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clinical review Ixabepilone
clinical review
Ixabepilone: A novel microtubule-stabilizing agent
for the treatment of metastatic breast cancer
Susan Goodin
I
mportant advances in the management of breast cancer include
the introduction of three main
classes of chemotherapeutic agents—
anthracyclines, taxanes, and fluorinated pyrimidines (e.g., capecitabine)—that have improved
overall outcomes for patients with
metastatic disease.1-3 However, the
clinical utility of these therapies has
become limited in some patients by
the emergence of drug resistance.4-7
The increasing use of anthracyclines
and taxanes as adjuvant therapies
has highlighted the need for new, effective, first-line therapies for metastatic disease.3 It has also led to the
investigation of ways to overcome the
problem of drug resistance in order
to maximize the impact of chemotherapy on survival. The epothilone
derivatives are one class of agents
resulting from this research.
The epothilones are microtubulestabilizing agents that have shown
promising activity in patients with
various cancers, including cancers resistant to taxanes and other cytotoxic
drugs.7-11 Epothilones are naturally
occurring macrolide compounds
(i.e., containing a macrocyclic lactone
ring) that constitute a novel class of
cytotoxic drugs. Naturally derived
epothilones have limitations such
Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, and
administration of ixabepilone in patients
with metastatic breast cancer are examined.
Summary. The clinical utility of the three
main classes of chemotherapeutic agents
used in breast cancer (i.e., anthracyclines,
taxanes, and fluorinated pyrimidines) is
limited in some patients by the emergence
of drug resistance which leads to disease
progression. A recent addition to the available drugs for the treatment of advanced
breast cancer is the epothilone B analog
ixabepilone, which has demonstrated clinical activity in patients who have tumors
that have progressed while on other chemotherapy regimens, including anthracyclines and taxanes. In Phase II clinical trials
of ixabepilone in patients with metastatic
breast cancer, clinically meaningful benefits have been achieved with ixabepilone
monotherapy in patients in whom anthracyclines, taxanes, and capecitabine
are no longer effective. Ixabepilone has
demonstrated activity in first-, second-, and
subsequent-lines of therapy and in different subtypes of patients with advanced
disease. In a Phase III trial in patients who
as metabolic instability and a low
therapeutic index; therefore, a number of synthetic and semisynthetic
derivatives have been developed to
improve the pharmacologic proper-
Susan Goodin, Pharm.D., FCCP, BCOP, is Professor of Medicine,
Robert Wood Johnson Medical School, University of Medicine and
Dentistry of New Jersey, Piscataway, and Director, Division of Pharmaceutical Sciences, The Cancer Center of New Jersey, 195 Little
Albany Street, New Brunswick, NJ 08901 ([email protected]).
Bristol-Myers Squibb provided funding to L. C. Shepherd, Ph.D.,
had previously received taxanes and anthracyclines, the combination of ixabepilone and capecitabine was significantly
more effective in producing an objective
response and in prolonging progressionfree survival than capecitabine alone. At
the recommended dose and administration schedule, ixabepilone is generally
well tolerated. The most clinically relevant
adverse events associated with its use have
been myelosuppression and peripheral
neuropathy, which is primarily sensory and
cumulative but reversible within six weeks
of a dosage reduction or the discontinuation of therapy.
Conclusion. Ixabepilone, the first drug in a
new class of microtubule-stabilizing agents
called epothilones, offers a new treatment
option for patients with metastatic or
locally advanced breast cancer who are
refractory to standard chemotherapy.
Index terms: Antineoplastic agents; Breast
neoplasms; Capecitabine; Combined therapy; Dosage; Ixabepilone; Mechanism of
action; Neoplasm metastasis; Resistance;
Toxicity
Am J Health-Syst Pharm. 2008; 65:2017-26
ties of naturally derived epothilones
and optimize their in vivo antitumor efficacy. 12,13 Currently, three
synthetic derivatives of epothilone
B are in various stages of clinical de-
for her editorial assistance during manuscript preparation.
Copyright © 2008, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/08/1101-2017$06.00.
DOI 10.2146/ajhp070628
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
2017
clinical review Ixabepilone
velopment: ixabepilone, patupilone, advanced breast cancer in patients
and sagopilone. One epothilone D whose tumors are resistant or refracderivative (KOS-1584) is in clinical tory to anthracyclines, taxanes, and
capecitabine.14
development.
This article reviews the pharmaCurrently, the only drug in this
class with labeling approved by the cology, pharmacokinetics, clinical
Food and Drug Administration efficacy, safety, dosage and admin(FDA) is ixabepilone (Ixempra, istration, and role in therapy of ixBristol-Myers Squibb).14 The clinical abepilone in patients with metastatic
activity of ixabepilone has been dem- breast cancer.
onstrated in patients with metastatic
breast cancer who had previously Pharmacology
As with the taxanes and other
been treated with other chemotherapy regimens, including anthracy- agents that target tubulin, 21 the
clines and taxanes.15-20 Ixabepilone epothilones, including ixabepilone,
is indicated for use in combination bind to the b-tubulin subunits of
with capecitabine for the treatment microtubules to induce microtubule
of patients with metastatic or locally polymerization and stabilization,
advanced breast cancer who are re- which lead to arrest of cells in the
sistant to treatment with an anthra- G2-M phase of the cell cycle and
cycline and a taxane, or in patients the induction of apoptosis (Figure
whose cancer is resistant to taxanes 1).12,22 Epothilones bind to a tubulinbinding pocket of microtubules in
and for whom further anthracycline
)XABEPILONEAI
therapy is contraindicated. It is also a manner that is different from that
indicated for use as monotherapy for of the taxanes.23 Furthermore, their
the treatment of metastatic or locally susceptibility to multidrug-resistance
mechanisms also distinguishes them
from the taxanes.24 Studies with ixabepilone have shown that it demonstrates antineoplastic activity against
tumors that are naturally insensitive
to paclitaxel or have developed resistance to paclitaxel, both in preclinical
models22 and a Phase I clinical trial
in patients with metastatic breast
cancer.25
Pharmacokinetics
Ixabepilone exhibits linear pharmacokinetics over the dosage range
of 15–57 mg/m2.26 After administration, ixabepilone is rapidly distributed across a large volume (>1000 L)
at steady state, indicative of extensive
tissue binding (67–77% to serum
proteins) and uptake.26
Ixabepilone is primarily eliminated by the liver. Over 30 metabolites
of ixabepilone are produced by oxidative metabolism via cytochrome
P-450 (CYP) isoenzyme 3A4, none of
which have demonstrated clinically
Figure 1. Mechanism of action of ixabepilone. Ixabepilone binds to the b-tubulin subunits of microtubules to induce microtubule polymerization and stabilization, which lead to G2-M arrest and the induction of apoptosis. Illustration by Taina Litwak, CMI.
0OLYMERIZEDTUBULIN
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Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
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RESULTINGINCELLDEATH
clinical review Ixabepilone
relevant cytotoxic activity.23 Sixtyfive percent of an intravenous dose
of 14[C]-ixabepilone is eliminated in
the feces and 21% eliminated in the
urine.26
A study of patients with mild-tosevere hepatic impairment (n = 56),
as defined by bilirubin and aspartate
aminotransferase (AST) levels, revealed that dosage modifications are
required in this patient population.
Compared with patients with normal
hepatic function (n = 17), the area
under the concentration-versustime curve (AUC0–∞) for ixabepilone
increased by 22% in patients with
either bilirubin levels of >1–1.5 times
the upper limit of normal (ULN)
or an AST level above the ULN but
with bilirubin levels of <1.5 times
the ULN. The AUC0–∞ increased by
30% in patients with bilirubin levels
of >1.5–3 times the ULN and by 81%
in patients with bilirubin levels of >3
times the ULN, irrespective of the
AST level.27
Ixabepilone has a terminal elimination half-life of approximately 52
hours.23 With the approved dosage
regimen, plasma accumulation is
not expected because the length of
the administration cycle is approximately 10 times that of the terminal
elimination half-life.26
Clinical efficacy in metastatic
breast cancer
The clinical efficacy of ixabepilone, administered as either monotherapy or in combination with
capecitabine, has been demonstrated
across the spectrum of patients with
advanced breast cancer and is described below.
Anthracycline and taxanerefractor y disease. Currently,
capecitabine represents the standard
reference treatment for patients with
metastatic breast cancer in whom
anthracyclines and taxanes are no
longer effective.28-31 The combination
of ixabepilone and capecitabine was
considered initially in these patients
because of the different mechanisms
of action and the demonstrated
synergy of the two drugs in human
xenografts.32 Therefore, the combination was investigated in an openlabel, Phase I/II study in 62 patients
with metastatic breast cancer who
were previously treated with a taxane and an anthracycline.33,34 In this
study, the combination of ixabepilone plus capecitabine demonstrated
synergistic antitumor activity and a
manageable safety profile. In patients
for whom response could be evaluated, the objective response rate was
30%. It was concluded that the dosage used in further studies should be
ixabepilone 40 mg/m2 administered
as a three-hour infusion on day 1 of
each 21-day cycle with capecitabine
1000 mg/m 2 administered orally
twice daily on days 1–14 of every
21-day cycle.
A randomized Phase III trial of
patients who had measurable locally advanced or metastatic breast
cancer and were previously treated
with or resistant to anthracyclines
and also resistant to taxanes demonstrated that a combination of
ixabepilone and capecitabine at the
dosages determined from the previous trial had superior clinical efficacy
to capecitabine alone (1250 mg/m2
twice daily on days 1–14 every 21
days). 19 Patients enrolled in this
large, multicenter, international trial
met predefined resistance criteria
(Table 1). Of the 752 randomized
patients, >90% had received previous chemotherapy for metastatic
breast cancer (48% had one previous
regimen for metastatic disease, 39%
had two previous regimens, and 5%
had three previous regimens). All
patients were resistant to taxanes.
Approximately 90% of patients had
two or more metastatic sites, over
80% had visceral metastases, approximately 25% had triple-negative
(estrogen receptor [ER]-negative,
progesterone receptor [PR]-negative,
and human epidermal growth factor
receptor 2 [HER2]-negative) tumors,
and 36% had progressive disease as
their best response with previous
taxane therapy. After a median of
four (capecitabine alone) or five (ixabepilone plus capecitabine) cycles
of treatment, median progressionfree survival (PFS)—the primary
endpoint—was significantly greater
with the combination regimen than
with capecitabine alone (5.8 months
versus 4.2 months, respectively;
hazard ratio [HR], 0.75; 95% Confidence Interval [CI], 0.64–0.88%; p
= 0.0003), as was the independent
radiology review-assessed response
rate (35% versus 14%, p < 0.0001).
Stable disease was reported for
41% and 46% of patients receiving
ixabepilone with capecitabine and
capecitabine monotherapy, respectively. Significant benefit with the
Table 1.
Criteria Used To Define Resistance to Anthracyclines and Taxanes
for Patients in Phase III Trial of Ixabepilone
Treatment
Definition of Resistance
Anthracyclines
Tumor progression of ≤3 mo after the last dose in a
metastatic setting
Recurrence of ≤6 mo after the last dose in a neoadjuvant or
adjuvant setting
Received minimum cumulative doses of doxorubicin (240
mg/m2) or epirubicin (360 mg/m2)
Tumor progression of ≤4 mo after the last dose in a
metastatic setting
Recurrence of ≤12 mo after the last dose in a neoadjuvant
or adjuvant setting
Taxanes
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
2019
clinical review Ixabepilone
combination regimen was consistently maintained across most
predefined subgroups of patients,
including those with ER/PR/HER2negative status and HER2-positive
status, and those with visceral
metastases.19 Overall survival data
from this study are pending.
A second randomized, Phase III
trial comparing ixabepilone plus
capecitabine with capecitabine alone
in patients with advanced breast cancer previously treated with anthracyclines and taxanes has completed
enrollment.35 Patients in this study
did not receive more than two previous chemotherapy regimens, and
those who did not receive treatment
for metastatic disease must have relapsed within one year of treatment.
The primary outcome measure in
this trial was overall survival. The
secondary outcome measured the
quality of life and time to progression, objective response rate, and
duration of response in patients with
measurable disease.
An earlier multicenter, single-arm,
Phase II study investigated ixabepilone monotherapy (40 mg/m2 as
a three-hour infusion every three
weeks) administered to 49 patients
with metastatic breast cancer who experienced disease progression while
receiving taxane therapy or within
4 months of it (6 months if taxanes
were used only in the adjuvant setting) and in patients who were
given a taxane as their last regimen.18
Previous therapy also included an
anthracycline-based regimen. An
objective response rate of 12% (all
partial responses) and a median time
to disease progression of 2.2 months
(95% CI, 1.4–3.2 months) after ixabepilone therapy were observed.18
The median survival time in these
patients (86% of whom had received
two or more previous chemotherapy
regimens and 84% had visceral disease) was 7.9 months. Stable disease
was observed in 41% of patients.
Anthracycline, taxane, and
capecitabine-refractory disease. In
2020
a multicenter, single-arm, Phase II
study, ixabepilone monotherapy (40
mg/m2 as a three-hour infusion every
three weeks) was investigated in 126
patients with metastatic breast cancer resistant to previous therapy with
anthracyclines, taxanes, and capecitabine.15 Of the 126 patients enrolled,
88% had received two or more previous chemotherapy regimens in the
metastatic setting, 64% had three
or more metastatic sites, 77% had
visceral disease, and 33% had triplenegative tumors; 113 patients were
assessable for response to ixabepilone
treatment. An investigator-assessed
objective response rate for all treated
patients was 18.3% (95% CI, 11.9–
26.1%), and an independent radiology facility-assessed response rate
of 11.5% (95% CI, 6.3–18.9%) was
observed.15 Fifty percent of patients
in the study had stable disease during
ixabepilone treatment. The median
PFS was 3.1 months (95% CI 2.7–4.2
months), and the median duration of
response was 5.7 months.15
Taxane-naive disease. A singlearm, Phase II study evaluated the
efficacy of first-line ixabepilone
monotherapy (40 or 50 mg/m2 i.v.
infusion over one or three hours every three weeks) in 65 patients with
metastatic breast cancer who had
received one (92%) or two (8%) previous anthracycline-based adjuvant
regimens.16 Although the patients
were permitted to have previously
received a taxane as part of an adjuvant regimen, provided one or more
years had elapsed since the completion of treatment, the majority of
patients (83%) had not received a
taxane before enrollment. The objective response rate with ixabepilone
monotherapy in this patient group
was 41.5% (95% CI, 29.4–54.4%),
and the median duration of response
was 8.2 months (95% CI, 5.7–10.2
months). Thirty-five percent of patients had stable disease during the
study, and the median overall survival time was 22 months (95% CI,
15.6–27.0 months).
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
Another single-arm, Phase II
study was conducted in 23 patients
with metastatic breast cancer who
had not received a taxane but were
permitted to have received other previous therapy (e.g., an anthracycline,
capecitabine, or both), which had
been received by 70% of patients.17
Ixabepilone was administered at a
dosage of 6 mg/m2 by i.v. infusion
over one hour on five consecutive days every three weeks. After a
median of 8 cycles of ixabepilone
treatment (range, 2–22 cycles), an
objective response rate of 57% (95%
CI, 34.5–76.8%) was achieved; 13
patients (57%) had partial responses,
and 6 (26%) had stable disease. The
median time to progression and
response duration were 5.5 and 5.6
months, respectively.
First-line therapy. A portion of
the patients included in the clinical
trials described received no previous chemotherapy or anthracyclines
and taxanes in the adjuvant setting
and were therefore treated with
ixabepilone as first-line therapy in
the metastatic setting. This included
all 65 patients in the study who had
previously been treated with an adjuvant anthracycline regimen,16 7 of
23 taxane-naive patients who had not
received any previous chemotherapy
and 9 of the 23 who had received
adjuvant anthracycline therapy,17
and 26 of 375 patients (7%) who
received ixabepilone plus capeci­
tabine in the randomized, Phase III
study in taxane-resistant patients
who had not received any previous
chemotherapy. 19 Higher response
rates were achieved for ixabepilone
administered as first-line therapy in
these studies in comparison with its
use in patients receiving the drug as
second-line or third-line therapy. In
a subset of 55 patients treated in the
randomized, Phase III study conducted by Thomas et al.,19 ixabepilone plus capecitabine maintained
superiority over capecitabine alone
when used as first-line therapy with
regard to median PFS (7.0 months
clinical review Ixabepilone
versus 2.1 months; HR, 0.46; 95% CI,
0.25–0.85; p = 0.0109) and objective
response rate (44% versus 10%, p =
0.0054).36 The median PFS time and
objective response rate for first-line
ixabepilone plus capecitabine were
greater than for the corresponding
results for the overall population
(5.8 months and 35%, respectively),
93% of whom had received at least
one previous therapy for metastatic
disease.19
Combination therapy with targeted agents. Trials investigating
ixabepilone in combination with
targeted therapy are planned or ongoing. These include a randomized,
Phase II trial comparing ixabepilone
plus trastuzumab with docetaxel plus
trastuzumab in patients with HER2positive locally advanced disease,
metastatic disease, or both,37 and a
Phase I trial of ixabepilone plus lapatinib (a dual HER1 and HER2 inhibitor) in patients with HER2-positive
metastatic breast cancer.38
A randomized, Phase II, threegroup trial comparing two schedules
of ixabepilone plus bevacizumab
with paclitaxel plus bevacizumab as
first-line therapy in patients with locally recurrent or metastatic disease
is ongoing.39 Results from these trials
will better define the role of ixabepilone in combination with targeted
therapies.
Clinical efficacy in different patient subgroups. In the clinical studies of ixabepilone, patients were enrolled regardless of their HER2 status
and hormone receptor status.15,16,18,19
Patients with HER2-positive tumors
were required to have previously
discontinued trastuzumab. In the
Phase III trial comparing ixabepilone
plus capecitabine with capecitabine
alone in patients with metastatic
disease resistant to taxanes, analysis
of PFS in prespecified patient subsets
revealed that the clinical benefits of
ixabepilone plus capecitabine were
achieved in the majority of patient
subgroups.19 There were significant
differences favoring the combination
regimen over capecitabine alone in
relation to receptor status (notably for HER2-positive and ER/PR/
HER2-negative tumors); previous
chemotherapy regimens for metastatic disease (anthracycline resistant
and taxane resistant); and patient
characteristics, including age (greater
or less than 50 years), Karnofsky performance status, and presence of visceral disease. No data were available
for patients in relation to ethnicity or
the presence of liver dysfunction.
Clinical trials of ixabepilone have
included patients with poor prognosis, patients with triple-negative
tumors, and patients with extensive
and aggressive tumor burden. In
three Phase II and III clinical trials
of ixabepilone, patients with triplenegative tumors accounted for approximately 25–35% of the patients
enrolled.15,18,19 Most of the patients
enrolled in the Phase II and III studies of ixabepilone had an extensive
and aggressive tumor burden, as
evidenced by the high percentages of
patients with visceral metastases and
multiple involved disease sites.15-19
The clinical activity of ixabepilone
was evident in both of these groups
of patients.15-19
Complete pathological response
(pCR) rate was documented in a
study in which up to four cycles of
ixabepilone (40 mg/m2 infused over
three hours every three weeks) were
administered as primary systemic
(neoadjuvant) therapy to patients
with invasive breast cancer (stages
IIA–IIIB) before undergoing surgery
(n = 164).40 A total of 29 patients
achieved pCR, and of those, 17 (11%)
also had pCR in the axillary lymph
nodes. This response rate compares
favorably with other monotherapy
regimens in this population.
Safety
Ixabepilone demonstrated a predictable and manageable safety
profile when used at the dosage and
administration schedule (40 mg/
m2 i.v. over three hours every three
weeks) during clinical trials, and its
toxicities do not appear to overlap
with those of capecitabine.15,16,18,19
In Phase II and III clinical trials,
the most clinically relevant adverse
events associated with ixabepilone
were myelosuppression (primarily
neutropenia) and peripheral neuropathy. Table 2 provides a summary of adverse events reported in
Phase II clinical trials of ixabepilone
monotherapy.15-18
In the Phase III trial, grade 3 or
4 neutropenia occurred in 68% of
patients receiving ixabepilone plus
capecitabine compared with 11% of
patients receiving capecitabine alone.
Febrile neutropenia was experienced
by 4% of patients with the combination versus less than 1% with capeci­
tabine alone. Grade 3 or 4 (i.e., severe
or disabling) neuropathy occurred
in 23% of patients receiving the
combination of ixabepilone plus
capecitabine versus 0% with capecitabine alone.19 The neuropathy was
primarily sensory and cumulative but
was reversible with a median time to
resolution of six weeks.19 Grade 3 or
4 hand–foot syndrome occurred with
equal frequency in the two groups
(18% versus 17%, respectively), as
did grade 3 or 4 gastrointestinal
disturbances such as nausea (3%
versus 2%), vomiting (4% versus
2%), and diarrhea (6% versus 9%).
These findings suggest that ixabepilone does not increase the hand–
foot syndrome and gastrointestinal
toxicity associated with capecitabine
and, similarly, that capecitabine
does not exacerbate neuropathy associated with ixabepilone.
Neutropenia. Myelosuppression
with ixabepilone primarily manifests as neutropenia. Grade 3 or 4
neutropenia occurred in 22–58% of
patients in the Phase II clinical trials
and in 68% of patients who received
the combination of ixabepilone and
capecitabine in the Phase III trial.19
Neutropenia is generally manageable
by delaying ixabepilone administration and dosage reduction (Table
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
2021
clinical review Ixabepilone
3). Although some patients have
required support with hematopoietic
growth factors (e.g., filgrastim), such
treatment was not mandated in the
protocols of the clinical trials reporting these events and management
was at the discretion of the treating
physician.17,18
Table 2.
Treatment-Related Adverse Events Reported in 10% or More of
Patients in Phase II Clinical Trials of Ixabepilone Monotherapy in
Metastatic Breast Cancera
Adverse Eventb
Nonhematologic toxicity
Peripheral sensory neuropathy
All
Grade 3 or 4d
Fatigue/asthenia
All
Grade 3 or 4
Myalgia/arthralgia
Alopecia
Nausea
Stomatitis/mucositis/pharyngitis
Vomiting
Diarrhea
Rash
Musculoskeletal pain
Anorexia
Constipation
Nail changes
Fever
Abdominal pain/cramping
Headache
Neuropathic pain
Pain, other
Infection without neutropenia
Infection with febrile neutropenia
Motor neuropathy
Taste disturbance/dysgeusia
Hematologic toxicity
Neutropenia
All
Grade 3 or 4
Leukopenia
All
Grade 3 or 4
Anemia
All
Grade 3 or 4
Thrombocytopenia
All
Grade 3 or 4
Ref. 15
(n = 126)c
No. (%) Pts
Ref. 16
Ref. 17
(n = 65)
(n = 23)
60
14
46 (71)
12 (52)
31 (63)
13 (20) 0 6 (12)
50
44 (68)
18 (78)
37 (76)
13 4 (6) 3 (13)
13 (27)
49
63 (97) 7 (30)
41 (84)
48
60 (92)
20 (87)
21 (43)
42
35 (54)
14 (61)
28 (57)
29
21 (32)
NR
14 (28)
29
17 (26) 9 (39)
20 (41)
22
19 (29)
11 (48)
15 (31)
NR
14 (22)
NR 6 (12)
20
NR
NR
NR
19
12 (18)
NR 9 (18)
16
13 (20)
13 (56)
10 (20)
9
11 (17)
13 (56) 4 (8)
NR 9 (14)
NR 8 (16)
13 5 (8)
NR 5 (10)
11 9 (14)
NR
NR
NR 8 (12)
NR 4 (8)
8 9 (14)
NR
32 (65)
NR 9 (14)
NR 6 (12)
NR 4 (6) 0 3 (6)
10 4 (6) 2 (9)
NR
6 7 (11)
15 (65)
NR
79
54
57 (89)
20 (87)
37 (58) 5 (22)
90
49
60 (92)
32 (50)
84
60 (92)
19 (83) 3 (6)
8 2 (3) 0 2 (4)
44
26 (40)
12 (52)
8 0 1 (4)
b
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
NR
53c
NR 3 (6)
NR 1 (2)
NR = not reported.
All toxicity grades unless otherwise noted.
c
This report did not include number of patients corresponding to the percentages listed.
d
Based on National Cancer Institute Common Toxicity Criteria.
a
2022
Ref. 18
(n = 49)
NR
NR
The incidence of febrile neutropenia reported in Phase II and III trials
has been low (Table 2).16,18,19
Peripheral sensory neuropathy.
Neuropathy is a characteristic adverse
event of microtubule-stabilizing
agents.42 The peripheral sensory neuropathy reported in clinical trials of
ixabepilone has primarily been mild
to moderate in severity and mostly
reversible within an acceptable time
frame (median time to resolution,
six weeks).19 Grade 3 or 4 neuropathy
occurred in 0–20% of patients treated with ixabepilone monotherapy
in Phase II trials (Table 2) and 23%
of patients treated with ixabepilone
plus capecitabine in the Phase III
trial.19 It has been postulated that less
peripheral neuropathy may occur
with ixabepilone when used as firstline therapy in taxane-naive patients,
but this remains to be confirmed.39
There are no proven treatments
for peripheral neuropathy associated with microtubule-stabilizing
agents.41 It is not possible to predict
the occurrence of this adverse event;
therefore, health care team members who care for patients receiving
ixabepilone should be aware of the
onset of symptoms (i.e., burning
sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, and
neuropathic pain) and take appropriate action, including delayed
administration of the next dose and
dosage reduction. Treatment should
not be restarted until neuropathy has
returned to baseline or is a grade 1 or
lower in severity.
Management of other adverse
events. As the ixabepilone infusion
solution contains Cremophor EL,
which may cause hypersensitivity
reactions in some patients, premedication with antihistamines (i.e., both
histamine H 1 -receptor and H 2 receptor antagonists) is necessary to
reduce the risk of such reactions.16
However, in contrast to premedication for taxanes,42,43 corticosteroid
premedication is not required with
ixabepilone unless the patient has
clinical review Ixabepilone
had a hypersensitivity reaction to
a previous administration of the
drug.
In addition to dosage adjustments and delay in administration,
supportive care interventions may
be required for specific adverse
events associated with ixabepilone
administered with or without capeci­
tabine.42,44 Interventions that may
be considered include the following:
analgesics for myalgia and arthralgia, anesthetic mouthwashes for the
treatment of stomatitis or mucositis,
antiemetics for nausea and vomiting,
emollients for hand–foot syndrome
due to capecitabine in combined
regimens, and antidiarrheals and
fluid replacement for diarrhea (prophylactic antibiotics may be indicated for patients with diarrhea and
neutropenia).
Dosage and administration
Multiple doses and schedules of
ixabepilone were evaluated during
the clinical development of the drug.8
Initially, dosages as high as 50 mg/
m2 every three weeks were evaluated;
however, the severity and extent of
the neuropathy forced a lowering
of the dosage for further evaluation to the current recommended
dosage.8,34 Other dosage schedules
have also been evaluated, including ixabepilone 6 mg/m2 daily for
five days every three weeks showing
activity and tolerability in women
who never received taxanes before
taking ixabepilone.17 However, the
ixabepilone dosage recommended
by the manufacturer is 40 mg/m2
administered i.v. over three hours every three weeks. Dosages for patients
with a body surface area greater than
2.2 m2 should be calculated based on
2.2 m2.26
Dosage adjustments for toxicities. If toxicities are detected during
treatment, therapy should be delayed
to allow recovery.26 Dosage adjustment guidelines for ixabepilone
monotherapy and combination
therapy are shown in Table 3.
Dosage adjustments at the start of
a cycle should be based on toxicity
assessments from the preceding cycle.
Patients should not begin a new cycle
of treatment unless the neutrophil
count is ≥1,500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and
nonhematologic toxicities have resolved or improved to grade 1 (mild).
If toxicities recur, an additional 20%
dose reduction is required.26
Dosage adjustments in patients
with hepatic impairment. Patients
with hepatic impairment should
receive ixabepilone based on the
guidelines in Table 3. In the case of
ixabepilone monotherapy, patients
with moderate hepatic impairment
should be started at 20 mg/m2. The
dosage in subsequent cycles may be
adjusted upward to, but not exceeding, 30 mg/m2 if tolerated. Use of
ixabepilone is not recommended in
patients with AST or alanine aminotransferase (ALT) levels more than
10 times the ULN or bilirubin levels
Table 3.
Ixabepilone Dosage Adjustments for Toxicities and in the Presence
of Hepatic Impairment or Coadministration of Other Drugs26
Condition
Nonhematologic toxicitya
Grade 2 neuropathy (moderate) lasting
≥7 days
Grade 3 neuropathy (severe) lasting
<7 days
Grade 3 neuropathy (severe) lasting
≥7 days or disabling neuropathy
Any grade 3 toxicity (severe)
Transient grade 3 arthralgia/myalgia
or fatigue
Grade 3 hand-foot syndrome
Any grade 4 toxicity (disabling)
Hematologic toxicity
Neutrophils <500 cells/mm3 for ≥7 days
Febrile neutropenia
Platelets <25,000/mm3 or platelets
<50,000/mm3 with bleeding
Hepatic impairment
Ixabepilone monotherapy
AST and ALT conc. ≤2.5 × ULN and
bilirubin conc. ≤1 × ULN
AST and ALT conc. ≤10 × ULN and
bilirubin conc. ≤1.5 × ULN
AST and ALT conc. ≤10 × ULN and
bilirubin conc. >1.5 × ULN – ≤3 × ULN
Ixabepilone and capecitabine combination
therapy
AST or ALT conc. >2.5 × ULN or bilirubin
conc. >1 × ULN
Coadministration with other drugs
Potent inhibitors of CYP3A4b
Suggested Ixabepilone Dosage
Adjustment
Decrease dose by 20%
Decrease dose by 20%
Discontinue treatment
Decrease dose by 20%
No change in dose required
No change in dose required
Discontinue treatment
Decrease dose by 20%
Decrease dose by 20%
Decrease dose by 20%
Recommended dose: 40 mg/m2
Recommended dose: 32 mg/m2
Recommended dose: 20–30 mg/m2
Contraindicated
Starting dose: 20 mg/m2
Toxicities graded in accordance with the National Cancer Institute Common Toxicity Criteria for adverse
events. ALT = alanine aminotransferase, AST = aspartate aminotransferase, CYP3A4 = cytochrome P-450
isoenzyme 3A4, ULN = upper limit of normal.
b
Inhibits oxidative metabolism of ixabepilone and may significantly increase exposure to the drug. Examples
of potent CYP3A4 inhibitors include ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, and voriconazole.
a
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
2023
clinical review Ixabepilone
more than 3 times the ULN. Limited
data are available for patients with
baseline AST or ALT levels more
than 5 times the ULN. Caution
should be used when treating these
patients.26
Patients receiving combination
treatment who have AST and ALT
levels less than or equal to 2.5 times
the ULN and bilirubin levels less
than or equal to 1 time the ULN may
receive the standard dose of ixabepilone (40 mg/m2).26
Dosage adjustments in patients
receiving CYP3A4 isoenzyme inhibitors. The use of concomitant
potent CYP3A4 inhibitors (e.g.,
ketoconazole) should be avoided.
Grapefruit juice may also increase
plasma concentrations of ixabepilone and should also be avoided.
Guidelines to follow in the event that
a potent CYP3A4 inhibitor must be
coadministered are given in Table 3.
If a potent CYP3A4 inhibitor is discontinued, approximately one week
of washout should be allowed before
escalating the ixabepilone dose.26 The
effect of mild or moderate CYP3A4
inhibitors (e.g., erythromycin, fluconazole, verapamil) on ixabepilone
pharmacokinetics has not been
studied; thus, caution should be used
when mild or moderate CYP3A4 inhibitors are administered in patients
receiving ixabepilone.
Premedication. To minimize the
risk of a hypersensitivity reaction,
all patients must be premedicated
approximately one hour before the
infusion of ixabepilone with an H1receptor antagonist (e.g., diphenhydramine hydrochloride 50 mg orally)
and an H2-receptor antagonist (e.g.,
ranitidine 150–300 mg orally).26
Patients who have had a previous
hypersensitivity reaction to ixabepilone require corticosteroid premedication (e.g., dexamethasone phosphate 20 mg i.v. 30 minutes before
infusion or dexamethasone 20 mg
orally 60 minutes before infusion)
in addition to pretreatment with H1and H2-antagonists.26
2024
Preparation and administration.
Ixabepilone is supplied as two vials,
one containing ixabepilone powder
and another containing mandatory
diluent. Only the supplied diluent
must be used for constituting
ixabepilone for injection. To minimize the risk of dermal exposure,
impervious gloves should be worn
when handling vials containing
ixabepilone.26
Both vials must be stored under
refrigeration at 2–8 °C (36–46 °F) in
the original package to protect them
from light. Before reconstitution,
the vials should be placed at room
temperature for 30 minutes. When
the diluent is first removed from
the refrigerator, a white precipitate
may be seen but will dissolve to form
a clear solution once the diluent
warms to room temperature. After
reconstitution, the concentration of
ixabepilone is 2 mg/mL. The solution
may be stored in the vial, not the syringe, for a maximum of one hour at
room temperature and room lighting
conditions.26
Before administration, the solution must be further diluted only
with Lactated Ringer’s Injection,
USP, supplied in di(2-ethylhexyl)
phthalate-free bags. This diluent is
specified because it has a pH range of
6.0–7.5, which is required to maintain ixabepilone’s stability. Other
diluents should not be used. The
final ixabepilone concentration for
infusion must be 0.2–0.6 mg/mL.
This solution is stable at room temperature and light for a maximum of
six hours. Administration of diluted
ixabepilone must therefore be completed within this period.26
Role in therapy
Ixabepilone is the first semisynthetic epothilone B analog with
labeling approved by FDA and represents an important addition to the
current armamentarium of drugs
for the treatment of metastatic and
locally advanced breast cancer. In patients with metastatic breast cancer,
Am J Health-Syst Pharm—Vol 65 Nov 1, 2008
ixabepilone has demonstrated a lack
of complete cross-resistance with
other drugs used to treat advanced
breast cancer.15,18,19 Clinically meaningful benefits have been achieved
with ixabepilone monotherapy in
patients in whom anthracyclines,
taxanes, and capecitabine all failed to
provide a response.15 The synergistic
activity of a combination of ixabepilone and capecitabine has been confirmed in a Phase III trial in patients
who had previously failed on taxanes
and anthracyclines; a combination
of ixabepilone and capecitabine was
significantly more effective in producing an objective response and in
prolonging PFS than capecitabine
alone.19 At the dosage and administration schedule recommended by
the manufacturer in patients meeting
the eligibility criteria for treatment,
the therapeutic ratio of ixabepilone
is generally favorable, and adverse
events are generally manageable and
reversible.
Ixabepilone has demonstrated
activity in HER2-positive and HER2negative patients. In the Phase III
trial, 9% of patients in the ixabepilone plus capecitabine group had received previous trastuzumab therapy
and 16% were HER2-positive.19 For
patients with advanced breast cancer
who have progressed following trastuzumab treatment, a combination
of lapatinib plus capecitabine is a
viable treatment option. The physician can determine whether a patient
with resistance is still a candidate for
anti-HER2 therapy. However, clinical
trials are underway to investigate the
potential of combining ixabepilone
plus trastuzumab or lapatinib for the
treatment of breast cancer.
Chemotherapy remains the treatment of choice for patients with
hormone-unresponsive or hormoneresistant metastatic breast cancer,
HER2-negative tumors, extensive
visceral disease, or life-threatening
and rapidly progressing disease. 3
The profiles of patients enrolled in
completed clinical trials that have
clinical review Ixabepilone
included patients previously treated
with anthracyclines and taxanes
across multiple lines of therapy for
metastatic breast cancer provide
guidance on the indications for the
use of ixabepilone and may help select patients who will likely benefit
from ixabepilone therapy.39 On the
basis of the results of these trials, appropriate indications for ixabepilone
can be suggested. These indications
include first-line, second-line, thirdline, or higher therapies in patients
with metastatic breast cancer previously treated with or resistant to anthracycline therapy, taxane therapy,
or both18,19,35; first-line therapy in
patients with metastatic breast cancer previously treated with anthracyclines or taxanes in the adjuvant
setting16; and third- or fourth-line
therapy in patients with metastatic
disease previously treated with anthracyclines, taxanes, and capeci­
tabine. 15 In addition, ixabepilone
has been evaluated in patients whose
disease progressed during treatment with anthracyclines because
of resistance (progressive disease) or
patients who reached the maximum
cumulative dose of anthracyclines.
Patients in these categories have been
evaluated in a clinical trial that compared ixabepilone plus capecitabine
with capecitabine alone.34
Significant efforts are ongoing to
identify predictive and prognostic
biomarkers to identify patients who
are most likely to respond to ixabepilone treatment. Although initial
results suggest that certain biomarkers (e.g., ER status, expression of the
microtubule-associated protein tau)
and gene signatures are predictive of
responsiveness to ixabepilone; however, these findings have not been
fully validated.40,45
Some patients may be at an increased risk for adverse events and
may not be candidates for therapy
with ixabepilone or may require
treatment using a reduced dosage
of ixabepilone. These include patients with abnormal liver function
tests (AST or ALT levels more than
2.5 times the ULN or bilirubin levels
more than 1 time the ULN), who
may be at increased risk of treatmentrelated mortality.19 In these patients,
the dosage of ixabepilone given as
monotherapy should be reduced
according to the degree of hepatic
impairment. Use of ixabepilone as
monotherapy is not recommended in
patients with AST or ALT levels more
than 10 times the ULN or bilirubin
levels more than 3 times the ULN,
and the combination of ixabepilone
with capecitabine is contraindicated
in patients with AST or ALT levels
more than 2.5 times the ULN or
bilirubin levels more than 1 time the
ULN.
The use of ixabepilone is also not
recommended in patients with a neutrophil count of less than 1,500 cells/
mm3, a platelet count of less than
100,000/mm3, or preexisting peripheral neuropathy of grade 2 or higher.
Patients with neuropathy of grade 2
or higher were not eligible for enrollment in clinical trials of ixabepilone.
Ixabepilone should be administered
with caution to patients with coexisting medical conditions associated
with peripheral neuropathy such as
diabetes mellitus or a substantial history of alcohol use, who also appear
to be prone to neurotoxicity with
paclitaxel.39,46 Patients with diabetes
mellitus treated with ixabepilone
may be at increased risk of severe
neuropathy.
Caution is also warranted in patients receiving treatment with other
drugs that are potent inhibitors of
CYP3A4 isoenzymes (i.e., ketoconazole, itraconazole, clarithromycin,
atazanavir, nefazodone, saquinavir,
telithromycin, ritonavir, amprenavir,
indinavir, nelfinavir, delavirdine, or
voriconazole).26 Since oxidative metabolism by CYP3A4 and CYP3A5
appears to be a prominent route
of biotransformation of ixabepilone, concomitant administration of
CYP3A4 inhibitors may significantly
increase exposure to the drug. In
such cases, the starting dose should
be reduced. In addition, use of ixabepilone is not recommended in
patients with a history of hypersensitivity to drugs formulated with
Cremophor EL because ixabepilone
infusion solution is formulated with
this compound.
Ixabepilone is indicated in combination with capecitabine for the
treatment of metastatic or locally
advanced breast cancer in patients
refractory to anthracycline and taxane therapy, and as monotherapy
for the treatment of metastatic or
locally advanced breast cancer in
patients after failure of an anthracycline, a taxane, and capecitabine.
As well as demonstrating benefits in
anthracycline- and taxane-pretreated
patients, ixabepilone appears to be
effective across all lines of therapy
and in different subtypes of breast
cancer patients with extensive or aggressive disease. Future studies will
further define the role of ixabepilone
in relation to the taxanes and other
drugs used in the treatment of breast
cancer.
Conclusion
Ixabepilone, the first drug in a
new class of microtubule-stabilizing
agents called epothilones, offers a
new treatment option for patients
with metastatic or locally advanced
breast cancer who are refractory to
standard chemotherapy.
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