U.S. patent application number 13/804570 was filed with the patent office on 2013-11-14 for methods of treating cancer using aurora kinase inhibitors.
The applicant listed for this patent is Millennium Pharmaceuticals, Inc.. Invention is credited to Arijit CHAKRAVARTY, Jeffrey A. ECSEDY, Robert W. KLEINFIELD, Kha N. LE, Wen Chyi SHYU, Karthik VENKATAKRISHNAN.
Application Number | 20130303519 13/804570 |
Document ID | / |
Family ID | 48048255 |
Filed Date | 2013-11-14 |
United States Patent
Application |
20130303519 |
Kind Code |
A1 |
ECSEDY; Jeffrey A. ; et
al. |
November 14, 2013 |
METHODS OF TREATING CANCER USING AURORA KINASE INHIBITORS
Abstract
Disclosed are methods for the treatment of various cell
proliferative disorders. Disclosed in particular are methods for
treatment of various cell proliferative disorders by administering
a selective inhibitor of Aurora A kinase in combination with
taxane-based chemotherapy, such as paclitaxel or docetaxel.
Inventors: |
ECSEDY; Jeffrey A.; (Newton,
MA) ; SHYU; Wen Chyi; (Cambridge, MA) ;
CHAKRAVARTY; Arijit; (Lexington, MA) ; KLEINFIELD;
Robert W.; (Upton, MA) ; LE; Kha N.;
(Danville, CA) ; VENKATAKRISHNAN; Karthik;
(Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Millennium Pharmaceuticals, Inc.; |
|
|
US |
|
|
Family ID: |
48048255 |
Appl. No.: |
13/804570 |
Filed: |
March 14, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61613258 |
Mar 20, 2012 |
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Current U.S.
Class: |
514/215 |
Current CPC
Class: |
A61K 31/337 20130101;
A61P 35/00 20180101; A61K 31/551 20130101; A61K 31/55 20130101;
A61P 43/00 20180101; A61K 31/551 20130101; A61K 2300/00 20130101;
A61K 31/337 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/215 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/337 20060101 A61K031/337 |
Claims
1. A method of treating a cell proliferative disorder in a subject
in need thereof, comprising administering to the subject on a
28-day dose schedule a twice-daily dose of alisertib in combination
with a once-weekly dose of paclitaxel, wherein the administered
twice-daily dose of alisertib is from about 30 mg to about 50 mg,
and is administered on days 1-3, 8-10, and 15-17 of the 28-day
schedule; and the administered once-weekly dose of paclitaxel is
from about 40 mg/m.sup.2 to about 80 mg/m.sup.2, and is
administered on days 1, 8, and 15 of the 28-day schedule.
2. The method of claim 1, wherein the administration of alisertib
is concomitant with the administration of paclitaxel.
3. The method of claim 1, wherein the twice-daily dose of alisertib
is from about 40 mg to about 50 mg.
4. The method of claim 1, wherein the twice-daily dose of alisertib
is from about 30 mg to about 40 mg.
5. The method of claim 1, wherein the twice-daily dose of alisertib
is about 35 mg.
6. The method of claim 1, wherein the twice-daily dose of alisertib
is about 40 mg.
7. The method of claim 1, wherein the twice-daily dose of alisertib
is about 45 mg.
8. The method of claim 1, wherein the once-weekly dose of
paclitaxel is from about 60 mg/m.sup.2 to about 70 mg/m.sup.2.
9. The method of claim 1, wherein the once-weekly dose of
paclitaxel is about 60 mg/m.sup.2.
10. The method of claim 1, wherein the cell proliferative disorder
is cancer.
11. The method of claim 10, wherein the cancer is ovarian cancer,
breast cancer, prostate cancer, gastric cancer, head and neck
cancer, bladder cancer, lung cancer or AIDS-related Kaposi's
sarcoma.
12. The method of claim 10, wherein the cancer is ovarian cancer,
breast cancer, lung cancer or AIDS-related Kaposi's sarcoma.
13. The method of claim 10, wherein the cancer is ovarian
cancer.
14. The method of claim 10, wherein the cancer is small-cell lung
cancer.
15. A kit, comprising alisertib, or a pharmaceutically acceptable
salt thereof paclitaxel, or a pharmaceutically acceptable salt
thereof and instructions for administering the alisertib or a
pharmaceutically acceptable salt thereof in combination with the
paclitaxel, or a pharmaceutically acceptable salt thereof.
Description
FIELD
[0001] This invention relates to methods for the treatment of
various cell proliferative disorders. In particular, the invention
provides methods for treatment of various cell proliferative
disorders by administering a selective inhibitor of Aurora A kinase
in combination with taxane-based chemotherapy, such as paclitaxel,
or docetaxel.
BACKGROUND
[0002] Cancer is the second most common cause of death in the U.S.
and accounts for one of every eight deaths worldwide. During 2010,
the American Cancer Society estimated approximately 1,529,560 new
cancer cases would be diagnosed in the U.S. alone, and an estimated
569,490 Americans would die from cancer. In 2008, an estimated 12.4
million new cancer cases were diagnosed, and 7.6 million people
died from cancer worldwide. Although medical advances have improved
cancer survival rates, there is a continuing need for new and more
effective treatment.
[0003] Cancer is characterized by uncontrolled cell reproduction.
Antimitotic agents and antimicrotubule agents have been explored as
targets for cancer therapy because of their important role in the
cell division cycle. The cell division cycle, which regulates the
transition from quiescence to cell proliferation comprises four
phases: G1, S phase (DNA synthesis), G2, and M phase (mitosis).
Non-dividing cells rest in quiescent phase, G0 Inhibition of the
mitotic machinery results in a diverse array of outcomes, primarily
leading to cell death or arrest.
[0004] As the effect of antimitotic agents is not limited to cancer
cells alone, the dose-limiting toxicities of these drugs in a
clinical setting frequently manifest in rapidly dividing tissue and
in the case of antimicrotubule agents are often accompanied by
severe peripheral neuropathy in the case of antimicrotubule agents.
Therefore, the narrow therapeutic index of antimitotic agents
necessitates an understanding of the mechanism of action of these
drugs to maximize the chances of rational development of these
therapies.
[0005] Traditional antimitotic agents include those that directly
interfere with microtubule dynamics, essential for mitotic spindle
assembly and the subsequent alignment and segregation of DNA to
daughter cells. Antimicrotubule agents, such as Taxanes are
currently being used in clinical setting. For example, paclitaxel
and docetaxel have a similar spectrum of clinical activity
including ovarian, lung, breast, bladder, and prostate cancers.
[0006] Taxanes stabilize microtubules by altering the kinetics of
microtubule depolymerization. In mammalian cells grown in culture,
high concentrations of paclitaxel cause the stabilization of
aggregated microtubules (Schiff and Horwitz (1980) Proc Natl Acad
Sci USA 77:1561-1565). At lower concentrations that resemble
exposures achieved in clinical settings, the primary effect of
paclitaxel is to stabilize microtubules, and thereby dampen the
dynamic instability of microtubules that is a requisite for
efficient spindle assembly. As a result of this dampening,
microtubules are unable to grow and shrink rapidly, and their
ability to bind to condensed chromosomes during mitosis is
compromised. Efficient chromosome alignment is thus affected, and
this failure of chromosome alignment leads to mitotic delays
mediated via the spindle assembly checkpoint.
[0007] The spindle assembly checkpoint ensures that chromosomes are
properly aligned to the metaphase plate prior to the anaphase
initiation where sister chromatids segregate to opposite poles.
Interestingly, at low concentrations of paclitaxel, inefficient
chromosome alignment has been shown to occur without prolonged
mitotic arrest, and the effect of paclitaxel is thus not dependent
on its ability to induce mitotic arrest or delays (Chen and Horwitz
(2002) Cancer Res 62:1935-1938). Kelling et al. (2003) Cancer Res
63:2794-2801).
[0008] For paclitaxel as well as its analog docetaxel, in vitro
studies have demonstrated the presence of abnormal DNA contents and
cell death even at concentrations where prolonged mitotic arrest
does not occur (Chen and Horwitz (2002) Cancer Res 62:1935-1938;
Hernandez-Vargas et al. (2007) Cell Cycle 6:780-783;
Hernandez-Vargas et al. (2007) Cell Cycle 6:2662-2668. Consistent
with this finding, preclinical studies in xenograft models have
failed to demonstrate a clear relationship between the degree of
mitotic arrest and tumor growth inhibition (Gan et al. (1998)
Cancer Chemother Pharmacol 42:177-182; Milross et al. (1996) J Natl
Cancer Inst 88:1308-1314; Schimming et al. (1999) Cancer Chemother
Pharmacol 43:165-172), and similar findings have been reported in a
clinical setting (Symmans et al. (2000) Clin Cancer Res
6:4610-4617).
[0009] It has been well established that antimitotic compounds
compromise the ability of cells to execute a successful division.
Cells will either fail to divide with a prolonged mitotic arrest
that leads directly to cell death, or they divide abnormally, with
an unequal distribution of DNA (Gascoigne and Taylor (2008) Cancer
Cell 14:111-122; Rieder and Maiato (2004) Dev Cell 7:637-651;
Weaver and Cleveland (2005) Cancer Cell 8:7-12). Following such an
unsuccessful division, cells may continue to cycle or undergo
cell-cycle arrest or death. This diversity of outcomes following
treatment with antimitotic agents has been shown to be dependent on
cell type as well as on concentration of the antimitotic agent used
(Gascoigne and Taylor (2008) Cancer Cell 14:111-122; Orth et al.
(2008) Mol Cancer Ther 7:3480-3489; Shi et al. (2008) Cancer Res
68:3269-3276).
[0010] The prolonged mitotic arrest model suggests that sustained
high concentrations of drug are required for antitumor effect.
Findings with weekly taxane therapies, which have equivalent
efficacy to the once every three weeks taxane therapy schedule,
suggest that the same effect can be obtained by splitting the total
dose of drug administered.
[0011] The toxicities associated with paclitaxel and docetaxel are
similar, and include neutropenia as the major dose limiting
toxicity, along with significant peripheral neuropathy. In fact,
dose reductions are frequent in heavily pretreated patients to
mitigate the severity of these toxicities. In clinical studies dose
reductions did not reduce the clinical response of the agents,
suggesting that the optimal biological dose may be lower than the
maximum tolerated dose (Salminen et al., (1999) J Clin Oncol
17:1127). Weekly administration of the taxanes has become more
frequently used as clinical data demonstrated less myelosuppression
with no decrease in clinical response (Gonzalez-Angulo et al.,
(2008) J Clin Oncol 26:1585). In breast cancer studies, weekly
paclitaxel showed better response rates than once every three weeks
dosing (Seidman et al., J Clin Oncol 26:1642 (2008)). However,
weekly paclitaxel has demonstrated greater neuropathy than the once
every three weeks schedule.
[0012] The cell division cycle also involves various protein
kinases that are frequently overexpressed in cancer cells. Aurora A
kinase, for example, is a key mitotic regulator that is implicated
in the pathogenesis of several tumor types. The Aurora kinases,
first identified in yeast (Ip11), Xenopus (Eg2) and Drosophila
(Aurora), are critical regulators of mitosis. (Embo J (1998) 17,
5627-5637; Genetics (1993) 135, 677-691; Cell (1995) 81, 95-105; J
Cell Sci (1998) 111(Pt 5), 557-572). In humans, three isoforms of
Aurora kinase exist, including Aurora A, Aurora B and Aurora C.
Aurora A and Aurora B play critical roles in the normal progression
of cells through mitosis, whereas Aurora C activity is largely
restricted to meiotic cells. Aurora A and Aurora B are structurally
closely related. Their catalytic domains lie in the C-terminus,
where they differ in only a few amino acids. Greater diversity
exists in their non-catalytic N-terminal domains. It is the
sequence diversity in this region of Aurora A and Aurora B that
dictates their interactions with distinct protein partners,
allowing these kinases to have unique subcellular localizations and
functions within mitotic cells.
[0013] Although Aurora B kinase and Aurora A kinase are both
members of the Aurora kinase family, they have distinct roles
during the process of mitotic division. In the course of normal
mitotic cell division, cells organize bipolar spindles, with two
radial arrays of microtubules each focused into a spindle pole at
one end, and connected to chromosomes at the other end. In the
instant before sister chromatids segregate into daughter cells, the
chromosomes are arranged in a straight line (the `metaphase
plate`). This process of organizing bipolar mitotic spindles with
fully aligned chromosomes serves to ensure the integrity of a
cell's chromosomal complement during mitosis.
[0014] The Aurora A gene (AURKA) localizes to chromosome 20q13.2
which is commonly amplified or overexpressed at a high incidence in
a diverse array of tumor types. (Embo J (1998) 17, 3052-3065; Int J
Cancer (2006) 118, 357-363; J Cell Biol (2003) 161, 267-280; Mol
Cancer Ther (2007) 6, 1851-1857; J Natl Cancer Inst (2002) 94,
1320-1329). Increased Aurora A gene expression has been correlated
to the etiology of cancer and to a worsened prognosis. (Int J Oncol
(2004) 25, 1631-1639; Cancer Res (2007) 67, 10436-10444; Clin
Cancer Res (2004) 10, 2065-2071; Clin Cancer Res (2007) 13,
4098-4104; Int J Cancer (2001) 92, 370-373; Br J Cancer (2001) 84,
824-831; J Natl Cancer Inst (2002) 94, 1320-1329). This concept has
been supported in experimental models, demonstrating that Aurora A
overexpression leads to oncogenic transformation. (Cancer Res
(2002) 62, 4115-4122; Mol Cancer Res (2009) 7, 678-688; Oncogene
(2006) 25, 7148-7158; Cell Res (2006) 16, 356-366; Oncogene (2008)
27, 4305-4314; Nat Genet (1998) 20, 189-193). Overexpression of
Aurora A kinase is suspected to result in a stoichiometric
imbalance between Aurora A and its regulatory partners, leading to
chromosomal instability and subsequent transforming events. The
potential oncogenic role of Aurora A has led to considerable
interest in targeting this kinase for the treatment of cancer.
[0015] As a key regulator of mitosis, Aurora A plays an essential
role in mitotic entry and normal progression of cells through
mitosis. (Nat Rev Mol Cell Biol (2003) 4, 842-854; Curr Top Dev
Biol (2000) 49, 331-42; Nat Rev Mol Cell Biol (2001) 2(1), 21-32).
During a normal cell cycle, Aurora A kinase is first expressed in
the G2 stage where it localizes to centrosomes and functions in
centrosome maturation and separation as well as in the entry of
cells into mitosis. In mitotic cells Aurora A kinase predominantly
localizes to centrosomes and the proximal portion of incipient
mitotic spindles. There it interacts with and phosphorylates a
diverse set of proteins that collectively function in the formation
of mitotic spindle poles and spindles, the attachment of spindles
to sister chromatid at the kinetochores, the subsequent alignment
and separation of chromosome, the spindle assembly checkpoint and
cytokinesis. (J Cell Sci (2007) 120, 2987-2996; Trends Cell Biol
(1999) 9, 454-459; Nat Rev Mol Cell Biol (2003) 4, 842-854; Trends
Cell Biol (2005) 15, 241-250).
[0016] Although selective inhibition of Aurora A kinase results in
a delayed mitotic entry (The Journal of biological chemistry (2003)
278, 51786-51795), cells commonly enter mitosis despite having
inactive Aurora A kinase. Cells in which Aurora A kinase has been
selectively inhibited demonstrate a variety of mitotic defects
including abnormal mitotic spindles (monopolar or multipolar
spindles) and defects in the process of chromosome alignment. With
time, monopolar and multipolar spindles may resolve to form two
opposing spindle poles, although some of these defects may lead
immediately to cell death via defective mitoses. While spindle
defects resulting from Aurora A kinase inhibition induce mitotic
delays, presumably through activation of the spindle assembly
checkpoint, cells ultimately divide at a frequency near that of
untreated cells. (Mol Cell Biol (2007) 27(12), 4513-25; Cell Cycle
(2008) 7(17), 2691-704; Mol Cancer Ther (2009) 8(7), 2046-56.).
This inappropriate cell division occurs following a slow-acting
suppression of the spindle assembly checkpoint due to loss of
Aurora A kinase function. (Cell Cycle (2009) 8(6), 876-88). Bipolar
spindles that are formed in the absence of Aurora A kinase function
frequently show chromosome alignment and segregation defects,
including chromosome congression defects at metaphase, lagging
chromosomes at anaphase, and telophase bridges.
[0017] Consistent with the chromosome segregation defects, cells
treated with MLN8054, a selective inhibitor of Aurora A kinase,
develop aneuploidy that increases over time. Subsequent to repeated
passages through defective mitotic divisions, cells treated with
MLN8054 will often undergo senescence, an irreversible growth
arrest with distinctive morphological characteristics. (Mol Cancer
Res (2010) 8(3), 373-84). In some cell lines, MLN8054-treated cells
exit from mitosis and activate a p53-dependent postmitotic G1
checkpoint, which subsequently induces p21 and Bax, leading to G1
arrest followed by the induction of apoptosis. (Mol. Cancer Ther
(2009) 8(7), 2046-56). Some cells may also exit mitosis without
cytokinesis. These cells enter the G1 phase of the cell cycle with
double the normal DNA content and are therefore referred to as G1
tetraploid cells. Lastly, some cells may divide, albeit with severe
chromosome segregation defects (Mol Cell Biol (2007) 27(12),
4513-25). In the latter two outcomes, the abnormal mitotic
divisions result in deleterious aneuploidy leading to cell death or
arrest. Alternatively, it is possible that a portion of these cells
may be resistant to these terminal outcomes and can reenter the
cell cycle, as aneuploidy has been demonstrated to be both a
suppressor and a promoter of tumor cell growth.
[0018] Given the importance of the protein kinases involved in
driving the cell cycle, it would be beneficial if more effective
treatment regimens, which target these kinases could be developed.
In particular, combined treatment regimens with antimitotics could
be helpful for patients suffering from cell proliferative
disorders, and might potentially even decrease the rate of relapse
or overcome the resistance to a particular anticancer agent
sometimes seen in these patients.
[0019] Drug tolerability and the prevalence of side effects are
important considerations in structuring dose and schedule selection
for the treatment of cell proliferative disorders. For example,
treatments that require the use of therapeutic agents, for example,
taxanes, that result in severe adverse events, such as neutropenia,
may become ineffective due to insufficient patient compliance or
because an effective therapeutic dose cannot be administered to the
patient. Similarly, treatments that result in a higher effective
concentration of the active ingredient for a longer period of time
may provide increased therapeutic efficacy. Thus, there is a need
for new cancer treatment regimens, including combination therapies,
which avoid or ameliorate harsh side effects resulting from
toxicity while providing increased therapeutic efficacy by
achieving improved exposure efficacy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows the antitumor activity (average tumor volume as
a function of time) of alisertib combined with paclitaxel in the
NCI-H69 small cell lung cancer tumor model.
[0021] FIG. 2 shows the antitumor activity (average tumor volume as
a function of time) of alisertib combined with paclitaxel in the
NCI-H82 small cell lung cancer tumor model.
[0022] FIG. 3 shows the antitumor activity (average tumor volume as
a function of time) of alisertib combined with paclitaxel in the
CTG-0166 primary small cell lung cancer tumor model.
DETAILED DESCRIPTION
1. General Description
[0023] As discussed above, there remains a need to provide
alternate therapies for the treatment of cancer, particularly those
that avoid or ameliorate the harsh side effects of currently
existing therapies. While additive and synergistic antitumor
activity has been demonstrated for the combination of selective
inhibitors of Aurora A kinase with taxanes, neutropenia is a common
dose limiting toxicity.
[0024] The present inventors have discovered that decreasing the
standard weekly paclitaxel dose from about 80 mg/m.sup.2 to about
60 mg/m.sup.2 allows achievement of surprisingly higher alisertib
(MLN8237) doses with an acceptable tolerability profile without
losing efficacy. An alisertib dose of about 10 mg BID (twice daily)
was the maximum tolerated dose that could be achieved in
combination with the standard weekly dose of about 80 mg/m.sup.2 of
paclitaxel. Unexpectedly, much higher doses of up to about 40 mg
BID of alisertib were tolerated in combination with paclitaxel when
the dose of weekly paclitaxel was reduced to about 60
mg/m.sup.2.
[0025] Accordingly, the present invention relates to methods for
the treatment of cell proliferative disorders comprising
administering to a patient in need thereof a selective inhibitor of
Aurora A kinase with the concomitant or sequential administration
of a taxane, such as paclitaxel or docetaxel, wherein the amounts
of each agent are therapeutically effective when used in
combination.
2. Definitions
[0026] As used herein, the terms "cell proliferative disorder" and
"cancer" refer to a cellular disorder characterized by uncontrolled
or disregulated cell proliferation, decreased cellular
differentiation, inappropriate ability to invade surrounding
tissue, and/or ability to establish new growth at ectopic sites.
The terms "cell proliferative disorder" and "cancer" include, but
are not limited to, solid tumors and bloodborne tumors. The terms
"cell proliferative disorder" and "cancer" encompass diseases of
skin, tissues, organs, bone, cartilage, blood, and vessels. The
terms "cell proliferative disorder" and "cancer" further encompass
primary and metastatic cancers. As used herein, the term "cell
proliferative disorders" includes, but is not limited to, cancerous
hyperproliferative disorders (e.g., brain, lung, squamous cell,
bladder, gastric, pancreatic, breast, head, neck, renal, liver,
kidney, ovarian, prostate, colorectal, colon, epidermoid,
esophageal, testicular, gynecological or thyroid cancer, acute
myeloid leukemia, multiple myeloma, mesothelioma, Non-small cell
lung carcinoma (NSCLC), neuroblastoma, and acute lymphoblastic
leukemia (ALL)); non-cancerous hyperproliferative disorders (e.g.,
benign hyperplasia of the skin (e.g., psoriasis), restenosis, and
benign prostatic hypertrophy (BPH)); and diseases related to
vasculogenesis or angiogenesis (e.g., tumor angiogenesis,
hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,
lung, pancreatic, prostate, colon and epidermoid cancer).
[0027] As used herein, the term "patient" means an animal,
preferably a mammal, and most preferably a human. In some
embodiments, the patient has been treated with an agent, e.g., an
Aurora A kinase selective inhibitor or a taxane, prior to
initiation of treatment according to the method of the invention.
In some embodiments, the patient is a patient at risk of developing
or experiencing a recurrence of a proliferative disorder.
[0028] The expressions "therapeutically effective" and "therapeutic
effect" refer to a benefit including, but not limited to, the
treatment or amelioration of symptoms of a proliferative disorder
discussed herein. It will be appreciated that the therapeutically
effective amount or the amount of agent required to provide a
therapeutic effect will vary depending upon the intended
application (in vitro or in vivo), or the subject and disease
condition being treated (e.g., nature of the severity of the
condition to be treated, the particular inhibitor, the route of
administration and the age, weight, general health, and response of
the individual patient), which can be readily determined by a
person of skill in the art. For example, an amount of a selective
inhibitor of Aurora A kinase in combination with an amount of a
taxane is therapeutically effective if it is sufficient to effect
the treatment or amelioration of symptoms of a proliferative
disorder discussed herein.
[0029] The expressions "prophylactically effective" and
"prophylactic effect" refer to a benefit including, but not limited
to, the prophylaxis of symptoms of a proliferative disorder
discussed herein. It will be appreciated that the prophylactically
effective amount or the amount of agent required to provide a
prophylactic effect will vary depending upon the intended
application (in vitro or in vivo), or the subject and disease
condition being prevented (e.g., nature of the severity of the
condition to be prevented, the particular inhibitor, the route of
administration and the age, weight, general health, and response of
the individual patient), which can be readily determined by a
person of skill in the art. For example, an amount of a selective
inhibitor of Aurora A kinase in combination with an amount of a
taxane is prophylactically effective if it is sufficient to effect
the prophylaxis of symptoms of a proliferative disorder discussed
herein.
[0030] As used herein, the term "Aurora A kinase" refers to a
serine/threonine kinases involved in mitotic progression. Aurora A
kinase is also known as AIK, ARK1, AURA, BTAK, STK6, STK7, STK15,
AURORA2, MGC34538, and AURKA. A variety of cellular proteins that
play a role in cell division are substrates for phosphorylation by
the Aurora A kinase enzyme, including, without limitation, p53,
TPX-2, XIEg5 (in Xenopus), and D-TACC (in Drosophila). The Aurora A
kinase enzyme is also itself a substrate for autophosphorylation,
e.g., at Thr288. Preferably, the Aurora A kinase is a human Aurora
A kinase.
[0031] The term "inhibitor of Aurora A kinase" or "Aurora A kinase
inhibitor" is used to signify a compound that is capable of
interacting with Aurora A kinase and inhibiting its enzymatic
activity. Inhibiting Aurora A kinase enzymatic activity means
reducing the ability of Aurora A kinase to phosphorylate a
substrate peptide or protein. In various embodiments, such
reduction of Aurora A kinase activity is at least about 75%, at
least about 90%, at least about 95%, or at least about 99%. In
various embodiments, the concentration of Aurora A kinase inhibitor
required to reduce an Aurora A kinase enzymatic activity is less
than about 1 .mu.M, less than about 500 nM, less than about 100 nM,
or less than about 50 nM. Preferably, the concentration that is
required to inhibit the enzymatic activity of Aurora A kinase is
lower than the concentration of the inhibitor that is required to
inhibit the enzymatic activity of Aurora B kinase. In various
embodiments, the concentration of an Aurora A kinase inhibitor that
is required to reduce Aurora A kinase enzymatic activity is at
least about 2-fold, at least about 5-fold, at least about 10-fold,
at least about 20-fold, at least about 50-fold, at least about
100-fold, at least about 500-fold, or at least about 1000-fold
lower than the concentration of the inhibitor that is required to
reduce Aurora B kinase enzymatic activity.
[0032] Inhibition of Aurora A and inhibition of Aurora B result in
markedly different cellular phenotypes. (Proc. Natl. Acad. Sci.
(2007) 104: 4106; Mol Cancer Ther (2009) 8(7), 2046-56; Chem Biol.
(2008) 15(6) 552-62). For example, inhibition of Aurora A in the
absence of Aurora B inhibition results in increased mitotic index
as measured by quantifying phosphorylated histone H3 on serine 10
(pHisH3). pHisH3 is a unique substrate of Aurora B in physiological
systems (e.g. intact cells). By contrast, inhibition of Aurora B or
dual inhibition of Aurora A and Aurora B results in a decrease in
pHisH3. Accordingly, as used herein, the term "selective inhibitor
of Aurora A kinase" or "selective Aurora A kinase inhibitor" refers
to an inhibitor that exhibits an Aurora A kinase inhibitor
phenotype at effective antitumor concentrations. In some
embodiments, the selective Aurora A kinase inhibitor causes a
transient mitotic delay, as measured by quantification of pHisH3,
when administered to mice at a dose where the free fraction
adjusted concentration (C.sub.ave) in plasma is equivalent to the
free fraction adjusted concentration achieved in plasma in humans
at the maximum tolerated dose (MTD). As used herein, "free fraction
adjusted concentration" refers to the plasma concentration of free
drug (not protein bound).
[0033] As used herein, the term "taxane" refers to a class of
diterpenes produced by the plants of the genus Taxus (yews).
Examples of taxanes include, but are not limited to, paclitaxel
(TAXOL.RTM.), docetaxel (TAXOTERE.RTM.), and ABRAXANE.RTM.
(Paclitaxel Injection).
[0034] As used herein, the term "in combination" refers to use of
both a selective Aurora A kinase inhibitor and a taxane in the
treatment of the same disease or condition in the same patient. As
further described below, unless explicitly specified, the term "in
combination" does not restrict the timing of administration of the
selective Aurora A kinase inhibitor or the taxane.
[0035] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10%.
[0036] As used herein, the term "comprises" means "includes, but is
not limited to."
[0037] The term "aliphatic" or "aliphatic group", as used herein,
means a substituted or unsubstituted straight-chain, branched or
cyclic C.sub.1-12 hydrocarbon, which is completely saturated or
which contains one or more units of unsaturation, but which is not
aromatic. For example, suitable aliphatic groups include
substituted or unsubstituted linear, branched or cyclic alkyl,
alkenyl, alkynyl groups and hybrids thereof, such as
(cylcoalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0038] The term "cycloaliphatic", used alone or as part of a larger
moiety, refers to a saturated or partially unsaturated cyclic
aliphatic ring system having from 3 to about 14 members, wherein
the aliphatic ring system is optionally substituted. In some
embodiments, the cycloaliphatic is a monocyclic hydrocarbon having
3-8 or 3-6 ring carbon atoms. Nonlimiting examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,
and cyclooctadienyl. In some embodiments, the cycloaliphatic is a
bridged or fused bicyclic hydrocarbon having 6-12, 6-10, or 6-8
ring carbon atoms, wherein any individual ring in the bicyclic ring
system has 3-8 members.
[0039] In some embodiments, two adjacent substituents on the
cycloaliphatic ring, taken together with the intervening ring
atoms, form an optionally substituted fused 5- to 6-membered
aromatic or 3- to 8-membered non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
Thus, the term "cycloaliphatic" includes aliphatic rings that are
fused to one or more aryl, heteroaryl, or heterocyclyl rings.
Nonlimiting examples include indanyl,
5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, or
tetrahydronaphthyl, where the radical or point of attachment is on
the aliphatic ring. The term "cycloaliphatic" may be used
interchangeably with the terms "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic".
[0040] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to a C.sub.6 to C.sub.14 aromatic hydrocarbon, comprising one
to three rings, each of which is optionally substituted.
Preferably, the aryl group is a C.sub.6-10 aryl group. Aryl groups
include, without limitation, phenyl, naphthyl, and anthracenyl. In
some embodiments, two adjacent substituents on the aryl ring, taken
together with the intervening ring atoms, form an optionally
substituted fused 5- to 6-membered aromatic or 4- to 8-membered
non-aromatic ring having 0-3 ring heteroatoms selected from the
group consisting of O, N, and S. Thus, the term "aryl", as used
herein, includes groups in which an aromatic ring is fused to one
or more heteroaryl, cycloaliphatic, or heterocyclyl rings, where
the radical or point of attachment is on the aromatic ring.
Nonlimiting examples of such fused ring systems include indolyl,
isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,
benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, fluorenyl, indanyl, phenanthridinyl,
tetrahydronaphthyl, indolinyl, phenoxazinyl, benzodioxanyl, and
benzodioxolyl. An aryl group may be mono-, bi-, tri-, or
polycyclic, preferably mono-, bi-, or tricyclic, more preferably
mono- or bicyclic. The term "aryl" may be used interchangeably with
the terms "aryl group", "aryl moiety", and "aryl ring".
[0041] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10 aryl(C.sub.1-6)alkyl, C.sub.6-10
aryl(C.sub.1-4)alkyl, or C.sub.6-10 aryl(C.sub.1-3)alkyl,
including, without limitation, benzyl, phenethyl, and
naphthylmethyl.
[0042] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., heteroaralkyl, or "heteroaralkoxy",
refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or
10 ring atoms; having 6, 10, or 14 .pi. electrons shared in a
cyclic array; and having, in addition to carbon atoms, from one to
four heteroatoms. The term "heteroatom" refers to nitrogen, oxygen,
or sulfur, and includes any oxidized form of nitrogen or sulfur,
and any quaternized form of a basic nitrogen. Heteroaryl groups
include, without limitation, thienyl, furanyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, and pteridinyl. In some embodiments, two adjacent
substituents on the heteroaryl, taken together with the intervening
ring atoms, form an optionally substituted fused 5- to 6-membered
aromatic or 4- to 8-membered non-aromatic ring having 0-3 ring
heteroatoms selected from the group consisting of O, N, and S.
Thus, the terms "heteroaryl" and "heteroar-", as used herein, also
include groups in which a heteroaromatic ring is fused to one or
more aryl, cycloaliphatic, or heterocyclyl rings, where the radical
or point of attachment is on the heteroaromatic ring. Nonlimiting
examples include indolyl, isoindolyl, benzothienyl, benzofuranyl,
dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,
isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and
pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be
mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroaryl"
may be used interchangeably with the terms "heteroaryl ring",
"heteroaryl group", or "heteroaromatic", any of which terms include
rings that are optionally substituted. The term "heteroaralkyl"
refers to an alkyl group substituted by a heteroaryl, wherein the
alkyl and heteroaryl portions independently are optionally
substituted.
[0043] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 3- to 7-membered monocyclic,
or to a fused 7- to 10-membered or bridged 6- to 10-membered
bicyclic heterocyclic moiety that is either saturated or partially
unsaturated, and having, in addition to carbon atoms, one or more,
preferably one to four, heteroatoms, as defined above. When used in
reference to a ring atom of a heterocycle, the term "nitrogen"
includes a substituted nitrogen. As an example, in a heterocyclyl
ring having 1-3 heteroatoms selected from oxygen, sulfur or
nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH
(as in pyrrolidinyl) or .sup.+NR (as in N-substituted
pyrrolidinyl). A heterocyclic ring can be attached to its pendant
group at any heteroatom or carbon atom that results in a stable
structure, and any of the ring atoms can be optionally substituted.
Examples of such saturated or partially unsaturated heterocyclic
radicals include, without limitation, tetrahydrofuranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,
pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and
quinuclidinyl.
[0044] In some embodiments, two adjacent substituents on a
heterocyclic ring, taken together with the intervening ring atoms,
for an optionally substituted fused 5- to 6-membered aromatic or 3-
to 8-membered non-aromatic ring having 0-3 ring heteroatoms
selected from the group consisting of O, N, and S. Thus, the terms
"heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic
group", "heterocyclic moiety", and "heterocyclic radical", are used
interchangeably herein, and include groups in which a heterocyclyl
ring is fused to one or more aryl, heteroaryl, or cycloaliphatic
rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl,
or tetrahydroquinolinyl, where the radical or point of attachment
is on the heterocyclyl ring. A heterocyclyl group may be mono-,
bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more
preferably mono- or bicyclic. The term "heterocyclylalkyl" refers
to an alkyl group substituted by a heterocyclyl, wherein the alkyl
and heterocyclyl portions independently are optionally
substituted.
[0045] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having multiple sites of unsaturation, but is not
intended to include aryl or heteroaryl moieties, as herein
defined.
[0046] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, which is substituted with one or more halogen
atoms. As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic
wherein the halogen is fluoro.
[0047] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
A substituted alkylene chain is a polymethylene group in which one
or more methylene hydrogen atoms is replaced with a substituent.
Suitable substituents include those described below for a
substituted aliphatic group. An alkylene chain also may be
substituted at one or more positions with an aliphatic group or a
substituted aliphatic group.
[0048] The term "substituted", as used herein, means that a
hydrogen radical of the designated moiety is replaced with the
radical of a specified substituent, provided that the substitution
results in a stable or chemically feasible compound. The phrase
"one or more substituents", as used herein, refers to a number of
substituents that equals from one to the maximum number of
substituents possible based on the number of available bonding
sites, provided that the above conditions of stability and chemical
feasibility are met. Unless otherwise indicated, an optionally
substituted group may have a substituent at each substitutable
position of the group, and the substituents may be either the same
or different.
[0049] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroaralkoxy and the like) group may
contain one or more substituents. Examples of suitable substituents
on the unsaturated carbon atom of an aryl or heteroaryl group
include -halo, --NO.sub.2, --CN, --R*, --C(R*)=C(R*).sub.2,
--C.ident.C--R*, --OR*, --SR.sup..smallcircle.,
--S(O)R.sup..smallcircle., --SO.sub.2R.sup..smallcircle.,
--SO.sub.3R.sup..smallcircle., --SO.sub.2N(R.sup.+).sub.2,
--N(R.sup.+).sub.2, --NR.sup.+C(O)R*,
--NR.sup.+C(O)N(R.sup.+).sub.2,
--NR.sup.+CO.sub.2R.sup..smallcircle., --O--CO.sub.2R*,
--OC(O)N(R.sup.+).sub.2, --O--C(O)R*, --CO.sub.2R*, --C(O)--C(O)R*,
--C(O)R*, --C(O)N(R.sup.+).sub.2,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R*,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR*,
--N(R.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--NR.sup.+SO.sub.2R.sup..smallcircle., --NR.sup.+SO.sub.2N(R.sup.+)
2, --P(O)(R*).sub.2, --P(O)(OR*).sub.2, --O--P(O)--OR*, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2; or two adjacent substituents,
taken together with their intervening atoms, form a 5-6 membered
unsaturated or partially unsaturated ring having 0-3 ring atoms
selected from the group consisting of N, O, and S.
[0050] An aryl (including the aryl moiety in aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including the heteroaryl
moiety in heteroaralkyl and heteroaralkoxy and the like) group may
contain one or more substituents. Examples of suitable substituents
on the unsaturated carbon atom of an aryl or heteroaryl group
include -halo, --NO.sub.2, --CN, --R*, --C(R*)=C(R*).sub.2,
--C.ident.C--R*, --OR*, --SR.sup..smallcircle.,
--S(O)R.sup..smallcircle., --SO.sub.2R.sup..smallcircle.,
--SO.sub.3R.sup..smallcircle., --SO.sub.2N(R.sup.+).sub.2,
--N(R.sup.+).sub.2, --NR.sup.+C(O)R*,
--NR.sup.+C(O)N(R.sup.+).sub.2,
--NR.sup.+CO.sub.2R.sup..smallcircle., --O--CO.sub.2R*,
--OC(O)N(R.sup.+).sub.2, --O--C(O)R*, --CO.sub.2R*, --C(O)--C(O)R*,
--C(O)R*, --C(O)N(R.sup.+).sub.2,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R*,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR*,
--N(R.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--NR.sup.+SO.sub.2R.sup..smallcircle.,
--NR.sup.+SO.sub.2N(R.sup.+).sub.2, --P(O)(R*).sub.2,
--P(O)(OR*).sub.2, --O--P(O)--OR*, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2; or two adjacent substituents,
taken together with their intervening atoms, form a 5-6 membered
unsaturated or partially unsaturated ring having 0-3 ring atoms
selected from the group consisting of N, O, and S.
[0051] Each R.sup.+, independently, is hydrogen or an optionally
substituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or
two R.sup.+ on the same nitrogen atom, taken together with the
nitrogen atom, form a 5-8 membered aromatic or non-aromatic ring
having, in addition to the nitrogen atom, 0-2 ring heteroatoms
selected from N, O, and S. Each R* independently is hydrogen or an
optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl
group. Each R.sup..smallcircle. is an optionally substituted
aliphatic or aryl group.
[0052] An aliphatic group or a non-aromatic heterocyclic ring may
be substituted with one or more substituents. Examples of suitable
substituents on the saturated carbon of an aliphatic group or of a
non-aromatic heterocyclic ring include, without limitation, those
listed above for the unsaturated carbon of an aryl or heteroaryl
group and the following: .dbd.O, .dbd.S, .dbd.C(R*).sub.2,
.dbd.N--N(R*).sub.2, .dbd.N--OR*, .dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup..smallcircle.,
.dbd.N--NHSO.sub.2R.sup..smallcircle., or .dbd.N--R*, where each R*
and R.sup..smallcircle. is as defined above.
[0053] Suitable substituents on the nitrogen atom of a non-aromatic
heterocyclic ring include --R*, --N(R*).sub.2, --C(O)R*,
--CO.sub.2R*, --C(O)--C(O)R*-C(O)CH.sub.2C(O)R*, --SO.sub.2R*,
--SO.sub.2N(R*).sub.2, --C(.dbd.S) N(R*).sub.2,
--C(.dbd.NH)--N(R*).sub.2, and --NR*SO.sub.2R*; wherein each R* is
as defined above.
[0054] Unless otherwise stated, structures depicted herein are
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structure except for the replacement of a hydrogen atom
by a deuterium or tritium, or the replacement of a carbon atom by a
.sup.13C- or .sup.14C-enriched carbon are within the scope of the
invention.
[0055] It will be apparent to one skilled in the art that certain
compounds described herein may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention. Unless otherwise stated, structures depicted herein are
also meant to include all stereochemical forms of the structure;
i.e., the R and S configurations for each asymmetric center.
Therefore, single stereochemical isomers as well as enantiomeric
and diastereomeric mixtures of the present compounds are within the
scope of the invention.
3. Detailed Description
[0056] Selective Inhibitors of Aurora A Kinase
[0057] Any molecule capable of selectively inhibiting the enzymatic
activity of Aurora A kinase may be used in the methods,
pharmaceutical compositions, and kits of the present invention. In
some embodiments the selective Aurora A kinase inhibitor is a small
molecular weight compound. In particular, selective inhibitors of
Aurora A kinase include the compounds described herein, as well as
compounds disclosed in, for example, US Publication No.
2008/0045501, U.S. Pat. No. 7,572,784, WO 05/111039, WO 08/021,038,
U.S. Pat. No. 7,718,648, WO 08/063,525, US Publication No.
2008/0167292, U.S. Pat. No. 8,026,246, WO 10/134,965, US
Publication No. 2010/0310651, WO 11/014,248, US Publication No.
2011/0039826, and US Publication No. 2011/0245234, each of which is
hereby incorporated by reference in its entirety, sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoate, KW-2449 (Kyowa), ENMD-2076
(EntreMed), and MK-5108 (Vertex/Merck). Also suitable for use in
the methods, pharmaceutical compositions, and kits of the invention
are solvated and hydrated forms of any of these compounds. Also
suitable for use in the methods, pharmaceutical compositions, and
kits of the invention are pharmaceutically acceptable salts of any
of the compounds, and solvated and hydrated forms of such salts.
These selective Aurora A kinase inhibitors can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis, including, but not limited to, the methods of synthesis
described in detail in the references referred to herein.
[0058] Aurora A kinase inhibitors can be assayed in vitro or in
vivo for their ability to selectively bind to and/or inhibit an
Aurora A kinase. In vitro assays include assays to determine
selective inhibition of the ability of an Aurora A kinase to
phosphorylate a substrate protein or peptide. Alternate in vitro
assays quantitate the ability of the compound to selectively bind
to an Aurora A kinase. Selective inhibitor binding may be measured
by radiolabelling the inhibitor prior to binding, isolating the
inhibitor/Aurora A kinase complex and determining the amount of
radiolabel bound. Alternatively, selective inhibitor binding may be
determined by running a competition experiment in which new
inhibitors are incubated with Aurora A kinase bound to a known
radioligand. The compounds also can be assayed for their ability to
affect cellular or physiological functions mediated by Aurora A
kinase activity. In order to assess selectivity for Aurora A kinase
over Aurora B kinase, inhibitors can also be assayed in vitro and
in vivo for their ability to selectively bind to and/or inhibit an
Aurora B kinase, using assays analogous to those described above
for Aurora A kinase. Inhibitors can be assayed in vitro and in vivo
for their ability to inhibit Aurora A kinase in the absence of
Aurora B kinase inhibition, by immunofluorescent detection of pH is
H3. (Proc. Natl. Acad. Sci. (2007) 104, 4106). Assays for each of
these activities are known in the art.
[0059] In some embodiments, the selective Aurora A kinase inhibitor
is represented by formula (V):
##STR00001##
or a pharmaceutically acceptable salt thereof; wherein: [0060]
R.sup.a is selected from the group consisting of C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, --R.sup.1-T-R.sup.1,
--R.sup.2, and -T-R.sup.2; [0061] T is a C.sub.1-3 alkylene chain
optionally substituted with fluoro; [0062] R.sup.1 is an optionally
substituted aryl, heteroaryl, or heterocyclyl group; [0063] R.sup.2
is selected from the group consisting of halo,
--C.ident.C--R.sup.3, --CH.dbd.CH--R.sup.3, --N(R.sup.4).sub.2, and
--OR.sup.5; [0064] R.sup.3 is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; [0065] each
R.sup.4 independently is hydrogen or an optionally substituted
aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R.sup.4
on the same nitrogen atom, taken together with the nitrogen atom
form an optionally substituted 5- to 6-membered heteroaryl or 4- to
8-membered heterocyclyl ring having, in addition to the nitrogen
atom, 0-2 ring heteroatoms selected from N, O, and S; [0066]
R.sup.5 is hydrogen or an optionally substituted aliphatic, aryl,
heteroaryl, or heterocyclyl group; and [0067] R.sup.b is selected
from the group consisting of fluoro, [0068] chloro, --CH.sub.3,
--CF.sub.3, --OH, --OCH.sub.3, --OCF.sub.3, --OCH.sub.2CH.sub.3,
and --OCH.sub.2CF.sub.3.
[0069] In some embodiments, R.sup.1 is a 5- or 6-membered aryl,
heteroaryl, or heterocyclyl ring optionally substituted with one or
two substituents independently selected from the group consisting
of halo, C.sub.1-3 aliphatic, and C.sub.1-3 fluoroaliphatic. In
certain embodiments, R.sup.1 is a phenyl, furyl, pyrrolidinyl, or
thienyl ring optionally substituted with one or two substituents
independently selected from the group consisting of halo, C.sub.1-3
aliphatic, and C.sub.1-3 fluoroaliphatic.
[0070] In some embodiments, R.sup.3 is hydrogen, C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, or --CH.sub.2--OCH.sub.3.
[0071] In some embodiments, R.sup.5 is hydrogen, C.sub.1-3
aliphatic, or C.sub.1-3 fluoroaliphatic.
[0072] In certain embodiments, R.sup.a is halo, C.sub.1-3
aliphatic, C.sub.1-3 fluoroaliphatic, --OH, --O(C.sub.1-3
aliphatic), --O(C.sub.1-3 fluoroaliphatic), --C.ident.C--R.sup.3,
--CH.dbd.CH--R.sup.3, or an optionally substituted pyrrolidinyl,
thienyl, furyl, or phenyl ring, wherein R.sup.3 is hydrogen,
C.sub.1-3 aliphatic, C.sub.1-3 fluoroaliphatic, or
--CH.sub.2--OCH.sub.3. In certain particular embodiments, R.sup.a
is selected from the group consisting of chloro, fluoro, C.sub.1-3
aliphatic,
C.sub.1-3 fluoroaliphatic, --OCH.sub.3, --OCF.sub.3,
--C.ident.C--H, --C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2OCH.sub.3, --CH.dbd.CH.sub.2,
--CH.dbd.CHCH.sub.3, N-methylpyrrolidinyl, thienyl, methylthienyl,
furyl, methylfuryl, phenyl, fluorophenyl, and tolyl.
[0073] Table 1 provides the chemical names for specific examples of
compounds of formula (V).
TABLE-US-00001 TABLE 1 Examples of Compounds of Formula (V)
Chemical Name V-1
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzaze-
pin-2- yl]amino}-2-methoxybenzoic acid V-2
4-{[9-ethynyl-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d|[2]benzaz-
epin-2- yl]amino}-2-methoxybenzoic acid V-3
4-({9-chloro-7-[2-fluoro-6-(trifluoromethoxy)phenyl]-5H-pyrimido[5,4-
d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid V-4
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(1-methyl-1H-pyrrol-2-yl)-5H-pyrimi-
do[5,4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-5
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(4-methyl-3-thienyl)-5H-pyrimido[5,-
4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-6
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methyl-2-furyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-7
4-({9-ethynyl-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimido-
[5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid V-8
4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2--
yl]amino}-2- methoxybenzoic acid V-9
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-methylphenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-10
4-{[7-(2-fluoro-6-methoxyphenyl)-9-prop-1-yn-1-yl-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-11
4-{[7-(2-fluoro-6-methoxyphenyl)-9-vinyl-5H-pyrimido[5,4-d][2]benzaze-
pin-2- yl]amino}-2-methoxybenzoic acid V-12
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-fluorophenyl)-5H-pyrimido[5,4-
d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-13
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methoxyprop-1-yn-1-yl)-5H-pyrim-
ido[5,4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid V-14
4-({7-(2-fluoro-6-methoxyphenyl)-9-[(1E)-prop-1-en-1-yl]-5H-pyrimido[-
5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid V-15
4-({9-chloro-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimido-
[5,4- d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid V-16
4-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-furyl)-5H-pyrimido[5,4-d][2]ben-
zazepin-2- yl]amino}-2-methoxybenzoic acid V-17
4-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-d][2]benzaz-
epin-2- yl]amino}-2-methoxybenzoic acid V-18
4-{[7-(2-fluoro-6-methoxyphenyl)-9-phenyl-5H-pyrimido[5,4-d][2]benzaz-
epin-2- yl]amino}-2-methoxybenzoic acid
[0074] In one embodiment, the compound of formula (V) is
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoic acid (alisertib (MLN8237)), or a
pharmaceutically acceptable salt thereof. In another embodiment,
the compound of formula (V) is sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoate. In yet another embodiment, the
compound of formula (V) is sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoate monohydrate. In another embodiment,
the compound of formula (V) is sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoate polymorph Form 2, as described in US
Publication No. 2008/0167292, U.S. Pat. No. 8,026,246, and US
Publication No. 2011/0245234, each of which is hereby incorporated
by reference in their entirety.
[0075] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also a selective inhibitor
of Aurora A kinase.
[0076] If a pharmaceutically acceptable salt of the selective
inhibitor of Aurora A kinase is utilized in pharmaceutical
compositions, the salt preferably is derived from an inorganic or
organic acid or base. For reviews of suitable salts, see, e.g.,
Berge et al, J. Pharm. Sci. 66:1-19 (1977) and Remington: The
Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro,
Lippincott Williams & Wilkins, 2000.
[0077] Nonlimiting examples of suitable acid addition salts include
the following: acetate, adipate, alginate, aspartate, benzoate,
benzene sulfonate, bisulfate, butyrate, citrate, camphorate,
camphor sulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate,
3-phenyl-propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate and undecanoate.
[0078] Suitable base addition salts include, without limitation,
ammonium salts, alkali metal salts, such as sodium and potassium
salts, alkaline earth metal salts, such as calcium and magnesium
salts, salts with organic bases, such as dicyclohexylamine,
N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine,
and choline, and salts with amino acids such as arginine, lysine,
and so forth.
[0079] Also, basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates,
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides, such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0080] Dosages and Administration of Selective Inhibitors of Aurora
A Kinase in Combination with Taxanes
[0081] The therapeutically effective amounts or suitable dosages of
the selective inhibitor of Aurora A kinase depends upon a number of
factors, including the nature of the severity of the condition to
be treated, the particular inhibitor, the route of administration
and the age, weight, general health, and response of the individual
patient. In certain embodiments, the suitable dose level is one
that achieves an effective exposure as measured by increased skin
mitotic index, or decreased chromosome alignment and spindle
bipolarity in tumor mitotic cells, or other standard measures of
effective exposure in cancer patients. In certain embodiments, the
suitable dose level is one that achieves a therapeutic response as
measured by tumor regression, or other standard measures of disease
progression, progression free survival or overall survival. In
other embodiments, the suitable dose level is one that achieves
this therapeutic response and also minimizes any side effects
associated with the administration of the therapeutic agent.
[0082] Suitable daily dosages of selective inhibitors of Aurora A
kinase can generally range, in single or divided or multiple doses,
from about 10% to about 100% of the maximum tolerated dose as a
single agent. In certain embodiments, the suitable dosages are from
about 15% to about 100% of the maximum tolerated dose as a single
agent. In some other embodiments, the suitable dosages are from
about 25% to about 90% of the maximum tolerated dose as a single
agent. In some other embodiments, the suitable dosages are from
about 30% to about 80% of the maximum tolerated dose as a single
agent. In some other embodiments, the suitable dosages are from
about 40% to about 75% of the maximum tolerated dose as a single
agent. In some other embodiments, the suitable dosages are from
about 45% to about 60% of the maximum tolerated dose as a single
agent. In other embodiments, suitable dosages are about 10%, about
15%, about 20%, about 25%, about 30%, about 35%, about 40%, about
45%, about 50%, about 55%, about 60%, about 65%, about 70%, about
75%, about 80%, about 85%, about 90%, about 95%, about 100%, about
105%, or about 110% of the maximum tolerated dose as a single
agent.
[0083] Suitable daily dosages of alisertib can generally range, in
single or divided or multiple doses, from about 20 mg to about 120
mg per day. Other suitable daily dosages of alisertib can generally
range, in single or divided or multiple doses, from about 40 mg to
about 80 mg per day. Other suitable daily dosages of alisertib can
generally range, in single or divided or multiple doses, from about
60 mg to about 80 mg per day. In certain embodiments, the suitable
dosages are from about 10 mg twice daily to about 40 mg twice
daily. In some other embodiments, the suitable dosages are from
about 20 mg twice daily to about 40 mg twice daily. In some other
embodiments, the suitable dosages are from about 30 mg twice daily
to about 50 mg twice daily. In some other embodiments, the suitable
dosages are from about 30 mg twice daily to about 40 mg twice
daily. In some other embodiments, the suitable dosages are from
about 40 mg twice daily to about 50 mg twice daily. In other
embodiments, suitable dosages are about 20 mg, about 25 mg, about
30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55
mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80
mg, about 85 mg, about 90 mg per day, about 95 mg per day, about
100 mg per day, about 105 mg per day, about 110 mg per day, about
115 mg per day, or about 120 mg per day. In certain other
embodiments, suitable dosages are about 10 mg, about 15 mg, about
20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45
mg, about 50 mg, about 55 mg, or about 60 mg twice daily.
[0084] It will be understood that a suitable dosage of a selective
inhibitor of Aurora A kinase may be taken at any time of the day or
night. In some embodiments, a suitable dosage of a selective
inhibitor of Aurora A kinase is taken in the morning. In some other
embodiments, a suitable dosage of a selective inhibitor of Aurora A
kinase is taken in the evening. In some other embodiments, a
suitable dosage of a selective inhibitor of Aurora A kinase is
taken both in the morning and the evening. It will be understood
that a suitable dosage of a selective inhibitor of Aurora A kinase
may be taken with or without food. In some embodiments a suitable
dosage of a selective inhibitor of Aurora A kinase is taken with a
meal. In some embodiments a suitable dosage of a selective
inhibitor of Aurora A kinase is taken while fasting.
[0085] Suitable weekly dosages of paclitaxel can generally range,
in single or divided or multiple doses, from about 40 mg/m.sup.2 to
about 80 mg/m.sup.2 per week. Other suitable weekly dosages of
paclitaxel can generally range, in single or divided or multiple
doses, from about 50 mg/m.sup.2 to about 75 mg/m.sup.2 per week.
Other suitable weekly dosages of paclitaxel can generally range, in
single or divided or multiple doses, from about 60 mg/m.sup.2 to
about 70 mg/m.sup.2 per week. In other embodiments, suitable weekly
dosages are about 40 mg/m.sup.2, about 45 mg/m.sup.2, about 50
mg/m.sup.2, about 55 mg/m.sup.2, about 60 mg/m.sup.2, about 65
mg/m.sup.2, about 70 mg/m.sup.2, or about 75 mg/m.sup.2 per
week.
[0086] Additionally, it will be appreciated that the frequency with
which any of these therapeutic agents can be administered can be
once or more than once over a period of about 2 days, about 3 days,
about 4 days, about 5 days, about 6 days, about 7 days, about 8
days, about 9 days, about 10 days, about 20 days, about 28 days,
about a week, about 2 weeks, about 3 weeks, about 4 weeks, about a
month, about every 2 months, about every 3 months, about every 4
months, about every 5 months, about every 6 months, about every 7
months, about every 8 months, about every 9 months, about every 10
months, about every 11 months, about every year, about every 2
years, about every 3 years, about every 4 years, or about every 5
years.
[0087] For example, an agent may be administered daily, weekly,
biweekly, or monthly for a particular period of time. In some
embodiments, a certain amount of the selective Aurora A kinase
inhibitor can be administered on a daily basis over a period of
three days. Alternatively, an agent may be administered daily,
weekly, biweekly, or monthly for a particular period of time
followed by a particular period of non-treatment. In some
embodiments, a certain amount of the selective Aurora A kinase
inhibitor can be administered daily for three days followed by four
days of no administration, followed by administration daily for
three days followed by four more days of no administration,
followed by administration daily for three days followed by four
more days of no administration. In some embodiments, a certain
amount of a taxane can be administered weekly over a three week
period.
[0088] In some embodiments, the selective Aurora A kinase inhibitor
and the taxane are cyclically administered to a patient. Cycling
therapy involves the administration of a first agent (e.g., a first
prophylactic or therapeutic agents) for a period of time, followed
by the administration of a second agent and/or third agent (e.g., a
second and/or third prophylactic or therapeutic agents) for a
period of time and repeating this sequential administration.
Cycling therapy can reduce the development of resistance to one or
more of the therapies, avoid or reduce the side effects of one of
the therapies, and/or improve the efficacy of the treatment.
[0089] In some embodiments, the treatment period during which an
agent is administered is then followed by a non-treatment period of
a particular time duration, during which the therapeutic agents are
not administered to the patient. This non-treatment period can then
be followed by a series of subsequent treatment and non-treatment
periods of the same or different frequencies for the same or
different lengths of time. In some embodiments, the treatment and
non-treatment periods are alternated. It will be understood that
the period of treatment in cycling therapy may continue until the
patient has achieved a complete response or a partial response, at
which point the treatment may be stopped. Alternatively, the period
of treatment in cycling therapy may continue until the patient has
achieved a complete response or a partial response, at which point
the period of treatment may continue for a particular number of
cycles. In some embodiments, the length of the period of treatment
may be a particular number of cycles, regardless of patient
response. In some other embodiments, the length of the period of
treatment may continue until the patient relapses.
[0090] For example, a certain amount of the selective Aurora A
kinase inhibitor can be administered twice daily for 3 days
followed by 11 days of non-treatment followed by 3 days of twice
daily administration. In some embodiments, the treatment and
non-treatment periods are alternated. In other embodiments, a first
treatment period in which a first amount of the selective inhibitor
of Aurora A kinase is administered can be followed by another
treatment period in which a same or different amount of the same or
a different selective inhibitor of Aurora A kinase is administered.
The second treatment period can be followed by other treatment
periods. During the treatment and non-treatment periods, one or
more additional therapeutic agents can be administered to the
patient.
[0091] In one embodiment, the administration is on a 28-day dose
schedule in which the selective Aurora A kinase inhibitor is
administered twice-daily in a schedule of 3 days on followed by 4
days off, repeated weekly for three weeks concomitantly with the
first dose of once-weekly paclitaxel, repeated weekly for 3 weeks
(the twice-daily selective Aurora A kinase inhibitor is given on
days 1, 2, 3, 8, 9, 10, 15, 16, and 17; and the weekly paclitaxel
is given on days 1, 8, and 15 of the 28-day schedule). In some
embodiments, the dose schedules for the selective Aurora A kinase
inhibitors described herein are dose schedules for administration
of alisertib.
[0092] In another embodiment, the administration is on a 28-day
dose schedule in which the selective Aurora A kinase inhibitor is
administered twice-daily in a schedule of 2 days on followed by 5
days off, repeated weekly for three weeks concomitantly with the
first dose of once-weekly paclitaxel, repeated weekly for 3 weeks
(the twice-daily selective Aurora A kinase inhibitor is given on
days 1, 2, 8, 9, 15, and 16; and the weekly paclitaxel is given on
days 1, 8, and 15 of the 28-day schedule). In some embodiments, the
dose schedules for the selective Aurora A kinase inhibitors
described herein are dose schedules for administration of
alisertib.
[0093] In one embodiment, the administration is on a 28-day dose
schedule in which the selective Aurora A kinase inhibitor is
administered twice-daily in a schedule of 3 days on followed by 4
days off, repeated weekly for two weeks concomitantly with the
first dose of once-weekly paclitaxel, repeated weekly for 3 weeks
(the twice-daily selective Aurora A kinase inhibitor is given on
days 1, 2, 3, 8, 9, and 10; and the weekly paclitaxel is given on
days 1, 8, and 15 of the 28-day schedule). In some embodiments, the
dose schedules for the selective Aurora A kinase inhibitors
described herein are dose schedules for administration of
alisertib.
[0094] In another embodiment, the administration is on a 28-day
dose schedule in which the selective Aurora A kinase inhibitor is
administered twice-daily in a schedule of 3 days on followed by 11
days off, repeated once, concomitantly with the first and third
dose of once-weekly paclitaxel, repeated weekly for 3 weeks (the
twice-daily selective Aurora A kinase inhibitor is given on days 1,
2, 3, 15, 16, and 17; and the weekly paclitaxel is given on days 1,
8, and 15 of the 28-day schedule). In some embodiments, the dose
schedules for the selective Aurora A kinase inhibitors described
herein are dose schedules for administration of alisertib.
[0095] The selective inhibitor of Aurora A kinase can be
administered by any method known to one skilled in the art. For
example, the selective inhibitor of Aurora A kinase can be
administered in the form of a composition, in one embodiment a
pharmaceutical composition of the selective inhibitor of Aurora A
kinase and a pharmaceutically acceptable carrier, such as those
described herein. Preferably, the pharmaceutical composition is
suitable for oral administration. In some embodiments, the
pharmaceutical composition is a tablet for oral administration,
such as an enteric coated tablet. Such tablets are described in US
Publication No. 2010/0310651, which is hereby incorporated by
reference in its entirety. In some other embodiments, the
pharmaceutical composition is a liquid dosage form for oral
administration. Such liquid dosage forms are described in US
Publication No. 2011/0039826, hereby incorporated by reference. In
certain embodiments, these compositions optionally further comprise
one or more additional therapeutic agents.
[0096] The taxane (e.g., paclitaxel or docetaxel) can be
administered by any method known to one skilled in the art. For
example, the taxane can be administered in the form of a
composition, in one embodiment a pharmaceutical composition of a
taxane and a pharmaceutically acceptable carrier, such as those
described herein. In some embodiments, the pharmaceutical
composition is a liquid dosage form, which can be administered via
an intravenous route, such as intravenous injection or intravenous
infusion. In one embodiment, paclitaxel is administered via
intravenous injection. In another embodiment ABRAXANE.RTM. is
administered via intravenous injection. Such pharmaceutical
compositions are described in U.S. Pat. No. 6,096,331 and U.S. Pat.
No. 6,506,405.
[0097] The term "pharmaceutically acceptable carrier" is used
herein to refer to a material that is compatible with a recipient
subject, preferably a mammal, more preferably a human, and is
suitable for delivering an active agent to the target site without
terminating the activity of the agent. The toxicity or adverse
effects, if any, associated with the carrier preferably are
commensurate with a reasonable risk/benefit ratio for the intended
use of the active agent.
[0098] The terms "carrier", "adjuvant", or "vehicle" are used
interchangeably herein, and include any and all solvents, diluents,
and other liquid vehicles, dispersion or suspension aids, surface
active agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington: The Science and
Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams
& Wilkins, 2000 discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate,
sodium bicarbonate, potassium carbonate, potassium bicarbonate,
magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid,
or potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, pyrogen-free water, salts or
electrolytes such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, and zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose, sucrose, starches such as corn starch and
potato starch, cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate,
powdered tragacanth; malt, gelatin, talc, excipients such as cocoa
butter and suppository waxes, oils such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil, glycols such as propylene glycol and polyethylene glycol,
esters such as ethyl oleate and ethyl laurate, agar, alginic acid,
isotonic saline, Ringer's solution, alcohols such as ethanol,
isopropyl alcohol, hexadecyl alcohol, and glycerol, cyclodextrins,
lubricants such as sodium lauryl sulfate and magnesium stearate,
petroleum hydrocarbons such as mineral oil and petrolatum. Coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0099] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain solvents, diluents,
and other liquid vehicles, dispersion or suspension aids, surface
active agents, pH modifiers, isotonic agents, thickening or
emulsifying agents, stabilizers and preservatives, solid binders,
lubricants and the like, as suited to the particular dosage form
desired.
[0100] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the present invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. Preferably, the compositions are
administered orally, intravenously, or subcutaneously. The
formulations of the invention may be designed to be short-acting,
fast-releasing, or long-acting. Still further, compounds can be
administered in a local rather than systemic means, such as
administration (e.g., by injection) at a tumor site.
[0101] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, cyclodextrins,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0102] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables. The
injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use. Compositions
formulated for parenteral administration may be injected by bolus
injection or by timed push, or may be administered by continuous
infusion.
[0103] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0104] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0105] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents such as
phosphates or carbonates.
[0106] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[0107] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0108] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0109] Compositions for use in the method of the invention may be
formulated in unit dosage form for ease of administration and
uniformity of dosage. The expression "unit dosage form" as used
herein refers to a physically discrete unit of agent appropriate
for the patient to be treated. It will be understood, however, that
the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within
the scope of sound medical judgment. A unit dosage form for
parenteral administration may be in ampoules or in multi-dose
containers.
[0110] The present invention is also directed to kits and other
articles of manufacture for treating proliferative diseases. In one
embodiment, a kit is provided that comprises a selective inhibitor
of Aurora A kinase, or a pharmaceutically acceptable salt thereof,
as described herein; a taxane, or a pharmaceutically acceptable
salt thereof, as described herein; and instructions. The kit may
optionally further include the one or more additional therapeutic
agents, as described herein. The instructions may indicate the
disease state for which the kit is to be used, storage information,
dosing information and/or instructions regarding how to administer
the selective inhibitor of Aurora A kinase, the taxane, and/or
additional therapeutic agent or agents. The kit may also comprise
packaging materials. The packaging material may comprise a
container for housing the contents of the kit. The kit may also
optionally comprise additional components, such as syringes for
administration of the contents of the kit. The kit may comprise the
selective inhibitor Aurora A kinase, the taxane, and/or additional
therapeutic agent or agents in single or multiple dose forms.
[0111] In another embodiment, an article of manufacture is provided
that comprises the selective inhibitor of Aurora A kinase, or a
pharmaceutically acceptable salt thereof; taxane, or a
pharmaceutically acceptable salt thereof; and packaging materials.
The article of manufacture may optionally further include the one
or more additional therapeutic agents. The packaging material may
comprise a container for housing the contents of the article of
manufacture. The container may optionally comprise a label
indicating the disease state for which the article is to be used,
storage information, dosing information and/or instructions
regarding how to administer the selective inhibitor of Aurora A
kinase, taxane, and/or additional therapeutic agent or agents. The
article may also optionally comprise additional components, such as
syringes for administration of the composition. The article may
comprise the selective inhibitor of Aurora A kinase, taxane, and/or
additional therapeutic agent or agents in single or multiple dose
forms.
[0112] A wide variety of therapeutic agents may have a
therapeutically relevant added benefit in combination with the
combination of a selective inhibitor of Aurora A kinase and a
taxane of the present invention. Combination therapies that
comprise the combination of a selective inhibitor of Aurora A
kinase and a taxane of the present invention with one or more other
therapeutic agents can be used, for example, to: 1) enhance the
therapeutic effect(s) of the methods of the present invention
and/or the one or more other therapeutic agents; 2) reduce the side
effects exhibited by the methods of the present invention and/or
the one or more other therapeutic agents; and/or 3) reduce the
effective dose of the selective inhibitor of Aurora A kinase and
the taxane of the present invention and/or the one or more other
therapeutic agents.
[0113] In some embodiments, the method of the invention comprises
administration of a selective inhibitor of Aurora A kinase in
combination with a taxane and an additional therapeutic agent,
wherein the amounts of each agent are therapeutically effective
when used in combination.
[0114] In certain embodiments, the selective inhibitor of Aurora A
kinase in combination with a taxane is administered with the
concomitant or sequential administration of cisplatin or
doxorubicin. It will be appreciated that combination therapy
includes administration of the therapeutic agents concurrently or
sequentially. Alternatively, the therapeutic agents can be combined
into one composition which is administered to the patient.
[0115] Examples of therapeutic agents that may be used in
combination with the combination of a selective inhibitor of Aurora
A kinase and a taxane of the present invention include, but are not
limited to, anti-proliferative agents, anticancer agents,
alkylating agents, antibiotic agents, antimetabolic agents,
hormonal agents, plant-derived agents, and biologic agents.
Examples of some of the above classes of additional therapeutic
agents are listed below for purposes of illustration and not for
purposes of limitation, as these examples are not all-inclusive.
Many of the examples below could be listed in multiple classes of
anti-cancer agents and are not restricted in any way to the class
in which they are listed.
[0116] Alkylating agents are polyfunctional compounds that have the
ability to substitute alkyl groups for hydrogen ions. Examples of
alkylating agents include, but are not limited to,
bischloroethylamines (nitrogen mustards, e.g. chlorambucil,
cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil
mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g.
busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin),
nonclassic alkylating agents (altretamine, dacarbazine, and
procarbazine), platinum compounds (carboplastin and cisplatin).
These compounds react with phosphate, amino, hydroxyl, sulfihydryl,
carboxyl, and imidazole groups. Under physiological conditions,
these drugs ionize and produce positively charged ion that attach
to susceptible nucleic acids and proteins, leading to cell cycle
arrest and/or cell death. Combination therapy including an
inhibitor of the present invention and an alkylating agent may have
therapeutic synergistic effects on cancer and reduce sides affects
associated with these chemotherapeutic agents.
[0117] Antibiotic agents are a group of drugs that produced in a
manner similar to antibiotics as a modification of natural
products. Examples of antibiotic agents include, but are not
limited to, anthracyclines (e.g. doxorubicin, daunorubicin,
epirubicin, idarubicin and anthracenedione), mitomycin C,
bleomycin, dactinomycin, plicatomycin. These antibiotic agents
interfere with cell growth by targeting different cellular
components. For example, anthracyclines are generally believed to
interfere with the action of DNA topoisomerase II in the regions of
transcriptionally active DNA, which leads to DNA strand scissions.
Bleomycin is generally believed to chelate iron and forms an
activated complex, which then binds to bases of DNA, causing strand
scissions and cell death. Combination therapy including an
inhibitor of the present invention and an antibiotic agent may have
therapeutic synergistic effects on cancer and reduce sides affects
associated with these chemotherapeutic agents.
[0118] Antimetabolic agents are a group of drugs that interfere
with metabolic processes vital to the physiology and proliferation
of cancer cells. Actively proliferating cancer cells require
continuous synthesis of large quantities of nucleic acids,
proteins, lipids, and other vital cellular constituents. Many of
the antimetabolites inhibit the synthesis of purine or pyrimidine
nucleosides or inhibit the enzymes of DNA replication. Some
antimetabolites also interfere with the synthesis of
ribonucleosides and RNA and/or amino acid metabolism and protein
synthesis as well. By interfering with the synthesis of vital
cellular constituents, antimetabolites can delay or arrest the
growth of cancer cells. Examples of antimetabolic agents include,
but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR),
methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),
mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine
phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
Combination therapy including an inhibitor of the present invention
and a antimetabolic agent may have therapeutic synergistic effects
on cancer and reduce sides affects associated with these
chemotherapeutic agents.
[0119] Hormonal agents are a group of drug that regulate the growth
and development of their target organs. Most of the hormonal agents
are sex steroids and their derivatives and analogs thereof, such as
estrogens, androgens, and progestins. These hormonal agents may
serve as antagonists of receptors for the sex steroids to down
regulate receptor expression and transcription of vital genes.
Examples of such hormonal agents are synthetic estrogens (e.g.
diethylstibestrol), antiestrogens (e.g. tamoxifen, toremifene,
fluoxymesterol and raloxifene), antiandrogens (bicalutamide,
nilutamide, and flutamide), aromatase inhibitors (e.g.,
aminoglutethimide, anastrozole and tetrazole), ketoconazole,
goserelin acetate, leuprolide, megestrol acetate and mifepristone.
Combination therapy including an inhibitor of the present invention
and a hormonal agent may have therapeutic synergistic effects on
cancer and reduce sides effects associated with these
chemotherapeutic agents.
[0120] Plant-derived agents are a group of drugs that are derived
from plants or modified based on the molecular structure of the
agents. Examples of plant-derived agents include, but are not
limited to, vinca alkaloids (e.g., vincristine, vinblastine,
vindesine, vinzolidine and vinorelbine), and podophyllotoxins
(e.g., etoposide (VP-16) and teniposide (VM-26)). These
plant-derived agents generally act as antimitotic agents that bind
to tubulin and inhibit mitosis. Podophyllotoxins such as etoposide
are believed to interfere with DNA synthesis by interacting with
topoisomerase II, leading to DNA strand scission. Combination
therapy including an inhibitor of the present invention and a
plant-derived agent may have therapeutic synergistic effects on
cancer and reduce sides affects associated with these
chemotherapeutic agents.
[0121] Biologic agents are a group of biomolecules that elicit
cancer/tumor regression when used alone or in combination with
chemotherapy and/or radiotherapy. Examples of biologic agents
include, but are not limited to, immuno-modulating proteins such as
cytokines, monoclonal antibodies against tumor antigens, tumor
suppressor genes, and cancer vaccines. Combination therapy
including an inhibitor of the present invention and a biologic
agent may have therapeutic synergistic effects on cancer, enhance
the patient's immune responses to tumorigenic signals, and reduce
potential sides affects associated with this chemotherapeutic
agent.
[0122] Cytokines possess profound immunomodulatory activity. Some
cytokines such as interleukin-2 (IL-2, aldesleukin) and interferon
have demonstrated antitumor activity and have been approved for the
treatment of patients with metastatic renal cell carcinoma and
metastatic malignant melanoma. IL-2 is a T-cell growth factor that
is central to T-cell-mediated immune responses. The selective
antitumor effects of IL-2 on some patients are believed to be the
result of a cell-mediated immune response that discriminate between
self and nonself. Examples of interleukins that may be used in
conjunction with inhibitors of the present invention include, but
are not limited to, interleukin 2 (IL-2), and interleukin 4 (IL-4),
interleukin 12 (IL-12).
[0123] Interferons include more than 23 related subtypes with
overlapping activities, all of the IFN subtypes within the scope of
the present invention. IFN has demonstrated activity against many
solid and hematologic malignancies, the later appearing to be
particularly sensitive.
[0124] Other cytokines that may be used in conjunction with the
inhibitors of the present invention include those cytokines that
exert profound effects on hematopoiesis and immune functions.
Examples of such cytokines include, but are not limited to
erythropoietin, granulocyte-CSF (filgrastin), and granulocyte,
macrophage-CSF (sargramostim). These cytokines may be used in
conjunction with an inhibitor of the present invention to reduce
chemotherapy-induced myelopoietic toxicity.
[0125] Other immuno-modulating agents other than cytokines may also
be used in conjunction with the inhibitors of the present invention
to inhibit abnormal cell growth. Examples of such immuno-modulating
agents include, but are not limited to bacillus Calmette-Guerin,
levamisole, and octreotide, a long-acting octapeptide that mimics
the effects of the naturally occurring hormone somatostatin.
[0126] Monoclonal antibodies against tumor antigens are antibodies
elicited against antigens expressed by tumors, preferably
tumor-specific antigens. For example, monoclonal antibody
HERCEPTIN.RTM. (Trastruzumab) is raised against human epidermal
growth factor receptor2 (HER2) that is overexpressed in some breast
tumors including metastatic breast cancer. Overexpression of HER2
protein is associated with more aggressive disease and poorer
prognosis in the clinic. HERCEPTIN.RTM. is used as a single agent
for the treatment of patients with metastatic breast cancer whose
tumors over express the HER2 protein. Combination therapy including
an inhibitor of the present invention and HERCEPTIN.RTM. may have
therapeutic synergistic effects on tumors, especially on metastatic
cancers.
[0127] Another example of monoclonal antibodies against tumor
antigens is RITUXAN.RTM. (Rituximab) that is raised against CD20 on
lymphoma cells and selectively deplete normal and malignant
CD20.sup.+ pre-B and mature B cells. RITUXAN.RTM. is used as single
agent for the treatment of patients with relapsed or refractory
low-grade or follicular, CD20+, B cell non-Hodgkin's lymphoma.
Combination therapy including an inhibitor of the present invention
and RITUXAN.RTM. may have therapeutic synergistic effects not only
on lymphoma, but also on other forms or types of malignant
tumors.
[0128] Tumor suppressor genes are genes that function to inhibit
the cell growth and division cycles, thus preventing the
development of neoplasia. Mutations in tumor suppressor genes cause
the cell to ignore one or more of the components of the network of
inhibitory signals, overcoming the cell cycle check points and
resulting in a higher rate of controlled cell growth-cancer.
Examples of the tumor suppressor genes include, but are not limited
to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1, and BRCA2.
[0129] DPC-4 is involved in pancreatic cancer and participates in a
cytoplasmic pathway that inhibits cell division. NF-1 codes for a
protein that inhibits Ras, a cytoplasmic inhibitory protein. NF-1
is involved in neurofibroma and pheochromocytomas of the nervous
system and myeloid leukemia. NF-2 encodes a nuclear protein that is
involved in meningioma, schwanoma, and ependymoma of the nervous
system. RB codes for the pRB protein, a nuclear protein that is a
major inhibitor of cell cycle. RB is involved in retinoblastoma as
well as bone, bladder, small cell lung and breast cancer. P53 codes
for p53 protein that regulates cell division and can induce
apoptosis. Mutation and/or inaction of p53 is found in a wide
ranges of cancers. WT1 is involved in Wilms tumor of the kidneys.
BRCA1 is involved in breast and ovarian cancer, and BRCA2 is
involved in breast cancer. The tumor suppressor gene can be
transferred into the tumor cells where it exerts its tumor
suppressing functions. Combination therapy including an inhibitor
of the present invention and a tumor suppressor may have
therapeutic synergistic effects on patients suffering from various
forms of cancers.
[0130] Cancer vaccines are a group of agents that induce the body's
specific immune response to tumors. Most of cancer vaccines under
research and development and clinical trials are tumor-associated
antigens (TAAs). TAA are structures (i.e. proteins, enzymes or
carbohydrates) which are present on tumor cells and relatively
absent or diminished on normal cells. By virtue of being fairly
unique to the tumor cell, TAAs provide targets for the immune
system to recognize and cause their destruction. Example of TAAs
include, but are not limited to gangliosides (GM2), prostate
specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic
antigen (CEA) (produced by colon cancers and other adenocarcinomas,
e.g. breast, lung, gastric, and pancreas cancer s), melanoma
associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),
papillomavirus E6 and E7 fragments, whole cells or portions/lysates
of antologous tumor cells and allogeneic tumor cells.
[0131] An adjuvant may be used to augment the immune response to
TAAs. Examples of adjuvants include, but are not limited to,
bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides,
keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2),
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
Cytoxan, a chemotherapeutic agent which is believe to reduce
tumor-induced suppression when given in low doses.
[0132] In certain embodiments, the one or more additional
treatments is selected from radiation, chemotherapy, immunotherapy,
or other targeted anticancer therapy.
[0133] Cancers to be Treated with the Selective Inhibitor of Aurora
A kinase or Combinations Thereof
[0134] The present invention provides new methods for the treatment
of cell proliferative disorders. As used herein, the term "cell
proliferative disorders" includes, but is not limited to, cancerous
hyperproliferative disorders (e.g., brain, lung, squamous cell,
bladder, gastric, pancreatic, breast, head, neck, renal, liver,
kidney, ovarian, prostate, colorectal, colon, epidermoid,
esophageal, testicular, gynecological or thyroid cancer, acute
myeloid leukemia, multiple myeloma, mesothelioma, Non-small cell
lung carcinoma (NSCLC), small cell lung cancer (SCLC),
neuroblastoma, and acute lymphoblastic leukemia (ALL));
non-cancerous hyperproliferative disorders (e.g., benign
hyperplasia of the skin (e.g., psoriasis), restenosis, and benign
prostatic hypertrophy (BPH)); and diseases related to
vasculogenesis or angiogenesis (e.g., tumor angiogenesis,
hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,
lung, pancreatic, prostate, colon and epidermoid cancer). Cell
proliferative disorders further encompass primary and metastatic
cancers.
[0135] In particular, the compounds are useful in the treatment of
cancers in a subject, including, but not limited to, lung and
bronchus, including non-small cell lung cancer (NSCLC), squamous
lung cancer, brochioloalveolar carcinoma (BAC), adenocarcinoma of
the lung, and small cell lung cancer (SCLC); prostate, including
androgen-dependent and androgen-independent prostate cancer;
breast, including metastatic breast cancer; pancreas; colon and
rectum; thyroid; liver and intrahepatic bile duct; hepatocellular;
gastric; endometrial; melanoma; kidney; and renal pelvis, urinary
bladder; uterine corpus; uterine cervix; ovary, including
progressive epithelial or primary peritoneal cancer; multiple
myeloma; esophagus; acute myelogenous leukemia (AML); chronic
myelogenous leukemia (CML), including accelerated CML and CML blast
phase (CML-BP); lymphocytic leukemia; myeloid leukemia; acute
lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL);
Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including
follicular lymphoma and mantle cell lymphoma; B-cell lymphoma,
including diffuse large B-cell lymphoma (DLBCL); T-cell lymphoma;
multiple myeloma (MM); amyloidosis; Waldenstrom's
macroglobulinemia; myelodysplastic syndromes (MDS), including
refractory anemia (RA), refractory anemia with ringed siderblasts
(RARS), (refractory anemia with excess blasts (RAEB), and RAEB in
transformation (RAEB-T); and myeloproliferative syndromes; brain,
including glioma/glioblastoma, anaplastic oligodendroglioma, and
adult anaplastic astrocytoma; neuroendocrine, including metastatic
neuroendocrine tumors; head and neck, including, e.g., squamous
cell carcinoma of the head and neck, and nasopharyngeal cancer;
oral cavity; and pharynx; small intestine; bone; soft tissue
sarcoma; and villous colon adenoma.
[0136] In one embodiment, diseases or disorders treatable by the
combination of Aurora A kinase selective inhibitors and taxanes,
include, but are not limited to, ovarian cancer, breast cancer,
prostate cancer, gastric cancer, head and neck cancer, bladder
cancer, lung cancer, epithelial ovarian cancer, fallopian tube
cancer, primary peritoneal cancer, and AIDS-related Kaposi's
sarcoma. In another embodiment, diseases or disorders treatable by
the combination of Aurora A kinase selective inhibitors and
taxanes, include, but are not limited to, ovarian cancer, breast
cancer, lung cancer, and AIDS-related Kaposi's sarcoma. In yet
another embodiment, the disease or disorder treatable by the
combination of Aurora A kinase selective inhibitors and taxanes is
ovarian cancer, epithelial ovarian cancer, fallopian tube cancer,
or primary peritoneal cancer. In another embodiment, diseases or
disorders treatable by the combination of Aurora A kinase selective
inhibitors and taxanes, include, but are not limited to, small cell
lung cancer.
[0137] Determining the Effect of the Selective Inhibitor of Aurora
A Kinase in Combination with Paclitaxel:
[0138] Preferably, the method according to the invention causes an
inhibition of cell proliferation of the contacted cells. The phrase
"inhibiting cell proliferation" is used to denote an ability of a
selective inhibitor of Aurora A kinase and/or taxane to inhibit
cell number or cell growth in contacted cells as compared to cells
not contacted with the inhibitors. An assessment of cell
proliferation can be made by counting cells using a cell counter or
by an assay of cell viability, e.g., a BrdU, MTT, XTT, or WST
assay, and comparing the size of the growth of contacted cells with
non-contacted cells. Where the cells are in a solid growth (e.g., a
solid tumor or organ), such an assessment of cell proliferation can
be made by measuring the growth, e.g., with calipers or
non-invasive imaging such as MRI and PET.
[0139] Preferably, the growth of cells contacted with a selective
inhibitor of Aurora A kinase and a taxane is retarded by at least
about 50% as compared to growth of non-contacted cells. In various
embodiments, cell proliferation of contacted cells is inhibited by
at least about 75%, at least about 90%, or at least about 95% as
compared to non-contacted cells. In some embodiments, the phrase
"inhibiting cell proliferation" includes a reduction in the number
of contacted cells, as compare to non-contacted cells. Thus, a
selective inhibitor of Aurora A kinase and/or a taxane that
inhibits cell proliferation in a contacted cell may induce the
contacted cell to undergo growth retardation, to undergo growth
arrest, to undergo programmed cell death (i.e., apoptosis), or to
undergo necrotic cell death.
4. Experimental Procedures
[0140] In the Examples described below, alisertib (MLN8237) refers
to the sodium salt, sodium
4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-
-2-yl]amino}-2-methoxybenzoate monohydrate.
Example 1
In Vivo Efficacy Studies of Alisertib Administration in Combination
with Paclitaxel Administration in a Breast Cancer Mouse Model
[0141] Experimental Procedure
[0142] Tumor Cell Culture and Primary Human Tumors.
[0143] MDA-MB-231 cells were obtained from ATCC and cultured in
DMEM medium supplemented with heat inactivated 10% FBS and 1%
L-glutamine. MDA-MB-231 cells (2.times.10 .sup.2) were injected
orthotopically into the mammary fat pad of nude mice. In vivo
efficacy studies. Nude mice bearing xenograft tumors (MDA-MB-231);
(n=10 animals/group) were dosed orally (PO) with vehicle or
alisertib (10, 20 mg/kg) for 21 days using a once daily schedule
(QD). Paclitaxel (5, 10, 20 and 30 mg/kg) was administered
intravenously (IV) on a once weekly schedule (QW) for a total of
three doses. Tumor growth was measured using vernier calipers and
tumor growth inhibition (TGI) was calculated using the following
formula: TGI=(.DELTA.control-.DELTA.treated)*100/.DELTA.control.
Tumor Growth Delay (TGD) is the time (days) for each treatment
group to reach an average tumor volume of 1000 mm.sup.3 relative to
the vehicle treated group. Statistical significance in the tumor
growth between pairs of treatment groups were assessed using linear
mixed effects regression models. These models account for the fact
that each animal was measured at multiple time points. A separate
model was fit for each comparison, and the areas under the curve
(AUC) for each treatment group were calculated using the predicted
values from the model. The percent decrease in AUC (dAUC) relative
to the reference group was then calculated.
[0144] Results
[0145] Table 1 illustrates that alisertib demonstrated additive and
synergistic antitumor activity in combination with paclitaxel in an
orthotopic breast cancer in vivo xenograft model. Moreover,
significant tumor growth delay occurred relative to the single
agents after discontinuing treatment.
TABLE-US-00002 TABLE 1 MLN8237 Days dose Paclitaxel dose TGI.sup.b
to 1000 Outcome Model.sup.a (QD) (Q7Dx3) (%) mm.sup.3 (AUC).sup.c
MDA- 20 mg/kg 30 mg/kg 101.4 35 Synergistic MB-231 20 mg/kg 20
mg/kg 95.3.sup.d 24.8.sup.d Synergistic 20 mg/kg 15 mg/kg 85.7 15.7
Additive 20 mg/kg 10 mg/kg 45.87 4.2 Additive 20 mg/kg 5 mg/kg 43.6
4 Additive 10 mg/kg 30 mg/kg 102.4 31.2 Synergistic 10 mg/kg 20
mg/kg 81.9 13.4 Additive 10 mg/kg 15 mg/kg 85.6 13.7 Additive 10
mg/kg 10 mg/kg 42.3 4.2 Additive 3 mg/kg 20 mg/kg 64.9.sup.d
8.8.sup.d Additive 3 mg/kg 10 mg/kg 21.7 1.9 Additive 3 mg/kg 5
mg/kg 20.8 2 Additive .sup.aOrthotopic breast cancer models were
grown in nude mice and treated daily with alisertib administered
orally for 21 days with paclitaxel dosed IV once per week
.sup.bTumor growth inhibition (TGI) = (.DELTA. treated/.DELTA.
control) .times. 100/.DELTA. control, was calculated on the last
day of treatment .sup.cSynergy analysis based on the area under the
curve (AUC) values days 0 through 20 .sup.dAverage of 2 studies
Statistical Analysis for In Vivo Data
[0146] For the MDA-MB-231 model, measurements from day 0 to 20 were
analyzed. All tumor volumes had a value of 1 added to them before
log.sub.10 transformation. These values were compared across
treatment groups to assess whether the differences in the trends
over time were statistically significant. To compare pairs of
treatment groups, the following mixed-effects linear regression
model was fit to the data using the maximum likelihood method:
Y.sub.ijk-Y.sub.i0k=Y.sub.i0k+treat.sub.i+day.sub.j+day.sub.j.sup.2+(tre-
at*day).sub.ij+(treat*day.sup.2).sub.ij+e.sub.ijk
where Y.sub.ijk is the log.sub.10 tumor value at the j.sup.th time
point of the k.sup.th animal in the i.sup.th treatment, Y.sub.i0k
is the day 0 log.sub.10 tumor value in the k.sup.th animal in the
i.sup.th treatment, day, was the median-centered time point and was
treated as a continuous variable, and e.sub.ijk is the residual
error. A spatial power law covariance matrix was used to account
for the repeated measurements on the same animal over time.
Interaction terms as well as day.sub.j.sup.2 terms were removed if
they were not statistically significant.
[0147] A likelihood ratio test was used to assess whether a given
pair of treatment groups exhibited differences which were
statistically significant. The -2 log likelihood of the full model
was compared to one without any treatment terms (reduced model) and
the difference in the values was tested using a Chi-squared test.
The degrees of freedom of the test were calculated as the
difference between the degrees of freedom of the full model and
that of the reduced model.
[0148] In addition to the statistical significance, a measure of
the magnitude of the effect for each treatment was found. The
predicted differences in the log tumor values (Y.sub.ijk-Y.sub.i0k)
vs. time were taken from the above model to calculate mean area
under the curve (AUC) values for each treatment group. A dAUC value
was then calculated as:
dAUC = 100 mean ( AUC control ) - mean ( AUC treatment ) | mean (
AUC control ) | ##EQU00001##
[0149] For synergy analyses, the observed differences in the log
tumor values were used to calculate AUC values for each animal. In
instances when an animal in a treatment group was removed from the
study, the last observed tumor value was carried forward through
all subsequent time points. The synergy score for the combination
of treatments A and B was defined as
100*(mean(AUC.sub.AB)-mean(AUC.sub.A)-mean(AUC.sub.B)+mean(AUC.sub.etl))-
/mean(AUC.sub.etl)
where AUC.sub.AB, AUC.sub.A, AUC.sub.B, and AUC.sub.etl are the AUC
values for animals in the combination group, the A group, the B
group, and the control group, respectively. The standard error of
the synergy score was computed based on the variation in the AUC
values among the animals. A two sided t-test was used to determine
if the synergy score was significantly different from zero. If the
P-value was below 0.05, and the synergy score was less than zero,
then the combination was considered to be synergistic. If the
P-value was above 0.05, then the combination was considered to be
additive.
Example 2
Semi-Mechanistic Neutropenia Model
[0150] As neutropenia is a common dose-limiting toxicity for
taxanes and alisertib, a semi-mechanistic model was developed to
predict the time course of plasma PK versus absolute neutrophil
count (ANC) to aid in dose and schedule selection for the
combination of alisertib and paclitaxel. This model accounts for
the time delay between agent exposure and ANC since the agents
affect the progenitor cells rather than the neutrophils
directly.
[0151] The model was used to describe neutropenia using PK and ANC
data from mice or rats dosed over multiple days with alisertib
and/or taxane treatment. To construct the model, rodents were
administered docetaxel and alisertib, or the combination of the
two, and ANC was quantified predose and on scheduled days dependent
on administration schedule. Rats received docetaxel (3.5 to 10
mg/kg IV on Day 1) and alisertib (5 to 35 mg/kg PO QDx3, 7, or 14)
or the combination of the two. ANC was quantified predose and on
Days 1, 2, 4, 6, 8, 11, 14, and 17.
[0152] A compartmental PK model was used to describe time dependent
drug concentrations and neutropenia was described using a
semi-mechanistic model as described by Friberg et al. (Friberg et
al J Clin Oncol. 2002; 20(24):4713-21). Alisertib human PK values
were projected from chimpanzee PK values and human systems and
taxane drug-related parameters were obtained from published sources
and in vitro data from rodent and human CFU-GM cell lines.
Differences in plasma protein binding and CFU-GM IC.sub.50s were
used to correct for human-rodent interspecies variation. The model
was extended from docetaxel to paclitaxel by replacing the drug
related parameters (PK and Slope) with published values for
paclitaxel.
[0153] This preclinical model predicted that decreasing the weekly
paclitaxel dose would allow achievement of higher tolerable
alisertib doses. This prediction was confirmed in the dose
escalation study, described in Example 3, below. The model also
predicted that skipping the second week of alisertib dosing would
further mitigate neutropenia, allowing for additional alisertib
dose escalation or dose modification in patients that suffer
mechanistic toxicities after cycle 1.
Example 3
Dose Escalation Study
[0154] Table 2 describes clinical evaluation of the safety and
antitumor activity of alisertib and paclitaxel in recurrent ovarian
cancer patients. In this clinical study, alisertib was dosed BID 3
days on/4 days off concomitantly with the first dose of QWx3
paclitaxel on a 28-day schedule. It was determined that with
paclitaxel dosed weekly at 80 mg/m.sup.2, 10 mg BID of alisertib
was tolerated (e.g. considered to be a safe dose) whereas with
paclitaxel dosed weekly at 60 mg/m.sup.2, 40 mg BID of alisertib
was tolerated.
TABLE-US-00003 TABLE 2 Dosage of Dosage of paclitaxel alisertib
Clinical Observation 80 mg/m.sup.2 weekly 10 mg BID No dose
limiting toxicities 80 mg/m.sup.2 weekly 20 mg BID 2 of 6 patients
with dose limiting toxicities.sup.a 60 mg/m.sup.2 weekly 20 mg BID
No dose limiting toxicities 60 mg/m.sup.2 weekly 30 mg BID 1 of 6
patients with dose limiting toxicities.sup.b 60 mg/m.sup.2 weekly
40 mg BID No dose limiting toxicities 60 mg/m.sup.2 weekly 50 mg
BID 3 of 3 patients with dose limiting toxicities.sup.c .sup.aDose
limiting toxicities include gastrointestinal toxicities (diarrhea,
nausea, vomiting) and oral mucositis .sup.bDose limiting toxicities
include neutropenia coincident fever. .sup.cDose limiting
toxicities include drowsiness/confusion, neutropenia, and oral
mucositis.
Example 4
Exposure-Efficacy Model
[0155] An exposure-efficacy model was developed to predict which
combination of alisertib and paclitaxel results in the greatest
antitumor efficacy. Isobolograms comparing alisertib and paclitaxel
exposures to tumor growth inhibition were generated from in vivo
efficacy studies in tumor-bearing mice, as described in Example 1.
The clinically achieved exposures of alisertib and paclitaxel from
the dose escalation study, described in Example 3, were mapped onto
the isobologram by correcting for mice-human variation in plasma
protein binding and maximum tolerated exposures for both agents.
These data demonstrate that 80 and 60 mg/m.sup.2 paclitaxel will
lead to similar levels of efficacy, consistent with clinical
observations in some cancer indications. The higher alisertib doses
(40 mg BID) attained with 60 mg/m.sup.2 paclitaxel in the dose
escalation study are predicted to lead to greater efficacy than 10
mg BID alisertib with 80 mg/m.sup.2 paclitaxel.
Example 5
In Vivo Tumor Models of Small Cell Lung Cancer
[0156] The antitumor activity of alisertib was tested in
combination with paclitaxel in multiple models of human SCLC when
grown in immunocompromised mice. The data presented here
demonstrate added antitumor benefit of alisertib combined with
paclitaxel in SCLC xenograft models.
NCI-H69.
[0157] Procedure.
[0158] NCI-H69 is an established small cell lung cancer cell line.
See, e.g., A. W. Tong; et al., Cancer Res. 1984 November;
44(11):4987-92. Treatments began when tumors reached approximately
200 mm.sup.3 following subcutaneous tumor implantation with NCI-H69
tumor fragments for all groups containing 10 female
immunocompromised nu/nu mice per group. MLN8237 was tested at a
dose of 20 mg/kg administered PO on a QIDx21-Q8Hx2 schedule and at
doses of 20 and 10 mg/kg on a QIDx21 schedule. Paclitaxel was
tested at doses of 30 and 15 mg/kg administered IV on a Q7Dx3
schedule. Each paclitaxel dose was combined with each MLN8237 dose
on the QDx21 treatment schedule. In the combination treatment
groups MLN8237 was administered first to the animals, followed
immediately by the administration of paclitaxel. One group served
as a vehicle-treated control group receiving PO treatment with the
MLN8237 vehicle on a QIDx21 schedule.
[0159] Summary.
[0160] In the SCLC cell line xenograft NCI-H69, alisertib at 10
mg/kg QD and paclitaxel at 15 mg/kg twice weekly (QW) led to marked
increase in antitumor activity, and alisertib at 20 mg/kg QD with
paclitaxel at 15 mg/kg QW led to sustained cures even after
terminating treatment. See FIG. 1 (BID=twice daily; IV=intravenous;
MLN8237=alisertib; PO=oral; QD=once daily. Tumor bearing mice were
treated for 21 days with alisertib (PO, QD, or BID), paclitaxel
(IV, QW), or the combination of both at the indicated doses. Tumors
were measured twice weekly. Bars represent standard error of the
mean. The shaded areas indicate the 21 day treatment period.). In
this model, alisertib and paclitaxel at their single agent maximum
tolerated doses in mice of 20 mg/kg BID and 30 mg/kg QD led to
prolonged regressions and sustained cures respectively.
NCI-H82.
[0161] Procedure.
[0162] NCI-H82 is an established small cell lung cancer cell lines.
See, e.g., Y. Nakanishi et al., Exp Cell Biol. 1988; 56(1-2):74-85.
Treatments began when tumors reached approximately 200 mm.sup.3
following subcutaneous tumor implantation with NCI-H82 tumor
fragments for all groups containing 10 female immunocompromised
nu/nu mice per group. MLN8237 was tested at a dose of 20 mg/kg
administered PO on a QIDx21-Q8Hx2 schedule and at doses of 20 and
10 mg/kg on a QIDx21 schedule. Paclitaxel was tested at doses of 30
and 15 mg/kg administered IV on a Q7Dx3 schedule. Each paclitaxel
dose was combined with each MLN8237 dose on the QDx21 treatment
schedule. In the combination treatment groups MLN8237 was
administered first to the animals, followed immediately by the
administration of paclitaxel. One group served as a vehicle-treated
control group receiving PO treatment with the MLN8237 vehicle on a
QIDx21 schedule.
[0163] Summary.
[0164] The antitumor activity of alisertib in combination with
paclitaxel was tested in the SCLC cell line xenograft NCI-H82.
Alisertib at 10 mg/kg QD and paclitaxel at 15 mg/kg QW as single
agents had no antitumor activity, but in combination led to
increased antitumor activity relative to the single agents. See
FIG. 2 (BID=twice daily; IV=intravenous; MLN8237=alisertib;
PO=oral; QD=once daily. Tumor bearing mice were treated for 21 days
with alisertib (PO, QD, or BID), paclitaxel (IV, QW), or the
combination of both at the indicated doses. Tumors were measured
twice weekly. Bars represent standard error of the mean. The shaded
areas indicate the 21 day treatment period.). A moderate increase
in antitumor activity also occurred with alisertib at 20 mg/kg QD
and paclitaxel at 30 mg/kg QW relative to the single agents and
relative to the alisertib single agent maximum tolerated dose of 20
mg/kg BID.
CTG-0166.
[0165] Procedure.
[0166] CTG-0166 is a small cell lung cancer cell line (Champions
Oncology, Baltimore, Md., www.championsoncology.com). Treatments
began when tumors reached between 180 and 250 mm.sup.3 following
subcutaneous tumor implantation with CTG-0166 tumor fragments for
all groups containing 8 female immunocompromised nu/nu mice per
group. MLN8237 was tested at a dose of 20 mg/kg on a QIDx21
schedule administered PO, paclitaxel was tested at a dose of 15
mg/kg on a Q7Dx3 schedule administered IV and topotecan was tested
at a dose of 1.5 mg/kg on a QDx5 schedule administered IV. In the
combination treatment groups MLN8237 was administered first to the
animals, followed immediately by the administration of paclitaxel.
One group served as a vehicle-treated control group receiving PO
treatment with the MLN8237 vehicle on a QIDx21 schedule.
[0167] Summary.
[0168] In human primary SCLC model CTG-0166, the combination of
alisertib at 20 mg/kg QD and paclitaxel at 15 mg/kg QW led to a
slight increase in antitumor activity relative to the respective
single doses. See FIG. 3 (BID=twice daily; IV=intravenous;
MLN8237=alisertib; PO=oral; QD=once daily. Tumor bearing mice were
treated for 21 days with alisertib (PO, QD), paclitaxel (IV, QW),
or the combination of both at the indicated doses. Topotecan (IV,
Q5D) was included as a control. Tumors were measured twice weekly.
Bars represent standard error of the mean. The shaded areas
indicate the 21 day treatment period.). In this model, topotecan at
its single agent maximum tolerated dose of 1.5 mg/kg Q5D was also
tested.
[0169] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods, devices and materials are herein
described. All publications mentioned herein are hereby
incorporated by reference in their entirety for the purpose of
describing and disclosing the materials and methodologies that are
reported in the publication which might be used in connection with
the invention.
* * * * *
References