Introduction

Ixabepilone (Ix) has been approved for advanced breast cancer patients.  It now has a new name, Ixempra. The specific approval indication is: Ixempra was approved for use in combination with another cancer drug, capecitabine, in patients who no longer benefit from two other chemotherapy treatments. These prior treatments included an anthracycline (such as doxorubicin or epirubicin) and a taxane (such as paclitaxel or docetaxel). Ixempra was also approved for use alone in patients who no longer benefit from an anthracycline, a taxane and capecitabine. For HRPC disease, it would be used off-label. The original designation for Ixempra was BMS-27550.

Other epothilone class drugs in development are: Epothilone B(patupilone, EPO906), desoxyepothilone B(epothilone D, KOS-862).  Patupilone is being studied in a phase II clinical trial for HRPC patients: http://clinicaltrials.gov/show/NCT00407251

The epothilones are derived from Sorangium cellulosum, a myxobacterium first discovered on the banks of the Zambezi River in Africa 20 years ago.  The epothilones appear to avoid developing resistance, unlike the taxanes. Epothilones also do not require steroid pretreatment as do the taxanes.  Avoiding resistance doesn't mean they there are no side effects that limit the amount of treatment. Compared to other microtubule-stabilizing agents, Ix appears similar for incidence of ≥ grade 3 sensory neuropathy:

• Ix: 3-22%

• paclitaxel: 0-33%

• docetaxel:0-14%

• Abraxane: 4-10%.

The following information pertains only to Ixabepilone (Ix). There are 4 different studies that have been run for HRPC patients.  These cover the use of ixabepilone as a single agent (PSA RR 33-48%)(1,4); ixabepilone combined with estramustine (PSA RR 69%)(1); ixabepilone and mitoxantrone used as 2nd line chemotherapies following taxane failure (Ix PSA RR 17%, mitoxantrone PSA RR 20%)(3) and the responses from using a taxane following 1st line Ix or Ix plus estramustine(PSA RR 51%)(2).

Can one draw any conclusions from all this data?   First of all, as a 2nd line chemotherapy, Ix by itself performs poorly(3).  As a first-line chemotherapy in chemo-naive men, Ix  or Ix +estramustine has promise (1, 4) and Ix or Ix + estramustine can be followed by a taxane as a 2nd line chemotherapy with at least a PSA RR of 36%.

A review article.

Nancy Dawson presented a review article of epothilones in prostate cancer -- clinical experience.  The symposium article is available free at http://annonc.oxfordjournals.org/cgi/reprint/18/suppl_5/v22 This was published in 2007 and provides an excellent summary of the epothilone development work.

Ixempra Studies with HRPC Patients

Studies published so far are summarized below. Although some patients might respond to 2nd line Ixempra, with such a low PSA RR and low measurable disease RR, it is questionable whether or not one would want to use this drug for a 2nd line chemotherapy.  See #3 below that is for 2nd line chemotherapy.

1. A phase II study of ixabepilone with or without estramustine (1) in HRPC Patients, MD Galsky et al. Chemo-naive patients.

• Number of patients: 92, all chemotherapy-naive.

• Randomized to Ix (35mg/m2 IV every 3 weeks) with oral estramustine phosphate (280mg 3 times/day days 1-5) vs Ix alone.

• PSA RR (declines of ≥ 50%) was for Ix alone 21 of 44 patients (48%) and for Ix+estramustine: 31 of 45 patients (69%).

• For measurable disease, the PR(partial response) was for Ix alone 32% and for Ix + estramustine 48%. 

• For bone metastases, the percentages for stable/improved bone scans was Ix alone 60% and for Ix + estramustine 78%.

• The time to PSA progression TPP for the combination arm was 5.2 months, and the TPP for the ixabepilone-alone arm was 4.4 months.

• Grade 3/4 toxicity for both arms included neutropenia, fatigue and neuropathy.

2. Chemo-naive patients who received Ixabepilone with or without estramustine who subsequently received a taxane (2).

• 2nd-Line Taxane after 1st line Ixabepilone, retrospective study.

• 28 patients Ix + estramustine --> taxane as 2nd line.

• 21 patients Ix alone --> taxane as 2nd line.

• PSA RR for all 49 patients was 51%.

• PSA RR for patients who had a PSA Response on Ix, was 61%.

• PSA RR for patients who did NOT have a PSA Response to Ix was 33%.

• Patients who discontinued Ix because of disease progression were less likely to have a PSA response to taxane 2nd-line compared to those who discontinued due to toxicity or patient preference (36% vs 71%, p=.01). But note that 36% did have a PSA response even though they were Ix-refractory.

3. A Phase II Clinical Trial of Ixabepilone or Mitoxantrone/ Prednisone, Rosenberg JE et al (3). HRPC patients as a 2nd line chemo for taxane-refractory men.

• All patients had prior taxane chemotherapy.
• 41 patients Ix 35mg/m2 IV every 3 weeks.
• 41 patients Mitoxantrone 14mg/m2 IV every 3 weeks + prednisone 5mg orally twice daily.
• Median survival Ix arm: 10.4 months and 9.8 months in the Mitoxantrone arm.
• PSA RR (≥ 50% decline) for Ix was 17% and for mitoxantrone it was 20%.
• Partial responses (evaluable measurable disease) for the Ix arm was 1 of 24 patients and for the Mitoxantrone arm it was 2 of 21.
• Median duration of second-line ixabepilone and Mitoxantrone treatment was 2.2 months and 2.3 months, respectively.
• Cross-over was allowed and therefore was a 3rd line use where PSA Responses for Ix was 3 of 27 patients and for mitoxantrone it was 4 of 15 patients.
• This study also found that those patients who had responded to a taxane had an increased chance of a response on 2nd line Ix or mitoxantrone.
• Neutropenia was the most common grade 3/4 toxicity associated with second-line treatment (54% of ixabepilone patients and 63% of mitoxantrone patients). 

4. Single Agent Ixabepilone in chemo-naive HRPC patients (4).

• 42 patients with metastatic HRPC.
• Ix dose/schedule: 40mg/m2 IV every 21 days.
• 13 of 42 patients discontinued due to toxicity.
• No grade 5 (treatment-related deaths) adverse events
• The only grade 4 toxicities were neutropenia (7%) and leucopenia (2%). The most common grade 3 adverse events were neurologic toxicity (19%), hematologic toxicity (17%), flu-like symptoms (12%), and infection (12%).
• PSA Response Rate was 33% with 72% of these patients having PSA declines of > 80%.
• Overall measurable disease RR was 15%.
• Estimated median progression-free survival is 6 months and the median survival is 18 months.
• The authors recommended phase III trials to compare Ix vs taxanes.

5. Combination of Ixabepilone plus Mitoxantrone plus prednisone as 2nd line chemotherapy (patients who had failed taxotere.) A phase I clinical trial. (5 and 5.1)

We'll have to await results from any phase II and phase III studies to see if this combination treatment has any chance of being beneficial to HRPC patients. The number of patients per dose level is very small in dose finding trials such as this phase I study. The recommended phase II dose is 12mg/m2 mitoxantrone plus 35mg/m2 Ix every 21 days with pegfilgrastim 6mg subcutaneously on day 2 with prednisone 5mg twice a day continuously.   Certainly, this combination improves the single agent results for Ix (17%) or mitoxantrone (20%)(3) as 2nd line post-taxotere chemotherapies. The following summary is an update from the abstract to the published phase I results.

References

For a paper written by Bill Aishman in 2003, see epothilones.