symposium article
Annals of Oncology 18 (Supplement 5): v9–v15, 2007
doi:10.1093/annonc/mdm173
Novel tubulin-targeting agents: anticancer activity
and pharmacologic profile of epothilones and
related analogues
P. Fumoleau*, B. Coudert, N. Isambert & E. Ferrant
Medical Oncology Department, Centre Georges-Franc
xois Leclerc, Dijon, France
Background: Epothilones are 16-member ring macrolides with antimicrotubule activity that share a similar
introduction
Epothilones are naturally occurring macrolides that constitute
a novel class of antimicrotubule-targeting agents. Although the
epothilones share a similar mechanism of action to the taxanes,
they exhibit more potent antiproliferative activity in various
tumor cell lines, particularly in cases of taxane resistance [1–3].
The epothilones have also demonstrated high levels of
antitumor activity in vitro against tumor cell lines that are
naturally resistant to paclitaxel (Taxol, Bristol-Myers Squibb,
Princeton, NJ) or acquire resistance to paclitaxel by specific
point mutations in the b-tubulin gene [1, 4]. Recently, several
derivatives of naturally occurring epothilones have been
designed to optimize in vivo antitumor efficacy, improve
pharmacologic properties, and enhance the ability to overcome
multiple mechanisms of drug resistance.
Currently, epothilone B (patupilone; EPO960) and its four
synthetic derivatives ixabepilone (aza-epothilone B; BMS247550), BMS-310705 (a water-soluble analogue of epothilone
B), ZK-EPO (ZK-219477), 20-desmethyl-20-methylsulfanyl
epothilone B (ABJ879), and epothilone D (desoxy-epothilone
B; KOS-862) and its derivative KOS-1584 are under clinical
*Correspondence to: Dr P. Fumoleau, Centre Georges-Franc
xois Leclerc, 1, Rue
Professeur Marion, BP 77 908 21034, Dijon Cedex, France. Tel: +33-3-80-73-75-06;
Fax: +33-3-80-73-77-16; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
investigation for the treatment of cancer. This review briefly
summarizes the current understanding of the mechanism of
action and data from preclinical and phase I clinical studies of
the epothilones.
chemical structure
The naturally occurring epothilones A and B were isolated
from the myxobacterium Sorangium cellulosum more than
a decade ago [5]. Subsequently, numerous natural epothilone
variants have been described. The epothilones are 16-member
ring macrolides that are combined with a methylthiazole
side chain (Figure 1). Naturally occurring epothilones are
classified as either epoxides (epothilones A, B, E, and F) or
olefins (epothilones C and D) based on the presence or
absence of an epoxide group in the C-12 to C-13 position of
the macrolide ring.
Modifications to the chemical structure of the macrolide ring
have been shown to alter the biologic activity and
pharmacologic properties of the epothilones [6, 7]. Secondand third-generation derivatives of epothilone B have been
synthesized that possess greater antitumor potency and
enhanced water solubility compared with the original natural
products. The second-generation semisynthetic epothilone B
derivative ixabepilone was synthesized by the substitution of an
azide group for oxygen at position 16 of the macrolide ring.
symposium
article
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mechanism of action to the taxanes but have demonstrated potent antiproliferative activity in several different
multidrug-resistant and paclitaxel-resistant tumor cell lines in vitro and in vivo.
Design: This review summarizes data from preclinical and phase I clinical studies of epothilone B (patupilone;
EPO960) and epothilone D (KOS-862) and their second-generation (ixabepilone, BMS-310705, KOS-1584) and
third-generation (ZK-EPO, ABJ-879) derivatives. Data were identified by searches of PubMed and the Proceedings
of the American Society of Clinical Oncology annual meetings from 2000 to 2006.
Results: Epothilones demonstrate a linear dose-dependent pharmacokinetic profile, are well tolerated, and exhibit
antitumor activity in a variety of tumor types in phase I studies of patients with cancer. Although similar in chemical
structure, the epothilones demonstrate a striking difference in toxicity profile in phase I studies. Diarrhea is the doselimiting toxicity (DLT) associated with patupilone, whereas neurotoxicity and neutropenia are the DLTs most commonly
encountered with other epothilones. Consistent with preclinical data, partial responses were observed with patupilone
and ixabepilone in patients with breast cancer previously treated with taxanes.
Conclusion: The epothilones demonstrate promising antitumor activity in a broad spectrum of taxane-sensitive
and -refractory tumors at doses and schedules associated with tolerable side-effects.
Key words: epothilone, mechanism of action, phase I study, preclinical, tubulin-targeting agents
symposium article
Annals of Oncology
Ixabepilone possesses increased water solubility and plasma
stability compared with epothilones B and D, but it exhibits
one-fold reduction in cytotoxicity compared with epothilone B
[6]. Additionally, a second semisynthetic derivative of
epothilone B, BMS-310705, which was created by the
substitution of the hydroxyl group with an amino group at
position C-21 of the methylthiazole side chain, is 10-fold
more water soluble than epothilone B and is more cytotoxic
than epothilone D in human tumor cell lines [2]. This
improved water solubility allows for the development of
a clinical formulation that does not contain Cremophor-EL
(BASF, Ludwigshafen, Germany). Collaboration between
research groups has led to the discovery of 20-desmethyl-20methylsulfanyl epothilone B, referred to as ABJ-879, which
exhibits more potent cytotoxicity than epothilone B in human
tumor cell lines [6]. The synthesis of the first fully synthetic
third-generation epothilone B derivative, ZK-EPO (ZK219477), was recently reported by a group of German
investigators [8]. This agent exhibits greater potency in vitro
relative to the other epothilones and retains activity even in
multidrug-resistant cancer cells. Unlike paclitaxel, ZK-EPO has
been shown to cross the blood–brain barrier, indicating the
potential for penetration into the central nervous system (CNS).
Finally, a second-generation epothilone D analogue, KOS-1584,
has been synthesized, which exhibits three- to 12-fold
increased potency compared with epothilones B and D, enhanced
tumor tissue penetration, and reduced CNS toxicity [6].
and stabilization, resulting in G2/M arrest and the induction
of apoptosis. The mechanism by which the epothilones
suppress microtubule dynamics appears to be similar to that
of the taxanes. The binding site of epothilones on the b-tubulin
subunit of tubulin is not known; however, data from studies
of tubulin-binding dynamics indicate that the epothilones
share common or overlapping pharmacophores with taxanes
on the b-tubulin subunit [9–11]. However, evidence from
other studies highlights the potential differences in the
mechanisms of action of the epothilones and taxanes.
Electron crystallography studies comparing the binding of
epothilone A and paclitaxel indicate that epothilone A binds
to the tubulin-binding pocket of microtubules in a manner
that is unique and independent of that of the taxanes [12].
Unlike the taxanes, the epothilones stimulate the formation
of microtubules from tubulin purified from the yeast
Saccharomyces cerevisiae. These findings indicate that the
interaction of epothilones with microtubules is functionally
distinct from that of the taxanes [13].
preclinical studies
In preclinical studies, the epothilones exhibit a broad
spectrum of potent antitumor activity in vitro in a variety of
taxane-sensitive and -resistant cell culture models [14, 15]
and in vivo in murine xenograft tumor models [16–18].
tumor cell lines
mechanism of action
Epothilones bind to the b-tubulin subunit of the a,b-tubulin
dimer of microtubules and induce microtubule polymerization
v10 | Fumoleau et al.
The epothilones are roughly one order of magnitude more
potent in cell culture models than is paclitaxel, with a median
inhibitory concentration (IC50) in the sub or low nanomolar
Volume 18 | Supplement 5 | July 2007
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Figure 1. Chemical structures of the epothilones under clinical development. (A) Structure of epothilone B, ixabepilone, and BMS-310705. (B) Structure of
epothilone D. (C) Structure of epothilone D second generation.
symposium article
Annals of Oncology
Table 1. Cytotoxicity (IC50) in nm of epothilones in comparison to
paclitaxel in human tumor cell lines [6]
Cell line
Epothilone Epothilone Epothilone Paclitaxel
A
B
D
HCT116 (colon)
2.51
SW620 (colon)
SW620AD (paclitaxel- NA
resistant colon
carcinoma subline)
PC-3M (prostate)
4.27
A549 (lung)
2.67
MCF-7 (breast)
1.49
MCF-7/ADR (breast)
27.50
KB-31 (epidermoid)
2.10
CCRF-CEM (leukemia) NA
0.32
0.1
0.3
NA
NA
NA
2.79
0.2
250
0.52
0.23
0.18
2.92
0.19
0.35
NA
NA
2.90
NA
2.70
9.5
4.77
3.19
1.80
9105
2.31
NA
NA, data not available.
xenograft models
The broad-spectrum in vitro antineoplastic activity
demonstrated in cancer cell lines was also evident in vivo by the
Volume 18 | Supplement 5 | July 2007
clinical development
The promising antitumor activity and improved
biopharmaceutical properties of the epothilones and their
synthetic derivatives have prompted a further evaluation of
these compounds in the clinical setting (Table 2) [22–36]. Phase I
data have been reported in the literature for patupilone and
ixabepilone in a variety of different solid tumor types. Phase I
data on BMS-310705, ZK-EPO, KOS-862, and KOS-1584 are
limited and have been reported primarily in abstract form.
doi:10.1093/annonc/mdm173 | v11
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range in breast, lung, colon, prostate, and ovarian cell lines
(Table 1) [14, 15]. Ixabepilone has demonstrated potent
cytotoxicity across a panel of cancer cell lines: breast (35 cell
lines, including MCF7/ADR, an established multidrugresistant cell line), colon (20 cell lines, including the multidrugresistant HCT116/VM46 cell line), and lung (23 cell lines),
with the majority of IC50 values between 1.4 and 45 nm [19].
The synthetic derivative of epothilone B, ABJ-879, has
exhibited greater potency than patupilone and paclitaxel across
a panel of human tumor cell lines [20]. The average IC50 of
ABJ-879 on a panel of drug-sensitive human tumor cell lines
was 0.09 nm, compared with 0.24 and 4.7 nm for patupilone
and paclitaxel, respectively. Importantly, in contrast to
paclitaxel, ABJ-879 retained full activity against cancer cells
overexpressing the drug efflux pump P-glycoprotein (Pgp) or
harboring tubulin mutations. KOS-862 exhibits reduced
antiproliferative activity in human cancer cell lines compared
with patupilone (Table 1), which may be related to its
reduced cellular uptake compared with patupilone.
The epothilones have also demonstrated potent
antiproliferative activity in multidrug-resistant and paclitaxelresistant cell lines. The overexpression of drug efflux transport
proteins such as Pgp has been implicated as an important
mechanism of resistance to the taxanes. Although the IC50 of
paclitaxel is increased significantly in multidrug-resistant cell
culture models, the overexpression of Pgp has minimal effect
on the cytotoxicity of patupilone, ixabepilone, and KOS-862.
KOS-862 appears to be least affected by the overexpression
of Pgp, whereas ixabepilone is most affected. Additionally, the
epothilones retain significant antiproliferative activity in cell
lines harboring the specific mutations of the b-tubulin that
confer resistance to paclitaxel [1]. Although these findings
indicate that the epothilones may be more effective than the
taxanes in patients with malignancies characterized by high
levels of Pgp expression or taxane resistance, the clinical
significance of these data needs to be established.
robust efficacy of epothilones against a wide array of human
cancer xenografts in mice. In vivo studies using different
formulations and schedules of administration of patupilone,
ixabepilone, and KOS-862 indicate that they are active in
paclitaxel-sensitive and -resistant tumor models. Ixabepilone is
highly active in a variety of human cancer xenografts when
administered intravenously (using an ethanol/Cremophor
formulation) or orally to mice using intermittent daily or
weekly schedules [15]. At doses producing clinically relevant
exposures, ixabepilone has demonstrated significant antitumor
activity in 33 of 35 human cancer xenografts evaluated [19]. In
the majority of tumors, prolonged tumor growth delay ‡1 log
cell kill was achieved, which was accompanied by significant
tumor regression rates. In addition, cures were observed in
50% of the tumor types. Ixabepilone also exhibited potent
antiproliferative activity in tumors expressing the Pgpmediated multidrug-resistance phenotype in vivo, reversing the
multidrug resistance of four established multidrug-resistant
models: MCF7/ADR and 16C/ADR breast, Pat-7 ovarian, and
HCT116/VM46 human colon carcinoma [19].
Similarly, patupilone produces either growth inhibition or
tumor regression in lung, breast, colon, and prostate xenografts
when administered intravenously (in a PEG300/water
formulation) on a weekly schedule [16]. The intravenous and
intraperitoneal administrations of KOS-862, BMS-310705,
and ZK-EPO have also been reported to induce the
regression of taxane-sensitive and -resistant tumors in certain
xenograft tumor models [18]. More recently, ZK-EPO has
demonstrated marked tumor growth inhibition in breast
cancer models of brain and bone metastasis [21]. ABJ-879
induces transient regressions and inhibition of tumor growth in
human xenograft models of slow-growing NCI H-596 lung
adenocarcinoma tumors and difficult-to-treat NCI H-460
large cell lung tumors [20]. A single administration of ABJ-879
has also been reported to induce long-lasting regressions and
cures in a xenograft model of paclitaxel-resistant KB-8511
epidermoid carcinoma [20].
Although patupilone exhibits more potent antiproliferative
activity in vitro, its therapeutic efficacy in vivo is limited by
substantial toxicity in animal tumor models. KOS-862 is less
toxic than patupilone and demonstrates greater therapeutic
efficacy than patupilone in vivo. Drug schedule had a
significant impact on the antitumor activity and toxicity of
epothilones in experimental models of human tumor xenografts.
For example, the antitumor activity of KOS-862
was enhanced when this agent given intravenously or
intraperitoneally every 2 days; however, toxicity associated with
a rapid infusion over 6 h resulted in death in animal models [16].
symposium article
Annals of Oncology
Table 2. Summary of clinical studies of epothilones in patients with advanced malignancies
Epothilones
Patient
(no.)
Drug/schedule evaluated
Dose
(mg/m2)
General toxicity
DLT
Reference
Ixabepilone
27
Days 1–5 of a 21-day cycle
1.5–8.0
Neuropathy, neutropenia, HSR,
fatigue, and hyponatremia
27
26
86
Days 1–3 of a 21-day cycle
Weekly infusion every 21
(n = 34) or 28 (n = 52) days
Day 1 of a 21-day cycle
8–10
1–30
Neutropenia at 8 mg/m2/day;
MTD 6 mg/m2
Neutropenia at 8 mg/m2/day
Grade 3 fatigue at 30 mg/m2/day;
MTD 25 mg/m2
Neutropenia, abdominal pain at
50–56 mg/m2; MTD 40 mg/m2
0.3–3.6
42
Days 1, 8, and 15 of a 28-day
cycle
Day 1 of a 21-day cycle
0.3–8.0
13
Days 1–3 of a 21-day cycle
16–100
30
Days 1, 8, and 15 of a 28-day
cycle
On day 1 of a 21-day cycle
Day 1 of a 14-day cycle,
over 24 h
Day 1 of a 14-day cycle,
over 72 h
Days 1, 8, and 15 of a 28-day
cycle
Day 1 of a 21-day cycle
1–6 mg/h
5–30
Grade 2 diarrhea, and HSR
Grade 3 diarrhea at 30 mg/m2
30
0.6–70
Grade 3/4 neuropathy,
neutropenia, fatigue,
diarrhea, and HSR
Grade 4 hyponatremia,
neutropenia at 70 mg/m2
31
Day 1 of a 21-day cycle
0.6–29
Neuropathy, nausea, and ataxia
Unknown
42
On days 1, 8, and 5 of a 28-day
cycle
Day 1 every 21 days
0.8–7.5
Fatigue and anorexia
Unknown
35
0.8–11.3
Diarrhea and fatigue
49
Patupilone
KOS-862
91
BMS-310705
21
59
ZK-EPO
KOS-1584
12
27
24–26
Diarrhea; MTD 2.5 mg/m2
23
Diarrhea at 8 mg/m2/day; MTD
2.5 mg/m2
22
Unknown
32
20–50
Neuropathy
33
9–185
Grade 3 chest pain, impaired gait, 34
and cognitive/perceptual changes
Neuropathy
Diarrhea, fatigue, nausea, and
vomiting
Neuropathy, fatigue, nausea,
and vomiting
1–1.7 mg/h
36
DLT, dose-limiting toxicity; HSR, hypersensitivity reaction; MTD, maximum tolerated dose.
patupilone, epothilone B
Three schedules of patupilone administration have been
reported in phase I studies [22, 23, 37]. Calvert et al. [22]
investigated a three-weekly schedule of patupilone in 42
patients with solid tumors; diarrhea was the dose-limiting
toxicity (DLT) when the medication was given at 8 mg/m2. A
partial response to treatment was reported in one patient with
a cancer of unknown primary site. A second phase I study
investigated two schedules of patupilone in patients with
advanced solid tumors [23]. In this study, patients received
patupilone, 0.3–3.6 mg/m2, administered on a 6-weeks-on/
3-weeks-off (n = 54) or 3-weeks-on/1-week-off (n = 37)
schedule. After a short infusion, patupilone blood
concentrations declined in a multiphasic manner, with
a terminal half-life of 4 days. The maximum tolerated dose
(MTD) was 2.5 mg/m2, with diarrhea being the most common
DLT for both schedules above this dose. No neurologic toxicity
or hypersensitivity reactions were observed with patupilone.
Partial responses were reported in three patients, two of whom
had received previous taxane therapy [23]. More recently, the
v12 | Fumoleau et al.
three-weekly schedule of patupilone, 6.5–11.0 mg/m2, has been
reexplored in a phase I/II study of 42 patients with non-smallcell lung cancer (NSCLC) using an intensive program of
diarrhea management [37]. As a result, the dose of
patupilone has been escalated to 11.5 mg/m2. DLTs have
included fatigue and diarrhea, and neurotoxicity has also
been noted. At the time of reporting, the MTD had not been
reached, and partial responses were noted in four patients.
Patupilone is mainly metabolized by the enzyme
carboxylesterase-1 to its hydrolytic-derived metabolite; the
oxidative metabolism by cytochrome P450 enzyme plays
a minimal role [38]. Based on data from other ongoing
phase I/II studies, a dose of 10 mg/m2 every 3 weeks has
been chosen for randomized phase III trials [39–41].
ixabepilone, a second-generation
epothilone B
Four different dosing schedules of ixabepilone (1.5 to 65
mg/m2) have been evaluated in phase I studies [24–28].
Ixabepilone is formulated in polyoxyethylated castor oil, and
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24
7.4–65.0
28
29
Annals of Oncology
BMS-310705, a second-generation
epothilone B
Two phase I studies have evaluated the water-soluble, secondgeneration, semisynthetic derivative of epothilone B, BMS310705 [30, 31]. In phase I studies, BMS-310705 was
administered as a 15-min infusion given either every 3 weeks or
weekly for three consecutive weeks [30]. Preliminary
pharmacokinetic data show increases in area under the time–
concentration curve (AUC) and maximum plasma
concentration (Cmax) that are dose related and are similar
between cycles 1 and 2. For the 40 mg/m2 dose in cycle 1, mean
Volume 18 | Supplement 5 | July 2007
pharmacokinetic values were Cmax, 3936 ng/ml; AUC, 2823 ng/
h/ml; elimination half-life, 42 h; clearance, 277 ml/min/m2; and
steady-state Vss, 443 l/m2. Neutropenia, diarrhea, and sensory
neuropathy were the most common toxic effects associated
with BMS-310705. In contrast to ixabepilone, no
hypersensitivity reactions were observed with this compound
in phase I studies. Partial responses to BMS-310705
treatment were reported in one patient with ovarian cancer
treated at 40 mg/m2 and one patient with bladder cancer
treated at 30 mg/m2. A complete response was achieved by
one patient with NSCLC treated with 40 mg/m2 [31].
Objective responses were also observed with the weekly
schedule of BMS-310705 in one patient with gastric cancer
and two patients with breast cancer [30].
ZK-EPO, a third-generation
epothilone B
One phase I study of ZK-EPO in patients with advanced
solid tumors has been reported in abstract form [42]. In this
study, ZK-EPO was given as a 30-min induction once every 3
weeks from a starting dose of 0.6 mg/m2. At the time of
reporting, 47 patients had been treated with ZK-EPO at
doses of up to 29 mg/m2. With regard to toxicity, the most
common adverse events were peripheral sensory neuropathy
and nausea. The DLT was grade 3 peripheral neuropathy;
grade 3 ataxia occurred in one patient each at the 16- and
29-mg/m2 dose levels. The MTD has not been reached. Two
partial responses were noted in patients with taxanepretreated breast cancer.
KOS-862, epothilone D
Three phase I studies have investigated several dosing schedules
of KOS-862 in patients with various malignancies [32–34].
Similar to ixabepilone, a Cremophor-based formulation has
been used in phase I studies. Linear pharmacokinetics were
reported in studies that evaluated KOS-862 given as a 90-min
infusion, 16–100 mg/m2, three of every 4 weeks; a single dose
of 9–185 mg/m2 every 3 weeks; or a 20- to 50-mg daily dose
given for three consecutive days every 3 weeks [32, 33]. The
safety of two (24- and 72-h) continuous intravenous schedules
of KOS-862 administered every 2 weeks has also been
investigated in 24 patients [34]. Neurologic toxicity was dose
limiting in all phase I studies of KOS-862. Neuropathy,
fatigue, nausea, and vomiting were also observed, though to
a lesser degree. Evidence of antitumor activity was noted in
patients with pancreatic, breast, testicular, and ovarian cancers.
KOS-1584, a second-generation
epothilone D
Two phase I studies of the epothilone D derivative KOS-1584
have recently been reported in abstract form (Table 2) [35, 36].
KOS-1864, at doses of 0.8–11.3 mg/m2, given as a 3-h
infusion once weekly every 3 weeks, was evaluated in 27
patients with solid tumors. At the time of reporting, no DLT
was observed in cycle 1, and common toxic effects included
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as a result, hypersensitivity reactions were seen in all phase I
studies, necessitating the use of prophylactic antihistamines.
Three studies have investigated the administration of
ixabepilone as a 1-h infusion given every 3 weeks [24–26]. In
these studies, the MTD was 40 mg/m2 and the DLT was
neutropenia. Grade 1 or 2 neuropathy was reported in all
patients treated at the MTD. The recommended dose of
ixabepilone for phase II studies of the three-weekly schedule is
25 mg/m2. The mean clearance, volume of distribution (Vss),
and apparent terminal elimination half-life at the 40 mg/m2
dose were 21 l/h/m2, 826 l/m2, and 35 h (excluding one outlier
of 516 h), respectively [24]. In one study [24], partial responses
occurred in two patients with paclitaxel-refractory ovarian
cancer, one patient with taxane-naive breast cancer, and
another patient with docetaxel-refractory breast cancer. Similar
findings were observed in a second study that evaluated a onceevery-3-week schedule in 17 cancer patients [25].
The final results of a third study investigating the weekly
schedule of ixabepilone were recently reported in abstract form
[29]. In this study, ixabepilone was administered weekly as
a 30-min infusion every 3 weeks or every 4 weeks. Due to
neurotoxicity, infusion time was increased to 1 h with a 1-week
break allowed. Doses ranged from 1 to 30 mg/m2. Thirty-four
patients were treated with the once-every-3-weeks schedule,
and 54 patients were treated with the once-every-4-weeks
schedule. The DLT was grade 3 fatigue, which occurred at the
30 mg/m2 dose level with the once-every-3-weeks schedule. No
DLTs were seen at doses of 25 mg/m2 on the once-every-3weeks schedule or at doses of 15, 20, or 25 mg/m2 on the onceevery-4-weeks schedule. Thus, the MTD was established at 25
mg/m2. Partial responses were noted in five patients. The
recommended doses for phase II studies of weekly ixabepilone
are 25 (30-min weekly infusion, 3-week schedule) and 20 mg/
m2 (1-h weekly infusion, 4-week schedule) [29]. The oxidative
metabolism by CYP3A4/5 appears to be a prominent route of
transformation in vitro [38].
Two phase I studies have evaluated ixabepilone given as a 1-h
infusion daily for either 3 (8–10 mg/m2) or 5 (1.5–8 mg/m2)
consecutive days every 3 weeks [27, 28]. Neutropenia was the
DLT with both schedules. Other grade 3 non-hematologic toxic
effects included fatigue, anorexia, and stomatitis. Peripheral
neuropathy was also reported but was generally mild. The
MTDs were 6 and 8 mg/m2/day with the 3- and 5-day
schedules, respectively. Antitumor activity was observed in
a number of tumor types, including mesothelioma, ovarian,
and renal cell carcinoma.
symposium article
symposium article
gastrointestinal disorders, fatigue, and increased aspartate
aminotransaminase levels. Linear pharmacokinetics were
reported over the dose range tested. The mean clearance,
Vss, and apparent terminal elimination half-life were 30.2 l/h,
741 l, and 17.7 h, respectively. The Vss and apparent
terminal elimination half-life were five- and two-fold higher
with KOS-1864 than with KOS-862.
Similar findings were reported in a second study
investigating the administration of KOS-1584, 0.8–7.5 mg/m2,
given as a 1-h infusion three times weekly every 4 weeks to 12
patients with advanced solid tumors [35]. A slower clearance of
KOS-1584, as determined by a higher Cmax and AUC total
values, was noted with the 1-h infusion than with the 3-h
infusion of the 5.0 mg/m2 dose. No DLT had been reached at
the time of reporting, and accrual is ongoing.
conclusion
disclosures
PF has reported that he has acted as a consultant for
GlaxoSmithKline and Sanofi-Aventis, and that he has acted as
a speaker for Pfizer and Sanofi-Aventis.
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The epothilones and their structural derivatives have
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symposium article