My presentation at the World Conference on Lung Cancer last week was on a trial I led for patients with previously treated advanced NSCLC, who received a combination of taxotere every three weeks along with a new drug called DN-101, or Asentar.  It’s actually a new formulation of calcitriol, which stimulates the vitamin D receptor in cells.  Now, calcitriol at normal body levels regulates calcium balance in the body, but the receptor also lives in the nucleus of cells and can impact several important signalling mechanisms of cells.

  (Click to enlarge)

But at higher than normal blood levels, calcitriol can have a wide range of anti-cancer activities, at least as shown in pre-clinical studies.  It has been been demonstrated to have anti-angiogenic activity, promotes apoptosis (programmed cell death) of cancer cells, and leads to arrest of the cellular growth cycle.

In actual people, the evidence of any value to vitamin D/calcitriol has been more indirect than direct.  In population studies, several cancers (although lung cancer not among them) have been shown to occur less commonly in people with greater sun exposure (which is a way of receiving vitamin D) or higher vitamin D levels.  A manuscript from the Harvard School of Public Health and Massachusetts General Hospital earlier this year revealed that patients with higher vitamin D circulating blood levels had a better survival than those with low levels, among those who underwent surgery for early stage NSCLC  (abstract here).  In clinical testing, the combination of taxotere with calcitriol was associated with a better survival and lower toxicity than taxotere with a placebo in a phase II trial of 250 patients with metastatic prostate cancer (abstract here).  A larger phase III randomized trial in prostate cancer is ongoing and could lead to the approval of Asentar in prostate cancer.  Meanwhile, Asentar is basically a reformulation of a form of calcitriol that is already approved for treating patients with kidney failure, but they need much lower doses than are used in the cancer trials.  Because of the high doses needed for anticancer activity, the new drug Asentar (DN-101) allows a patient to take just a few capsules instead of 100 or more:

   The trial I ran (ASCO abstract here) was a phase I/II study in which previously treated patients with advanced NSCLC received standard taxotere every three weeks in combination with escalating doses of DN-101.  A larger group of patients received DN-101 on one day, followed by taxotere on day two, with cycles repeating every two weeks.  We went up to a maximum target of 180 micrograms (180 mcg), which was felt to be enough to reach high blood levels.  There were no significant safety problems, and a total of 53 patients received a combination of this high dose of DN-101 along with taxotere.  Then, also to test feasibility and to get a sense of whether weekly dosing of DN-101 might be better, another group of 21 patients were later enrolled to receive the same 180 mcg of DN-101 on day 1, taxotere on day 2, and then escalating doses of DN-101 on day 8 and 15 of each 21-day cycle.  We were again able to get up to the maximum target dose of 180 mcg weekly along with taxotere, although at this level we saw that nearly 30% of patients developed abnormally high blood calcium levels, nearly 10% more severely.  This hypercalcemia, also sometimes associated with developing kidney stones and spilling calcium into the urine, is the main problem associated with high dose calcitriol.

   In terms of activity, the results looked encouraging, but not astounding.  Both the every 3 week and the weekly DN-101 recipients had a response rate in the 10-12% range, perhaps a little better than you’d get with taxotere alone, but not clearly better.  A total of about 60% of patients on both schedules had either a response or stable disease, which is also a little better than you expect to see with chemo alone, but as I’ve said about many trials that weren’t mine, patients on smaller phase II trials often do better than those on large phase III studies, likely largely because these patients are more cherry-picked and get unusually vigilant follow-up.  The survival numbers on the every 3 week DN-101 arm were very similar to chemo alone.  While the median survival of nearly 9 months and one-year survival of 40% in the weekly DN-101 recipients looked particularly favorable, these patients only received a median of 2 cycles of this treatment and there were only 21 people involved, so I am reluctant to read too much into these moderately encouraging results.

   What I found more intriguing was the toxicity profile, which looked notably lower on this trial than you’d expect with taxotere by itself:

It’s possible that some of the difference in low blood counts was from much more aggressive use of drugs like neupogen or neulasta in recent years compared with the earlier studies of taxotere alone, and reported incidence of fatigue may be dependent on how carefully you look for it, but the differences may be real.  In addition, it appears that some gastrointestinal toxicities like stomatitis (mouth sores), diarrhea, and vomiting could be lower when DN-101 is added to taxotere.  Finally, this idea of improved side effect profile is less of a stretch when we know that this combination also led to a significantly lower rate of serious adverse effects compared with taxotere and a placebo on the aforementioned prostate cancer trial ASCENT-1.  Perhaps this is similar to the improvements in side effect profile of Alimta conferred by adding B12 and folate…

   We can only clarify this with further studies, but it’s not clear whether or when any additional clinical research will be done on DN-101 in lung cancer.  The company that makes this agent, Novacea, is very small and really hasn’t had enough money to fund everything they’d like to.  Now that Novacea has entered into a partnership with Schering-Plough, I’d imagine money will be less of a problem, but there’s no question that getting approved in prostate cancer is their first order of business.  In addition, my understanding is that there may be one or more other tumor types that are considered a higher priority for developing DN-101, but perhaps there will be further study of this agent in lung cancer.  In the meantime, I don’t think the findings are enough for me to recommend that my patients take high doses of vitamin D, but it may be that certain vitamins really do help reduce the toxicities of some chemo drugs.  The problem, though, is the mixed results that can also be associated with some vitamins interfering with chemo drugs, and because of this, I don’t recommend more than a basic multivitamin to most patients at this point.  But I hope we get better answers to these questions.