Urologic Oncology

SLIDES & TRANSCRIPTS
Saturday, December 6, 2003

Highlights of GU SPORES

Paul Matthew, M.D.

Slide 1:

Good afternoon. Thanks for hanging around. I'd like to thank Dr. Linehan and Dr. Gomez for the invitation.

What I want to speak about today is specifically a project that I am involved in as principal investigator that is part of M.D. Anderson's SPORE, but has also been linked to an inter-SPORE trial in which Dana-Farber and Sloan Kettering are planning to join up.

Slide 2:

I'd like to review in the next ten minutes the rationale and preclinical data behind this study, that addresses targeting the platelet-derived growth factor receptor in prostate cancer, review the phase one results from a trial that was completed at our institution, and briefly describe the design of the inter-SPORE trial that is currently under way.

Slide 3:

Why target bone metastasis to this audience? It is well known that this is the most common cytometastases apart from lymph nodes, and that the burden of morbidity and mortality is well correlated to the burden of bone disease.

It is hypothesized that targeting epithelial bone interactions might modify the natural history of the disease in a favorable way.

Slide 4:

Some evidence for this hypothesis is provided by a trial from my institution, in which he incorporated a strontium consolidation arm to patients responding as stable after cytotoxic chemotherapy in androgen independent prostate cancer.

A recent update of his results show that these survival differences hold up.

Slide 5:

In the histochemical and expression profile from bone marrow aspirates from patients with prostate cancer and bone metastases, it is confirmed that platelet-derived growth factor receptor alpha and beta are expressed in this organ site.

In an orthotopic model of bone metastases in Dr. Fiddler's laboratory at M.D. Anderson, she was able to demonstrate that prostate cancer cells injected into bone acquired a high degree of PDGF-R expression,

Slide 6:

particularly in tumor cells adjacent to bone. This is the tibia of nude mice, suggesting some sort of paracrine effect that might be inducing the expression of this receptor tyrosine kinase in prostate cancer cells.

Slide 7:

In this admittedly rather artificial model, the tumor grew out from the bone marrow environment into surrounding muscle where the expression of the receptors and ligands to PDGF was diminished.

Slide 8:

So what they did was to use the potent PCGF-R inhibitor in gleevec, alone or in combination with pacletaxel, and showed that the best results were in combination. Although the results were not reflective of synergistic activity, they were additive. So whether it was tumor weights, the incidence of tumors or incidence of lymph node metastases, combination therapy appeared to provide the best results.

Slide 9:

These were reflected in these radiographs of hind legs from animals injected in the various treatment groups as outlined here, showing that with combination therapy the best results were achieved.

Slide 10:

Mechanistically, what was interesting was that the platelet-derived growth factor receptors seen here in green was expressed in tumor, but also co-localized with CD31 in endothelial cells of tumor in the bone micro environment, in contrast to tumor in the muscle micro environment. With therapy it was apparent that the apoptotic index of tumor and endothelial cells was enhanced most in combination therapy, suggesting that there was a specific target for combination therapy in endothelial cells of tumor expressed PDGF-R.

Slide 11:

So the summary of the preclinical work was that the target for therapy for PDGF-R for prostate cancer cells going into the micro environment of bone was both in the tumor cells themselves, but also in the endothelial cells of the tumor vasculature.

Slide 12:

I'd like to review what we did subsequently. We chose to explore whether matemalon(?) alone, the PDGF-R inhibitor or in combination with docetaxel was feasible in the clinic and had any sort of activity against androgen independent prostate cancer patients with bone in metastases. These are patients who had any prior therapy.

Slide 13:

At baseline, patients were registered to the study. They received matemalon at 600 milligrams a day, uninterrupted for 30 days, and then they were looked at with PSA and pain outcomes, and then initiated on weekly docetaxel at modified dose levels as part of a phase one schema and then cycles were repeated every six weeks.

Slide 14:

Briefly, the characteristics of the patients, only to emphasize that this was a heavily pretreated group. The majority of them had at least two prior regimens, and over half had taxane based therapy.

Slide 15:

With respect to the PSA outcomes, with Imatinib alone,

Slide 16:

this was rather unimpressive, with a less than 50 percent response rate in two patients, and no patients with more than a 50 percent decline in PSA.

Slide 17:

With combination therapy however, 38 percent of patients had greater than 50 percent decline in their PSA, including one patient who bona fide progressed on docetaxel alone, and overall, 67 percent declined in PSA.

Slide 18:

What is interesting about these patients was that -- and here are two PSA curves showing the first 30 days of therapy in Imatinib alone, showing the increases in PSA that were almost invariably seen in these patients, a median of almost twofold rise in the PSA accompanied by an almost twofold increase in pain index.

Subsequent responses to the 50 percent mark were rather slow. There was a median of 150 days before these responders described a 50 percent decline in their PSA, and not infrequently were these PSA fluctuations during therapy.

The patients were treated indefinitely, and until progression or toxicity supervened. Now we have two patients with over two years of continuing therapy with no long term toxicity, with good performance score, and another two over 12 months.

Slide 19:

This is summarized here, with a median freedom from progression on responders, that is to say, of 16 months.

Slide 20:

With respect to toxicity,

Slide 21:

this was not dissimilar to other inhibitors of receptor tyrosine kinase, with ischemia and GI toxicity predominating, and a very odd threatening edema syndrome, but it is largely manageable with dose interruptions and dose reductions.

Slide 22:

Just to summarize, the toxicity we defined in MTD at the 30 milligram per meter squared dose level of docetaxel. I didn't go into the details of the other dose levels that we explored. This is the dose we took forward to the phase two setting.

Slide 23:

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Slide 24:

At baseline, we had a few patients who consented to bone marrow biopsies and a few in whom you should be able to characterize tumor with immunohistochemistry. With the work being done at the University of Washington to detect epithelial cells and characterize them in the absence of bioticular(?) e very interesting for us to look at, listening to today's talk.

At any rate, here is an example of a patient who after 30 days of Imatinib showed no appreciable change in PDGFR expression, either phosphorylated PDGFR or the native receptor. But after combination therapy in this responding patient, there is a marked decline in PDGFR expressing tumor, both the phosphorylated as well as the native form.

The implications of this are still uncertain, but it does raise the possibility that with combination therapy, you may be able to eliminate PDGFR expressing tumor, and this residual tumor population may represent a mechanism of resistance to therapy.

Slide 25:

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Slide 26:

In summary, the work suggested that it is feasible to combine PDGF-R inhibitor and cytotoxic therapy with manageable toxicity. We are seeing long term responders in heavily pre-reated patients, with some of this pattern of persistent stepwise and slow PSA reductions. We have seen examples of PDGF-R modulation in tumor, including a response in a patient who had bona fide docetaxel refractory disease prior to entry in the study.

Slide 27:

With that, we generated these hypotheses, that combination therapy is required for clinically useful PDGF-R targeting in patients with prostate cancer, and that Imatinib may reverse taxane resistance.

Slide 28:

So we designed this randomized trial of 144 patients with placebo controlled -- of docetaxel /Imatinib versus docetaxel /placebo, the principal end point being time to progression. We have allowed crossover to combination therapy to examine the secondary hypothesis that Imatinib may reverse docetaxel resistance in a fraction of these patients.

Slide 29:

These are the objectives of the study. Once again, the secondary end points include traditional response outcomes with measurable disease and PSA toxicity, quality of life and modulation of bone markers. We are attempting to characteristic PDGF-R expression in tumor as baseline to see if this might predict for subsequent response. We are asking patients to submit to additional serial bone marrow biopsies to see whether we can see dynamic changes in PDGF-R expression over time between the experimental arm and the control arm.

Slide 30:

These are the principal collaborators in the study. Thank you.