The important things to know about phase 1 trial design

Last week we talked a little bit about phase 1 trials. The major point that you should have walked out of that discussion is that phase 1 trials are generally not aimed at being therapeutic. They are all about finding dose. In this way, phase 1 trials are good for quickly finding the maximum tolerated dose. This is for the greater good of children with neuroblastoma. It is good for the group as a whole. Unfortunately, it is not necessarily good for any particular child. It is, however, what we are given. Like this disease, it is the hand that has been dealt. Now, it is our job to figure out what we should do for our child given these imperfect circumstances.

Again, I routinely advocate for phase 1 trial designs that have a better chance at providing good for the individual patient. The point is not to say that the current system can't be improved. However, right now, it is what it is and we have to make intelligent decisions based on the options we have before us.

Most phase 1 trials that are ongoing right now use what is called a 3+3 design. The trial begins with 3 patients at the smallest dose. This dose is usually 80% of the adult maximum tolerated dose. This is good news because the trial is already starting at a dose which is 80% of what the adults could tolerate. The first 3 patients that start the trial are then watched over a certain period time for side effects or other toxicities. If none of these children experience significant toxicities the investigators then raise the dose to a higher level and 3 new patients are tested at the new dosing level. Keep in mind that in this system the first 3 patients never receive a higher dose. They are, in effect, stuck at the dosing level at which they began. This process of raising the dose, watching 3 patients and then raising the dose again, continues until they begin to see some significant toxicities. At some point, they generally hit a level where there are too many toxicities. At that point, they go backwards and reduce the dose back down to the level of the previous group of patients. They then expand that cohort and add 3 more patients. Assuming their is little toxicity in this group this becomes the maximum tolerated dose (MTD) 0r the highest dose we can give safely of the drug or combination.

Now, it should be noted that this is generalized. The system is more specific than this but it gives you the general idea of how this design works. Assuming you are considering a trial with a 3+3 design, you now understand the gist of it.

You may have noticed that I never said the maximum efficacious dose or the dose that works best. You are correct. That is not the purpose of this trial. It is to find the maximum tolerated dose not the dose that works best.

So, what do you learn from this? First, you realize that the dose is changing. Most likely, if you participate early in a trial you are less likely to receive benefit because you are less likely to achieve a high enough dose to provide benefit. If you participate at the higher dosing levels, you are probably more likely to see some benefit but, you are also more likely to experience toxic side effects. Your job as a parent is to figure out where your child fits in.

Ask questions. At what dosing level is the trial? What were the side effects of the patients that were in the cohort before the current one? What were the responses? What side effects do you expect to see? At what level?

You may not get answers to all of these questions but it is a good start. By asking about and investigating what happened with the drug in adults or in animal studies you may be able to get a better picture of whether or not this will be likely to work for your child. At what kind of plasma levels did the drug start to work in mice? In adults? Given the current dosing level, what do we believe the current levels are? In other words, are we at a dosing level where we can expect to see benefit?

You see there are lots of questions and they are critical if you are going to make an informed decision. It is not as simple as asking if phase 1 trial drug X is good? It may turn out that the perfect drug may be in a phase 1 trial for your child. However, if the drug is at too low of a dosing level or too high it may not be a good decision for your family. Secondly, you may be in a position where you can wait and do something else while the trial gets to a more appropriate dosing level. There are some options. You just have to learn enough to know what they are. I am not guaranteeing answers - just more opportunities to find them. It is not a perfect world.

So, here are some rules that you should also consider:

• Don't expect the highest dosing level to be the best. There are a couple of great examples in neuroblastoma where more is not necessarily better. In other words, the drug appears to work better at a dose lower than the MTD.
• Don't assume your primary oncologist knows the answers to these questions. Do your own research. Email the primary investigator or pick up the phone.
• Talk to previous patients if you can find them. These are brand new drugs or combinations. There is no history. Talking to someone that has been through the trial will give you valuable information that is not available anywhere else.

There you go. Some of the things you should be thinking about in relation to phase 1 trials. This, however, has only to do with the structure of the phase 1 trial. In the next article I will tell you how to go about answering many of these questions and some other considerations.

The most important thing you need to realize is that phase 1 tirals have different dosing levels. Different results and toxicities can be expected at each dosing level. This is one of the biggest points that people miss. They try to compare one phase 1 trials with a phase 2 or something else. I can't tell you how many times I have heard someone claim that treatment A was better than B because treatment B only had a few responses in its phase 1 trial. Well, what if all of those patients that had responses all had them at the same dosing level. In that case, if you can get drug B at the right dosing level it may be a better option than anything else. It may actually be better than drug A. In fact, it could be the cure. Bottom line, be analytical. Understand the trial so that you can make the best of it for your child.

I am off to more purpose.