I’ve got a lot of things on my list of things to cover in the near future…patient sex differences in lung cancer and estrogen, an update I’m trying to generate on DCA (dichloroacetate), the concept of pharmacodynamic separation of chemo and EGFR inhibitors, more on the trials from ASCO that may be changing our practice in treating locally advanced NSCLC, not to mention the discussion I’d like to start on Michael Moore’s new movie Sicko, which I went to see with my wife this past weekend. And then there’s the long list of topics I’ve been meaning to get to for several weeks before ASCO. Yikes. Well, at least we all know we’re not going to run out of things to talk about anytime soon.
Today, since member Spanky3 is starting a trial with the agent vorinostat (you can offer encouragement at the end of this forum thread), I’ll provide some introduction about this new agent. It’s also known as SAHA, which stands for suberoylanilide hydroxamic acid, which is why we always want to call it vorinostat or SAHA or its marketed name, Zolinza. Vorinostat is an oral medication that is approved for treating cutaneuous T-cell lymphoma, or CTCL, and it works as a histone deacytylase (HDAC) inhibitor. A what? Basically, DNA is wrapped up in a form better designed for compact storage rather than use for transcribing genes when it’s not being used, and those histones are what bind DNA into the storage form. Whether they release the DNA for transcription of genes on that DNA into protein depends on whether the histones have an acetyl group (iwhich you don’t need to know — it’s not on the quiz — but if you’re really interested or very bored, info is here) is added or not, so HDAC controls gene expression, and inhibition of this enzyme can inhibit some cancer cells. This is part of a whole new field called epigenetics, which is basically the study of how DNA is modified, in terms of the packaging that leads to more or less use, without changing the underlying instructions.
(Click to enlarge)
If you look at the figure above and a big light bulb doesn’t go on over your head, don’t fret if you still don’t understand it — the scientists are also not sure out it works. In fact, HDAC inhibitors may have other anticancer effects by acetylating proteins other than histones, and they may also interfere with the proteins controlling cell division by acetylating the centromeres, which are important cellular machinery for mitosis.
It’s pretty early in study of lung cancer, but knowing that it has activity in other cancer types like CTCL certainly makes it appealing. Vorinostat is an oral drug taken with food, typically at 400 mg per day. My friend Suresh Ramalingam at the University of Pittsburgh Medical Center has been among the first to move ahead with this drug in lung cancer, and he actually won an award from ASCO to continue to develop this line of research. He combined vorinostat with standard carboplatin/paclitaxel for patients with solid tumors (abstract here), and the most recent presentation I’ve seen has included 25 evaluable patients with cancer, 19 patients with NSCLC. Among those 19, 10 (53%) had a partial response.
That’s pretty encouraging, and the figure has the before and after CT scans for a patient that had a great response. (Oncologists, so many other people, try to be rational and carefully judge the data, but we’re still hugely swayed by a single impressive case, whether it’s a set of CT scans showing a great result, or Jared the Subway guy who lost 200 pounds eating Subway sandwiches). But it’s always a problem when new drug is added to an established treatment to try to determine how well these patients would have done with just chemo. There are lots of drugs that have shown great results in small trials with standard chemo and then turned out to do no better than chemo in larger trials. In fact, a small trial of vorinostat as a single agent (just 14 patients) hasn’t shown any objective responses when given every day to patients with previously treated (usually just a single line of chemo) advanced NSCLC (abstract here).
But the carbo/taxol/vorinostat trial is absolutely encouraging despite its small size, and it’s being followed up with a larger trial being led by Dr. Ramalingam through the California and Pittsburgh Cancer Consortium, in which patients are randomized between chemo alone or chemo with vorinostat:
The most common side effects of vorinostat are fatigue, diarrhea, nausea, low platelet countsk, and diminished appetite and weight loss. There is a patient information handout on this drug from the manufacturer (Merck) here. And there’s a list of trials with vorinostat, including several for NSCLC and one for mesothelioma, here.
Good luck to Spanky3. I’ll provide more information on this agent as I hear more.
posted by Dr. West @ 4:44 pm link to this post
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July 17th, 2007 at 10:02 am
My wife received a CT scan a few months ago to see if she was eligible for a trial with vorinstat and tarceva. At that time she had no measurable disease and was ineligible. Since she had a malignant pleural effusion we went ahead with tarceva by itself which she had to discontiue due to severe rash and blisters. With no measurable disease it was too much to handle as she felt too embarassed to leave the house and walking was limited due to the foot blisters. Now she has measurable disease but is ineligible for the trial as she had already briefly taken tarceva. I’m sorry for the longwindedness. I guess my point is that anyone who wants to seriously consider trials needs to be aware that jumping too fast from one treatment to another can greatly limit their options as far as trials. I had great hopes for this trial.
July 17th, 2007 at 11:49 am
Please — no pop quizzes Doc! Although I can always look over NeilB’s shoulder to get the right answers.
My concern is similar to Hubbies. What happens to a person who has been through many different regimens when new trials with new treatments come out? Are they just left out in the cold? My husband cannot take anymore platinum based drugs so he doesn’t seem to fit into most of the clinical trials with the “new” stuff. This is frustrating — options are not being made available. You don’t have anything going trial-wise at the moment, do you Doc?
I look forward to hearing your comments on the film. A discussion has already erupted at the LCSC, but I’d rather see it here. Glad you will be addressing this. (Can’t imagine your take — LOL)
July 17th, 2007 at 6:16 pm
Wow Dr. West, you sure did help me understand a heck of a lot more about Vorinostat and the trial I will take soon. A lot of words I dont understand but read and re-read and the 53% with a partial response is a start for a new drug I think. I do hope when I go to the trial I get it and not a placebo. Bless you for your time. It really really helped me Dr. West. And by the way, I am doing this trial thru the UPMC Cancer Center out of Pittsburgh which is headed by Dr. Ramalingam. I didnt know if you knew that or not. I go to a UPMC Cancer Center here by my home.
Thank you again sooooooooooo much for taking the time to do a discussion topic on this.
July 17th, 2007 at 6:40 pm
Spanky3–As I’ve mentioned before, Dr. Ramalingam is my oncologist. You’re in good hands with him! Good luck!–Neil
P.S. Now if I can only figure out which drug I can sell Dr. Rama on trying for me along with Vorinostat if and when Tarceva fails me…
July 17th, 2007 at 6:44 pm
Welthy–Thanks for the compliment. You can look over my shoulder for the test on the statistical part of the post (the second half)–if you can find someone for me to cheat off of on the first half. The biology is all Greek (or is it Latin?) to me!–Neil
July 17th, 2007 at 7:45 pm
I’m glad people have found this topic so valuable. And don’t worry about the biology. It’s always tough trying to figure out what to include and what it worth just stripping down. It’s there if people are really motivated, but just like your phone or TV, you don’t need to know how it works to use it.
I’m running several trials, but it’s definitely true that the majority that are sponsored by big companies focus on first or second line treatment, leaving people who have already received multiple lines of treatment with fewer options. I’ve got two trials that I wrote that are deliberately designed to allow patients to have received multiple lines of prior treatment, but both of these trials are for never-smokers or patients with BAC — one is with sutent as a single agent, and the other is with nexavar (sorafenib). I’d like to write more trials that are very inclusive, but there’s a lot of things I’d really like to do, if only the day had 30 hours.
-Dr. West
July 18th, 2007 at 10:29 am
Neil: Sorry to say Dr. Ramalingam is not my onc on this. He heads study out of PGH but I have another at the UPMC Cancer Center near my home. But in case you didnt read my post on regular forum I had a set back yesterday, so may not be getting any help afterall. BUMMER!! Wish I knew Dr. Ramalingam and could talk him into it for me. I figure I have nothing to lose anyway and I do know they have guidelines they must follow. Thank you, you have been so nice and supportive.
July 18th, 2007 at 11:39 am
Spanky3–Sorry I missed your post (lots going on yesterday), and sorry about your setback. I believe that the standard for doing chemotherapy is different from the standard for any particular clinical trial, so maybe you can still do the standard part of the treatment (the other two drugs), which, as I mentioned before, has a proven benefit. I can certainly understand your frustrations, but I hope you will press on with your treatment.
Best,
Neil
July 18th, 2007 at 11:56 am
Just recieved phone call. They consulted with my cardiologist and Dr. Ram(as I will call him) and they decided to NOT let me into trial. Im really disappointed over this. They plan to just do standard like you said. AND hopefully start next week. They said I think I will just get infusions every 3 wks but its another wait and see.
Thanks Neil