Take Away Points:
- Trials for relatively rare cancers such as CLL have traditionally taken a long time to plan, get approval, accrue patients and get results.
- This bottleneck slows new drugs getting to market and the clinical science moving forward.
- This was less of a problem when there were fewer drugs to treat CLL.
- With so many new possible treatments, we need a faster way to test the safety and efficacy of therapies both alone and in combination.
- TAP (Trials Acceleration Programme) is an attempt to safely speed up research.
- One way to accelerate the research is the use of extensive ancillary blood testing to help quickly predict what therapies make the most sense to further explore.
In the first of a three-part interview, Professor Hillmen from the University of Leeds begins to outline the many intertwined strategies employed in the United Kingdom in an attempt to sort out the best ways to quickly answer important clinical questions such as which combinations of drugs make the most sense.
The TAP or Trials Acceleration Programme uses small patient groups and assesses results in as soon as six months by using multiple telltale markers in the blood, rather than waiting for what is sometimes years to see a statistically survival difference play out.
With all the new drugs and all the potential permutations and combinations, we simply don’t have enough time or patients to do it all the old way. TAP offers coordinated resources across the UK, including help with the extra staff and the extensive bureaucratic machinery needed to set up and run a clinical trial. The goal is to reduce the amount of time from when a trial begins to when we see results. In the past, it could take as long as ten years, but in the future it could take two years or less.
But I will let Professor Hillmen explain it. His excitement and pride are palpable.
Brian Koffman 5/7/15
Take Away Points:
- Biological markers may inform who will do best with any particular therapy and which combinations make the most sense.
- MRD (minimal residual disease) negativity is probably still an important predictor of long-term disease control even with targeted therapy.
- Molecular changes precede clinical changes and suggest who might benefit from adding a second agent.
In the second part of my interview with Professor Hillmen at the ASH (American Society of Hematology) 2014 annual meeting in San Francisco, the professor explains the important role played by surrogate markers in predicting relapse and suggesting logical combinations of therapies.
Dr. Hillmen is of the school that MRD negativity remains a critical indicator of how well we will do long-term even in the era of targeted therapies. I tend to agree.
I would however question his reflection that the speed to reach MRD negative status is also important.
That maxim does hold true for chemo-immunotherapy. We know that mutated patients can take longer than unmutated patients to resolve the early lymphocytosis (raised lymphocyte counts) often seen with the new signal blockers such as ibrutinib and idelalisib. This early lymphocytosis occurs as cancer cells leave the bone marrow and the shrinking lymph nodes for the less protective environs of the blood stream. Those same ‘slow to get back to normal’ mutated patients may do better in the long run than their unmutated friends. Slow and steady may be better than quick and mercurial. See this article in Blood out of Ohio State University for more details. I quote from the paper by Dr. Jennifer Woyach: “Most interesting is the finding that patients with persistent lymphocytosis over 1 year have a similar PFS [progression free survival], with a trend toward a superior outcome compared with those who achieve an objective response within this time frame.”
We are still discovering the similarities and differences of these new therapies compared to standard chemo-immunotherapy. That’s why Professor Hillmen’s research is so important.
Please give a listen.
Brian Koffman 5/9/15
Take Away Points:
- Adaptive trials design is the science and art of applying a sophisticated statistical approach to the mixing and matching of therapies without compromising data.
- Co-ordinated large-scale trial efforts are enabled in the UK with a national health service. In the USA, the logistics and the subsequent accrual in trials are often more challenging.
- Trial design is changing to better serve the patients.
In the third and final segment of our interview from ASH 2014, Professor Hillmen out of Leeds, England describes how, with quick data analysis (months instead of years) and astute addition of new trial arms, we can get fast answers to complex clinical questions without confounding the data.
This will be an increasingly important issue as more and more clinical trials take the humane move to allow crossovers. Crossovers, while good for patients, can make the data harder to tease out. This is the subtext of our discussion on just how much more explanation was necessary to interpret some trial results at ASH 2014. Please see this post or this for more on the ethics underlying this issue and the resulting change in trial designs in the last few years.
The professor’s explanations in our interview are somewhat complex and technical, but the bottom line good news is that we are beginning to move away from the “glacier” paced trials that predominated the cancer research landscape until very recently. We should increasingly be able get answers and access to better care much sooner with the innovative changes that are starting to happen with Europe leading the way.
Please give a listen to Professor Hillmen who heads up CLL research in the United Kingdom.
Brian Koffman 5/7/15