Urologic Oncology

SLIDES & TRANSCRIPTS
Saturday, December 14, 2002

Calcitrol in Advanced Prostate Cancer

Tomasz Beer, M.D.

Slide 1:

I would like to thank the organizers for giving me this opportunity to be here with you today, and share the results of a series of clinical trials that led up to a phase II clinical trial of high dose calcitrol, which is a natural vitamin D receptor ligand, and docetaxel in androgen-independent prostate cancer.

Slide 2:

I'm going to very quickly run through the pre-clinical rationale for this concept. I have one slide on a phase I trial where we developed the high dose calcitrol regimen that we later deployed. I'm going to review very briefly with you, the background for the activity of single agent docetaxel in advanced prostate cancer. And then go over the results of a phase II trial that combined high dose calcitrol with docetaxel.

Slide 3:

Now, this slide attempts to summarize the work of many, many authors over a dozen years or so, and it certainly can't do all that work justice. But there is ample evidence that vitamin D receptor ligands in pre-clinical systems, exert a variety of anti-proliferative activities in a number of preclinical tumor models, both in vitro and in vivo.

Specifically, cell cycle arrest and inhibition of cell cycle progression have been demonstrated, as well as induction of apoptosis. In some models there has been also the suggestion that vitamin D receptors may mediate invasiveness and angiogenesis. Several investigators have also demonstrated additive or synergistic effects with a variety of cytotoxic agents.

Now, one of the critical issues with trying to translate these findings into patient care is that all of these effects that we observe in the pre-clinical models occur at calcitrol concentrations that are substantially above the physiologic levels, and that would not be attainable with conventional dosing of vitamin D compounds due to predictable hypercalcemia.

Slide 4:

I just have a couple of quick examples of that pre-clinical data. This is a dose response curve of two commonly used antigen prostate cancer cell lines. This is a slide from our lab, although Scoronski first reported this type of experiment as early as 1993.

What you can see here is increasing concentrations of calcitrol and percent cell survival. And just to orient you, at Point 1 nM, right here, is roughly the mid-point of the physiologic level of calcitrol that we all have in our blood. At that concentration it is difficult to see any inhibition of cancer proliferation. But one log higher and above we can demonstrate dose-dependent growth inhibition of both of these vitamin D sensitive prostate cancer cell lines.

Slide 5:

Now, primarily Candace Johnson and Skip Trump, formerly of the University of Pittsburgh, now at Rosell Park, have done the work on synergy with chemotherapeutic agents. This is just one slide showing an example from our lab, but really that group deserves most of the credit for the pre-clinical work for that concept.

This is a clonogenic assay using PC3 cells incubated with either the calcitrol, docetaxel, or both, showing at least the additive, and perhaps synergistic inhibition of colony formation.

Slide 6:

Then moving onto clinical results, this is a one slide attempt to summarize a phase I clinical trial. The details were published in Cancer a couple of years ago. What we tried to do here, is to dose escalate calcitrol by dosing it intermittently. We reasoned that intermittent dosing may permit us to attain potentially therapeutic calcitrol levels without attendant toxicity.

And we in fact found that we were able to get well above 1 nanomolar concentrations with weekly dosing. We also found that with the currently commercially available formulation of calcitrol, there appeared to be an absorption ceiling, and we weren't able to get much beyond about 2 nanomolar, despite heading up to doses of 2.8 micrograms per kilogram. This drug was delivered with half microgram capsules, so these doses were about 300 capsules in a sitting.

Slide 7:

We then tested weekly calcitrol at half a microgram per kilogram, or about 80 or 90 capsules as a single agent in prostate cancer. We chose hormone-sensitive prostate cancer. These were patients with a rising PSA, after either radiation or prostatectomy.

This trial was important for us, because it provided us much longer safety data than we had in our phase I trial. And, in 22 patients treated for a median of 10 months we did not see any grade 3 or 4 toxicity. We had no definitive evidence of activity. We did see some hints of activity.

Perhaps there were 3 patients out of 22 who had declines in their PSA, but short of the 50 percent standard. Another three patients had significant reductions in the rate of rise of the PSA. Neither of these endpoints of course is a validated endpoint in prostate cancer, so these findings would have to be reviewed as hypothesis generating only.

Slide 8:

Now, turning to the available data on docetaxel as a single agent, I'm going to review this quickly, because it serves as a comparator of the clinical trial I'll present to you last. There have been four published trials of docetaxel in androgen-independent prostate cancer. Two of them looked at the every 21-day dosing, and two at weekly dosing.

Slide 9:

As you can see, the PSA activity of this drug is relatively close from trial to trial. And in a poor man's meta-analysis, the average response rate reported is 42 percent.

Slide 10:

Measurable disease is a little bit tougher to comment on. There are only 31 patients in the literature, and overall 28 percent of those responded.

Slide 11:

And time to progression and overall survival were only reported in the trials from US Oncology and from our center, with a weekly docetaxel and/or 5 months and 9 months. So these numbers at the bottom are roughly what we were using as a comparator to design our phase II trial with the combination of calcitrol and docetaxel.

Slide 12:

This slide summarizes briefly the design of this trial. The target patient population were men with metastatic androgen independent prostate cancer who were naive to chemotherapy.

The treatment regimen was a very straightforward one. We used the same weekly docetaxel regimen that we had used in our single agent trial previously, standard dexamethasone premedication, but we added half a microgram per kilogram of calcitrol approximately 24 hours prior to the docetaxel administration.
The statistical design was that of a standard phase II trial. We assumed that docetaxel alone, would produce a 45 percent response rate by PSA, and sought to detect a 65 percent response rate to move the concept forward.

Slide 13:

This slide summarizes the characteristics of the patients that we treated on this trial. There were 37 patients with a median age of 73, and a median ECOG performance status of 1, median PSA of about 100. All of these patients had metastases, almost all of them had metastases to the bones.

Slide 14:

This is a summary of the grade 3 or higher treatment-related toxicity that we saw. Although leukopenia and neutropenia were relatively commonly seen, we did not seen any neutropenic fevers. Hyperglycemia, which one would expect with a dexamethasone premedication was seen in a quarter of the patients; peptic ulcer disease in 11 percent; and pneumonia in 8 percent, and one of those patients died as a result of pneumonia.

With the possible exception of peptic ulcer disease, this toxicity profile is quite similar to weekly docetaxel alone.

Slide 15:

This slide summarizes the efficacy results of the trial by the commonly used available measures. By PSA we saw an 81 percent response rate. The confidence intervals are shown on the right. In measurable disease there were 15 patients with measurable disease; 8 of those or 53 percent responded to therapy. The median time to progression was 11 and a half months, and median overall survival was 19 and a half months.

Slide 16:

We also, in a small group of patients, did a very preliminary and exploratory evaluation of the pharmacokinetics of docetaxel and calcitriol to try to see whether there were any effects of one drug on the other. These are PK parameters of docetaxel in the same five patients with and without calcitriol. We saw no differences there.

Slide 17:

And this is a busy table, looking at the same five patients, calcitriol PK with and without docetaxel. We saw quite a bit of variability in absorption of calcitriol with the current commercially available formulation. But, overall, we were not able to detect any differences in the pharmacokinetics of calcitriol when we added docetaxel.

Slide 18:

So what we concluded from this is that in a single institution, non-randomized phase II clinical trial, the combination of high dose calcitriol and docetaxel is well tolerated, and yields promising efficacy results as measured by PSA measurable disease response rate, time to progression, overall survival.

We also in a very small and exploratory effort were not able to detect any differences in the pharmacokinetic profile of either agent when the companion agent was introduced.

Slide 19:

Now, clearly, these results are preliminary. They are from a single institution, and confirmation is essential. So we recently initiated a national randomized trial that will attempt to confirm the results of this phase II study by randomizing patients to docetaxel plus calcitriol or plus placebo.

Slide 20:

I would like to acknowledge the folks that contributed to this program, primarily my patients with prostate cancer, who were willing to participate in experimental therapies; Dave Henner, who is my former mentor; Bruce Lowe and Mark Garzotto, my urology collaborators; Scott Cruickshank, the statistician; my entire clinical research group staff here on the right; and the NCI, Aventis, and Roche for financial and drug support.

Thank you very much.