And this report from ASCO on epothilones. KOSN's epo-D should have much lower toxicity than the BMS drug:
Epothilone B Analogue Exhibits Antineoplastic Activity in Prostate Cancer
Two multicenter phase II trials reported that the investigational drug BMS-247550 (ixabepilone), a semi-synthetic analogue of epothilone B, has antineoplastic activity in patients with chemotherapy-naïve metastatic hormone-resistant prostate cancer. In one trial, BMS-247550 was the sole agent. The other trial compared this agent alone and in combination with estramustine phosphate with no significant difference in adverse events except for severity of thrombosis and nausea. In each study, the primary endpoint was a prostate-specific antigen (PSA) decrease of 50% or more with stability or regression of measurable disease.
In a trial conducted by the Southwest Oncology Group (SWOG) that was reported by Maha Hussain, MD, of the University of Michigan (abstract #4510), 41 men who had had either medical or surgical androgen ablation and who were chemotherapy naïve were treated with ixabepilone 40 mg/m2 administered intravenously over three hours every three weeks. Data for 22 evaluable patients indicated that the drug has antineoplastic activity in this disease based on nine PSA responses and three objective responses among 10 patients who had measurable disease at the time of enrollment. Eighty percent of patients who had experienced treatment-induced PSA responses had decreases of 70% or greater. The estimated one-year survival was 75%, and the median survival had not been reached at the time of analysis.
William K. Kelly, MD, of Memorial Sloan-Kettering Cancer Center, reported updated results from a randomized trial comparing single-agent ixabepilone with a regimen of ixabepilone plus estramustine phosphate in 92 chemotherapy-naïve patients with progressive castrate-metastatic prostate cancer (abstract #4509). Patients who received the combination therapy were also treated with daily anticoagulant therapy. Combination therapy resulted in PSA responses in almost 70% of patients, compared with 56% for monotherapy. Partial regression of measurable disease occurred in 44% and 23% of patients, respectively. There were 81 surviving patients at a median follow-up of seven months.
Although each of these trials successfully demonstrated the antineoplastic activity of ixabepilone in chemotherapy-naïve patients with hormone-refractory prostate cancer, the agent was associated with extensive toxicities. In the SWOG trial, treatment was discontinued for 29% of patients because of adverse hematologic (primarily neutropenia) and/or neurologic effects. There were no grade 4 or 5 toxicities other than hematologic. The toxicity profile was similar in the study presented by Dr. Kelly, except that the addition of estramustine led to more frequent nausea (grades 1 and 2). Both with and without estramustine, ixabepilone was associated with grade 1-3 neuropathy in more than half of patients.
When asked by Eric J. Small, MD, of the University of California, San Francisco, if further development of ixabepilone can be justified in light of its toxicity profile, Dr. Hussain responded that the future of this agent depends on ?our learning to deal with the neurotoxicities.? In contrast, Dr. Kelly noted that in his study, neuropathy associated with ixabepilone ?was prominent but has proven manageable, though it requires further characterization.? Daniel P. Petrylak, MD, of Columbia University challenged the justification of phase III trials of the ixabepilone/estramustine regimen due to the toxicity of estramustine in phase II trials. Dr. Kelly acknowledged the need for additional trial data on the efficacy and adverse effects of estramustine.
?Do the epothilones represent new therapy for prostate cancer or more of the same?? This provocative question introduced the discussion by George Wilding, MD, of the University of Wisconsin. BMS-247550 is a semi-synthetic analogue of epothilone B, which has been shown in preclinical studies to have activity against taxane-resistant and taxane-sensitive cell lines, and in clinical trials to have cytotoxic activity against a range of tumors both sensitive and resistant to taxanes. Like the taxanes, the epothilones are targeted at the mitotic spindle, where they induce microtubule stabilization resulting in mitotic arrest at the G2/M transition.
In light of these similarities, Dr. Wilding said, it is important to compare the epothilones with the taxanes with respect to both efficacy and toxicity in prostate cancer, except in those tumors that are resistant or refractory to taxanes. During the Plenary Session on Monday, two phase III taxane trials in androgen-independent prostate cancer will be presented. One is a study by Dr. Petrylak utilizing taxotere plus estramustine compared with mitoxantrone plus prednisone (abstract #3). The second trial, to be reported by Mario A. Eisenberger, MD, of Johns Hopkins University, evalulates taxotere plus prednisone (abstract #4). The PSA and tumor-response data from those trials are similar to those reported by Dr. Hussain and Dr. Kelly.
Ideally, patients who have a response to epothilones would be different from those in whom the taxanes are efficacious, thus presenting two ?activity realms? justifying?even requiring?parallel drug development. Regarding this point, Dr. Wilding referred to a phase IIa trial in which Epo-906 was selected as ?an appropriate alternative to taxane therapy in patients with hormone-resistant prostate cancer? because ?it is not a substrate for multidrug-resistance protein? (abstract #4563). This trial will be presented at a Poster Discussion Session on Monday (11:00 AM ? 12:00 PM, room 293). In order to illustrate the differences among epothilones, Dr. Wilding pointed out that in that study, the primary toxicities were gastrointestinal rather than neurologic.
?Are there possible molecular predictors of response to epothilones that might differ from those for taxanes?? Dr. Wilding asked. There is some evidence that prostate tumor cells with mutated P53 genes may respond better to epothilones than those with wild-type P53. Additional findings may provide molecular bases for predicting which patients will have a better response to taxanes or to epothilones. In search of such markers, ECOG 3803 will address the issue of neoplastic activity in hormone-refractory prostate cancer utilizing another epothilone, BMS-550, in patients who are chemotherapy-naïve or have previously been treated with either mitoxantrone or taxanes. The trial design calls for identifying predictive values for response. In another effort to identify post-taxane therapeutic alternatives, a multicenter randomized trial organized by the Prostate Cancer Foundation involved treatment with either mitoxantrone or BMS-550 in patients for whom taxane therapy has failed.
Repeating his opening question, ?Do the epothilones represent new therapy for prostate cancer or more of the same?? Dr. Wilding concluded that for today, the answer has to be ?maybe.? ?Hopefully, tomorrow we will have sufficient molecular and clinical evidence on which to base a definitive answer.?
Peter |
