Introduction

There are at least 3 or more different versions of the epothilones currently under development, although none at this time have received FDA approval. BMS-247550 is furthest along in development and is now called Ixempra (ixabepilone(Ix)) and is approved for metastatic breast cancer as a 2nd line chemo.  Epothilone B(patupilone, EPO906) is also in development and there is also a 3rd epothilone, 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%.

How far ixabepilone will get in the development cycle remains to be seen.  Current plans as far as I know will only focus on using Ix for 1st line chemotherapy. So far, there are no phase III trials in progress.  More details on the studies done so far are below.

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

• 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.

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.

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). 

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.

References

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