Dear PAC2,

Today, we follow up our October chat with Donna Ludwinski, the Co-Director of Research Programs at Solving Kids' Cancer with the second part of our discussion.   In our first interview, we learned about Donna’s background, her connection to the childhood cancer world, and her work with Solving Kids Cancer (if you missed it you can find it here).  Today, we are pleased to present Donna’s unique perspective on the bread and butter of childhood cancer research:  clinical trials. 


The drivers, expectations, and processes associated with clinical trials can be complex and a little intimidating.  Our community is fortunate that Donna is willing to wade into those waters and help translate the issues for us.  For instance, in this part of the interview, Donna steps through “good” clinical trial design, so that we can become better “consumers” and “advocates” on behalf of our children.  She is also well aware that just like we enlist and train parent advocates to raise awareness and funding levels, we also need a parallel set of parent research advocates who can raise awareness and inform the research community about better clinical trial design.


We hope you find Donna’s perspectives interesting and informative, even if you are someone who occasionally feels overwhelmed by the science details.  Her insights can help us understand, and possibly reframe the traditional approach to childhood cancer research.  For instance, as a community we may need to rethink the focus on five-year survival statistics (which she [and we] feels are misleading) and to consider the deadly impact of our slow and methodical clinical trial framework.


Part 2

Beyond the fundamental success or failure, what are the most common challenges to trials, and how can they be overcome?


Good clinical trials are important to advance the field of pediatric oncology with the goal of increased response rate and duration of responses in children who have relapsed or are refractory, and improve cure rates for children who are treated for newly diagnosed disease. But what is a good clinical trial?


Clinical research is a mystifying business for most of us parents, and there are some important features to note of the different phases. At the risk of over-simplifying, below are some challenges and brief points about “good” clinical trial design:


  • Agents – has the agent or combination of agents shown promise of activity against tumor in prior preclinical or earlier phase studies? Should patients, money, and time be spent testing this particular agent or are there better choices that should be prioritized?


  • Eligibility – are the appropriate tumor types included or excluded? Is the appropriate disease burden allowed? Are the age limits appropriate? Is the organ function required reasonable?


  • Administration – is the dosing and or administration and timing designed with the best interest of the patient in mind, for the best possibility of cure?


  • Family burden – is the trial designed to allow for families to travel home between cycles of therapy, and are they permitted to have testing or scans done at their home hospital? Some trials require excessive time away from home for families.


  • “Low Bar” Research and Endpoints – if you spend a lot of time reading results of clinical trials, it is very discouraging how dismal the response rates are in phase 1 and 2 trials. Frank Balis gave a revealing presentation at ASCO in 2010 showing the outcome of 755 children enrolled on 6 phase 2 single agent trials. He showed the objective response rate (partial or complete response) was only 4%. There is an ongoing effort to select more sensitive endpoints to detect evidence of activity in the absence of response, which is understandable from the scientific point of view. However, parents are not so excited about incremental approaches that may modestly increase the progression free interval (by days or weeks) but not improve the overall survival. Below are two examples of this issue – low response rates in recent phase 2 trials, and very low overall survival in phase 1 trials.


Examples – Phase II trials in pediatric solid tumors (OR = objective response)

Phase I overall survival in pediatric solid tumors

Overall survival in 262 pediatric subjects with refractory solid tumors who were enrolled in a phase I trial at NCI. 

Source: Kim, A. et al. Oncologist 2008;13:679-689  Full text


How can these challenges be overcome?

Research advocacy. Better clinical trials are conceived and designed when thoughtful input from parent research advocates is included.


What do you think are the most promising new research areas?

This is my favorite question. I am so glad you asked!  I am very, very excited about immunotherapy. We just attended the annual meeting of Society for Immunotherapy of Cancer (SITC) in Bethesda, MD and the advances in understanding and harnessing the immune system to fight cancer have been nothing less than exponential during the past decade, especially. Numerous immunotherapy approaches exist: antibodies, NK cells, engineered T-cells, dendritic cells, combinations and adjuvants, stem cell transplants, oncolytic viruses, to name a few. What was regarded with great skepticism in the mainstream oncology community in the recent past is now showing sustained and durable (up to 7 years) complete responses using Adoptive T Cell Transfer and Cell Therapy in melanoma and other metastatic cancers. In neuroblastoma and some pediatric sarcomas some very promising early trials have shown improved outcomes. The reason we are so excited about focusing on immunotherapy is because the approach is potentially curative, potentially much less toxic than cytotoxic therapy, and the therapies do not depend on typical drug development/pharma/biotech issues where the drug can be dropped if no adult indication is ever established.


What do you see as the biggest challenges we face in increasing awareness and funding?

This is also important. The advocates at work raising awareness and bringing attention to the need for funding are my heroes. While I am not well versed in the specifics since I focus so much more on the research and priorities, I can say that we should all be careful with our use of the oft-repeated phrase “80% of childhood cancers are now cured.” This message is terribly misleading because it does not include the morbidity and late mortality – only that at 5 years after diagnosis 80% of the children are alive, with nothing noted about their condition, or risk of late relapse or other cancers. This is a sore point for me because my son is included in this happy statistic, yet he died of disease at 24, which I do not consider a cure!  (PAC2 - read more at Childhood Cancer – Long Term Outcomes)

One more advocacy-related issue was coined by Rupert Hangretinger (German physician presenting to parent group at SIOP meeting in London last month) -- “regulatory-related mortality.” He made an impassioned case for layers of regulators to put children first instead of agendas that ultimately prevent children from getting the treatments they need. Jonathan Agin’s editorial presents a good example of this.

This is kind of an off-the-wall question, but a serious one.  I work with engineers in my other life, and I know you are a chemical engineer.  I've always thought that engineers can bring a different viewpoint, new approaches to solving kids cancer.  Is that happening? 

Another interesting question! I would like to think that the more disciplines brought to bear on pediatric cancer, the better. I have met a few physician-researchers who proudly mention their undergraduate degree was in engineering. I am not sure how to tell what (if any) impact there is from having engineers in the mix. Engineers do think differently, certainly quantitatively, and in order to solve very complex problems we had to learn to reduce the unnecessary variables to a minimum and retain the most impactful elements. But which ones are the most impactful and which ones are not, just confounding the analysis? So I can’t help but always question, what are the most important elements? This is one of the reasons I often look at broad questions, such as clinical trial design, numbers of patients and trials, variety of targets and duplicated efforts with the same or similar agents, quality of the data and evidence of efficacy, and looking for gaps in what is available for difference diseases and even categories within certain tumor types, such as NED after relapse, etc.

Donna, we can't thank you enough for taking the time and energy to do this.  Please PAC2, support Solving Kid's Cancer along with all the other great orgs fighting for a cure!

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