloughesy and colleagues enrolled 167 patients with GBM whose cancer had relapsed. They were randomized to either an Avastin alone or Avastin with irinotecan chemotherapy group, and all patients had received prior temozolimide. The treatment was administered every other week for up to two years (104 weeks).

The main outcome measure was PFS, which was defined as the “absence of any event of cancer progression or death”. The researchers also assessed overall survival and safety. As well as the six-month PFS rates of 36 and 51 per cent in the Avastin only and Avastin with chemotherapy groups, the results also showed that:

Preliminary estimates of tumour response were seen in 21 per cent (18 of 85) of patients treated with Avastin only. The figure for Avastin with chemotherapy was 34 per cent (28 out of 82). Adverse events linked to Avastin were similar to previous trials.

The most common severe (grade 3 or higher) toxicities in the Avastin only group were: hypertension (8 per cent), and convulsion (6 per cent). The figure for the Avastin plus chemotherapy group were: convulsion (13 per cent) and neutropenia (9 per cent); neutropenia is a condition where there is a low count of neutrophils, a type of white blood cell.

Grade 1 and grade 3 intercranial (brain) hemorrhage occurred in 2 participants in the Avastin only group. One patient had a grade 4 hemorrhage in the Avastin plus chemotherapy group. Two deaths were linked to adverse events in the Avastin only group, and one in the Avastin plus chemotherapy group.

So far, the findings have turned out better than the researchers expected and have prompted the company to spur efforts to discuss the findings with the US Food and Drug Administration (FDA) and find out what the next step should be in getting the drug to this new group of patients.

The trial is still ongoing and final figures for safety and other efficacy results will be available in 2008, said the researchers.

Avastin was first approved by the FDA in February 2004, to treat metastatic colorectal cancer in combination with chemotherapy. Since then it has been approved for particular types of lung cancer. There are currently over 300 trials worldwide assessing the drug’s potential to treat over 20 different types of tumour.

Avastin (bevacizumab)
http://www.fda.gov/cder/drug/infopage/avastin/default.htm
FDA approves Avastin (bevacizumab) as a first-line treatment for patients with colorectal cancer that has spread to other parts of the body.

FDA Approves First Angiogenesis Inhibitor to Treat Colorectal Cancer
P04-23 February 26, 2004
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FDA today approved Avastin (bevacizumab) as a first-line treatment for patients with metastatic colorectal cancer — cancer that has spread to other parts of the body. Avastin, a monoclonal antibody, is the first product to be approved that works by preventing the formation of new blood vessels, a process known as angiogenesis. Avastin was shown to extend patients’ lives by about five months when given intravenously as a combination treatment along with standard chemotherapy drugs for colon cancer (the “Saltz regimen” also known as IFL). IFL treatment includes ironotecan, 5-fluorouracil (5FU) and leucovorin.

Avastin is a genetically engineered version of a mouse antibody that contains both human and mouse components. (Antibodies are substances produced by the body’s immune system to fight foreign substances.) Special technology also allows it to be produced in large quantities in the laboratory.

This new monoclonal antibody is believed to work by targeting and inhibiting the function of a natural protein called “vascular endothelial growth factor” (VEGF) that stimulates new blood vessel formation. When VEGF is targeted and bound to Avastin, it cannot stimulate the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth. Angiogenesis inhibitors such as Avastin have been studied, first in the laboratory and then in patients, for three decades with the hope they might prevent the growth of cancer. This is the first such product that has been proven to delay tumor growth and more importantly, significantly extend the lives of patients.

“The approval of Avastin is the result of many years of research and development exploring a promising new approach to fighting cancer, and it is one of a number of recent new treatments for colorectal cancer that taken together, have significantly improved the armamentarium for fighting this disease,” said Mark B. McClellan, M.D., Ph.D., FDA Commissioner. “These medical achievements reflect the innovation of drug developers and the hard work of FDA’s cancer review teams, and they are proof of the promise offered by biomedical innovation. The dedication of everyone involved in these efforts is making a real difference in the lives of cancer patients.”

Colorectal cancer — cancer of the colon or rectum — is the third most common cancer affecting men and women in the U.S. and, according to the Centers for Disease Control and Prevention (CDC), is the second leading cause of cancer-related death. Colorectal cancer is also one of the most commonly diagnosed cancers in the U.S.; approximately 147,500 new cases were diagnosed in 2003.

The safety and efficacy of Avastin was primarily shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer designed to find out whether Avastin extended the lives of patients. Roughly half the patients received IFL, the standard chemotherapy combination, and the other half received Avastin once every two weeks in addition to IFL. Overall, patients given Avastin in combination with IFL survived about five months longer and the average time before tumors started regrowing or new tumors appeared was four months longer than patients receiving IFL alone. The overall response rate to the treatment was 45% compared to 35% for the control arm of the trial.

Serious, but uncommon, side-effects of Avastin include formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to intra-abdominal infections, impaired wound healing, and bleeding from the lungs or internally. Other, more common, side-effects are high blood pressure, tiredness, blood clots, diarrhea, decreased white blood cells (lowering immunity to diseases) headache, appetite loss and mouth sores.

Avastin is manufactured by Genentech, Inc., South San Francisco, Calif.

What is Avastin (bevacizumab), and how does it work?
Avastin is a monoclonal antibody that works by attaching to and inhibiting the action of vascular endothelial growth factor (VEGF) in laboratory experiments. VEGF is a substance that binds to certain cells to stimulate new blood vessel formation.  When VEGF is bound to Avastin, it cannot stimulate the formation and growth of new blood vessels (angiogenesis).  Avastin enhances the effects of chemotherapy, but does not appear to be effective when given alone in patients with colorectal cancer.

What are monoclonal antibodies?
Antibodies are substances produced by the immune system in response to foreign substances such as bacteria, viruses or toxins).  They are the body’s natural defense mechanism against infection, as they help to destroy these foreign substances. Monoclonal antibodies are antibodies produced in a laboratory to target a very specific part of the foreign substance (antigen).  Because of their precision, it is expected that they may be more effective than standard chemotherapy with fewer side effects.

What are angiogenesis inhibitors?
Angiogenesis inhibitors prevent the formation of new blood vessels, including those that surround and supply cancer cells, with the oxygen and nutrients they need to survive and grow.  By taking away the blood supply, angiogenesis inhibitors may reduce tumor cell growth and cause cancerous tumors to grow more slowly or to become smaller.

What is Avastin used to treat?
Avastin is used to treat cancer of the colon or rectum that has spread to other parts of the body. Avastin is given along with the chemotherapy combination known as IFL. IFL consists of irinotecan, 5-fluorouracil (5-FU), and leucovorin.

Is Avastin a cure for metastatic colorectal cancer?
No, Avastin will not cure metastatic colorectal cancer. In clinical trials there was longer survival and tumor control in patients who received the combination of IFL plus Avastin than among those who received IFL without Avastin. Overall, patients given Avastin survived about five months longer. In addition, the average time before tumors restarted growing or new tumors appeared was four months longer than patients who did not receive Avastin.

How is Avastin given?
Avastin is given intravenously (into a vein) every 14 days.

What are the possible side effects of Avastin?

• Serious side effects include:
• holes in the colon requiring surgery to repair (gastrointestinal perforation)
• impaired wound healing
• bleeding leading to disability (stroke) or death (especially in lung cancer patients)
• heart failure in certain patients (those given or receiving other anti-cancer treatments that may injure the heart muscle)
• kidney damage

Other more common side effects of Avastin treatment are:

• high blood pressure
• tiredness/weakness
• clot in the vein (thrombophlebitis)
• diarrhea
• decreased white blood cells
• headache
• loss of appetite
• mouth sores

Where can I find more information on Avastin and colorectal cancer?

• Go to FDA’s Avastin web page at: http://www.fda.gov/cder/drug/infopage/Avastin
• National Cancer Institutes web page: http://www.cancer.gov/cancerinfo/types/colon-and-rectal

This is a summary of the most important information about Avastin. For details, talk to your healthcare professional.

What is Avastin used for?
Avastin is used in combination with:

• intravenous 5-FU based combination chemotherapy regimens as the first-treatment or second-treatment for patients with metastatic colon cancer (cancer of the colon or rectum that has spread to other areas of the body).
• carboplatin and paclitaxel for first‑treatment of patients with unresectable (unable to remove by operation), locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Avastin will not cure colorectal cancer or lung cancer.  Overall, patients given Avastin plus chemotherapy for treatment of either colon cancer or lung cancer that has spread live longer than those who receive only chemotherapy.

Special Warning(s) with Avastin:   

• Avastin may cause gastrointestinal perforation (holes in the stomach, intestines or colon) requiring surgery to repair.
• Avastin may impair wound healing or cause wounds to open up.  Avastin should not be started for at least 28 days following major surgery and full wound healing, and should be stopped before a scheduled surgery.
• Mild bleeding (such as nosebleeds) is common in patients who receive Avastin.  Serious bleeding from the lungs or digestive system, requiring blood transfusions, occur in less than 5% of patients receiving Avastin.  When very severe, patients have died from blood loss.
• Avastin may cause a severe increase in blood pressure so patients receiving Avastin should have their blood pressure checked regularly.
• Avastin may cause proteinuria (protein in the urine, a sign of kidney damage).
• Avastin may cause blood clots.  The chances of blood clots are highest in patients who are elderly.
• Avastin may cause congestive heart failure (failure of the heart to pump blood well) especially when given with chemotherapy that is known to damage the heart (such as doxorubicin).

General Precautions with Avastin:

• Avastin should be used with caution in patients who are allergic to Avastin or to any of the ingredients in Avastin.
• Avastin may cause severe infusion reactions such as trouble breathing. This usually happens during the first dose, so patients should receive treatment in a doctor’s office or clinic.

What should I tell my healthcare provider?
Tell your healthcare provider if you:

• have or had liver or kidney problems
• have high blood pressure
• have congestive heart failure or other heart problems
• are pregnant, are trying to become pregnant, or are breast-feeding
• have recently had surgery or are planning to have surgery

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.  Some medicines may affect how Avastin works or Avastin may affect how your other medicines work.

What are some possible side effects of Avastin? (This list is NOT a complete list of side effects reported with Avastin.  Your healthcare provider can discuss with you a more complete list of side effects.)

Serious side effects include of Avastin treatment include:

• gastrointestinal perforation
• impaired wound healing
• severe bleeding
• a dangerously high increase in blood pressure
• kidney damage
• blood clots
• congestive heart failure

More common side effects of Avastin treatment include:

• tiredness and weakness
• stomach pain
• headache
• high blood pressure
• diarrhea
• nausea and vomiting
• loss of appetite
• mouth sores
• constipation
• lung infections
• nose bleeds
• shortness of breath
• decreased white blood cells
• skin peeling
• protein in the urine

For more detailed information about Avastin (bevacizumab), ask your healthcare provider.

Patients in Study Show No Signs of New Cancer Growth in Area of Original Tumor
By Charlene Laino

April 15, 2008 (San Diego) — Adding the cancer drug Avastin to standard treatment stopped cancer spread in 22 of 24 patients with rectal tumors, researchers report.

The patients were given Avastin, chemotherapy, and radiation prior to surgery to have their tumors removed. Three years later, all the patients were alive and 91% had no signs their disease was getting worse.

And none had new cancer growth in the area of the original tumor, says Rakesh Jain, PhD, the Andrew Werk Professor of Tumor Biology at Harvard Medical School.

“I know of no other therapy in this patient population where we can even get close to 100% tumor control. Although this needs to be confirmed in a randomized trial against a placebo group, these are very impressive numbers,” he says.

Avastin was one of several drugs that took center stage during the annual meeting of the American Association for Cancer research this week. Other researchers report that a drug that starves tumors of their blood supply shows promise for the treatment of one of the deadliest forms of brain cancer.

Still other researchers have had early success turbo-charging the body’s own immune system to fight prostate cancer.

Avastin Fights Rectal Cancer
Avastin is already approved to treat metastatic colorectal cancer, advanced lung cancer, and metastatic breast cancer.

Its cancer-fighting abilities have been attributed to its ability to prevent tumors from growing new blood vessels, thereby choking them to death.

The new research in rectal cancer patients suggests that it works in another remarkable way as well: It also repairs remaining blood vessels, Jain tells WebMD.

“Some of the blood vessels are pruned away immediately. But the vessels that remain become less abnormal. This creates a less hostile environment so radiation and chemotherapy can work better,” he says.

The researchers monitored the repair of blood vessels using imaging scans and blood tests for biomarkers known to be involved in cancer growth, according to Jain.
Experimental Drug Shows Promise for Brain Cancer

In a second study, the experimental drug cediranib helped shrink tumors and prolong the lives of people with a relatively common but often fatal type of brain cancer called glioblastoma.

“These patients have a very poor prognosis, with fewer than 5% alive five years after diagnosis. There’s a significant need for new therapies,” says Tracy Batchelor, MD, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at the Massachusetts General Hospital Cancer Center in Boston.

The researchers gave the pill to 31 people who had failed to respond to radiation, chemotherapy, and surgery.

After six months, about 25% were alive without signs that their cancer had grown or spread. That might not seem like much, but with traditional treatment, only about 15% of the patients would fare this well, Batchelor tells WebMD.