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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)


Rare Mutation? Submit to Your Master (Protocol): It May Well Revolutionize Clinical Trials for the Molecular Era
Howard (Jack) West, MD

Over the past 10 years we've come to recognize that what is lumped together as "lung cancer" is actually a wide range of different cancers that behave in their own patterns and respond very differently to different treatments. Some of our greatest advances in the field have come from the recognition of the complex patterns, but it has also become more challenging to do trials for small groups that represent just 1 or 2% of the larger whole. How can oncologists all over have access to the most interesting new trials and drugs if they only see 1 patient with a particular mutation every year or two? How can patients with rare mutations get treated for their specific cancer subtype without getting on a plane to travel to one of the 3 places in the country or world running a trial on that small group? And how can we practically begin to implement genomic sequencing, the screening of cancers for dozens or even hundreds of mutations all at one time, on a large scale to channel a large population of patients into the right trial and drug for them?

I'm optimistic about a new mechanism of clinical trial for the era of molecular oncology, called a "master protocol", that is being developed with a target of launching in 2014.  I think it has the potential to accelerate molecular testing, detection of different markers, and research in a wide range subgroups.  By doing so, it also has the promise of getting new drugs approved and available to the potential beneficiaries of these drugs much sooner than we might have envisioned with the old, sclerotic model of trials that has trudged along up to now but has become obsolete in a new era of targeted medicine and small subgroups.

Here's how it works: a group of patients within a big category, in this case advanced squamous cell NSCLC after prior chemotherapy, will have their tumor tested by Foundation Medicine in Boston for a series of potentially "actionable" mutations that have a drug for their target.  Under the master protocol, there may be 4 or 6 or 10 different "sub-protocols" running simultaneously (typically randomization of patients to standard chemo with or without novel agent X) that will all share a basic process and be able to open and close as they become available or fill up.  An institution that is part of a large network, in this initial case the SouthWest Oncology Group (SWOG), can open this master protocol and then be able to offer their patients with squamous NSCLC any of a changing number of novel agents that are matched for the particular mutation found in that person's tumor. And if they don't have one of the specific targets, there will be a safety net protocol for all of the other people who are eligible for the master protocol but don't fall into one of the narrow subgroup protocols.

The early iteration of the trials will be smaller "phase II" trials, but any that achieve a threshold level of activity will then transition readily into larger phase III testing that are designed to lead to fast approval and commercial availability of the agents being tested.

What do I like about this approach? Patients can enroll in any of hundreds of sites throughout North America on a trial that is tailored to their specific molecular pattern.  They can be treated close to home, and their doctors can participate in exciting research with a wide range of new agents. Molecular marker testing can be implemented on a large scale to a broad range of people, and the results will actually be able to direct treatment effectively. We will have a mechanism to expedite the development of a wide array of new drugs for uncommon to rare targets, without leaving these patients abandoned if they can't make it to one of the few centers offering a trial for them.  New targets and agents can be added quickly, without waiting for the paralyzing bureaucracy that hyper-regulates trials to the point that research slows to nearly a grinding halt.

The master protocol concept is untested, so we will need to see whether institutions far and wide can implement it efficiently, whether it is feasible to process far more tumor samples efficiently with rapid turn-around, and whether patients are OK with randomization between standard treatment and and treatment with a novel therapy. But I think it holds the promise of expanding clinical trials in cancer to a much larger number than the 2-3% who participate now, and it can lead to faster discoveries and new treatments by doing so.

Best of all, if it achieves its promise, the master protocol concept can be applied to many other groups in lung cancer, in other cancer types, and even other medical fields that need to adapt to a breakdown of a large population into smaller groups based on molecular markers.

What do you think? Would you be interested if the master protocol were available to you?


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