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.

CH14.18 Survival Results (+20%) Published at ASCO

http://www.abstract.asco.org/AbstView_65_35748.html

What everyone should know about phase 1 trials - part 1

When you step into the relapse world, all of a sudden, you are faced with phase 1 trials. The problem with phase 1 trials is that we, as parents of children with neuroblastoma, see them as therapeutic - in other words we see them as hope to make our kiddos better. The problem is that, by their very nature, these trials are not aimed at producing a result. The true intent of these trials is not to cure the cancer. In fact, it is not even to help it. Phase 1 trials have one mission in life. That is to see how much of a drug or combination of drug we can give without creating horrible side effects.

Do not make the mistake of assuming that these trials are designed for the benefit of your child.

THEY ARE NOT!

The trick, however, is to figure out how to use them so that they will work for your child's benefit!

I do not mention phase 1 trials in this context to keep people from participating in phase 1 trials. I believe they are extremely important. After all, Sydney was a part of one. They are a necessary step in trying any new drug or combination. We must first see if it is safe enough to give and how much of it we can give safely. This "test" has to be performed somewhere and on someone. That is the purpose of the phase 1 trial.

This "purpose" is not because the researchers do not care about our children. It is not because the government is beating down on the man. It isn't because of bureaucracy or because people don't understand.

It is simply because, if we are ever going to make any discoveries of new drugs and therapies, we must first define their safety in some test subjects - yes, our kiddos. It is a necessary evil. It has to happen.

Again, the trick is still to figure out how we can use them to our child's advantage.

So, why do I tell you this? Well, this is one of the most common issues I see with parents facing phase 1 trials. Often many of the most important points are missed. This is critical because even though phase 1 trials are not designed to be therapeutic they still can provide benefit and we, as parents, must understand them well enough to evaluate them. We must understand all of the issues related to the trial design and the drugs preclinical and adult track record to make the best decision possible. This is often often complicated by the fact that our children have a very small window to start the next therapeutic option. Chances are we will never have perfect timing on any one trial. Thus, we have to be able to evaluate them quickly and prioritize them so that we can make the best choice possible. Often the chance of a particular drug or combination working in a phase 1 trial has less to do with the drugs and more to do with the timing. That is the critical determining factor. Does your child have disease that will be susceptible to the drug or combination? Is he or she eligible for the drug at a time when the drug is most likely to work. Is the drug at a dosing level where it is even expected to work? Is the trial even open when you need it or is it in a planned closure to review toxicity? This last point is one of the most overlooked. Most phase 1 trials have planned closures at the end of each dosing level to evaluate toxicity. This means that during these times no one can become part of the trial until it is reopened. Did you know that some of our most effective phase 1 trials actually spent more time being closed than open. Again, this is not because the researchers are mean and ill hearted. This is federally regulated stuff. Our investigators don't have a choice. It is simply a reality that we must interpret and determine how it effects our child.

Regardless, my point is that timing is usually a bigger issue than anything else in evaluating a phase 1 trial and in determining the likelihood of whether it will work for your child. To me, it is almost more important than the drug(s) itself(themselves).

So I could write a series of entries about phase 1 trials. As many of you know this is one of my biggest areas of interest. I have advocated for years for better (more therapeutic) phase 1 trials. Through this process I have learned a ton. I now have a pretty good understanding of the issues from both sides. It is from this perspective that I have learned that while it is nice to advocate for better trials, drugs, and designs it is also important that parents really know how to deal with and interpret the options that are before them now.

Over the next few weeks I will be writing several articles on this topic. It is too complex to discuss in one simple entry. After all, I have just spent a page talking about the issues of phase 1 trials and I haven't even begun to mention their structures which are another important aspect of judging the appropriateness of their timing.

So, for a bit, you will have to put up with reading my technical dribble. The good news is that, by the end, I promise you will know exactly what to ask and how to evaluate the appropriateness of any phase 1 trial. You will be equipped to find the absolute best answer for your child in a world that seems full of a bunch of half-baked questions.

Think of it as your own personal purpose gun.

Twerplet Injection

Good morning! After two days of technical neuroblastoma rants I figured I had probably give an update on the fam before I received a slew of angry email from our loyal twerplet followers. First, you should know that, as of this very moment, everyone is healthy. I do not know what tomorrow will bring but, considering the fact that they have been rather dedicated to dipping themselves into a 76 degree swimming pool, I honestly have no idea of how long that will hold. So, let's begin with what we know now.

Ainsley - Well Ainsley is apparently on a diet. I don't know what has gotten into her but her appetite has undergone a drastic change. In fact, I really don't know when she eats. I am hoping that she is really wolfing down her lunch because what I see at breakfast and dinner is unimpressive. I have grown tired of cooking foods that she does not eat. Now, you may be thinking that we are feeding her something she does not like. Nope! In fact, with the exception of one meal we have had in the last two weeks, all of the meals have been ones that she has previously cleaned her plate. She has even refused to eat her bananas or her eggs in the morning - 2 staples that she has always eaten. I have watched all of the kids go through episodes like this so I am not too concerned but it is something we are watching. It is a bit alarming when the carrot of candy can't seem to keep her motivated to eat. I think this is just a momentary spell in twerphood but we are watching. Outside of that she is a champ - completely and utterly normal for her. She is doing great at school and at home.

Sydney - Sydney has been the busiest of all. In fact, yesterday she had another crown placed on one of her baby teeth. You may recall that these were due more to the structure of her teeth and less to do with brushing. Although, if I am being totally honest, the child does need to be a better brusher. Everyone at the dentist was amazed at her calm composure and her ability to calmly go through the procedure. I, on the other hand, was not so impressed. I guess I have become complacent with her extraordinary tolerance. It is a pretty amazing trait and when I really think about it, it is pretty impressive. Her ability to stay calm, cool, and collected when it comes to many things is developed well beyond even my own. There is a relaxedness about her that absolutely fills the room.

On the other hand, she had difficulty with one of the new kicks that she was learning at Tae Kwon Do. For once, Graham was able to pick up something more quickly that she and it sent her into a free fall. There were tears and she tried, politely, to quit trying. If I am being honest, I love opportunities like this. This is the training ground and the exact reason we signed her up for Tae Kwon Do. We want her to learn that you can't be perfect at everything on your first try. I want her to know, though, as long as she keeps trying she can accomplish anything she sets her mind too. It is only when she fails at learning this important lesson that we get to address it and help her get through it. So, if I am being honest, I like it when she fails. This is when we have the opportunity to face it and to learn from it. It is these experiences that will help her get through the rest of her life.

Graham - What can I say about Graham? Graham is probably the hardest for me to write about. You see, I always write about what is different. You know, what exploded today, what emergency, what ridiculous event transpired. That is generally not Graham. He is my consistent one. Nothing ever shocks me about Graham. He is the most kind hearted little person I have ever met. I have never seen anyone try harder at being good. I put nothing past him and I can always guarantee that he will give his absolute all to whatever he does. Day to day there aren't many surprises with or in his life. It is because of this that I do not think he gets the coverage in my diary that he deserves. I don't want, however, his incredible contributions to go unnoticed. He is an incredible wonderful little boy. He is my dudely - my little hero. I live him with all of my heart. He is a keeper.

So, there you go - a twerplet recap.

I love my purpii.

So I am in a tizzy, eh?

Good morning! So, yesterday I received a ton of email. It was very supportive. Well, that, or emails from people curious as to which trials had me all in a tizzy.

I am not going to mention them.

I really genuinely hesitate mentioning any of the trials. Yes, I personally believe some are worse than others. I believe from the standpoint of helping a child with neuroblastoma there are many options that at many times are completely inappropriate. To me, it is much less about the actual drug or trial itself and far more about the patient, the disease, and the timing. For example, everyone knows I believe in antibody therapy. It is no secret (and by the way it is now proven by a phase III trial.) However, there is a time and a place for antibody therapy. There are points in therapy where it works best. It works when you have minimal disease. It works when you have marrow disease. It works to a lesser extent on bony disease. However, given current medical technology, it is absolutely useless against solid tumor.

So, I would say that I think antibodies are probably a worthwhile consideration if you have have minimal residual disease. However, if you were going to use them with a big tumor in your child's belly and you were expecting great success I would be concerned, very concerned. I would tell you to talk to other parents of children that used antibodies with big tumors. I would tell you to review the research and I would tell you to talk to an expert. I would hope and pray that you would pick a different direction - at least initially. This is because, chances are, the antibodies would do nothing but cause pain and give the tumor some opportunity for progression.

So, that was a hypothetical situation but, believe it or not, over the years I have actually seen that decision made.

No, my concerns were with current trials. It was not so much that the trials were bad or the drugs were bad but more that the timing of the therapy was inappropriate either due to the treatment itself, the toxicity, or the dosing level of the trial. Finally, there are also a few trials out there that are very popular but with which the data simply does not support. There are a few trials out there that parents have made incredible claims that are flat out false. They have literally claimed that incredible responses that were never proven.

That bothers me.

That is why I always suggest that people look further. This is why I ask people to ask questions. In many of these cases these miraculous "responses" were actually quickly followed by death. In many cases these responses were not actually considered responses by the medical community. They sounded good but they were ultimately nothing. Remember, changes in HVA/VMA alone do not constitute response unless they are hugely significant. Second, solid tumor necrosis needs to be confirmed by biopsy. The list goes on.

Just be skeptical. Ask questions.

Step purposefully.

What do you do?

This is one of those entries that will probably brand me forever for being full of myself. However, I run into this problem more often than I would really care to admit. With the exception of maybe 2 or 3 families, I really have not said anything when I truly felt like I should. It is always a hard decision. What right do I have?

What do you tell another family of a child with neuroblastoma when you know they are making a bad decision?

I know. It sounds like I am offering an opinion. But, I am not. What do you do? What if you know the outcome? Do you tell them? And how do you do that?

I have spent years talking to other families. I absolutely never offer any medical advice but you can be sure that I will put them in touch with experts who will. I arm them with questions to get to the truth. I try to guide them without providing any bias. That is a relatively simple thing to do. The problem seems to be that even given my best efforts they still make a poor choice.

Why do I know it is a poor choice?

Because I know the outcome. I guess I have been in this game too long and have seen too much but at some point it all becomes pretty predictable. It happens over and over. Patient with disease has treatment X. Patient responds for Y. Patient progresses. Patient marrow spent. Patient succumbs to disease. I know that sounds cold. Yet, child after child and family after family will follow this pattern. It happens every time. There aren't surprises. I guess if they know what the outcome is then it is fine to make that decision. However, when you walk into that situation with the expectation that something different is going to happen, I think there needs to be something that raises the red flag.

I don't say this to be full of myself. I say this so that others are aware. Weigh your options. Look for successes. Balance your child's exposure to toxicities. Don't just participate in a trial because someone says so. Don't just participate in a trial because some one says they had great success. Look at the outcome. The question is not how they think they responded to the first dose. The question is where is the child 1 or 2 years down the road. Did they ultimately survive? Did the therapy routinely work? At what cost? How did this one trial fit into the overall picture? What was the quality of life?

I don't ask these questions because I feel like going on a rant. I do it because I don't believe these questions are actually being raised. If 95% of kids that do treatment X die within 6 months (regardless of their miraculous responses), and 20 to 30 % of kids with treatment Y eventually end up in remission and 75% are alive at 1 year, which treatment would you choose?

Believe it or not, I can't tell you how many people I see choosing path X over path Y. I don't know what they are being told but I see them all with great expectations.

I think it was Einstein that said insanity was doing the same thing over and over again and expecting different results.

Yet, we do it. I cringe nearly everyday.

Be skeptical. Ask questions. See the proof for your own eyes.

Okay, so I probably deserve a public lashing. But, at least, this may make someone think twice.

It may save lives.

I just can't keep my purpose shut.

Ah, Mother's Day

Okay, so, I get Mother's Day. It is really not that hard to grasp the concept. My job as Daddy is to make sure that Mommy is happy on Mother's Day. I take all of the kiddos the week before the big day. I help them buy presents for Mom that are from the bottom of their hearts. I even help them make their own cards. I have this Daddy thing down. In fact, I have it ingrained in my psyche so much that I even know that I am supposed to do everything in my power to make sure that Lynley has as easy a day as possible.

I get it.

The kids, too. They know. I have branded it into their scheming little brains. This is Mom's Day. No fighting. No making messes. Today is about Mommy. Not you. That means being nice to each other, cleaning up after yourself, and doing everything in your power to help Mommy have a great day.

You see. I run a tight ship. Even though I am generally a complete failure at Valentines Day, I have Mother's Day down. I have got skills.

What I don't have is a wife that listens very well. She is supposed to be relaxing and enjoying. But, no, is that what she chose to do on Mother's Day? Of course, not. I wake up at 5:30 in the morning to find her mopping the floors and dusting the house. This, of course, was being done to a house that was neither dirty or dusty. I was not very successful at getting her to slow down. So, I did the next best thing. I emptied the dishwasher, cleaned out the recycling bin, and tried to look busy cleaning things whether they need it or not.

It, by the way, is very difficult to clean things that aren't dirty. I felt completely guilty and entirely stupid. There I was busily wiping down counters that were only dirtied because I sprayed Lysol on them. It felt goofy cleaning something that clearly did not need to be cleaned. I felt dirty. Regardless, she mopped the clean floor and I wiped down the clean counters and although it felt really awkward it, none the less, made her very happy - a sense of accomplishment I guess.

yYou should also know that I did not plan Mother's Day. It is supposed to be relaxed. But, other than that, I leave it to Lynley to lead us in whatever direction she wants to go. I am a smart enough husband to know that I can't read her mind. I also know her well enough to know that strict plans are not what she wants. She is looking for freedom.

So, we did what she wanted to do. We started with breakfast which was quick, but yummy. It was not at the house so there would be no clean up. It was also fast so we could get on the road to do all of the things that she wanted - like running errands.

Yes, you heard me again.

We took the dogs to the vet for some shots because, well, she wanted to. Then, we ran by Redbox to pick up a movie because, well, she thought that would be fun. Then, we shot to the grocery store because she wanted to go as a family instead of me going alone. We made it home just in time to put the groceries away and feed the kiddos "picnic style" before some family visited. By about 1:30, thoroughly exhausted, the house was clean, Graham and Ainsley were down for naps, the dogs were free of disease, and the groceries were shopped for. All that was left was to sit down and quietly watch a movie.

Being a professional at relaxing I had fallen asleep within about 15 minutes of the movie that she wanted to see. When I woke up I found the movie still playing and Lynley out in the yard cleaning out the flower beds.

That lasted until about 5:00 PM.

That evening we had my mother over and shish ka bobs for dinner.

At the end of the night I asked Lynley how her Mother's Day was.

She said it was nice but too busy. I was smart enough not to say a word.

I get Mother's Day but I don't know if I will ever understand mothers.

It just never gets out of their system.

They never stop being mothers. They overflow with purpose.