Researchers compared progression-free survival between patients who got either FOLFOX or FOLFIRI chemotherapy with Avastin and a group who got the same chemo regimen with GDC-0449. There was no difference

GDC-0449 was being developed by Genentech in collaboration with Curis.

Hopes for the new treatment were raised at ASCO earlier this month where reports showed no increased side effects with the new combination.

Researchers thought that blocking the Hedgehog gene on the surface of cancer cells would stop a series of signalling events in a pathway inside the cell leading to cell death and lengthening the time until cancer began to grow again.

Hedgehog is involved in embryonic development, particularly in growth of limbs. It was first observed in fruit flies where mutations led to many spiky extra legs making the curled up fly look like a hedgehog. You can watch a video of how it works.

Read the news release from Curis.

Disclosure: C3 has received funding from Genentech in the form of unrestricted educational grants. C3 has ultimate control over website content.

All of the patients in the NO147 trial had cancer that had spread to their lymph nodes and had surgery before beginning chemotherapy. They had normal or wild-type KRAS genes in their tumors.They were randomly assigned to FOLFOX chemotherapy for 6 months or FOLFOX plus Erbitux. 

The trial was closed before the planned number of patients were enrolled because an analysis showed that there was no benefit to the additional Erbitux and continuing the trial would not help patients.

NO147 randomized 1,760 patients with wild-type KRAS to either FOLFOX — oxaliplatin, leucovorin, and continuous infusion 5-FU — or FOLFOX plus cetuximab for 12 treatments.   The primary goal of the trial was to discover which therapy resulted in the best disease-free survival three years later.  Researchers also wanted to measure three-year overall survival and compare serious side effects.

They found:

• For all patients there was no difference in disease-free survival with 74.1 percent of patients getting FOLFOX alone disease-free at 3 years compared to 73.3 percent on the FOLFOX plus cetuximab regimen.
• FOLFOX only patients had a trend toward better overall survival with 87.3 percent alive at 3 years compared to 82.1 percent when cetuximab was added.
• Disease-free survival for patients over the age of 70 was worse in the cetuximab arm with 63.8 percent alive without colon cancer at three years compared to 78.0 who only got FOLFOX.

Serious side effects were worse with cetuximab.  65 out of every 100 patients had a grade 3 or worse side effect when they got both FOLFOX and cetuximab compared to 45 of every 100 on the FOLFOX only treatment. In addition to a skin rash that is typical for Erbitux, patients on the drug also had more risk for severe diarrhea.

Fewer patients were able to complete all 12 treatment cycles when cetuximab was added.

Both serious side effects and differences in disease-free and overall survival were increased in patients who were 70 and over.

Erbitux has shown benefits both as a single drug and when it is combined with chemotherapy for patients with metastatic colorectal cancer that has already spread to sites beyond the colon so it was unclear why this benefit didn’t extend to patients without metastases.

Dr. Stephen Alberts, the Mayo Clinic oncologist who led the trial said,

The sum of data to date from trials for metastatic colorectal cancer suggested that cetuximab would provide benefit in these stage III patients with KRAS wild-type tumors, and so our findings are unexpected. It is difficult to understand how an agent that helps patients with metastatic cancer is not beneficial to those with less advanced disease. At this point we are focusing our efforts on identifying a biological explanation for these findings.

He went on,

Based on what we found, any use of cetuximab in stage III colon cancer is not supported by the results of our trial.

Dr. Alberts and the trial team concluded,

In this randomized phase III trial the addition of cetuximab to modifiedFOLFOX6 was of no benefit for patients with resected stage III wild-type KRAS colon cancer.

SOURCE:  Alberts et al., 2010 ASCO Annual Meeting Abstracts, #CRA3507

Dr. Alberts discusses the trial and its results below.

Disclosure:  C3 has received educational grants from Bristol-Myers Squibb, ImClone, sanofi-aventis, and Pfizer who were sponsors of the NO147 trial in addition to the National Cancer Institute. C3 has ultimate control over content of our website.

We have learned that tumors with mutations in KRAS will not benefit from this treatment. All patients should be tested for KRAS mutation if they have advanced or metastatic disease.

However patients who have mutations of the KRAS gene don’t do worse than patients with wild type. The only difference is that the drugs which target EGFR will not work.

We really have had no marker which identifies patients who have a tumor which is very aggressive and grows independently of whatever treatment we initiate. Recent data suggest we may have identified a marker like this. The marker is called BRAF.

Only about 5 percent of patients with metastatic disease carry a mutation in this gene. Preliminary studies suggest that patients with tumors harboring this mutation do much worse. However more studies are needed to validate these findings.

The reason I am sharing this with you is because we have now therapies available which may inhibit this particular mutation. BRAF mutations are common in melanomas and bile duct cancers, and recent developments show that we may have very powerful inhibitors for patients with this mutation.

In our practice we are screening for these mutations since we have a number of clinical trials allowing patients to be tested with a BRAF inhibitor.

Please discuss these options with your oncologist if your first line therapy is not working to see  if you are eligible for clinical trials when you have either a mutant KRAS or mutant BRAF gene in your tumor.

The trial will test the effectiveness of infusing the drug melphalan through the artery that feeds the liver.

Colorectal cancer patients with liver metastases are eligible for the trial if they have already had chemotherapy including irinotecan or oxaliplatin.  Limited cancer outside of the liver is acceptable if the most serious problem is within the liver itself.

Treatment involves placing catheters in both the hepatic artery and hepatic vein.  Melphalan is pumped through the hepatic artery for about  15 to 30 minutes and the liver bathed in the chemo drug (hepatic perfusion). The infusion will be repeated every 3 to 8 weeks up to 4 times.

The trial and its treatment takes place at the NIH Clinical Center in Bethesda, MD, just outside of Washington, DC.

There is no cost for care received at the NIH Clinical Center.  Travel expenses and reasonable costs for meals and lodging are also paid to trial participants.

Patients with primary liver cancer, neuroendocrine tumors, or liver metastases that have spread from other gastrointestinal cancers are also eligible for the trial.

For more information, you can contact:

• Itzhak Avital, MD
• Principal investigator
• Phone: 301-402-0083
• Fax: 301-496-0734
• avitali@mail.nih.gov

Or make a referral through:

• Carole Webb, RN
• Research Nurse
• Phone: 301-451-6940
• Webbcc@mail.nih.gov

More information for patients about the trial is available on the National Cancer Institute website.

NCI-04-C-0273: A Phase II Study of Hepatic Arterial Infusion of Melphalan With Venous Filtration via Peripheral Hepatic Perfusion (PHP) for Unresectable Primary and Metastatic Cancers of the Liver

• The Colorectal Cancer Association of Canada is sponsoring a contest for print and video ads that raise awareness of colorectal cancer.
• Clinical trials at the NIH Clinical Center in Bethesda, MD are an option for cutting-edge treatment at no cost.
• When co-pays are raised for Medicare, the elderly make fewer outpatient visits but are hospitalized more often and stay in the hospital longer.

Raise CRC awareness with an ad or video and win!

Your print or video public service announcement to raise awareness of colorectal cancer and its prevention could be a winner.

The Colorectal Cancer Association of Canada will award $2,500 for the best video and $1,000 for the best print ad that reduces colorectal cancer by encouraging:

• Prevention= health lifestyles, diet and exercise, screening
• Awareness= signs, symptoms, stats
• Education= knowledge about treatments
• Support= cancer coaching and psychosocial aspects
• Advocacy = access to diagnostics and medicine

Entries must be submitted online and be received by March 31, 2010.

Cancer clinical trials at the National Institutes of Health in Bethesda

The National Cancer Institute Center for Cancer Research in Bethesda, MD, just outside of Washington D.C., conducts cancer clinical trials, including trials for colon and rectal cancer.

There is no cost to participate in a clinical trial at the NIH Clinical Center.  In addition, transportation expenses are paid and there is a per diem to cover meals and lodging for outpatients.

Higher co-pays for Medicare end up costing more

When Medicare co-pays are raised for ambulatory visits, plan members make fewer out-patient visits, but are hospitalized more often and for more days.

In plans that raised co-pays, there were 20 fewer out-patient visits per 100 enrollees each year, but 2 more hospitalizations and 13 more days in the hospital compared to plans that kept co-pays stable.

For every 100 patients in plans that raised co-pays, the plan got $5,950 in extra money from co-pays and saved $1,200 from fewer outpatient visits for a net savings to the insurance plan of $7,150.  However, with an average cost of $11,o65 for each hospitalization of a patient 65 to 84, the increase in hospitalization cost $24,000 for each 100 plan enrollees.

Increased co-pays hit low-income, black, and less-educated patients particularly hard, decreasing numbers of visits and increasing hospitalizations.

Writing in the January 28, 2010 issue of the New England Journal of Medicine, lead author Amal N. Trivedi, MD, MPH and team concluded,

Increasing copayments for ambulatory care reduced the use of outpatient care among elderly enrollees in managed-care plans, but this decline was offset by an increase in hospitalizations, particularly among enrollees with low socioeconomic status and those with chronic disease. Increasing copayments for ambulatory care among elderly patients may have adverse health consequences and may increase spending for health care

Because the analysis showed that patients were not benefiting from adding Erbitux to FOLFOX chemotherapy, the trial has been closed according to a news release from the National Cancer Institute.

The study — N0147 — randomized patients with stage III colon cancer after surgery to receive either FOLFOX chemotherapy alone or FOLFOX and Erbitux.  Once information about the importance of the KRAS gene for Erbitux benefit was discovered, all patients in the trial had their tumors tested for KRAS mutations and only those with normal or wild-type KRAS were included in the DMC analysis.

According to the NCI news report , there was some initial evidence that addition of Erbitux may have been harmful, especially in patients older than 70.

The study was led by the North Center Cancer Treatment Group (NCCTG) and sponsored by the NCI.

NCCTG N)-147 was officially titled: A Randomized Phase III Trial of Oxaliplatin Plus 5-Fluorouracil/Leucovorin With or Without Cetuximab After Curative Resection for Patients with Stage III Colon Cancer

Currently the use of Erbitux for colorectal cancer is limited to patients with metastatic disease who do not have mutations in the KRAS gene.

Disclosure: C3 has accepted funding for projects and educational programs from ImClone Systems and Eli Lilly in the form of unrestricted educational grants. C3 has ultimate authority over website content.

It is important to know that in the UK Avastin is not approved, and Erbitux was only recently approved in patients with organ limited disease based on the chance of curative resections in patients initially deemed not to be resectable. However it is difficult to judge what the COIN results mean. The response rates in the patients with wild-type KRAS was significantly increased to 64%, so far so good. The problem is that the time to tumor progression and overall survival was not improved in patients with wild-type KRAS and Erbitux therapies.

I would caution not to jump quickly to conclusions since these data require a closer look. It is certainly surprising that about 40 percent of patients died in the first year which is much higher than any other study, which is usually about 20 percent, suggesting that these patients were sicker than in other trials.

In the UK, which reflects a pretty frugal health system, CT scans to monitor success of therapy are done every three months, not every six weeks as  in  United States or other parts of Europe. This makes it much more difficult to see a difference in results, particularly when we expect a time to tumor progression between 7 and 9 months. We also have to recognize that the CT findings are not centrally reviewed which means they can change when scans are reviewed by an expert panel (numbers always change from the investigator reading to an independent panel).

However the most interesting data are that the patients who received Erbitux and Xeloda had significant side effects leading to two dose reductions meaning that these patients received much less chemotherapy. This group seemed to have no benefit from Erbitux, but the patients who received FOLFOX did. We don’t know for sure why there are why are there more side effects with Xeloda and Erbitux, but both have overlapping GI and skin toxicities.Whether there is also some biological interaction we don’t know yet.

These data certainly need more evaluation and detailed review to be able to fully understand them.

Disclosure: C3 has accepted funding for projects and educational programs from Bristol-Myers Squibb and ImClone Systems in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Oxford University

Nancy Roach is the Founder of C3 and Chair of the Board of Directors.

On September 5 -6, I put on my sensible black shoes to attend the second Sensible Guidelines for the Conduct of Clinical Trials meeting at Oxford University in England.  This invitation-only meeting convened research leaders to discuss how to improve large randomized clinical trials.

Why “Sensible Guidelines”?

People are the ‘experimental subjects’ of clinical research. Since World War II, laws and regulations have been passed to make sure that research participants are protected during the conduct of clinical trials. Over time – and especially in the last decade – many of the well-meaning laws and regulations have had an unintended consequence:  bureaucracy that does not always protect or help patients, but does eat up resources. Patients in trials often see only the tip of the bureaucratic iceberg, while research staff, academic institutions, government agencies and drug companies struggle with the rest of it.

For example, trials require that investigators show that they are credible researchers, and often include a criminal background check.  This sounds very reasonable; however, when researchers participate in multiple trials, the same paperwork is required multiple times.  In England, researchers are now issued “passports” that certify their credentials.  Once they are certified, they don’t need to re-apply for each trial.  This simple step saves time and paperwork.  The saved time allows researchers and their staff to spend more time with patients and conducting research.

Patient protection is central to all clinical research.  The goal of the Sensible Guidelines group is to support regulations and practices that promote meaningful patient protection and safety while not adding unnecessary paperwork or extra rules that only slow down research.

Meeting Report

After the first Sensible Guidelines meeting in 2007, several papers were published in the February 2008 issue of Clinical Trials (pages 38-84. A subscription is required to read the full text) that documented the impact of unhelpful bureaucracy, and suggested ways to reduce it.

The second meeting’s goals this September were to:

• Update the review of the main barriers preventing efficient trials;
• Share the experiences of those who are attempting to deal with these barriers; and
• Agree on possible solutions to the main difficulties and encourage their promotion through international collaboration.

I was the only patient advocate invited and was a little worried that I would be a ‘lone voice’ for patients.  Once the meeting started, I realized I didn’t need to worry.  I was struck by the passion of everyone involved, and their frustration with today’s reality. They want:

• trial monitoring which monitors patient safety;
• informed consents that help patients understand the trial and its risks and benefits; and
• adverse event reporting that reveals meaningful side  effects.

More than anything else, they want to see time and money going into patients and research projects instead of process and paperwork which doesn’t add to the value of the research.   Once again, I was reminded that many people involved with clinical research can also be advocates for patients.

Some meeting highlights for me:

• Progress was reported from the “bureaucracy-busting” work led by Dr. Sally Davies in England.  The Best Research for Best Health effort was lauded by many in the audience as saving time and energy for patients and researchers.

• Dr. Judith Kramer presented the work being done by the FDA-Duke Clinical Trials Transformation Initiative (CTTI).  CTTI is conducting research to identify best practices in adverse event reporting and clinical trial monitoring.

• Dr. Zhang Jingli, Deputy Commissioner of China’s State Food and Drug Administration, described how the Chinese version of our Food and Drug Administration (FDA) regulates drug safety.   The complexity was astounding  given China’s size, growth and mix of both traditional and Western medicines.

Nancy Roach Chair C3 Board

Changing the way research is conducted is complicated.  At the end of the meeting, participants puzzled over exactly what steps are necessary.  A small group will develop recommendations, and proposals for sensible monitoring of trials will be published.

C3 is involved with several ongoing efforts to streamline research, including the National Cancer Institute, CTTI and Brookings /Friends of Cancer Research.  So stay tuned!

R935788 or Fostamatinib, a protein kinase inhibitor, is in a Phase II clinical trial for patients with several types of advanced cancer, including colorectal cancer.  Patients whose cancer has gotten worse on previous treatment are eligible to participate.  The trial is being conducted at the NIH Clinical Center in Bethesda, Maryland.

Patients will take fostamatinib twice a day during 4 week cycles.  They’ll see a doctor at the NIH Clinical Center at the beginning of each cycle.  Weekly blood tests and blood pressure checks can be done in an outpatient clinic or by the patient’s own doctor.

There is no charge for medical care received at the National Institutes of Health (NIH) Clinical Center in Bethesda. Patients need to pay their own travel costs for the first screening visit, but once enrolled, the National Cancer Institute pays for transportation to the Washington area.  During outpatient visits, NCI pays a small daily amount for for hotel and meals.

Patients are encouraged to maintain their own insurance to cover health care costs outside of the NIH Clinical Center.

To be considered for the trial, patients or their doctors should contact research nurses:

• Janelle Bingham, R.N.
• Phone: 301-435-2715
• jbingham@mail.nih.gov

or

• Mary Ann Yancey, R.N.
• Phone: 301-435-9227
• yancym@mail.nih.gov

Shivaani Kummar, MD is leading the study.  She can be reached at 301-435-5402 or  kummars@mail.nih.gov

Find more answers to  your questions about the trial.  A full description is on the NCI Clinical Trials PDQ.

MUC1 is a protein found in precancerous colorectal polyps and in colon cancer. The experimental vaccine causes the body’s immune system to develop antibodies against MUC1, killing tissue that contains it and potentially preventing polyps from returning.

Participants in the Phase II clinical trial have already been diagnosed with an advanced adenoma — a colorectal polyp that has a high risk of becoming cancer.  They receive three doses of the vaccine, injected into their thigh.  In the 20 patients already enrolled, there haven’t been serious side effects beyond some redness where the injection was given.

Researchers are measuring immune system response to the vaccine including looking forT-cell activity and antibodies against MUC1.

Future colonoscopies will test whether the vaccine reduces new adenomas.

If the vaccine is successful, it could reduce the number of colonoscopies necessary to watch for new polyps in  for people with a history of adenomas.

Not all colorectal tumors develop MUC1, so it would still be possible to develop colon cancer, but if the vaccine works, it would reduce the risk.  It probably would not replace colonoscopies entirely.

Robert E. Schoen, professor of medicine at the University of Pittsburgh School of Medicine, who is leading the study, explained,

This is taking it in a different direction. We’re now trying to use immunotherapy as a means of prevention. You would be using your immune system as a surveillance mechanism to prevent the development of malignancy.

Contact information is available from Lynda Dzubinski in the Digestive Disorders Clinic at the University of Pittsburgh Medical Center.  Call 412-648-9116.

SOURCE: Jocelyn Rice, A Vaccine for Colon Cancer, MIT Technology Review,July 27, 2009.