In Q&A during ANR2016, prof Glenn Marshall asked me “How do you pick a clinical trial?”.
This is an incredibly hard and loaded question to answer, but I wanted to give a shot answering it within my context, and hopefully hear some more from others on this topic.
Where we are today?
Shalev was diagnosed in October 2015 with MYCN amplified stage 3 Neuroblastoma. We have been treated under SIOPEN high risk protocol and been through rapid Cojec induction, Surgery, BuMel transplant, local radiation and have just started immunotherapy (first round of CH 14:18/CHO in 2 weeks).
The tumour has responded very well to chemotherapy and was completely removed during surgery. We are lucky to be in one of the “best case scenarios” for HRNB.
Our immunotherapy will not include IL2 or GM-CSF as SIOPEN have recently dropped it from the study.
If we are lucky and continue with this trend, we are looking at finishing our frontline treatment in December 2016.
If all goes according to plan there are 2 numbers we are faced with.
- There is a 25%-35% chance of relapse after we are done treatment if all goes well.
- The first 6 months after treatment ends are the riskiest, historically half the relapses will happen in the first 6 months.
How would I go about picking a trial?
As a parent even 1% chance of relapse is a hard number to live with. We want our kids to be cured and for all to be done.
It is incredibly hard living with the odds around HRNB and going back to normal life.
I am torn between wanting to keep on going with treatment till I know there is only a tiny chance of relapse, to commencing normal life.
One tragedy with Neuroblastoma is that some are receiving highly aggressive treatment that could end up causing other disease despite being cured. There is a chance we were done with our Neuroblastoma after surgery and that it would never come back (say 5-10%) but there was an even more significant chance it would come back. So we keep treating, until our odds are better. Despite possibly being cured many months ago.
When evaluating trials I have a few sources:
My oncologist and team are my primary source of advice. As it stands there is no clinical trials available in Sydney after frontline therapy.
The internet, with all its curses, is another source of advice. In particular I can read through https://clinicaltrials.gov/ searching for Neuroblastoma. I can ask advice from other parents (internationally as well) online.
I can seek advice from other oncologists and specialists in the field
Should we consider any phase 1 trials?
The first question that is trivial to answer is “Should I consider any phase 1 clinical trials?”
Phase 1: Studies that are usually conducted with healthy volunteers and that emphasize safety. The goal is to find out what the drug’s most frequent and serious adverse events are and, often, how the drug is metabolized and excreted.
Firstly, there are no existing Phase 1 trials available for healthy patients that just completed HRNB protocols so the question is kind of moot.
Even if there was an available Phase 1 trial I would not be interested as
The goal is to determine toxicity, I would be risking making my child very ill for a complete unknown.
What about long term effects?
I would definitely consider phase 1 trials if I was at the end of my tether, and looking at a very morbid prognosis. But given stuff is reasonably positive, I see zero reason for layering any more risk.
Should we consider phase 2 trials?
This is where stuff gets a lot more tricky.
As it stands there are 2 trials I have been investigating that are available after frontline treatment:
(There is a 3F8 trial that also seems to be available, though it does not make sense to go through the pain of immunotherapy again after already being through it with CH 14:18)
The goal of phase 2 trials is:
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance, called a placebo, or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.
Meaning, we are not sure if the treatment will help or not, but at least we are trying to figure out.
The enormous cost of overseas treatment
Sometimes, as parents, we like to think that any cost to increase odds is reasonable. Yes, I will mortgage my house to increase the odds my son will be cured.
The reality, of course, is more complicated:
- The monetary cost of even a trivial trial in the US can be astronomical.
For example: take the DFMO trials. The drug itself, Elfornithine, is listed under the WHO Model List of Essential Medicines. It is easily accessible in all countries and been used for many years for sleeping sickness and facial hirsutism.
On the face of it the cost for such a trial should be low. But… if you live in Australia or Europe or anywhere that is not the USA the cost skyrockets.
To participate in the trial you must travel to the US every 3 months (estimated cost $6000 AUD * 8 = 48,000AUD =~ 35K USD)
To participate in the trial you must complete scans in the participating hospital every 3 months, this will cost approx 10K USD per scan which add up to 80K USD.
So we are already up to 115K USD just for the privilege of helping figure out if DFMO actually helps.
Similarly the cost of completing the vaccine trial can be enormous as well, though I am finding it much harder to estimate. It will include at least 4 comprehensive scans and more 6 or so trips to the US including first 1-2 months where it makes no sense to complete a 20 hour journey back to Sydney just to return in a week or 4.
Add on to this, there are a pile of other risks and costs that can not be ignored
The risk of getting sick during frequent air travel
The risk of the negative effect on siblings during this period (especially if relocating temporarily)
The strain on the family during this time
The unknown nature of phase 2 trials
A medication or treatment is still in an unknown state during phase 2
- It may do nothing
- It may cure
- It may cause harm (short term or long term)
At the end of the day, only time we “know” a medication is sure to help is after it is out of phase 2 (and ideally phase 3 trials). During phase 2 we do not know. We like to think that preliminary results are “promising” or that “mouse models” showed incredible promise but we just don’t know.
We do not know if the vaccine helps or not, we guess that odds are it does not cause any long term harm, historically no latent effects have been pinned on the immunotherapy drugs. But… we just don’t know. Which is why we are running the trial.
Similarly we do not know if the DFMO trial helps. We hope it does, but we do not know.
When should I start a preventative trial?
One key piece of information our NB trends teach us is that if we are going to be improving relapse rates we got to start treating back-to-back after the frontline treatment.
For example, if we are to survive without relapse for 6 more months after we finish treatment our odds of event free survival jump up to 82-87%, our odds for event free survival for the 2 following years become around 91%.
It is my view that any trials looking at prevention should strictly start within days of finishing frontline treatment. Otherwise we miss out on the most risky period. There is going to be some significant statistical variation between people who start a trial a day after frontline therapy and 2 months after it.
The impossible task of interpreting initial results
In the case of the DFMO trial we have recently seen initial results 2 year EFS for 91% (± 4%). Which on the face seem much better that the 50% event free survival we get when we started treatment.
But … it’s complicated:
- The longer we survive, the better our odds are
- The less severe side effect we have experienced the better our odds are (what about the children with permanent liver of kidney damage that are excluded from trials)
- If we happen to have survived event free 6 months after frontline we are expecting 2 year EFS of 90%+
We can not cherry pick numbers that feel good. If we want to make informed decisions we have look at published, peer reviewed publications and have to consult experts.
Where do I stand today on the 2 phase preventative trials?
If I was living in New York, I would certainly consider the vaccine trials. However, it is super hard to justify the enormous cost of travel and uprooting family just to get access to the trial.
As a parent I am angry that the vaccine trial is only available in NY, I feel that science could progress significantly faster if MSKCC made the vaccine available elsewhere and we could answer the question of efficacy significantly faster.
With the DFMO trial there are still no published results, and I find it incredibly hard to justify the international travel and huge cost. If I lived closed to a participating center I would consider it provided the concerns raised by COG and SIOPEN are addressed.
Navigating the maze of even 2 trials is an enormously complicated experience. I don’t envy the pain many of the relapse families are going through when they have no option but to pick 1 of 100s of open trials.