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.

On November 4, the National Cancer Institute (NCI) held the 9th meeting of the Clinical Trials and Translational Research Advisory Committee (CTAC). CTAC advises NCI on the implementation of the 2006 recommendations from Clinical Trials Working Group and the 2008 recommendations for the Translational Research Working Group. There’s more information about NCI’s initiatives here.

I am one of two advocates who serve on CTAC, and as an ex-systems analyst, I’m always looking for ways to make government more efficient and accountable.  At the November 4 meeting, recommendations were presented to increase the efficiency of the clinical trial development process – from the time that a researcher presents a concept to NCI to the time that the trial is actually activated.  Under the leadership of Dr. James Doroshow, NCI and its partners are taking aggressive steps to de-bureaucratize publicly-funded cancer research, which will ultimately benefit patients by putting resources into research instead of process.

Following is a very brief overview of the background and the recommendations, with links to additional documentation. And believe it or not, zombies did come up in the discussion!

Editorial Comment:

C3 has made “bureaucracy-busting” a priority of its research program.  Much of the unproductive process is an unintended consequence of well-intentioned changes that evolved over time.  At the end of the day, patients are best served by an efficient research system that can get answers to important clinical questions safely and quickly.  We applaud the efforts of everyone involved with this effort, and look forward to the implementation of the changes.

Improving Operational Efficiency Initiative – Background

One of the initiatives that came out of the Clinical Trials Working Group was the Operational Efficiency Initiative, which is looking at two areas where operational efficiency could be improved:

• Increasing the rate of patient accrual so that trials can be completed faster
• Identifying and reducing institutional barriers (aka bureaucracy) that stretch the time needed to develop and launch clinical trials

NCI and CTAC took aim at the “institutional barriers” first.  Step one was analysis.  David Dilts and Alan Sandler reviewed and documented the process involved with starting trials.  Their analysis showed many places where the process was broken:

• Starting a phase 3 trial in a cooperative group takes from one to three YEARS
• 40% of phase 3 cooperative group trials enrolled fewer than 20% of the patients needed to get a result
• Trials that take longer than two years to develop enroll fewer patients
• Fixing the system required changes by everyone involved, including NCI and the cooperative groups.

Some problems they identified included:

• Tweaking – multiple reviews that changed “just one thing” which then required an additional round of reviews
• Deadline-denial – when deadlines were broken, there were no consequences
• An inability to say “no” – reviewers would ask submitters to “revise and resubmit” a trial proposal, instead of just saying “no” to the trial.

This is a very quick summary – Dilts’ papers are listed at the end for those who want to learn more, and his very entertaining presentation to NCI is here:

Activating and Opening Phase III Clinical Trials: A Process and Timing Study
Presented at 2007 NCI Clinical Trials Operations Committee (CTOC)

Step two involved further analysis to identify areas that need change. To that end, CTAC formed the Operational Efficiency Working Group (OEWG) which was charged with identifying ways to decrease the time needed to take a trial from concept submission to protocol launch.

The OEWG included 63 members:

• 10 Cooperative Group Chairs
• Pharma/Biotech
• 8 Cancer Center Directors
• Patient Advocates
• Clinical Investigators
• FDA
• Statisticians
• CMS
• Protocol/Trial Specialists
• CTSU
• NCI Clinical Trials Leadership and Staff
• Community Oncologist

The group looked at ways to decrease trial development time without impacting the quality of science or patient safety in 4 types of trials:

• Cooperative Group Phase III Trials
• Cancer Center Investigator Initiated Trials
• Investigational Drug Branch (IDB) Early Drug Development Phase II Trials
• Cancer Center Activation of Cooperative Group Trials

OEWG recommendations

Step 3 was developing the recommendations for what to change and how to change it. The OEWG set timeline targets which dramatically cut the time that NCI, cooperative groups and cancer centers spend on protocol development.  In the chart below, the current median days to activation are shown in blue, and the OEWG targets are in red.  The OEWG targets do not include interactions with Institutional Review Boards (IRB) or industry.  In addition, NCI set firm termination deadlines (green) which provide some “give” to the targets in order to deal with IRBs and industry.

Generated from information presented at 11-4-2009 CTAC meeting

The firm termination deadlines (green) take effect in January 2011.  In other words, if a phase III trial takes longer than 2 years to develop and activate, the trial is terminated.

Here’s where zombies come in. In the past, some trials have hung around the development process for years, clogging up the system.  There wasn’t a clear path to getting those trials out of the system, even though a trial that takes more than two years to develop is very unlikely to succeed. Those trials have been nicknamed zombies.   Effective January 1, 2011, current zombies will be terminated, and the clock will start ticking as new trials enter the system.

The implementation of firm termination deadlines – no excuses allowed – is very new in the public research arena.   In order to get there, OEWG identified 11 specific recommendations which focus on streamlining the development of scientifically significant trials.   The recommendations emphasize:

• Real-time resolution of issues
• Working in parallel processes instead of sequential processes where possible
• Limiting the ability for concept and protocol tweaking
• Use of new specialists such as medical writers and dedicated trial development managers, and new tracking tools so that protocol progress can be monitored.

NCI will provide resources to implement these recommendations over the next year.

The full presentation from the November meeting is online:

Operational Efficiency Working Group (OEWG) Update – Dr. Doroshow (PDF)

The presentation contains more data that explains the timeline decisions, and gets into the detail of the recommendations and the support that will be provided to re-align the protocol development process at NCI, cooperative groups and cancer centers.

The next steps are:

• Prepare Phase I OEWG Final Report and begin implementation
• Launch OEWG Phase II addressing rate of accrual and time to trial completion

The next CTAC meeting is March 3, 2010, and I look forward to hearing a progress report.  These meetings are open to the public, and are held at Building 31, C Wing, 6th Floor, Conference Room 10 at the National Institutes of Health campus, 9000 Rockville Pike, Bethesda, Maryland.

References:

• Development of Clinical Trials in a Cooperative Group Setting:  The Eastern Cooperative Oncology Group, Dilts et al. Clinical Cancer Research, 14(11) June 1, 2008
• Processes to Activate Phase III Clinical Trials in a Cooperative Oncology Group: The Case of Cancer and Leukemia Group B, Dilts et al, Journal of Clinical Oncology, 24(28) October 1, 2006
• Invisible barriers to clinical trials: the impact of structural, infrastructural, and procedural barriers to opening oncology clinical trials. Dilts and Sandler, Journal of Clinical Oncology 24(28) October 1, 2006
• Activating and Opening Phase III Clinical Trials: A Process and Timing Study Presented at 2007 NCI Clinical Trials Operations Committee (CTOC)

On September 22, I participated in a meeting that looked at some of the profound implications of the growing amount of publicly-available data, and grappled with questions around reporting research results using this data.  The day’s agenda was titled “Interpreting and Communicating Clinical Data in the Public Domain,” and the meeting was convened by the FDA Clinical Trials Transformation Initiative (CTTI).

The meeting delved into a lot of detail:

• Legislation which requires research sponsors to make summary data publicly available in www.clinicaltrials.gov, both positive and negative results;
• Existing guidelines and best practices for both clinical trials and meta-analyses; and
• Existing efforts to clarify guidelines for meta-analyses.

At the end of the day, my personal conclusion was that meta-analyses will be used in the future to make health care recommendations, and that strong guidelines are critical.  The meeting results are still being processed, so no formal recommendations have occurred yet.

Rather than report the nuts and bolts of a very long and technical day (I typed 8 pages of single-spaced notes), I’ll talk about some of the substance that we discussed, and why it matters to us, the non-scientists in the room.   Warning – this is complicated, and I’m explaining it at a very high level.  All mistakes are mine.

What does a meta-analysis look like?

We’ve all seen headlines like:

• Aspirin Is Found to Be Fighter Against Colorectal Cancer (New York Times, August 12, 2009)
• Diabetes Drug Linked to Higher Risk of Death (New York Times, November 25, 2008)
• The Claim: Being Left-Handed Adds to the Risk of Migraines (New York Times, April 15, 2008)

The common link between the stories is that the results being reported come from a meta-analysis – a combination of multiple trials and/ or studies – rather than a clinical trial.

First, clinical trials

In a clinical trial, researchers define the question they’re asking (hypothesis), how they will collect the data they need to answer the question and how they will analyze the data (analysis plan).  All of that is called “pre-specification” – saying what you’re going to do and how you’re going to do it before actually starting the analysis.  All of that is written up in a document called a protocol.  At that point, patients are enrolled on the trial and the data is collected.

Once all of the data is collected, the results are analyzed and sometimes reported through medical journal articles and presentations at professional meetings.  If the results are meaningful to patients, they may be seen in the popular press.   Medical journals have endorsed guidelines that recommend standard ways to report randomized clinical trials, so that readers can be sure that they have a complete understanding of how the research was done, including whether appropriate pre-specification occurred.   Journals may refuse to publish research that doesn’t meet the guideline criteria.

Pre-specification is fundamental to clinical research.  Over my years of advocacy, I’ve heard Dr. Robert Temple from the Food and Drug Administration (FDA) say that without pre-specification,  data can be manipulated to show just about anything.  In other words, research that is not pre-specified can generate other research questions, but should not be used to make critical decisions in patient care.

Clinical trials are designed to answer specific questions, and are not always large enough to show infrequent or small effects. Also, data from a specific clinical trial cannot be legitimately  extrapolated to answer broader questions that were not asked in the original clinical trial.  So, is there a way to look at multiple, somewhat similar, clinical trials that may have varying results?

Now, meta-analysis

A meta-analysis combines results from several trials and/or studies, and the large combined data set can show  impacts – both bad and good – which aren’t always seen in the original trials.  And doing a meta-analysis is much faster and cheaper than doing yet another even larger clinical trial, especially a large phase 3 clinical trial which can cost over $100 million and take 5-10 years to complete.

Because they can involve tens of thousands of people, represent a great deal of research effort and financial cost, meta-analysis results can influence public policy.  For example, the April 30, 2009 New England Journal of Medicine contains an article titled, Ounces of Prevention — The Public Policy Case for Taxes on Sugared Beverages. The article cites meta-analyses to make its case.  And meta-analyses frequently ask questions that are interesting to the public, generating articles like the ones listed above.

Thus, I assumed that meta-analyses were performed and reported with the same scientific rigor as clinical trials.  As I prepared for the meeting in September, I was surprised to learn that my assumption was wrong.  Many meta-analyses do pre-specify:

• The questions they are asking
• The inclusion and exclusion criteria for potential data sources
• The list of potential data sources
• The analysis plan

For example, the Cochrane Collaboration is famous for its carefully done, completely reported meta-analyses and systematic reviews.    However, reporting standards for meta-analyses do not require that these issues be addressed in articles.  Existing guidelines for meta-analysis such as the Prisma Statement stress documentation of what was done, but not pre-specification.

Why should we care?

Between the Internet and calls for transparency in clinical research, more data is publicly available than ever before.   Medical journals are accessible, and result reporting on www.clinicaltrials.gov has opened a floodgate of data (note:  you can listen online to Deborah Zarin from the National Library of Medicine explain the requirements).

Meta-analysis is a valuable tool that can help us look at trends from multiple clinical trials and/or studies, but as with all research data, it has limitations.  As patients and advocates, it is important for us to look at all research data with a critical eye to fully understand what conclusions can be drawn from them and what might just be suggestive and require further study.

Remember the quote from Field of Dreams?  If you build it, they will come. The research translation of that is:  If the data exists, it will be analyzed. And the analyses will continue to be used to guide health policy, clinical guidelines and public opinion.

Thus, accurate and complete reporting of meta-analysis results is critical.  The Institutes of Medicine and Food and Drug Administration are working on separate guidelines, each of which will take at least two years to complete.  In the meantime, I plan to be careful about the conclusions I draw from health care articles.

On September 14, I participated in the second Conference on Clinical Cancer Research, hosted by Friends of Cancer Research and the Engelberg Center for Health Reform at the Brookings Institute.  The 2008 conference identified specific areas of clinical research that could be “de-bureaucracied”.  In 2009, the conference presented the progress made in the past year, and identified next steps.

Following is background and a report on my panel’s discussion regarding centralized review of scans to determine progression free survival in phase 3 trials.

Warning: this meeting delved into highly technical aspects of clinical research, so the following is a little geeky!

Background

The Food and Drug Administration (FDA) regulates drugs in the United States.   Before a cancer drug such as Avastin (bevacizumab) or Erbitux (cetuximab) can be sold to patients, the company making the drug must provide clinical trial results that show:

• How the drug should be used – in what patients, at what dose?
• Side effects, especially common or serious side effects
• Impact – does the drug help patients live longer?  Shrink tumors?

When a drug shows clear patient benefit and acceptable side effects, the FDA review process can be very straightforward.  Gleevec (imatinib) for chronic myeloid leukemia (CML) patients is an example of this type of review.  Patients in Gleevec clinical trials were not only living longer, but also many of them showed signs that their CML had gone away. FDA approved Gleevec in 2 months, one of the shortest reviews on record.

Unfortunately, many cancer drugs don’t show such striking results.  The clinical trial data taken to FDA might show that the drug makes tumors shrink (response rate) or keeps tumors from growing for a longer time (progression free survival), but not that the drug helps patients live longer (overall survival).  Ultimately, increasing survival or improving quality of life while patients are alive is the goal.  When FDA reviews data, they frequently grapple with questions like:

• If a drug increases progression free survival but not overall survival, and if the drug has significant side effects, how do patients benefit?
• If overall survival is increased by a few weeks, do patients benefit?
• If trial results show tumor shrinkage, were the scans that show the shrinkage read correctly?

FDA works through these questions in private meetings with sponsors (generally drug companies).  FDA also has the ability to convene an official Oncology Drug Advisory Committee meeting where they can raise these issues publicly, get advice from ODAC members and comment from the public.

Goal of the Conference

The conference convenes groups that “dive into the weeds” of drug review, and look for ways to improve the process.  This year’s conference focused on four specific areas:

• How much side effect (safety) data needs to be collected in clinical trials for drugs that are already used to treat different forms of cancer?
• If a trial is using scans to document tumor growth (progression), do all of the scans need to be double-checked by a blinded central review group?
• As research finds biomarkers that predict whether a patient will respond to a drug, how can the tests identifying the biomarkers be effectively regulated?
• As combinations of targeted treatments are tested in clinical research, what guidelines do companies need to ensure that the right data are produced for FDA review?

Panel 2: Local Evaluation vs Blinded Central Review of Scans, and PFS

I represented patients on the 2^nd panel, which is looking at ways to manage the review of scans.  Companies bringing new drugs to market have blinded centralized review (BCR) of all scans in phase 3 trials.  BCR is very expensive, and the question we considered is:  Does BCR result in better data?  Is it possible to audit a specific proportion of scans and perform BCR only if warranted?  The panel was chaired by Dan Sargent from the Mayo Clinic, a world-renowned clinical trial statistician and member of C3’s Medical Review Network.  The other panelists were:

• Will Bushnell, GlaxoSmithKline
• Ohad Amit, GlaxoSmithKline
• Lori Dodd, National Institute of Allergy and Infectious Diseases
• Richard Pazdur, FDA

Will, Ohad and Lori presented a couple of different ways to approach BCR auditing, rather than 100% BCR.  The slide presentations can be viewed here. At that point, I was asked to present the “patient perspective”, which I did without slides.

Representing the patient perspective on these “in the weeds” issues can be challenging.  Patients want drugs that work.  Most aren’t wondering if a drug was approved because it increased overall survival or progression free survival.  I raised these questions with C3’s Research Advocacy Listserv, a group of advocates involved with research projects, and used their feedback to generate my remarks, which follow in outline form:

• We support pilot projects to test the auditing proposals.  At the same time, we need to maintain a healthy skepticism about auditing vs 100% BCR until we see data.
• Putting on a consumer hat, we have some questions:
  
  • Progression free survival (PFS) can be a meaningful benefit to patients when the increase is ‘significant’ and data exists that shows PFS results in longer survival or improvement in quality of life.  When PFS provides questionable benefit rather than meaningful benefit – for example, if the increase in PFS is a few weeks, and quality of life does not improve – should auditing be handled differently?
  • We all agree that auditing is appropriate only in blinded trials.  While some trials are technically blinded, they may not be blinded to patients and doctors because of different side effects.  For example, if the new drug causes a rash, the local site will know which patients are on the trial drug.  How does that effect auditing?
  • The auditing proposals relay on a “large” treatment effect.  In that situation, who defines “large”?  Will it be defined prospectively or retrospectively?
• Our perspective is cautious and conservative.  This is because when Sponsors and FDA are negotiating these point behind closed doors, the bar for approval must be set high.  Patients need drugs that provide significant benefit.
• Conclusion:  Let’s test the auditing proposals.  If they hold, let’s put together solid regulatory standards that maintain a high bar for approval.

Richard Pazdur from FDA closed out our panel.  He emphasized FDA concerns about the use of PFS as a surrogate endpoint, and suggested that FDA would hold an advisory committee meeting to clarify FDA’s position on appropriate use of PFS and the role of auditing.

C3 appreciated the opportunity to be involved with this discussion.  We recognize that the drug development process is not “one-size-fits-all”, and work in many forums to streamline the process for the development of great drugs.

I’ll end with two quotes from our research advocates which I thought captured the essence of the patient perspective:

There are reasons that local investigators might want to judge progression as happening or not happening and be biased. They might want to enable a patient to continue on an experimental drug, or they might want to discontinue that individual’s treatment so they could cross over to what seems to the investigator to be the more promising arm.

To me, every scan should be verified because from the patient’s point of view, that individual may be continued in a trial or dropped from active treatment based on the scan.  Whether research results can be considered valid if only a percentage of scans are verified is a statistical question.  However, behind that black, white, and very gray image is an individual person whose future depends on an unbiased reading.

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!

C3 has submitted comment to the Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), recommending that FDA implement a Special Restriction Distribution Program for Erythropoiesis Stimulating Agents (ESAs), to maximize patient safety and ensure the rapid collection of patient information.

ESAs, better known under brand names, Procrit, Epogen and Aranesp, were approved by the Food and Drug Administration (FDA) to reduce the need for blood transfusions and have been used widely to aid with chemotherapy-induced anemia. Research results have indicated that higher doses of ESAs could actually cause a patient’s cancer to grow faster, and increase mortality, pointing out the need for future research to nail down the risk/benefit ratio of ESA use.

C3, in partnership with other advocacy organizations, has been working with FDA and ESA manufacturers (Amgen and Johnson & Johnson) to ensure that patients are helped, not harmed, by these supportive care drugs.

ODAC will be meeting on March 13, 2008 to discuss new research findings, future research plans and the current clinical situation. Carlea Bauman, C3 President, will speak during the open public hearing. In addition, C3 has submitted comments identifying questions such as:

• What is the plan for answering the question of whether ESAs have a tumor-promoting effect?
• What is the plan for answering the question of whether ESAs provide patient benefit when dosed according to the FDA label?
• What is the appropriate clinical use of ESAs pending the answers to these questions?

Ultimately, C3 recommends that ESA use be closely monitored, similar to the way that thalidomide use is monitored.

For additional information, see:

• www.ESAFacts.org presented by the Marti Nelson Cancer Foundation
• Briefing information from the May 10, 2007 ODAC meeting

Disclosure: C3 believes in fully disclosing sources of financial support, per our disclosure policy which can be viewed here. In 2006 and 2007, C3 received funding from Amgen in the form of a charitable donation. Since the May 2007 Oncology Drug Advisory Committee (ODAC) meeting, C3 has met with Amgen and Johnson & Johnson (J&J) to increase our understanding of these issues and express our concerns. J&J held a meeting on February 19, 2008 in Washington, DC, and paid the travel expenses of a C3 Board member so that she could attend the meeting.

150 patients will be recruited from the United States, and will receive FOLFIRI — Irinotecan, leucovorin, and continuous infusion 5FU – plus Vectibix (panitumumab)

Who is eligible?

• Patients with confirmed colorectal cancer that has spread to organs beyond the colon (metastatic disease); and
• Patients whose tumor has been removed by surgery and who have paraffin-embedded tumor tissue available; and
• Patients with cancer that can be seen by scans, and which cannot be removed by surgery alone; and
• Patients whose overall organ functioning is adequate based on blood tests; and
• Patients who have received first-line treatment of FOLFOX – oxaliplatin, leucovorin and continuous infusion 5FU – plus Avastin (bevacizumab), and who had to discontinue FOLFOX plus Avastin because:
  • Their cancer progressed; or
  • They were unable to tolerate treatment

Who is not eligible?

• Patients who have received radiotherapy within two weeks of starting the trial; or
• Patients who have taken CYP3A4 enzyme inducers, inhibitors, and substrates (eg, phenytoin, phenobarbital, carbamazepine, ketoconazole, rifampin, rifabutin, and St. John’s Wort) within two weeks of starting the trial; or
• Patients who have had systemic infections and are taking antibiotics within 2 weeks of starting the trial; or
• Patients with a history of:
  • cardiovascular disease; or
  • pneumonitis or pulmonary fibrosis
• Patients who have had a significant thromboembolic event such as pulmonary embolism or deep vein thrombosis within 8 weeks of starting the trial; or
• Patients who have had significant bleeding within 6 weeks of starting the trial; or
• Patients with active or uncontrolled gastroduodenal ulcer(s) within 4 weeks of starting the trial; or
• Patients with a condition that could increase the risk of toxicity (eg, dihydropyrimidine deficiency, significant ascites, or pleural effusion); or
• Patients who have had major surgery (requiring general anesthesia), open biopsy, or significant traumatic injury within 4 weeks of starting the trial; or
  Patients who experienced treatment toxicities which were unable to be controlled; or
• Patients who have had prior treatment that included irinotecan, any anti-EGFr therapy, or vaccine for the treatment of mCRC

The trial will examine:

• If patients with specific genetic mutations in their tumors have different responses to the combination of FOLFIRI plus Vectibix
• Safety

For more information about the trial, call Amgen at 1-866-572-6436

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

Two hundred patients will be recruited from the United States, and will be randomized to receive either:

• FOLFIRI — Irinotecan, leucovorin, and continuous infusion 5FU – plus Avastin (bevacizumab)
• FOLFIRI plus Vectibix (panitumumab)

Who is eligible?

• Patients with confirmed colorectal cancer that has spread to organs beyond the colon (metastatic disease); and
• Patients whose cancer cannot be removed by surgery alone; and
• Patients whose overall organ functioning is adequate based on blood tests; and
• Patients who have received first-line treatment of at least 4 cycles of FOLFOX – oxaliplatin, leucovorin and continuous infusion 5FU – plus Avastin (bevacizumab), and who had to discontinue FOLFOX plus Avastin because:
  • Their cancer progressed; or
  • They were unable to tolerate treatment

Who is not eligible?

• Patients who experienced treatment toxicities which were unable to be controlled; or
• Patients who have had prior treatment that included irinotecan, any anti-EGFr therapy, or vaccine for the treatment of metastatic colorectal cancer.

The trial will examine:

• Amount of tumor shrinkage
• How long tumors either shrink or do not grow
• Safety

For more information about the trial, call Amgen at 1-866-572-6436

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

In this trial*, patients receiving FOLFOX and bevacizumab chemotherapy were also randomized to Magnesium Sulfate and Calcium Gluconate before and after oxaliplatin in a double-blind placebo controlled fashion.  The preliminary data from the first 174 patients on the trial showed that patients who had received calcium/magnesium had significantly less tumor shrinkage than patients who did not receive calcium/magnesium.  The data is based on scans of patients’ tumors.

As a result, the trial was closed and all patients on the trial will receive future treatment without calcium/magnesium.

The data will be verified as follows:

• An independent committee of expert radiologists is being convened;
• The committee will examine all scans from the trial. Their examination will be blinded (they will not know which patients received which treatment); and
• The results of their examinations will be analyzed, and compared to the preliminary data.

The verification process is expected to take several months.  Final results may be available in early 2008.

On July 31, the Journal of Clinical Oncology published a letter from the trial’s primary investigators.  The investigators say the following:

At present, bearing in mind the preliminary and unconfirmed nature of these data, we would like our colleagues to be aware of this unexpected finding. Oncologists should recognize the possibility that calcium and magnesium may reduce the activity of FOLFOX and bevacizumab in the treatment of colorectal cancer and exercise appropriate clinical judgment when using these agents in the neuroprotective setting until definitive data are available. For the time being, we would urge that calcium and magnesium salts particularly be avoided in the adjuvant setting, where reduced efficacy could lead to reduced benefit, and be reserved for those with symptomatic acute neurotoxicity.

Full letter text available here. 

C3 asked sanofi-aventis (the manufacturer of oxaliplatin) how this information was being disseminated to the oncology community. Sanofi-aventis indicated that its sales force was carrying the information to oncologists and oncology nurses, and that these efforts would continue.

WHAT THIS MEANS TO PATIENTS:
If you are receiving calcium-magnesium as treatment for neuropathy related to your FOLFOX regimen, talk to your doctor to be sure that s/he is aware of this preliminary data.  If your doctor is unaware, s/he can contact sanofi-aventis Medical Information Service at 1-800-633-1610 option 1 for additional information.

While this data is preliminary, patients and doctors should take it into account when planning treatment.

Source:
Sanofi-aventis website
Hochster et al, Journal of Clinical Oncology, July 31 2007

* CONCEPT Trial – a Phase IV, Randomized, Prospective Multicenter comparison of an Intermittent Schedule of Oxaliplatin combined with 5-Fluorouracil/Leucovorin (FOLFOX) / Bevacizumab Versus the Conventional Mode of Administration of FOLFOX/Bevacizumab PLUS Neuroprophylaxis With Calcium/Magnesium for the Optimization of First-Line Therapy of Metastatic Colorectal Cancer.  Available here.

Disclosure: C3 has accepted funding for projects and educational programs from sanofi-aventis in the form of charitable donations. C3 has ultimate authority over website content.

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