1. Will recurrence rates go down if both FOLFOX and celecoxib (a non-steroidal anti-inflammatory drug similar to aspirin) are used for treatment?

2.  Will recurrence rates stay the same and long term side effects decrease if FOLFOX is used for three months?

FOLFOX can cause short- and long-term neuropathy, a numbness and tingling in hands and feet that makes activities like buttoning shirts hard.  Long-term neuropathy seems to be related to the total amount of FOLFOX received. Celecoxib has been shown to prevent the formation of polyps, and the development of colon cancer in patients who have had polyps.

Patients in the trial will be randomized to one of four treatment arms:

• Six months of FOLFOX (standard of care)
• Six months of FOLFOX plus celecoxib for three years
• Three months of FOLFOX
• Three months of FOLFOX plus celecoxib for three years

Patients will be monitored for the course of the clinical trial by the treating physicians.  Overall patient safety and treatment efficacy will be monitored by a Data Safety Monitoring Committee. As always, patients who participate in clinical trials may or may not directly benefit from the trial.  They contribute to the treatment of future patients, whose treatment will be influenced by the results of this trial.

This trial is called the CLEAR Colon Trial. It is being conducted by a national, publicly-funded clinical trial network called the Cancer and Leukemia Group B (CALGB) and is supported by the National Cancer Institute. For more information, read or download this informational document or visit the Fight Colorectal Cancer Clinical Trial Matching Service.

The trial compares the effectiveness of adding perifosine to Xeloda® (capecitabine).

Led by Johanna Bendell, M.D., from the Sarah Cannon Research Institute in Nashville, TN, the trial is being conducted at 65 sites in the United States.

X-PECT is randomized and double-blinded.  Neither patients or their doctors will know if they are receiving perifosine in combination with Xeloda or a placebo plus Xeloda.

The primary trial endpoint is overall survival time, but it will also be studying complete and partial response rates, time to progression, and side effects.  Tissue is being collected to find out if there are biomarkers that might indicate which patients benefit from perifosine treatment.

Perifosine is an oral drug that blocks AKT signalling in the PI3K pathway leading to cancer cell death. Results from a smaller Phase II trial were reported at ASCO in 2010 and showed an improvement over Xeloda alone when perifosine was added.

The X-PECT trial is sponsored by Keryx Biopharmaceuticals, which has been granted the North American license for perifosine by Aeterna Zentaris Inc.

SOURCE

News release from Keryx Biopharmaceuticals , July 27, 2011.

What This Means for Patients

Results from the X-PECT trial are not yet available, although completing enrollment is an important step.  It is difficult to predict when we will know if perifosine improves survival time for people who have had cancer get worse on standard treatments.

Perifosine is still an experimental drug and is not on the market.

Fight Colorectal Cancer will watch for more information and report it when it is available.

The Colorectal Cancer Clinical Trial Call to Action campaign matches colorectal cancer patients with currently recruiting clinical trials based on their individual medical situation. The easy-to-use resources, powered by EmergingMed, help patients discuss with their doctor clinical trials that may be appropriate for them.  The personalized service is free, confidential, and available to patients, loved ones and healthcare professionals.

“Patients who participate in clinical trials also help further colorectal cancer research,” said Carlea Bauman, President of Fight Colorectal Cancer. “Today’s clinical trial could be tomorrow’s standard treatment. Unfortunately the process of finding an appropriate trial can be mind-boggling to patients, which is why Fight Colorectal Cancer is pleased to join with EmergingMed and the Colon Cancer Alliance on this vital program.”

Read the entire press release from EmergingMed, Fight Colorectal Cancer and the Colon Cancer Alliance.

Will you help answer a question about how to help colon cancer survivors  increase their physical activity?

You’ll learn more about colon cancer and may be randomly assigned to a special interactive program that is designed to help recovering colon cancer patients develop a healthy lifestyle.

The Survivorship Comprehensive Health Enhancement Support System (CHESS) study is available in centers in Wisconsin, Texas, North Carolina, and Connecticut.  To be part of the research, you need to have completed treatment for stage I, II, or III colon cancer within the past 12 months. 

Evidence has shown that exercise can reduce risk of recurrence for people with colon cancer, but some people may have trouble returning to their pre-cancer activity or improving on old habits.  The CHESS study will test a new intervention that may help those folks.

If you are a colon cancer survivor — or are close to finishing your treatment — get more information or join the study by calling a program director:

• University of Wisconsin Carbone Cancer Center in Madison — 1-800-361-5481
• University of Texas MD Anderson Cancer Center in Houston — 1-877-554-6061
• University of North Carolina Lineberger Cancer Center in Chapel Hill — 1-877-404-7255
• Helen and Harry Gray Cancer Center at Hartford Hospital, Connecticut — 1-860-545-4681

Survivorship CHESS is designed to help colon cancer patients develop

• competence in gathering information making decisions, and learning about behaviors they are trying to change.
• social support systems to help deal with their cancer experience.
• autonomy that comes when they regain a sense of control over their lives.
• ways to adopt or maintain healthy lifestyle behaviors and improve their quality of life.

During the study:

A new interactive cancer communication system (ICCS) called Survivorship Comprehensive Health Enhancement Support System (CHESS) will be developed and tested to promote lifestyle change among colon cancer survivors. The study will test the efficacy of Survivorship CHESS to help newly diagnosed colon cancer survivors increase their physical activity, decrease distress, and improve quality of life.

The study is funded by the National Cancer Institute and headed by David Gustafson, PhD., University of Wisconsin-Madison & Deborah Mayer, PhD., University of North Carolina.  More information from ClinicalTrials.Gov.

Dr. Lenz

Because of the overwhelming response to my earlier post on PRI724, I wanted to clarify a little bit more about this trial and other trials available for patients with advanced colorectal cancer who have received all standard of care regimens including FOLFOX, FOLFIRI, Avastin and Erbitux (if they were wild-type KRAS).

Of course we will have PRI724. The reason we are so excited because it is the first in class to inhibit a pathway so essential for colon cancer stem cells.

The IND is filed at the FDA, which means we need to wait 30 days for the FDA to respond. If they have concerns, we need to answer them. When they agree, we will go ahead to get institutional review board (IRB) approval. We already have scientific approval from the Cancer Center Scientific Review. Once we have IRB approval we are ready to go.

In the first phase any solid tumor is eligible. However, phase I trials are heavily regulated, so patients need to meet eligibility criteria, which means almost normal function of renal, liver, blood etc. They have to be in reasonable shape (able to do their daily activities). We anticipate that this trial may open at the beginning of November.

This is a phase I trial, which means we are dose escalating to find out if there are any side effects. We don’t expect any. In fact we are worried that there will be none, which will make it difficult for us to decide what dose to use to move forward.

We have decided to measure concentrations of the drug in the blood stream and changes in the tumor cells to determine when the drug is effective, and then expand the dose to colon and pancreas cancer.

In addition, over the last year a lot of novel therapies have been developed and we have two trials open for patients with mutant KRAS,  one for patients who received FOLFOX/Avastin who never had irinotecan, have mutant KRAS, and whose tumors continue to grow.  For patients who had all therapies we have another trial.

We also have trials with novel compounds which focus on the VEGFR, but not VEGF like Avastin does. VEGFR is the receptor to which VEGF binds and may work when anti-VEGF does not work. This is a phase III randomized trial using an antibody against VEGFR. The control arm is no treatment.

We have openied a novel trial using lapatinib and LBH and LBH with 5-FU. These novel drugs attack specific alteration in the colon cancer cells. Both combinations were tested in vitro and in animals showing promising data, so we wrote them up for clinical trial.

We have a EPO906 trial which has shown to shrink tumors in patients who had all standard treatments and where those treatments stopped working.

We have phase I trials with inhibitors of Hedgehog, NOTCH, MEK, and others, which are novel smart drugs effecting specific genetic switches turned on in colon cancer. Also there are other trials which also make a lot of sense depending on the molecular make up of your tumor.

I hope this clarifies some of the questions that readers had.

From the Editor

You can find a complete list of gastrointestinal cancer clinical trials currently available at the University of Southern California Norris Cancer Center online.  Look for Dr. Lenz’s name as Principal Investigator and for colorectal somewhere in the name of the trial.

Some trials may also be available closer to where you live.  Others are limited to USC Norris.

The Clinical Investigation Support Office at (323) 865-0451 at USC Norris can give you more information and answer your questions.  Here are answers to some Frequently Asked Questions about clinical trials at USC Norris.

Call the Colorectal Cancer Coalition Answer Line for more help with understanding these trials or finding other clinical trials to meet your needs. 877-4CRC-111 (877-427-2111).

Update: View a video from Dr. Lenz about the drug’s development:

USC Norris Comprehensive Cancer Center and Hospital: Beyond the Fight from Ryan Ball on Vimeo.

The bill provides that the first $2,000 per year received by an individual for participation in a clinical trial shall not be counted as income for the purpose of calculating Social Security benefits.  This provision was included in the House-passed health care reform bill last November, but was not included in the final bill the President signed into law in March.

The Senate already passed this bill on August 5.  House passage later today will clear the bill for review and signature by the President.

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