Ceritinib - easing side effects - 1270512

Hi Alicia,

Since this is a new and readily changing area of treatment I'll ask one of our faculty what the most recent thought in scheduling is. It will be tomorrow before we hear something.

What I do know is trials decide dose and other treatment standards. The highest dose that can be tolerated in trials is the dose set and tested and whether or not a drug is taken on an empty stomach is also determined by the trial set up. In short it doesn't mean that it is the only way a drug can be taken but the only way a drug was tested to be effective. Changing those standards may work or may not work. When tarceva was found to be effective at lower doses for those very sensitive to the drug it was known if it would work but it was either that or not taking the drug. I imagine the same is true for ceritinib, though I don't know what clinical practicing oncologists have found to be best. The practice of specialist has been to start treatment at a standard dose schedule then change if needed.

I hope you'll do very well for a very long time.

Janine

FYI, we should hear from Dr. Walko in the morning.

I found this from Dr. West about dose reduction, "Toxicity is a potential challenge, more so than with XALKORI, especially gastrointestinal issues. Nausea was noted in 82%, diarrhea in 75%, vomiting in 65%, fatigue in 47%, and liver function tests were noted to be abnormally elevated in 35%. These issues were dose-related, and many of the researchers with the greatest experience with this agent have conveyed that the dose of 750 mg daily may be too high for many people, but that they have often had a more successful balance of efficacy and tolerability after reducing the dose to 600 mg or sometimes 450 mg per day (4 or 3 tablets, respectively)." http://cancergrace.org/lung/2014/04/30/new-approval-for-zykadia-ldk378c…

Until tomorrow

Alicia,

Thank you again for your message/question.

The current recommendation is on an empty stomach (2 hours before or after a meal) because taking the drug with food can increase the amount of drug that gets absorbed. This depends on the fat and other aspects of the meal and exposure can actually be increased more than 70%. The food study being done is currently enrolling (NCT02299505) and is specifically looking at whether giving a lower dose of ceritinib with a lower fat meal may achieve the same drug levels as the higher dose on an empty stomach. The goal is still the same drug level exposure so I would not expect this to change the side effects significantly.

In terms of how splitting the doses might change the side effect profile, I cannot comment and would not recommend doing this unless discussed with your doctor. The drug is eliminated slowly from the body (half life of around 40 hours) so this is likely why the once daily dose was recommended.

As Janine noted above from Dr. West, dose reductions are common. The package insert notes that about 60% of patients starting on the full dose of 750 mg once daily needed at least one dose reduction and the median time to the first dose reduction was about 7 weeks.

I know that nausea and diarrhea can be significant side effects, even when they occur at "mild" levels, but fortunately they are side effects we have drugs to treat. I would definitely recommend discussing your concerns with your medical team so they can make sure you have a treatment plan in place if the side effects happen.

Let me know if you have any other questions!
Best wishes for more success with the ceritinib.
Dr. Walko

Alicia,

Crizotinib is not affected by food and so the amount that gets absorbed does not change in the presence or absence of food. There can certainly be a mild direct irritant effect causing mild "quesiness" but the type of nausea generally caused by ceritinib is more due to activation of certain receptors in the brain and this is related to the amount of drug in the body. The goal of the food study being done with ceritinib is more of a dose finding study rather than to see if food will decrease the side effects or to assess the efficacy of the drug. The challenge with drugs like ceritinib is that the amount of fat in every meal taken with the drug has to be closely monitored and consistent, which is why it is easier and safer to take the drug on an empty stomach.

The "half life" of the drug is a measure of how long the drug stays in the body and helps to determine the dosing interval that can be used. Drugs with a short half life have to be dosed more frequently. For example, ibuprofen (Advil) has a much shorter half life than naproxen (Aleve) and so ibuprofen is dosed 4 times per day compared with naproxen that is usually twice per day. Ceritinib's long half life of 40 hours means that it can be dosed once per day and will stay in the body for a long period of time. Generally, when a drug is being developed, once per day is the easiest for patients and so what the drug company will try to do. It is also important to consider the amount of drug that is needed to be at the site of action (ALK, in certinib's case) and so larger, once daily doses may be more effective at getting enough drug to the site of action than lower doses given more frequently. I cannot find that dosing the drug twice per day was tried with ceritinib.

Hope that is a little more helpful. Happy to answer to any other questions you may have!
Best wishes,
Dr. Walko

Alicia,

I'm glad to hear that you did so well with the crizotinib, not everyone tolerates very well. I also completely agree with you regarding the need to find ways to maintain efficacy while also reducing toxicity. As we continue to move towards therapies that allow us to think of cancer (even stage IV lung in some instances!) as more of a chronic disease, the grade 1 and 2 side effects that aren't enough for dose reduction but can have huge effects on daily quality of life are definitely a concern. I was actually very happy to see (and hear!) the voices of several patient advocates at the annual ASCO meeting in Chicago in June that reminded researchers of exactly this. My area of research is trying to look at genetics and drug levels in the body as ways to predict and decrease these side effects while still keeping the efficacy of the drug, so it is definitely an area of active research.

Hopefully the ceritinib will be as good to you as the crizotinib was and you will be able to love this newbie drug too. Please continue to share you experience, it's so valuable to hear and benefits both the medical team and other patients. I will be very interested to see if since you tolerated the crizotinib if you also have an easier time with the ceritinib.

Best wishes,
Dr. Walko