HOW TO THINK ABOUT CHOOSING A CLINICAL TRIAL – As A PARENT

Currently, there is no standard of care for relapsed/refractory osteosarcoma. There are numerous ways to think about treating relapsed/refractory osteosarcoma, and a clinical trial is one of the options. This post discusses how to think about choosing a clinical trial. Please keep in mind that this post is my thinking from the perspective of a parent who put her child in a clinical trial, and what I have learned over the years since that experience, partially based on my research, but also on what I wish I had known back then.

While there is medical information contained in this post, I’ve tried to put together a way for parents and patients to think about how they could/would select a clinical trial assuming that there are multiple options to choose from. I have not written this post from the perspective of a scientist because, as a parent, I looked at the trial as a means to possibly cure Daniel’s disease or at least prolong his life.

If you are considering a clinical trial, there are several questions to consider when selecting a clinical trial.

1) Is the disease surgically ressectable?

If the disease is surgically ressectable, this is almost always the course to take since local control is essential for long term survival. However, doing surgical resection also means that only those trials which require a surgical NED are an option. When Daniel relapsed, his doctor tried to convince us not to operate because of clinical trial requirements. I did not follow his advice because I knew that based on historical data, surgical resection is almost always needed for long-term survival. It also turned out that the only clinical trial available to Daniel required a surgical NED. If the disease is not surgically ressectable, then any clinical trial needs to require at least evaluable disease, if not measurable disease.

2) Has the tumor been genetically tested?

If the tumor has been genetically tested, then looking at those results may lead to one clinical trial over another. For example, a CDK4 amplified tumor would be a good fit for a clinical trial involving a CDK4/6 inhibitor such as palbociclib or abemaciclib. And even if there aren’t clear results from a test, it can sometimes provide some indication about which trials not to choose. For example, a tumor which has RB1 loss shouldn’t go into a trial using a CDK4 inhibitor because RB1 loss has been shown to be a contra-indication for CDK4 inhibitors in breast cancer. Another thing to try to determine from the genetic testing is whether or not the tumor has Alternative Lengthening of Telemores (ALT+). Somewhere between 35-50% of osteosarcomas do have this, and there is a new clinical trial testing a drug combo for this in adults with solid tumors. It can be exceedingly difficult to determine if a tumor is ALT+ from a genetic test and most docs don’t know how to do it. If a tumor has ATRX loss, then it is ALT+ almost certainly, and there are a few other things which may indicate ALT+ tumors, but it is far from easy to determine. Of course, it’s also possible that the tumor was not genetically tested or that it was genetically tested and the results showed nothing useful. In this case, just skip looking at biomarkers for trials and consider the other factors.

3) How strong are you/is your child?

The osteosarcoma MAP protocol is considered among the most damaging, difficult, and aggressive in all of oncology. There are always long-term side effects. And this is assuming that there is no relapse. At relapse, there’s an impact to health. How much of an impact is highly subjective and highly variable, however, it’s important to consider overall strength when choosing a clinical trial because some trials are more difficult than others. That difficulty might involve side effects like bleeding, vomiting, GI tract issues, or it might include pain, delayed wound healing or any number of other potential side effects. It’s also possible that during a clinical trial, a patient will experience a new, unknown side effect to the drug which will then be added to the clinical trial drug side effect list. When Daniel did his clinical trial, it impaired his wound healing very significantly and after lots of discussion, the docs all agreed that the clinical trial drug was the cause and impaired wound healing was added to the list of drug side effects. It was a completely new side effect to a drug which was considered to be “well-known”.

There is no right answer to this question, but it’s important to think it through carefully and try to choose a trial which the patient can tolerate well, so that the quality of life is good.

4) Clinical trial questions:

a. What are the admission criteria for the clinical trial?
There are two big questions here: what is the minimum and maximum age for admittance into the trial and are there any prior medications which mean that a person cannot participate in this trial? Many trials do not admit patients under 18 and sometimes under 12. And some pediatric trials will not accept patients over 30 or 40. Both of these limitations can be problematic for osteo for obvious reasons. Particularly in immunotherapy trials for drugs designed for a particular target (i.e. GD2), the prior use of a different drug designed for the same target may preclude someone from entering the clinical trial.

In general, it’s important to look at the inclusion and exclusion criteria carefully, because if you or your child do not meet them, then you will not be admitted to the clinical trial.

b. Does the trial require measurable disease, evaluable disease, or a surgical NED?
Measurable disease usually means at least 1 tumor > 1 cm, or 3 tumors > 5mm Evaluable disease usually means that there are tumors but they are smaller than measurable disease requirements And surgical NED means that all measurable and evaluable disease was surgically resected before the trial.

c. Is the trial single agent or multiple agent?
Historically, osteosarcoma trials over the last 2 decades or so have been single agent. However, none of these single agent trials has actually been successful. So, the most recent approach is to start with multiple agent trials. The current MAP chemotherapy protocol was started as a multi-agent trial involving Cisplatin and Doxorubicin. Methotrexate was added later. A posterior analysis of all of the single agent clinical trials with measurable disease showed that at four months, only 12% of osteosarcoma patients did not have disease progression. In my opinion, if prolonging life and a potential cure are the goal, then a multi-agent trial especially in a setting of measurable disease is preferable to a single agent trial if your kid is strong enough to tolerate it. And being strong enough to tolerate a multi-agent trial is THE big question because many (most?) multi-agent trials include some form of traditional chemotherapy with all of the associated nasty side effects.

When analyzing trials, it’s also important to realize that a multi-agent trial could include radiation with a drug, or two drugs in which one is a booster agent for another or for the immune system (i.e. GMCSF).

d. Do any of the agents used in the trial have biomarkers for usage?
This question links to the tumor genetic testing above. If the trial drug has a biomarker associated with it, does the tumor have this biomarker? If so, this trial is a good choice. If not, it’s not clear. And some drugs do not have any known biomarker associated with them yet, so this question may or may not be relevant. If there are no known biomarkers skip this question.

5) Where is the nearest trial location and how logistically feasible is it for you and your family?

In an ideal world, logistics and money would have no impact on health care. We live in a far from ideal world. Whether you are looking for yourself or your child, there are always family logistics to consider. A trial which is far away and requires a long stay may not be logistically or economically possible. When I was looking at trials for Daniel, I was a single parent, sole-provider, and health insurance carrier for the three of us. There was only one clinical trial option available for Daniel and logistically it was doable. However, had a trial required a long stay on the other side of the country, it would have been a difficult decision economically and logistically.

6) What is the quality of life during the trial?

Different trials have very different qualities of life and it’s important to find this out beforehand insofar as possible. In what form are the trial drugs administered? Pills? Shots? IV infusions? How often? How many and for how long are in-patient stays required?
Pills that the patient takes from home and goes into the hospital once every 3-4 weeks for a check-up are generally going to provide a high quality of life as compared to in patient infusions for a week at a time every three weeks. There are all sorts of in between options as well. How often and in what way a medication or treatment is given is highly variable and it definitely affects quality of life.

Find out as much as possible what quality of life you or your child can expect to have during the trial. Poke around. Ask other parents or patients on the trial if you can find them. The docs won’t lie but they may not discuss everything in full detail unless you prod them. My personal recommendation is to maximize the quality of life so that you or your child can do as much as you can for as long as you can, but it’s also important to note that everyone has different criteria here for this.

Above all, I want everyone to understand that there is no right answer to which clinical trial to choose: no one knows if it will work. No one. Participating in a clinical trial is an act of selflessness and courage. It is only because of the many thousands of people who have participated in clinical trials that we even have the MAP protocol and some long-term survivors. And it is only through clinical trial participation that better therapies and more cures for this disease will be found.