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Ixempra (Ixabepilone(Ix)) - Does it have any use for HRPC patients as a
2nd Line Chemotherapy?
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:
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:
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
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
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
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
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 +
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.
patients who received Ixabepilone with or without estramustine who
subsequently received a taxane (2).
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%.
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
- 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
- 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
- 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.
36 patients with metastatic HRPC
who were progressing during or after taxane-based chemotherapy.
Mitoxantrone doses ranged
from 8-12 mg/m2 every 21 days.
Ixabepilone doses ranged from
20-35 mg/m2 every 21 days.
Prednisone 5mg twice a day
Hematologic serious adverse
events were: 21/36 pts (58%) had grade 3/4 neutropenia, 1 pt had grade
3 febrile neutropenia, and 1 pt had a grade 5 neutropenic infection.
There was 1 episode of grade
3 diarrhea with dehydration and one episode of grade 3 emesis.
Pegfilgrastim was used at
highest dose levels (Mitoxantrone 12mg/m2 and Ix 30-35mg/m2) due to prolonged neutropenia.
11 patients (31%) experienced
confirmed PSA declines ≥ 50%. Mitoxantrone ranged from 10-12mg/m2.
9/21(43%) patients receiving 12
mg/m2 mitoxantrone had a PSA response (≥50% decline in PSA.)
Partial objective RECIST -
defined responses ("measurable disease) were seen in 2 of 20 patients,
one at 10mg/m2 M and 30mg/m2 Ix. This is only a 10% response rate.
Responders had a median time
to progression of 5.3 months (range, 3.0 to 11.1 months).
For a paper written by Bill Aishman in 2003, see
(1) Galsky MD, Small EJ, Oh WK, et al. Multi-institutional
randomized phase II trial of the epothilone B analog ixabepilone
(BMS-247550) with or without estramustine phosphate in patients with
progressive castrate metastatic prostate cancer. J Clin Oncol.
(2) Rosenberg JE, Galsky
MD, Rohs NC, Weinberg VK, Oh WK, Kelly WK, Small EJ, A retrospective
evaluation of second-line chemotherapy response in hormone-refractory
prostate carcinoma: second line taxane-based therapy after first-line
epothilone-B analog ixabepilone (BMS-247550) therapy, Cancer. 2006 Jan
(3)Rosenberg JE, Weinberg VK, Kelly WK, Michaelson D, Hussain MH, Wilding G,
Gross M, Hutcheon D, Small EJ, Activity of second-line chemotherapy in
docetaxel-refractory hormone-refractory prostate cancer patients :
randomized phase 2 study of ixabepilone or mitoxantrone and prednisone,
Cancer. 2007 Jun 18; [Epub ahead of print].
(4) Hussain M, Tangen CM, Lara PN Jr, et al.
Ixabepilone (epothilone B analogue BMS-247550) is active in
chemotherapy-naive patients with hormone-refractory prostate cancer: a
Southwest Oncology Group trial S0111. J Clin Oncol. 2005;23:8724-8729.
(5) A. L. Harzstark, V. K. Weinberg, J. Sharib, D. C.
Smith, M. H. Hussain, T. M. Beer, C. W. Ryan, P. Mathew, C. J. Ryan, E. J.
Small, J. E. Rosenberg, Second-line combination chemotherapy: A phase I
study of ixabepilone, mitoxantrone, and prednisone in patients with
metastatic hormone-refractory prostate cancer (HRPC) refractory to
J Clin Oncol 26: 2008 (May 20 suppl; abstract # 5151).
(5.1) Rosenberg JE, Ryan CJ, Weinberg VK, Smith
DC, Hussain M, Beer TM, Ryan CW, Mathew P, Pagliaro LC, Harzstark AL, Sharib
J, Small EJ, Phase I study of ixabepilone, mitoxantrone, and prednisone in
patients with metastatic castration-resistant prostate cancer previously
treated with docetaxel-based therapy: a study of the department of defense
prostate cancer clinical trials consortium, J Clin Oncol. 2009 Jun
10;27(17):2772-8. Epub 2009 Apr 6.
Author: Howard Hansen, 25 June 2007. Updated 14 January